KAIMRC Innovations Issue 7

JUNE 2020 - Issue No.7

ISSN 7901-2398 innovations.kaimrc.med.sa

TAKING ON THE COVID-19 PANDEMIC K A IMRC BUIL D S ON I T S K NO W L E DGE OF ME R S T O C ON T R IBU T E T O T HE GL OB A L E F F OR T S T O F IGH T C O V ID -19 P.5 0

BIOSTATISTICS & BIOINFORMATICS

It focuses on conducting state of the art biomedical research SERVICES • Novel statistical and bioinformatics methods/tools • Biostatistics, mathematical modeling, protein modeling, next generation OMICS analysis, and artificial intelligence • Large collaborative initiatives that cover several disease areas • Independent research projects

• Outreach program for general technical advice as well as systematic educational activities

KAIMRC-DBB@NGHA.MED.SA

B L AC KJ AC K3 D / I S TO C K / GE T T Y I MAG ES P LU S

• Collaborations with mega projects that align with KAIMRC strategic initiatives

TABLE OF CONTENTS

P.8 A CLOSE LOOK AT LEUKAEMIA IN SAUDI ARABIA

P.10 TRAINING PLACENTA STEM CELLS AGAINST CANCER

Saudi researchers examine records of leukaemia cases in the kingdom over the past 15 years

Stem cells that usually protect the human foetus could be preconditioned to enhance their abilities to combat tumours

P.11 MICROPARTICLES PACK A BIG PUNCH

P.12 A NEW BOOSTER FOR HODGKIN LYMPHOMA PATIENTS

P.14 STEM-CELL BOOST TO IMMUNE CELLS COULD HELP QUELL CANCER

Saudi researchers have developed tiny iron oxide particles that can carry multiple drugs deep into the core of tumours

Adding a known antibody-drug conjugate to a standard chemotherapy regimen may help overcome drug resistance

Stimulating immune cells with placental stem cells could enhance the body’s natural anti-cancer activity

P.16 PARENTAL STRESS LINKED TO HEALTH OUTCOMES FOR CHILDREN WITH TYPE 1 DIABETES

P.18 STREAMLINING CARE FOR THE CRITICALLY ILL

Improved parental wellbeing could lead to better management of type 1 diabetes in children

More treatment is not always better, finds a Saudi-led trial into the prevention of deep-vein thrombosis

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TABLE OF CONTENTS

P.20 DIABETES: IDENTIFYING COMPLICATIONS EARLY

P.22 SUPERCHARGED IMMUNE CELLS TO FIGHT LYMPHOMA

An 11-year study exposes the high incidence of children with diabetic ketoacidosis (DKA) in Saudi Arabia

Immunotherapy adapting a patient’s immune cells to tackle specific cancer cells shows promise against rare lymphoma

P.23 A ROADMAP FOR PUBLIC SAFETY

P.24 WEARING DIABETES CARE LIGHTLY

Seatbelts and eschewing mobile phones are essential for reducing injury toll

A new wearable, flexible nanosensor could help monitor glucose levels without the need for blood tests

P.26 A MOTHER’S PROTECTIVE GIFT TO PRETERM BABIES

P.27 DIAGNOSTICS: NIX THE MIX

Preterm babies have a similar arsenal of maternal antibodies to those of full-term babies

Vitamin D testing does not require the mixing of samples, a finding that could save lab technicians time and effort

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TABLE OF CONTENTS

P.28 SPEEDY TEST FOR ANTIBIOTIC RESISTANCE

P.29 THE MOLECULAR MECHANISM LINKING MELATONIN AND MEMORY

A test for antibiotic-resistant bacteria shows scope for further development

Revealing how melatonin alleviates memory defects opens new therapeutic avenues

P.30 THE BATTLE OF THE DIAGNOSTICS

P.32 STEM CELL THERAPY: INSIGHTS INTO HEART REPAIR MECHANISMS

New study compares CT scans with MRIs for cervical spine injury detection in unconscious paediatric patients

Injecting stem cells into the heart following cardiac arrest induces an immune response that helps repair damaged tissues

P.34 ORAL MAGNESIUM IS NOT AN EFFECTIVE ASTHMA TREATMENT

P.36 ARTIFICIAL INTELLIGENCE ENHANCES IN-SURGERY TUMOUR ANALYSIS

Despite low magnesium levels being linked to asthma cases, new research shows that oral magnesium supplements do not help

An automated system can provide diagnostic information during surgery for a brain tumour as accurately as pathologists

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FEATURE

FEATURE

P.38 SCOPE FOR GREATER USE OF DIGITAL TOOLS IN SAUDI HEALTHCARE

P.40 MERS VIRUS SHRUGS OFF ANTIBIOTIC ASSAULT

P.42 CLINICAL TRIALS: A HOPEFUL START IN SAUDI ARABIA

Despite high penetration rates, medical workers are reluctant to use smartphones for work purposes

Macrolide antibiotics cannot effectively fight MERS-CoV, study shows

Study suggests that Saudi Arabians are willing to participate in the new clinical trials programme

P.46 UNCOVERING THE GENETIC ROOTS OF METAL METABOLIC DISORDERS

P.47 SEARCHING FOR SIGNATURES OF A RARE DISEASE

Next-generation sequencing sheds light on genetic disorders associated with metals, paving the way to new therapeutic approaches

DNA sequencing can reveal mutations underlying a vitamin deficiency in newborns

FEATURE

P.48 SALMONELLA IN THE SPOTLIGHT

P.52 REPURPOSING RESOURCES TO TAKE ON COVID-19

Investigating Salmonella serotypes in Saudi Arabia could lead to a reduction in food-borne illness, and the development of a vaccine

KAIMRC is working hard to contribute to the search for an effective treatment for COVID-19

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TABLE OF CONTENTS

FEATURE

FEATURE

P.54 LIFE ON THE COVID-19 FRONTLINE

P.58 STICKING TO THE FACTS IN THE PANDEMIC

Egyptian anesthetist in London speaks about the realities of COVID-19 for health workers

Bombarded with advice, and pseudo-science presented as facts, it is time to debunk some of the misinformation around COVID-19

FEATURE

FEATURE

P.62 THE MOST DISCUSSED COVID-19 THERAPIES

P.64 COVID-19 RESEARCH EFFORTS DRAW ON SAUDI ARABIA’S MERS EXPERIENCE

While the world waits for a vaccine, there are several treatment options being considered for use on COVID-19 patients

KAIMRC is central to the kingdom’s efforts to slow COVID-19 as it builds on MERS research infrastructure and previous coronavirus outbreaks

KAIMRC Innovations is published for the King Abdullah International Medical Research Center (KAIMRC) by Nature Research Custom Media.

King Abdullah International Medical Research Center (KAIMRC) P.O. Box 3660 Riyadh 11481 Mail Code 1515, Saudi Arabia Email: kaimrc@ngha.med.sa Web: kaimrc.med.sa

KAIMRC Innovations Phone: +966 11 429 4516 Email: innovations@ngha.med.sa Web: innovations.kaimrc.med.sa

Springer Nature The Campus – 4 Crinan Street – London, N1 9XY, UK Email: nature@nature.com Web: www.nature.com

The Researcher Newsletter Phone: +966 11 429 4516 Email: theresearcher@ngha.med.sa Web: innovations.kaimrc.med.sa/en/newsletter

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A close look at leukaemia in Saudi Arabia

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he Saudi Cancer Registry (SCR) ranked leukaemia, a type of cancer affecting blood cells and bone marrow, as the fifth most prevalent type in Saudi Arabia. Globally, the number of leukaemia cases had risen from 297,000 to 437,000 between 1990 and 2018, and it often affects children. Similarly, Saudi Arabia has seen an upward curve in leukaemia rates, increasing from 2.4 incidence per 100,000 in 2001, to 3.9 in 2013, with a higher rate in males, according to a recent study published in BMC Cancer.

The study also found that 57.2% of leukaemia patients were males, and that the two most diagnosed types of leukaemia, accounting for 36% of the cases, were the Precursor B-cell lymphoblastic leukaemia (18.76%), and the Precursor cell lymphoblastic leukameia (17.3%).

Researchers from King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) and KAIMRC explored the trend and incidence of leukaemia in the kingdom over a period of 15 years (1999-2013). The study intends to provide the Ministry of Health and other decision-makers with facts to enhance their understanding of leukaemia demographics, and to

innovations.kaimrc.med.sa

take the proper action to reduce the burden of such diseases, says KSAU-HS’s Amen Bawazir, who is the lead author of the study.

Bawazir and his team analysed 8,712 leukaemia cases based on data by the SCR. The most common types of leukaemia were classified by gender, age, and region.

Key findings of the study indicate that the leukaemia trend showed a likely increase in the rate particularly in males with a high incidence reported from the central region. Overall, a third of cases occurred in the central region. Children under the age of 5 from the central region were affected remarkably. The authors conclude that the results of the central region need more investigation.

To eliminate non-specific diagnosis, Bawazir recommends that “more training and facilities should be provided to the healthcare facilities to bring a good early diagnosis and accordingly appropriate therapy with possible better standard of cure.”

Cancer incidence in Saudi Arabia has increased similarly to other developing countries.

The author assumes factors such as the “improvement of health care facilities, diagnostic procedures, and an easy

referral system for further diagnosis and treatment,” play a role. Better registration methods through the National Cancer Registry led to increased reporting of cancer cases. Furthermore, increased wealth, lifestyle changes, longer life expectancy, and population growth may explain the upward trend of leukaemia incidence.

“Leukaemia is considered as an important public health problem in Saudi Arabia for its impact in causing deaths among young people,” study reported. Leukaemia ranked first amongst children under 14. About a quarter of the Saudi population is under 14, which highlights the magnitude of this malignant blood disease.

Leukeamia requires long and costly therapy, Bawazir explains, which implies a financial strain on the healthcare system.

“The Saudi Ministry of Health recently has empowered the health education section in hospitals and primary care centers in order to take early action in fighting the disease,” says Bawazir.

Bawazir, A., Al-Zamel, N., Amen, A. et al.

The burden of leukemia in the Kingdom of

Saudi Arabia: 15 years period (1999– 2013). BMC Cancer 19, 703 (2019).

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JX F ZS Y / I S TOC K / G ET T Y I M AG ES P LU S

Saudi researchers examine records of leukaemia cases in the kingdom over the past 15 years

“The study is believed to be the first to examine how the properties of DPMSCs are affected by exposure to a culture in which cancer cells have previously been grown.”

Placenta stem cells can be trained to better fight cancers Stem cells that usually protect the human foetus could be preconditioned to enhance their abilities to combat tumours

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ells in human placentas can be trained to enhance their anti-cancer properties, according to scientists at KAIMRC. Mesenchymal stem cells (MSC), found in connective tissue all over the body, modify their phenotype and functional effects on their surrounding cells depending on the microenvironment they are exposed to, differentiating into bone, fat, and cartilage cells. Many research groups are investigating their potential to replace damaged or unhealthy tissue.

A group led by cell biologist, Mohamed Abumaree, from KAIMRC has previously isolated and studied the MSCs in a part of

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the pregnant uterus lining called decidua parietalis, MSCs (DPMSCs), from the human placenta. They found DPMSCs, which are exposed to inflammation and oxidative stress during pregnancy, enhance the activity of natural killer cells, which play an important role in anti-cancer defences.

Other researchers have, however, found that tumours can pump out proteins that undermine the therapeutic properties of MSCs, and some have suggested the cells may help drive the growth of tumours.

In this study, Abumaree and colleagues cultured DPMSCs in the presence of different concentrations of a medium previously used to grow breast cancer cells.

The researchers concluded this reduced proliferation meant DPMSCs were unlikely to stimulate tumour growth, as other scientists have previously suggested for other types of MSCs. When the DPMSCs were preconditioned for 72 hours in breast cancer cell medium they regained their ability to interact with and attach themselves to other nearby cells. They were also less able to invade endothelial cells derived from the umbilical, compared to DPMSCs that did not undergo preconditioning.

“DPMSCs are located at the interface between the mother and the foetus, and have to be durable because, during pregnancy they are exposed to a stressful, oxidative environment,” said Fawaz Abomaray, based at the Karolinska Institute in Stockholm, Sweden, and a member of the research team. “Our study shows that educating them with cancer-conditioned medium in this way could improve their anti-cancer properties.”

The study is believed to be the first to examine how the properties of DPMSCs are affected by exposure to a culture in which cancer cells have previously been grown.

Abumaree’s team also identified some of the genes likely to be responsible for the effects of the cancer medium on DPMSC properties.

Bahattab, E. Cancer Conditioned Medium Modulates Functional and Phenotypic Properties of Human

Decidua Parietalis Mesenchymal Stem/Stromal Cells.

Tissue Engineering and Regenerative Medicine 16 (6), 615–630 (2019).

B S I P SA / A L A M Y S TOC K PHOTO

They found the cells were able to survive, even when exposed to high concentrations of cancer cell medium, but with reduced ability to proliferate and attach themselves to neighbouring cells.

Microparticles pack a big punch

Saudi researchers have developed tiny iron oxide particles that can carry multiple drugs deep into the core of tumours

innovations.kaimrc.med.sa

fields. They further tested the drug loading and release kinetics of the iron oxide particles using the hormonal anticancer drug Tamoxifen and two well-known hydrophilic chemotherapeutic drugs, doxorubicin and daunorubicin. Their results showed that one milligram of iron oxide particles could carry up to 165, 227 and 235 microgram of Tamoxifen, doxorubicin, and daunorubicin, respectively.

They also found that the drugs would be released when the environment became slightly acidic, much like that surrounding cancer cells.

The researchers were able to use the drug-loaded iron oxide particles to kill breast and colorectal cancer cell lines. When applied on breast tumours, the iron oxide particles would accumulate deep inside the core, thus demonstrating their potential for use in cancer therapy.

El-Boubbou, K., Ali, R., Al-Zahrani, H., Trivilegio, T., Ala-

nazi, A. H., et al. Preparation of iron oxide mesoporous

magnetic microparticles as novel multidrug carriers for synergistic anticancer therapy and deep tumour penetration. Scientific Reports 9, 9481 (2019).

FO O D & D RU G A D M I N I S TR AT IO N / S C I E N CE PH O TO LI B R A RY

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espite all the encouraging advances in cancer therapy, the eradication of cancer cells or removal of tumours from patients is still largely a hit-or-miss proposition. One way to improve the chance of success is to use a combination of drugs with different fighting properties. However, delivering this into the core of tumours, where it works most effectively, can be a challenge.

Kheireddine el-Boubbou and co-workers from KAIMRC have now developed a porous type of iron oxide particles that can absorb a variety of drugs for use in cancer treatment. Because the particles are microscopic and made of a magnetic material, they have the potential to penetrate deep into the core of tumours to be used as carriers for controlled drug delivery.

To prepare the porous iron oxide particles, the researchers impregnated tiny porous silica balls known as acid-prepared mesoporous spheres (APMS) with iron chloride. These APMS have interconnected pores measuring 4–6 nanometers in diameter and were selected for their rigid framework, chemical inertness, and good controllability. Next, the researchers used a sintering process to reduce the iron chloride to iron oxide. Finally, the silica that served as the template for constructing iron oxide particles, was etched away using basic sodium hydroxide solution.

The researchers observed the iron oxide particles under a microscope and found that they all had bumpy surface and a porous interior. Further experiments revealed that the pores had relatively large volume, ideal for carrying cancer drugs.

The researchers were able to separate the iron oxide particles from water using a permanent magnet, indicating their potential to be manipulated by magnetic

The iron oxide particles can penetrate deep into the core of tumours for controlled drug delivery

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A new booster for Hodgkin lymphoma patients Adding a known antibody-drug conjugate to a standard chemotherapy regimen may help overcome drug resistance, new research shows

remission rate are greatly dependent on the response rate.

To further improve the response rate of IGEV, Moussab Damlaj and colleagues at KAIMRC have now examined its efficacy when combined with targeted therapy using the monoclonal antibody–drug conjugate brentuximab vedotin. Monoclonal antibodies are substitute antibodies engineered from cloned immune cells.

Brentuximab vedotin has been widely used as the first line of treatment for Hodgkin lymphoma because it selectively targets and kills CD30-expressing cells, including Hodgkin lymphoma cells.

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cientists at KAIMRC have created a ‘supercharged’ cocktail that combines salvage chemotherapy treatment with targeted therapy for patients with recurrent Hodgkin lymphoma.

The combination drug help patients stay in remission, the researchers say.

Hodgkin lymphoma, a cancer that develops in the lymphatic system, is highly curable in 70-80% of patients. In some cases, lymphomas come back, or are resistant to treatment; the latter is referred to as refractory Hodgkin lymphoma.

For patients with refractory or relapsed Hodgkin lymphoma, salvage chemotherapy — a treatment regimen that often

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employs a mix of three to four strong, sometimes highly toxic drugs — is often considered as a last-ditch measure.

One of the more commonly used ‘salvage’ combination is IGEV— a mix of ifosfamide, gemcitabine, and vinorelbine at high dosage, which has been reported to have a good response rate, meaning that the percentage of patients whose cancer has shrunk or disappeared after treatment is high. This particularly benefited autologous stem cell transplant patients, who use their own stem cells to replace damaged bone marrow and blood cells after chemotherapy, since their post-transplantation outcome, overall survival, and

The researchers analysed records of 28 patients with relapsed or refractory Hodgkin lymphoma who had received brentuximab vedotin in addition to IGEV at KAIMRC between 2013 and 2017. Their preliminary results showed that the complete metabolic response rate — as indicated by positron emission tomography and computed tomography — after one or two cycles of treatment was 71%.

All patients who received the cocktail had favourable post-transplantation outcomes.

The experimental treatment, however, had side effects, the most common of which were problems related to the blood.

Approximately 96% and 89% of patients had reported low neutrophil levels and low blood platelet counts, respectively. No patients were transferred to the intensive care unit or died during salvage chemotherapy.

Eid, R. A., et al. Chemoimmunotherapy with brentuximab

vedotin combined with ifosfamide, gemcitabine, and vinorelbine is highly active in relapsed or refractory clas-

sical Hodgkin lymphoma. Bone Marrow Transplantation 54, 1168–1172 (2019).

FLUXFOTO/ E+/ GET T Y IMAGES

“This particularly benefited autologous stem cell transplant patients since their post-transplantation outcome, overall survival and remission rate are greatly dependent on the response rate. “

INFECTIOUS DISEASES RESEARCH

Is dedicated to enhancing prevention and treatment of infectious diseases through diversified basic, translational, and clinical research activities, surveillance programs and reference laboratory services. It aims to become the underpinning of the infectious disease public health research for the Kingdom of Saudi Arabia.

THE LABORATORY IS DIVIDED INTO • Microbial Genomics and AMR Unit, • Virology and Vaccine Development unit, and • Biosafety Level 3 laboratory (BSL3).

KAIMRC-ID@NGHA.MED.SA

KAIMRC researchers have shown the potential for placental-derived stem cells to enhance the expression of anti-tumour and antiinflammatory molecules.

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Stem-cell boost to immune cells could help quell cancer

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esenchymal stem cells (MSCs), or the cells that differentiate into bone, cartilage, muscle or fat cells, have a versatile use in developing new therapies. They can trigger activities in other cells or change how cell populations respond to certain stimuli, and this versatility creates a multitude of possibilities for scientists when it comes to tackling complex diseases like cancer.

Dunia Jawdat and colleagues at KAIMRC’s Stem Cell and Regenerative Medicine Department, and co-workers across Saudi Arabia have now demonstrated that MSCs taken from the foetal part of the human placenta can influence how natural killer (NK) immune cells express anti-inflammatory and anti-tumour molecules. Their results could inform future cancer therapies.

NK cells are a key component of the innate immune system, and can either prevent pathogenic cell growth and replication, or destroy cells by bursting or dissolving them. Receptor proteins on the surface of NK cells mediate these activities by binding to target cells and either activating or inhibiting a destructive response.

Previous studies, including research conducted by the KAIMRC team, have demonstrated that pMSCs can suppress immune responses and may be able to control immune cell functioning. However, precisely how pMSCs interact with different immune cell populations is unclear.

In their study, published in Stem Cell

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Research and Therapy, Jawdat’s team used both non-activated ‘fresh’ NK cells, and NK cells which had been activated by cytokine signalling prior to use. They cultured each NK cell population at different ratios with pMSCs to determine whether NK cells would interact with or destroy the stem cells.

While the activated NK cells actively destroyed the pMSCs, the fresh NK cells did not. The team identified an NK cell receptor that could be responsible for the attack on pMSCs, and could potentially be inactivated to prevent damage to pMSCs. Notably, preconditioning NK cells with pMSCs did not reduce the NK cells’ ability to destroy breast cancer cell lines.

Further examination showed that co-cultured NK cells significantly increased their production of anti-tumour molecules, including the secretion of IL1ra, a natural anti-inflammatory cytokine.

“Our data suggest that pMSCs could be used to treat cancers by enhancing the anti-cancer activity of NK cells in vitro,” the researchers reported in their paper. “Before realising this possibility, further studies are needed to elucidate the molecular mechanisms that underlie the enhancement of the anti-tumour activities of NK cells by pMSCs.” Abumaree, M.H. et al. Preconditioning human natural killer

cells with chorionic villous mesenchymal stem cells stimulates their expression of inflammatory and anti-tumour molecules. Stem Cell Research and Therapy 10 (2019).

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S C I EN C E P H OTO LI B R A RY / A L A M Y S TOC K P H OTO

Stimulating immune cells with placental stem cells could enhance the body’s natural anti-cancer activity

Parental stress linked to health outcomes for children with type 1 diabetes Improved parental wellbeing could lead to better management of type 1 diabetes in children

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recent study conducted in Riyadh explored the effects of parental care on children with type 1 diabetes and found a correlation between parenting, parent-child interactions, emotional wellbeing and achieving better glycemic control in a child. By understanding the connection, the researchers could target parent-child interactions as points of intervention.

Type 1 diabetes is a chronic illness characterised by the body’s inability to produce enough insulin which is used to balance glucose levels. According to the study, the rate of diabetes among people below the age of 20 is increasing between 2 and 5% globally each year. In Saudi Arabia, T1 diabetes affects 1.095 per 1,000 children and adolescents.

Diabetes management involves insulin injections, dietary control and adjustment of doses in relation to exercise and insulin sensitivity during the day. Family structure and education were found to be factors that affected the children’s glycaemic index. The study showed that, “parents of children with type 1 diabetes in Riyadh experience a considerable level of stress, correlating with the child’s glycaemic profile that could affect the diabetes control.”

The research focused on four main concepts: communication, emotional distress, medical care, and role function.

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This cross-sectional study was conducted in Riyadh with 390 parents. The findings showed that “the higher the involvement of the family, the better the outcome of disease management.” Of the 390 parents, 95% were mothers. The mothers’ health knowledge and socioeconomic status had a major influence on glycaemic control in type 1 diabetes pediatric patients.

Parent-child communication and parent-doctor communication were both considered pivotal areas. The study suggests, “Communication can be improved during clinic visits by using simple language when explaining specific procedures.”

The study also found that the parent’s feelings about the child’s wellbeing, as well as waiting for stressful news are factors that cause emotional distress. The study suggested that parents attend education programmes to learn about their child’s disease.

The study authors recommend, with the correlation of the child’s hypoglycaemic index to the parental stress level, that “the parental level of stress should be periodically assessed, and to provide optimum care, psychosocial support should be incorporated as part of routine care for these patients and their families.”

Aldubayee, M. et al. Parental levels of stress managing

a child diagnosed with type 1 diabetes in Riyadh: a cross sectional study. BMC Psychiatry 20, 5 (2020).

VA DI M G UZH VA / I S TOC K / G ET T Y I M AG ES P LUS

Family structure and education were factors affecting a child’s gylcaemic index

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Streamlining care for the critically ill

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hen multiple treatment regimes exist for a medical in the prophylaxis and treatment of blood clots. Alongside hepcondition, deciding on the most effective course of arin, the second group also underwent Intermittent Pulmonary action is crucial. A recent study by the Saudi Critical Compression, in which the legs are placed in inflatable sleeves Care Trials Group may prevent unnecessary medwhich intermittently compress the legs to promote blood flow. ical intervention by showing that critically ill patients on drugs to After 28 days, researchers found no significant difference in prevent deep-vein thrombosis (DVT) don’t benefit further from DVT incidence between the two groups, indicating that IPC didn’t mechanical compression therapy. provide any additional benefit to patients already taking heparin.

DVT occurs when blood clots in veins deep within the body, The study also investigated secondary health indicators, such as usually the legs. The disease can occur as a result of prolonged pulmonary embolism and death rates. The addition of IPC had no inactivity, such as when on long-distance flights, or during hosinfluence on these outcomes. pital stays. When the legs are “IPC was found to be helpstill for extended periods, ful in previous studies involvThe study followed 2,003 patients at muscles contract less, leading ing patients who were not to less blood circulation and an on pharmacologic prophyICUs across four countries. After 28 days, increase in the likelihood of laxis,” explains Arabi. “Our clots. DVT can cause swelling, researchers found no significant difference study addressed specifically redness and/or pain, and a whether adding IPC had in DVT incidence between patients life-threatening complication added benefits, and the study called pulmonary embolism, it did not.” receiving heparin and those also undergoing showed when a clot travels to the lungs While this might be seen and causes potentially fatal as a disappointing result, Intermittent Pulmonary Compression. lung damage or heart failure. the knowledge gained from People hospitalised for the study can greatly benelengthy periods are at a greater risk of DVT, critically ill patients fit patients undergoing DVT prophylaxis. IPC is cumbersome, are a particularly vulnerable group — with an incidence rate “as reduces patient mobility, and can cause skin injury. Knowing high as 25%” in some populations, says Yaseen Arabi, of Saudi that IPC won’t provide extra benefit, patients on pharmacological Arabia’s Ministry of National Guard Health Affairs, who led the prophylaxis for DVT can preserve their quality of life by avoiding group’s study. This makes them an ideal population to test the unnecessary treatments. effectiveness of DVT-preventative therapies.

The study followed 2,003 patients at Intensive Care Units across Arabi, Y.M., Al-Hameed, F., Burns, K.E.A., Mehta, S., Alsolamy, S.J. et al. Adjunctive Interfour countries. The patients were assigned to one of two groups. mittent Pneumatic Compression for Venous Thromboprophylaxis. New England Journal The first group received heparin, a standard pharmacological agent of Medicine 380, 1305-1315 (2019). innovations.kaimrc.med.sa

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AG EF OTOS TOC K / A L A M Y S TOC K P H OTO

More treatment is not always better, finds a Saudi-led trial into the prevention of deep-vein thrombosis

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Diabetes: Identifying complications early

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n 11-year study exposed the high incidence of children with diabetic ketoacidosis (DKA) in Saudi Arabia, a life-threatening complication of uncontrolled diabetes. The study highlights the need for more campaigns to raise awareness of type 1 diabetes mellitus (T1DM).

Type 1 diabetes mellitus (T1DM) is one of the most common metabolic disorders affecting children. In people with T1DM, the body’s immune system attacks and destroys the cells that produce insulin, so patients become dependent on lifelong daily insulin injections to maintain their blood glucose levels. Unlike type 2 diabetes, which is often caused by an unhealthy lifestyle, the risk factors associated with T1DM are not fully understood, though genetics and autoimmune diseases seem to play a role.

DKA happens when an acute lack of insulin causes the body to use fat to release energy. It causes chemicals called ketones to be released into the blood, making it acidic. “This study sought to assess the incidence and severity of DKA in children with previously undiagnosed T1DM and explore the potential association with autoimmune conditions,” explains Adnan Al Shaikh, paediatric endocrinologist at King Abdulaziz Medical City, Jeddah, and KAIMRC researcher.

The incidence rate of T1DM has grown in Saudi Arabia over the last 40 years.

According to the International Diabetes Association, there are more than 30 new cases of T1DM per 100,000 people in Saudi Arabia, compared with 2.5 in Oman or 22.3 in Kuwait. With 16,000-plus children

innovations.kaimrc.med.sa

with T1DM in Saudi Arabia, there is an urgent need to identify the reasons and to prevent complications, such as DKA, arising from the condition.

“DKA is the most common cause of diabetes-related deaths in children; understanding the factors associated with DKA could lead to interventions,” Al Shaikh says.

The study looked at 390 newly diagnosed T1DM patients between 2005-2015 in children ranging from 3 months to 17 years old.

The incidence of DKA was 37.7%. “The DKA frequency in Saudi Arabia is similar to that reported in Kuwait and Oman, but higher than in Scandinavian countries, where T1DM is historically and genetically more prevalent than in the Middle East, and ranges around 20%,” says Al Shaikh.

Although they did not find differences in the incidence of DKA between sexes, the severity of DKA was higher among girls.

Body mass index (BMI) was lower among patients presenting with DKA, suggesting that it could be a predictor of DKA. No significant association was found between DKA and thyroiditis or celiac disease, two autoimmune diseases previously associated with T1DM. “Further studies on the factors associated with DKA and increasing awareness among healthcare workers and parents of DKA as the initial presentation of T1DM will help reduce the short-term risks and long-term consequences of DKA,” Al Shaikh concludes.

Al Shaikh, A. et al. Incidence of diabetic ketoacidosis in newly diagnosed type 1 diabetes children in western

Saudi Arabia: 11-year experience. J Pediatr Endocrinol

Metab 32, 857– 862 (2019).

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FATC A M ER A / I S TOC K / G ET T Y I M AG E S P LU S

A study on diabetic ketoacidosis in Saudi Arabia shows the need for more awareness of type 1 diabetes mellitus

Mantle-cell lymphoma is a rare and aggressive type of B-cell non-Hodgkin’s lymphoma

Supercharged immune cells to fight lymphoma

An immunotherapy approach, based on adapting a patient’s immune cells to tackle specific cancer cells, shows promise against rare lymphoma

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antle-cell lymphoma is a rare and highly aggressive form of B-cell non-Hodgkin lymphoma. Patients often relapse after treatment, or their cancer becomes resistant to BTK inhibitors, a leading therapy for the disease.

For the first time, an international team of scientists, led by Michael Wang at the University of Texas in Houston, US, have used an immunotherapy approach to treat patients with advanced mantle-cell lymphoma.

The team’s phase II clinical trial was conducted at 20 sites across the US and

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Europe between 2016 and 2019. The researchers used a form of CAR T-cell therapy, where samples of immune cells called T cells are collected from patients.

The cells are then altered in the lab to enhance the expression of a specific protein that helps the T cells bind to particular cancer cells. Large numbers of these ‘super-charged’ immune cells are grown in the lab, then injected back into the same patient. This induces a more potent attack by the patient’s own immune system against cancer.

In total, 74 patients from the United States and Europe were enrolled in the

“This trial showed that a single infusion of KTE-X19 CAR T-cell therapy was capable of inducing durable remissions in patients with relapsed or refractory mantle-cell lymphoma.“ In promising results, 93% of trial patients responded to the therapy, and 67% experienced complete remission. Those patients that responded well showed robust T-cell levels and reduced cancer cell activity at their first assessment after treatment. Follow-ups with patients a year after the treatment had run its course showed that 57% remained in remission.

However, CAR T-cell therapy is known for its potentially severe side-effects and toxicity, and almost all the trial cohort experienced adverse effects, including low red blood cell counts and infections.

No patients died as a result of the side-effects, although some were seriously ill for several weeks following the administration of the therapy.

“Patient-reported outcomes suggested no long-term quality-of-life defects after [therapy] receipt,” state the researchers in their paper published in The New England Journal of Medicine in April 2020. “This trial showed that a single infusion of KTE-X19 CAR T-cell therapy was capable of inducing durable remissions in patients with relapsed or refractory mantle-cell lymphoma.”

Wang, M., Munoz, J., Goy, A., Locke, F.L., Jacobson, C.A.,

et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. The New England Journal

of Medicine 382 (2020).

S T EVE G S C H M EI SS N ER / S C I E N C E P HOTO L I BR A RY

study, and 68 patients completed the treatment. Most of the patients had received at least three previous types of treatment for their lymphoma, and had either relapsed or their cancer had become treatment resistant. The team arranged for an independent radiology review committee to assess the clinical response of each patient to the therapy.

Seatbelts and eschewing mobile phones are essential for reducing injury toll

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audi Arabia has a lower incidence of brain and spinal cord injuries than many other countries in the Middle East, but the kingdom could still do more to improve road safety and reduce the public health burden of head and neck trauma, a new study found.

An international research team that included scientists from KAIMRC led an extensive survey of more than 145 countries that tallied all the non-fatal cases

In 2017, Saudi’s interior ministry said that more than 460,000 road accidents happen every year in Saudi Arabia, at an average of one per minute. of traumatic brain injury (TBI) and spinal cord injury (SCI) in 2016, and documented the causes of bodily harm.

The team counted more than 27 million new incidents of TBI and almost a million new cases of SCI around the world in that year — with Saudi Arabia accounting for around 120,000 and 3,000 injuries of each type, respectively.

After accounting for differences in age demographics and populations, the researchers found that Saudi Arabia was a fairly typical country when it came to these types of injuries.

Compared to global averages, the kingdom’s incidence of TBI was slightly higher, while the incidence of SCI was somewhat lower. Looking back at data from a prior survey, they found that Saudi Arabia had made substantial progress in bringing down the incidence innovations.kaimrc.med.sa

of both injuries by approximately 14% from 1990 levels. Over the same time period, occurrence of TBI went up around the world.

In many regions, falls accounted for most injuries. And in conflict-ravaged countries, war and terrorism are to blame. But in Saudi Arabia —where only around one-third of adults wear seatbelts, and talking on mobile phones while driving is routine — the main cause was traffic accidents.

In 2017, Saudi’s interior ministry said that more than 460,000 road accidents happen every year in Saudi Arabia, at an average of one per minute.

GBD 2016 Traumatic Brain Injury and Spinal Cord Injury

Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurolology 18, 56–87 (2019).

Traffic accidents account for most brain and spine injuries in Saudi Arabia

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G CS HU T T E R / E + / G E T T Y I M AG E S

A roadmap for public safety

There are simple measures to reduce road injuries, notes Suliman Alghnam, an epidemiologist and public health researcher at KAIMRC who contributed to the study. He issues this warning to anyone driving down the Riyadh-Qassim Highway or the Makkah-Jeddah Expressway at the newly increased speed limit of 140 kilometres per hour, “Buckle up and put down the phone.”

Saudi Arabia may not have the same injury levels as war-torn Yemen but there are lessons to be learned from another country in the Arabian Peninsula, Oman, which has taken significant steps in recent years to improve road safety.

“Injuries are predictable, preventable, and treatable,” Alghnam says. “We need to ensure the message is out to invest in primary prevention, because it will save lives and resources.”

Wearing diabetes care lightly

A new wearable, flexible nanosensor could help monitor glucose levels without the need for blood tests

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egular measurement of blood sugar allows people with diabetes to work out how much medication to take and when to eat — avoiding serious complications, including sight loss and limb amputations.

However, some don’t keep track because measuring involves taking blood with a finger prick test or wearing a device with an embedded needle.

Levels of glucose in the blood can also be estimated from its concentration in sweat, tears, and saliva, but this can be challenging to incorporate into a wearable device because its concentration is much lower, and results can be affected by movement.

Researchers at the Center of Excellence for Green Nanotechnologies (CEGN), a

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collaboration between the King Abdulaziz City for Science and Technology (KACST), in Riyadh, and the University of California, Los Angeles, have developed a flexible, ultra-thin biosensor. The sensor retains its sensitivity even when bent 100 times, and can be incorporated into a wearable device, such as a watch.

In tests, the new biosensor, which measures less than 1 square millimeter, could detect glucose concentrations ranging from 10 nanomolars to 1 millimolar in saliva, sweat and tears. This is sensitive enough to pick up levels in people with diabetes.

The sensor could also distinguish between sweat samples taken from someone before and after they consumed a glucose drink.

The nanobiosensor is based on field effect transistors (FETs), which allow an electrical current passing through two electrodes to be controlled by the voltage applied to a third terminal. Nanobiosensors based on FETs can measure levels of specific substances based on the interaction of the molecules of that substance with one electrode, affecting the current reaching the other electrode.

The CEGN researchers used nanoribbons of indium oxide as semiconductor channels in their new FET-based nanobiosensor because of the material’s high sensitivity and reliability. They coated the electrodes with the enzyme glucose oxidase, which kicks off a chain of reactions that produce an electrical signal when it interacts with glucose. Single-walled carbon nanotubes were added to increase the sensitivity and a chitosan film to hold the enzyme in place.

“We have shown our biosensor can detect glucose, and that it is extremely sensitive,” says Moh Amer, director of the CEGN. “We’d like to develop our proof of concept into something that can be integrated into a cell phone to allow people to monitor glucose levels in real time.”

Liu, Q., Liu, Y., Wu, F., Amer, M. R., Zhou, C. et al. Highly

Sensitive and Wearable In2O3 Nanoribbon Transistor

Biosensors with Integrated On-Chip Gate for Glucose Monitoring in Body Fluids. ACS Nano 12 (2), 1170–

1178 (2018).

A N DR I Y P OP OV / A L A M Y S TOC K P H OTO

A new nanosensor could help people with diabetes monitor their glucose levels instantly and noninvasively

MEDICAL GENOMICS RESEARCH

Is equipped with the latest technologies and poised to carry out cutting-edge research aimed at addressing medical problems with an emphasis on the people of Saudi Arabia.

The major areas of research are in the fields of human genetics, medical and cancer genomics, hepatology besides cellular/gene therapy.

SERVICES • Next generation sequencing • Microarray • Sanger sequencing • Prevention genetics technology • Functional studies & real-time PCR

KAIMRC-MGRD@NGHA.MED.SA

A mother’s protective gift to preterm babies

Preterm babies have a similar arsenal of maternal antibodies to those of full-term babies, suggesting that their higher infection risk is due to other factors

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he immunity conferred to preterm babies by their mothers may be more extensive and protective than previously thought, according to researchers from the Karolinska Institute in Stockholm, Sweden.

Their findings could influence infant vaccine development and the treatment of disease in newborns.

Immunity to diseases develops when the body generates antibodies — proteins that are programmed to find and destroy or neutralise specific diseased cells. Newborn babies have not been exposed long enough to generate antibodies, and so anti-viral and anti-bacterial antibodies called immunoglobin G (IgG) are passed to babies from their mothers during pregnancy. These antibodies provide passive immunity for up to the first three months

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of life. However, pre-term infants are known to be more susceptible to infection, and scientists previously believed that this was because they did not receive the same levels of IgG from their mothers as those babies born full-term.

Now, Christian Pou and co-workers at the Karolinska Institutet have overturned this theory, following the first analysis of the full range of antibodies present in both full-term and preterm babies and their mothers.

The study involved 78 mothers and their babies, 32 of whom were born before week 30 of pregnancy. The researchers used ground-breaking bacteriophage technology to scan samples taken from all participants. Bacteriophages are viral components that can be designed to display specific proteins on their surfaces.

Antibodies related to specific diseases then bind to the phage-displayed proteins, allowing researchers to determine which antibodies are present in each sample. The bacteriophage library used by the team displayed thousands of proteins from 206 viral species; covering every virus known to infect humans, except the relatively new Zika virus.

Pou’s team were surprised to find that pre-term and full-term babies have a very similar range of IgG, regardless of their gestational age at birth. The range of maternal antibodies in babies as premature as 24 weeks mirrored those of their mothers, with immunity conferred for common viruses.

As the team states in their paper, published in Nature Medicine in 2019, “These findings suggest that the elevated risk of infection in preterm over full-term newborns is not determined by a lack of maternal antibodies; instead, it might be explained by weaker physical barriers in the skin, intestine, and lung or differences in exposure due to intensive care, intravenous catheters, and breathing tubes.”

The results also highlight the specific parts of viral proteins that the antibodies target, which could prove invaluable for vaccine development.

Pou, C., Nkulikiyimfura, D., Henckel, E., Olin, A., Laksh-

mikanth, T. et al. The repertoire of maternal anti-viral antibodies in human newborns. Nature Medicine 25, 591-596 (2019).

DPA P I C T UR E A LLI A N C E / A L A M Y S TOC K P H OTO

Babies are born with immunity provided by their mothers until they start producing their own antibodies.

KAIMRC’s Anwar Borai now recommends diagnostic service providers skip the vortex mixing step recommended for vitamin D testing.

Blood samples do not require vortex mixing ahead of vitamin D testing

Diagnostics: Nix the mix

Vitamin D testing does not require the mixing of samples, a finding that could save lab technicians time and effort

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creening for vitamin D deficiency has proliferated in recent years, and diagnostic laboratories are struggling to keep up.

However, lab technicians, may be able to omit at least one sample preparation step that was long thought essential to getting an accurate reading on vitamin D levels for patients.

According to a new KAIMRC report, there is no need to vortex blood samples ahead of measuring concentrations of 25-hydroxyvitamin D, the active form of vitamin D in the body. The study also found that tubes of serum — the yellowish fluid left behind when cells and innovations.kaimrc.med.sa

clotting factors are removed from the blood — can be analysed immediately or stored frozen for up to 30 days without affecting test results.

To help deal with the increased workload, KAIMRC clinical biochemist, Anwar Borai, now recommends diagnostic service providers skip the vortex mixing step recommended for vitamin D testing in most procedure manuals. “This will save time for the lab techs in clinical and research laboratories without affecting results,” says Borai, who led the study.

Putting tubes in a vortex mixer may only take around 10 seconds per sample. But with huge numbers of tests now

energy for vitamin D synthesis in the skin. But with extreme temperatures and cultural practices forcing many people indoors, low levels of vitamin D are common, increasing the risk for bone fractures, diabetes and heart disease, among other health problems.

Scrutinising the need for certain storage and mixing conditions, Borai and his students from the KAIMRC-affiliated King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) in Jeddah, performed standard vitamin D assays on 31 patient samples, both with and without vortexing and with up to 30 days of cold storage. Statistically speaking, they observed some significant differences in 25-hydroxyvitamin D concentrations, depending on mixing status and the length of time in the freezer. However, as judged by vitamin D analytical quality-control guidelines, the differences were too small to be clinically significant, Borai says.

His team published their findings in the February 2020 issue of Journal of Clinical Laboratory Analysis.

Borai, Aa. Khalil, H., Alghamdi, B., Alhamdi, R., Ali, N. et al. The pre-analytical stability of 25-hydroxyvitamin D:

Storage and mixing effects. Journal of Clinical Labora-

tory Analysis 34, e23037 (2020).

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performed each year, those seconds quickly add up. Doing away with blending samples could free technicians to analyse many more samples — and thereby help identify more individuals who could benefit from vitamin D supplementation.

This could be especially important in Saudi Arabia where around 80% of the population suffers from vitamin D deficiency. Low levels of the vitamin seem counterintuitive since the region has ample sunshine, a natural source of

KAIMRC’s Hosam Zowawi assessed the ‘beta’ version of a test for antibiotic-resistant bacteria the ‘SpeeDx Carba (beta) multiplex realtime PCR assay .

Speedy test for antibiotic resistance A test for antibiotic-resistant bacteria shows scope for further development

A

n international research team, including KAIMRC’s Hosam Zowawi, has assessed the early ‘beta’ version of a test for antibiotic-resistant bacteria; the ‘SpeeDx Carba (beta) multiplex real-time PCR assay.’ The test is based on detecting key genes responsible for antibiotic resistance.

Zowawi contributed to the study’s conception and design, and the samples tested came from seven countries, including Saudi Arabia.

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June 2020

The targeted bacteria produce enzymes called carbapenemases, which can break down some of the most common antibiotics, including penicillins, cephalosporins, monobactams, and carbapenems.

The authors point out that carbapenemase-producing organisms (CPOs) are of global concern. The World Health Organisation identifies several CPOs as being at risk of becoming untreatable.

A key aspect of combatting the CPO threat will be to develop more sensitive

The team focused on identifying five types of genes that code for the carbapenemase enzymes of some of the most troublesome antibiotic-resistant bacteria.

In trials using bacterial samples whose identity is known, the test positively identified the carbapenemase genes in 152 of 154 samples. It also successfully yielded negative results for all samples lacking the target genes. The test also gave promising results when used directly on faecal samples.

“The initial results from the direct faecal sample testing suggest the Carba (beta) assay may be suitable for screening purposes, but more work is needed,” the authors conclude. This further development will include testing the procedure on a variety of different clinical and environmental samples.

“We are pleased with the performance of the test in this evaluation,” says Elisa Mokany, SpeeDx chief technology officer and founder of SpeeDx, the Australian biotech company developing the test.

Bordin, A., Trembizki, E., Windsor, M., Wee, R., Tan, Lit Y.,

et al. Evaluation of the SpeeDx Carba (beta) multiplex real-time PCR assay for detection of NDM, KPC, OXA-

48-like, IMP-4-like and VIM carbapenemase genes.

BMC Infectious Diseases (2019)

R ED_ M OON _ R I S E/ E+ / G ET T Y I M AG ES

and simpler methods to detect them in saliva, blood and faeces, as well as in the environment.

The SpeeDx test uses the technique called polymerase chain reaction (PCR), which employs a combination of a DNA copying enzyme (the polymerase) and DNA fragments called primers that match parts of the genes of interest. The primers combine with the bacterial DNA, initiating multiplication by the polymerase enzyme to make readily detectable levels.

The molecular mechanism linking melatonin and memory

M R .S UP H AC H A I P R AS ER DUM R ON G C H A I / I S TOC K / G E T T Y I M AG E S P LU S

Revealing how melatonin alleviates memory defects opens new therapeutic avenues

A CT scan of the brain

K

AIMRC researchers have identified melatonin as a potential treatment for memory loss from cerebral hypoperfusion (CHP), a condition in which reduced blood supply to the brain can compromise memory and cognitive functions.

By clarifying the molecular mechanisms linking CHP and memory loss, their work also identifies other molecules which could serve as therapeutic targets.

Previous experiments had shown that melatonin can improve memory and learning deficits resulting from a range of disorders, including CHP, which is common in elderly people. A team led

by KAIMRC physiologist, Hussain Al Dera, used this as a tool to investigate the molecular underpinnings of CHP-induced memory loss.

Al Dera and his team compared rats with and without induced CHP, some of which had been treated with melatonin, to test its effectiveness. Their study confirmed that melatonin improved how well the rats did in two different

innovations.kaimrc.med.sa

memory tests. While this improvement was seen even in rats without CHP, which did better than the normal rats, the important finding was that the performance of the CHP-induced rats was restored to normal.

“This is a double advantage, where melatonin serves as both a preventive and a therapeutic agent simultaneously, which can especially benefit the geriatric population as well as injury-induced memory dysfunction,” says Al Dera.

Next, the team measured the expression level of SK channels, which are molecular channels in neurons which have been linked with memory and learning. Their data revealed that the SKs were more strongly expressed following CHP induction, and melatonin treatment decreased the expression of the SKs in both the CHP and non-CHP rats.

Finally, they showed that the activation of the SKs in response to CHP happens through the activity of a group of proteins known as MAPKs. Melatonin inhibits the activity of the MAPKs, blocking them

from increasing SK expression in CHP and causing memory dysfunction.

The study shows that the memory loss caused by CHP involves increased expression of the SK channels via MAPKs. Melatonin can reverse this memory loss in rats by interacting with the MAPKs to block regulation of the SK channels.

By identifying the molecular actors underlying CHP-induced memory loss, this work points towards possible therapeutic interventions in humans.

Building on these findings “could lead to the recommendation of melatonin as a protective agent against age-related memory loss as well as the identification of other therapeutic agents for CHP-induced memory deficits,” says Al Dera, though he adds that more work is needed before clinical trials can begin.

Al Dera, H., Alassiri, M., Eleawa, S.M. et al. Melatonin Improves Memory Deficits in Rats with Cerebral Hypoperfusion, Possibly, Through Decreasing the Expression

of Small-Conductance Ca2+-Activated K+ Channels.

Neurochem Res 44, 1851–1868 (2019).

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The battle of the diagnostics

New study compares CT scans with MRIs for cervical spine injury detection in unconscious paediatric patients

D

efinitive diagnosis of cervical spine injuries in unconscious paediatric patients can be difficult. Researchers at KAIMRC have conducted a retrospective cohort study evaluating effective diagnosis by computed tomography (CT) and magnetic resonance imaging (MRI).

Children involved in motor vehicle accidents, sports injuries, and falls are susceptible to cervical spine injury. If left untreated, cervical spine injury can lead to neurologic deterioration, paralysis, and death, so medical professionals must immediately check for the possibility of cervical spine injury in paediatric patients following a traumatic event.

To compare diagnostic methods, researchers, started by observing all patients admitted to a level I trauma centre built to serve Saudi Arabian national guards

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MRI is more cost-efficient and shortens patients’ recovery time in cervical spine injury detection

“CT scans, according to the study, accurately identified 28 children

with cervical spine abnormalities, such as straightening, fractures, hematomas or subluxation.”

S C I EN C E H I S TORY I M AG ES / A L A M Y S TOC K P HOTO

and their families inside King Abdulaziz Medical City (KAMC) between January 2005 and July 2018.

For their study, they looked at 62 unconscious paediatric cases of patients aged 15 or under with suspected cervical spine injury. They collected data that includes age, gender, injury mechanism and severity, method used to detect cervical spine injury, radiological findings, clearance time, and patient outcome.

After analysis, the researchers found that CT performed quite well in the initial assessment of injury.

CT scans, according to the study, accurately identified 28 children with cervical spine abnormalities, such as straightening, fractures, hematomas or subluxation (misalignment of the vertebrae).

However, the diagnostic method was not very reliable when it came to problems related to soft tissues and ligaments. MRI was able to detect five cases with abnormalities that were not previously detected by CT. The abnormalities varied in severity from mild ligamentous to unstable craniocervical ligamentous injury.

The paediatric patients’ average age was eight.

Approximately three quarters of them were male. The most common cause of injury was road traffic accidents (59.7%), followed by pedestrian accidents (21%) and falls (14.5%). The patients stayed in the intensive care unit between 18 and 29 days, respectively.

“Most of these were not managed surgically, except for one case,” says Saud Al-Sarheed, one of the co-authors of the paper. “This translates to 84.8% and 100% CT sensitivity and specificity, respectively.”

Although MRI is more expensive than CT the researchers concluded that it was cost-efficient and shortened the patients’ recovery time.

Al-Sarheed, S., et al. Cervical spine clearance in unconscious pediatric trauma patients: a level l trauma center experience. Child’s Nervous Sys-

tem 36, 811–817 (2020).

innovations.kaimrc.med.sa

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The injection of stem cells into the heart following cardiac arrest induces an innate immune response that helps repair damaged tissues

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he use of stem cell therapy to repair the damage caused by a heart attack has shown promise in recent clinical trials, but the underlying mechanisms are unclear.

A new US study has challenged the prevailing theory.

Scientists had thought that after injection, the stem cells would trigger the production of new heart cells, or cardiomyocytes, strengthening the

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heart and aiding recovery. But now, Jeffery Molkentin at the University of Cincinnati and colleagues across the US have demonstrated that the injection of stem cells into the heart triggers an innate immune response, and that it is this response that facilitates tissue repair. No new cardiomyocytes were formed in any part of the heart.

“We have shown that the injection of living cells, dead cell debris, or even

Vagnozzi, R.J., Mallet, M., Sargent, M.A., Khalil, H., Johansen, A.K.Z. et al. An acute immune response underlies the benefit of cardiac stem cell therapy. Nature 577, 405-409 (2020).

W E S T EN D 61 / G E T T Y I M AGE S

Stem cell therapy: Insights into heart repair mechanisms

substances that induce inflammation can all uniformly provide a minor healing benefit to the heart by inducing a targeted immune response,” says Molkentin. “This suggests that adult stem cell injections may not be needed in the first place and has significant implications for the treatment of patients after heart attacks.”

The team decided to explore the mechanisms behind using adult stem cells to treat heart tissue injury, which are now commonly studied in clinical trials and have proven to provide a mildly protective effect to the heart.

Molkentin and colleagues conducted a series of experiments on mouse models with heart attack injury.

The team split the mouse models into groups, and injected the hearts of the mice with two different types of adult stem cells.

“The body immediately sensed that the injected cells did not belong in the heart, and produced a rapid immune response to kill them,” says Molkentin. “As part of this response, immune cells, called macrophages, accumulated in the heart, clearing the dying ‘foreign’ cells and inducing wound healing activity on the damaged heart tissue.”

Further investigations showed that subtypes of macrophages present in the damaged tissue regions were preferentially altered to ensure that scarring was minimised. The macrophages altered the activity of fibroblasts — cells that generate scar tissue and can remodel the heart — and this enhanced the physical properties of the forming scar.

“This meant the heart healed better with a more optimised scar, meaning that the heart’s contractile properties were improved,” notes Molkentin.

The team then tried injecting mice with zymosan — an inert chemical compound that strongly induces the innate immune response — rather than stem cells. Zymosan triggered the same healing process in the damaged hearts.

MEDICAL BIOTECHNOLOGYPARK

The Medical Biotechnology Park is a strategic project of KAIMRC/ MNG-HA to contribute to the Saudi Vision 2030 through: • The development and commercialization of biomedical R&D products, technologies and services • The contribution to economic and health improvement through science and innovations in medical and health sectors

WEBSITE: KAIMRC-BIOTECH.ORG.SA E-MAIL: KAIMRC-KMBP@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516 TWITTER: @MEDICALBIOTECH

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June 2020

Oral magnesium is not an effective asthma treatment

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here is no evidence that oral magnesium supplements can help treat asthma, according to an analysis by KAIMRC doctors, despite the utility of intravenous magnesium in controlling asthma.

Asthma afflicts 235 million people around the world, according to the World Health Organization (WHO). While most cases are relatively mild and easily controlled, complications can make the condition life-threatening. Roughly 300,000 deaths are attributed to asthma each year.

Studies have shown a connection between asthma and low magnesium levels, though the mechanism linking them remains unclear. Low levels of dietary magnesium may be involved in the development of asthma, and people with asthma have been found to have lower magnesium levels than those without the condition, especially in cases where an asthmatic person has reported to the emergency department due to complications.

These findings have led to the use of intravenous or inhaled magnesium to treat asthma. While these treatments help manage the condition, it’s not known whether oral magnesium supplements have a similar effect. To find out, a team of researchers at KAIMRC carried out a meta-analysis of studies testing the use of oral magnesium to control chronic asthma.

The researchers identified eight trials which met their criteria for analysis. The trials were carried

innovations.kaimrc.med.sa

out in Hungary, the UK, the US, Brazil, Iran, and Russia, and comprised 917 participants, including children and adults.

The analysis showed that magnesium supplements didn’t cause patients to improve their performance in a lung responsiveness test or in the amount of breath they could exhale at once — two markers of asthma. Based on this, the researchers conclude that there is no reason to recommend magnesium supplements as a treatment for patients with mild to moderate asthma. However, they note that the outcome of ongoing registered trials may alter their conclusions.

The conclusions are also tempered by shortcomings in the trials. For example, the sample sizes were relatively small and some trials were missing important data. The trials also did not always clearly divide patients based on the magnesium dose, or the treatment making it difficult to carry out a precise analysis.

Given these caveats, future work may provide evidence supporting the use of oral magnesium for asthma treatment. Currently, however, the researchers conclude that oral magnesium cannot be recommended for mild to moderate cases of asthma.

Abuabat, F. et al The role of oral magnesium supplements for the management of stable bronchial asthma: a systematic review and meta-analysis. NPJ Primary Care Respiratory Medicine 29 (2019.)

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M A ZVON E / A L A M Y S TOC K P H OTO

Despite low magnesium levels being linked to asthma cases, new research shows that oral magnesium supplements have no effect on the condition

Artificial intelligence enhances in-surgery tumour analysis An automated system can provide diagnostic information during surgery for a brain tumour with a similar accuracy to pathologists

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June 2020

A

rtificial intelligence can provide surgeons with near realtime diagnostic information during removal of brain tumours, a study published in Nature Medicine has shown. The work, led by Daniel Orringer, a neurosurgeon at NYU Langone Health, USA, could improve surgical care of brain tumours.

During surgery to remove a brain tumour, analysis of resected tissue is innovations.kaimrc.med.sa

essential to identify the type of tumour and to ensure that as much cancerous tissue as possible is removed while minimising removal of healthy tissue. The conventional process involves transferring samples to a laboratory for staining and analysis by a pathologist, but this is time-consuming, expensive, and limited by resources and expertise.

Technological advances have led to the introduction of stimulated Raman

Hollon, T.C. et al. Near real-time intraoperative brain tumour diagnosis using stimulated Raman histology

and deep neural networks. Nat Med 26, 52–58 (2020).

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T H I ER RY D O S O G N E / S TO N E/ GET T Y I M AG ES

AI provides near real-time diagnostic information during brain tumour removal

histology (SRH), a technique that enables simple, rapid microscopic analysis of tissue samples in the operating room.

“SRH offers the surgeon the ability to see a tumour at a microscopic scale that would otherwise be invisible and to rapidly diagnose the type of tumour they’re operating on,” explains Orringer.

“However, while SRH rapidly produces high-resolution microscopic images, the interpretation of those images still requires considerable expertise.”

Orringer and colleagues aimed to overcome this limitation by developing a system for automated analysis of SRH images. They used artificial intelligence to generate deep convolutional neural networks that could analyze samples. These networks were trained with more than 2.5 million classified images of tumour samples to identify tumour subtypes on the basis of distinguishing characteristics.

The team tested their system with a series of 278 patients who underwent surgery for a brain tumour. Samples from each patient were analysed with both the automated system and by a pathologist, and the accuracy of the techniques was compared.

With the automated system, 94.6% of tumours were accurately classified, compared with 93.9% with the conventional technique. The automated result was also generated approximately ten times faster, typically within 2.5 minutes. “Our system could reliably predict diagnosis in brain tumour patients in minutes with accuracy comparable to that of expert neuropathologists,” summarises Orringer.

The system has clear implications for improving diagnosis and tumour removal, effectively offering immediate diagnostic information to surgeons in the operating room. “To some extent, it’s like having the expertise of a pathologist there, even if the pathologist cannot physically be present,” explains Orringer. “This is particularly important in settings where the expertise of a pathologist is needed but a lab, a pathologist or infrastructure are lacking.”

FEATURE

Scope for greater use of digital tools in Saudi healthcare A study on the use of smartphones in the Saudi healthcare system shows that while penetration rates are high, medical workers in the kingdom are reluctant to use mobiles for work purposes 38

June 2020

W

ith the Saudi healthcare industry expanding to meet growing needs, incorporating digital technology seems like a natural progression, and one that many countries are embracing.

To study one aspect of the healthcare industry embracing digital technology in Saudi Arabia, KAIMRC’s Mostafa A. Abolfotouh analysed the use of smartphones among healthcare workers in the kingdom, concluding that most workers do not use their smartphones for work purposes.

G I PH O TO S TO C K / C U L T U RA / G ET T Y I M AGE S

Smartphones can be used in healthcare for more efficient operations and communication

innovations.kaimrc.med.sa

reasons for applying smartphones in healthcare practice were as a source of drug information (69.8%), for disease diagnosis (56.4%), to access medical websites (42.5%), to review guidelines and protocols related to healthcare (34.1%), for procedure documentation (23.5%), and as a source of patients’ education materials (22.3%).

Almost all healthcare workers owned one or more smartphones (96.6%), but only 42.3% used them for professional purposes.​ Abolfotouh’s study concludes that adoption of smartphone technology among healthcare workers in Saudi Arabia is low.

The study demonstrated that “beliefs of healthcare providers in smartphone use, in terms of usefulness and practicality was less than satisfactory, with only 11% reporting positive attitude.”

Abolfotouh adds that the finding might be attributed to the lack of a formal system implemented in the healthcare facilities in

Saudi Arabia. Such a system would provide practitioners with immediate access to medical and health information could convince healthcare providers to use smartphones as a new technology that would impact healthcare quality.

“There must be a necessary intervention from higher health authorities to enforce the importance of use of smartphones in clinical practice,” he explains.

A barrier to the usage of smartphones in healthcare might be the concern for patient safety and patient record confidentiality, explains Alzahrani, adding that when the issue is discussed in wider discourse, “the main argument was related to cyber security for patient record confidentiality.”

On a global level, current events may start to shape healthcare workers’ attitudes to the use of mobile devices. The current COVID-19 pandemic has already initiated change. “COVID-19 heavily shifted attitudes towards use of smartphone,” says Alzahrani.

Abolfotouh, Mostafa A. Use of smartphone and perception towards the usefulness and practicality of its medical applications among healthcare workers in Saudi Arabia. BMC Health Services Research (2019).

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NI K A DA / E + / G E T T Y I M AG E S

“Increasing use of smartphone applications among healthcare professionals has gained wide acceptance as a training and information tool,” says Abolfotouh.

Modern software provides clinicians with a range of benefits, including reducing potential human errors, improving the quality of patient care, and making inter-hospital communication smoother and more reliable.

More specifically, benefits of adopting mobile technology in healthcare extend to direct communication with patients.

“Mobile devices allow providers to more easily engage patients through secure text messaging, patient portals and telemedicine,” says Khalid Alzahrani, the director of Advanced Computing & Technologies at KAIMRC. “Mobile apps that connect providers to electronic health records (EHRs) have grown in popularity as a way to enhance clinical documentation and optimise electronic medical record (EMR) workflow.”

Abolfotouh’s research examined the pattern of smartphone use in healthcare facilities and the perception towards its use among healthcare workers.

The cross-sectional survey, which took place at King Abdulaziz Medical City (KAMC) in Riyadh from October to November 2016, included 351 healthcare workers from various departments, including nursing, laboratories, radiology, infection control and paramedics.

The survey results showed that almost all healthcare workers owned one or more smartphones (96.6%), but only 42.3% used them for professional purposes. In contrast, about 60% of all respondents said they used other devices like tablets, and fewer than half of them installed applications for clinical practice (45.5%).

In terms of frequency, one third use their smartphone regularly, but only 6.1% said they always use the applications in their practice, the remaining 26.2% used it sometimes. The numbers are low compared to international figures on using mobile devices in healthcare.

A survey by the Accreditation Council for Graduate Medical Education (ACGME) in California showed that more than 85% of respondents used a smartphone. The

There are still no proven vaccines for MERS-CoV, the virus causing the Middle East Respiratory Syndrome

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MERS virus shrugs off antibiotic assault

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widely used class of antibiotics has shown potential in in the 90 days following the start of treatment was slightly supressing certain viral infections but offers no signiflower in the macrolide-treated group (60.3% versus 70.4%). icant benefit to patients with Middle East Respiratory But, according to the researchers, these differences are not Syndrome (MERS), say researchers at KAIMRC. statistically significant.

Macrolide drugs, typically used in the treatment of acute and This treatment also had no meaningful impact in terms of chronic infections, and which include erythromycin, roxithroacceleration the clearance of the virus responsible for MERS. mycin, azithromycin and clarithromycin, are useful weapons in There is a possibility that this analysis may have been affected the arsenal against bacterial infections of the respiratory tract. by factors outside the researchers’ control. But Arabi believes They also offer some addithat this may simply reflect tional benefits. the underlying complexity of “There are multiple studthe immune response to mac“There were no meaningful differences ies that show that macrolides rolides, which in turn explains in terms of clinical outcomes between have immune-modulatory the seemingly contradictory patients who received macrolide effects and may be benefiresults obtained to date with cial in viral infection,” says these drugs. “These are difantibiotics and others who didn’t. “ Yaseen Arabi, who leads the ferent viruses, and different KAIMRC team. study designs,” he says.

Unfortunately, the data is not always clear-cut, with some studies There seems to be more hope for MERS patients, however, in showing that these drugs can relieve symptoms in patients infected the ‘MIRACLE’ study, a clinical trial spearheaded by KAIMRC with influenza or respiratory syncytial virus, while others do not. that Arabi and his colleagues are currently recruiting subjects Pneumonia is a common feature of MERS, a viral respiratory for. illness caused by a coronavirus, and many patients with this MIRACLE will be investigating the extent to which a combisymptom receive macrolides as a first line of treatment and nation of multiple antiviral drugs and the immunomodulatory well before formal diagnosis. In order to determine whether protein interferon β-1b bolster the survival of infected patients. this treatment influenced the length of disease, Arabi and colThe trial’s coordinators aim to finish collecting their clinical data leagues looked at the medical data from 349 hospitalised MERS by the end of this year. patients at 14 hospitals across Saudi Arabia in which 136 of these patients were given macrolide antibiotics.

Arabi, Y.M., Deeb, A.M., Al-Hameed, F., Mandourah, Y., Almekhlafi, G.A. et al. Macrolides There were no meaningful differences in terms of clinical in critically ill patients with Middle East Respiratory Syndrome. Int. J. Infect. Dis. 81, outcomes between the two sets of patients. The mortality rate 184–190 (2019). innovations.kaimrc.med.sa

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NIAID

Macrolide antibiotics cannot effectively fight MERS-CoV, study shows

FEATURE

Clinical trials: a hopeful start in Saudi Arabia Early signs suggest that Saudi Arabians are willing to participate in the kingdom’s new human clinical trials programme

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o fully test drugs and vaccines, clinical trials on human volunteers are critical. While many countries around the world have conducted such ‘first-in-human’ (FIH) clinical trials for decades, Saudi Arabia launched their first FIH clinical trial center at KAIMRC, Riyadh, in December 2019. Its first phase I clinical trial is now underway to test a novel MERS-CoV vaccine on healthy volunteers.

FIH clinical trials help scientists confirm the safety of new drugs and vaccines, as well as clarifying their precise mechanisms of action — exactly how a drug works and behaves once it is inside the body. Such FIH trials are preceded by years of work on a specific molecule in the lab and on animals, in order to maximise the chances of a safe, positive, and valuable outcome once a drug reaches FIH trial level.

An ongoing challenge for FIH programmes is the need to recruit and retain volunteers. Depending on the drug to be tested, scientists may require healthy subjects, or sometimes trials are conducted on consenting patients who have a specific disease. Access to a willing and diverse selection of people from different backgrounds, age-groups, and states of health can be an invaluable asset to clinical researchers. Also, the ability to test new medicines on different nationality groups is of great interest to the wider international research community.

With a new era of FIH trials dawning on Saudi Arabia, Adel Almutairi, Badriah

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Almutairi, and their team at KAIMRC’s Science and Technology Unit and Clinical Trial Services under Research Office conducted a survey of 657 Saudi nationals to examine their attitudes towards participating in FIH clinical trials. Their findings showed a positive attitude, and a strong willingness to participate, especially among younger respondents.

“In the run-up to the establishment of the KAIMRC unit in the kingdom, we began to wonder: Are we ready for this?” says Adel Almutairi. “We wondered if people would pay more attention to FIH clinical trials in general, and if we could tap into that interest to encourage volunteers. We were curious to see if our society would be open-minded and willing to participate in such trials.”

In February 2018, the team distributed an electronic questionnaire that was completed by equal numbers of male and female respondents from a variety of ages and backgrounds. The respondents had indicated interest in the study on social media, or were approached during the annual cultural and heritage festival in Riyadh (Al Janadriyah). The questions sought to probe the Saudi public’s motivations and willingness to take part in FIH trials.

Almost 72% of participants stated their intention to enrol in trials, and those who had high regard for the country’s healthcare services were more likely to have a positive attitude towards the importance of such programmes. Further, over 80%

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FEATURE

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role in explaining the importance of trial completion. It is also vital to understand the perceptions built around the wider history of clinical trials.”

Based on their study’s findings, the KAIMRC team has put a comprehensive, strategic plan in place, which includes a public education campaign to raise awareness of all phases of clinical trials.

The campaign covers topics such as the aims of each trial phase, the rights of participants and the role of ethics committees to protect them, alongside practical information about the approval process and how to register.

“We have now launched our Clinical Trials Community Members database, a registry for healthy volunteers,” says Badriah Almutairi. “Around 400 people have registered in a short period, and some of them have been invited for screening to be enrolled in the current MERS-CoV vaccine trial.”

She further explains that they have set up a Twitter account (@KAIMRC_RF) specifically for the dissemination of accurate, easy-to-follow scientific information about clinical trials. They have also distributed printed media across the kingdom.

The ability to engage those who will ultimately benefit from trials can increase interest and participation. Perhaps, given the current global COVID-19 pandemic,

there may be an opportunity to help more people understand the importance of clinical trials, adds Huang.

“We will maintain an honest conversation with our society going forward,” says Badriah Almutairi. “We will communicate accurate information with the public, and we will share study results with all participants in simple, non-scientific language, so they can see the importance of their actions and difference they are making.”

KAIMRC is in the process of establishing a Subject Recruitment and Engagement office that is dedicated to keeping people engaged long-term. The office will answer all participants’ questions and invite them to workshops on pertinent topics like subject’s rights, provide protocol rehearsals, and gather feedback to enhance the quality of engagement.

“We believe that educating people is the best way to ensure current and future participation,” says Adel Almutairi. “We have already received feedback from our volunteer registry stating that they feel they are helping humanity by helping to find cures and save lives.”

Almutairi, A.F., Almutairi, B.M., Alturki, A.S., Adlan, A.A., Salam, M., Al-Jeraisy, M.I., & Balkhy, H.H. Public motives

and willingness to participate in first-in-human clinical trials in Saudi Arabia: A new era in the making. Journal

of Infection and Public Health 12 673-680 (2019).

Abderrezak Bouchama and his team at the Experimental Medicine Department at KAIMRC

OZGU R D O N M A Z / I S TO C K / GE T T Y I M AGE S PLUS

said that they would take part if their physician suggested it, highlighting a strong respect for the medical profession in the kingdom.

“Previous research studies have shown that a key reason for people across the world participating in clinical trials is altruism – people really want to help others,” says Grant Huang, director of the Cooperative Studies Program at the Department of Veterans Affairs in Washington DC in the United States who was not part of the study. Huang’s expertise lies in designing and conducting national and international clinical trials and large-scale epidemiologic studies. “Many active participants share a desire to benefit mankind, and others have a strong personal interest in medicine and science,” he adds.

The Saudi research shows that “young people (under the age of 30) and single people appeared to be most interested in enrolling in the trials,” says Adel Almutairi. “There might be a certain degree of cultural influence bias among the younger participants since wider perspectives on FIH clinical trials appear to have been shared and discussed rigorously through social media here.”

While the general outlook on FIH clinical trials in Saudi Arabia appears positive, participants in Almutairi’s study also highlighted a number of concerns. The respondents were asked to rank a series of statements according to how strongly they agreed or disagreed with them. Among the ‘concern’ statements, ranked most highly were a fear of the unknown, and a concern that people would be treated like guinea pigs. Respondents (57%) favoured shorter trials of one to three days in length, rather than a week or more. Other factors for concern included conflict with religious, social, and moral beliefs.

“It is important to understand that behind it all we are dealing with people - their own beliefs, experiences and other personal factors must be considered,” says Huang. “To shift such beliefs and encourage participation in trials, the general public needs help in understanding the value and role of clinical trials. Governments, scientific and clinical communities, and patients can all play a

KAIMRC EXPERIMENTAL MEDICINE

Three state of the art vivarium facilities are located in Riyadh, Jeddah and Al Hasa.

The vivariums are planned and designed according to international standards.

They aim to assist biomedical research by providing animals and veterinary expertise. Moreover, they offer training and education in animal use for research.

The facilities also work on the development and implementation of institutional policy, animal care and use policy including animal husbandry and veterinary care.

EMD@NGHA.MED.SA

Uncovering the genetic roots of metal metabolic disorders Next-generation sequencing sheds light on genetic disorders associated with metals, paving the way to new therapeutic approaches

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olecular-level high-throughput gene sequencing could help spot specific mutations responsible for metal metabolic disorders and develop new treatments, suggest KAIMRC researchers.

Metal and metalloid nutrients play a pivotal role in many structural and functional processes in the body. Although these biological processes only require infinitesimal quantities of nutrients, any imbalance causes numerous health problems. KAIMRC’s Majid Alfadhel, one of the two authors of the study, explains that imbalances in metal ions are linked to several abnormalities, including cardiovascular diseases, metabolic disorders, and neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases.

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Specifically, insufficient amounts of nutrients in the daily diet and metabolic disorders lead to deficiencies that can trigger mild to serious health issues. An excess of metal nutrients from food or exposure to toxic metals promotes build-up in tissues and organs, especially in the brain, which results in adverse health effects and impedes normal processes.

Metabolic disorders related to metals originate from defects in the proteins and enzymes involved in nutrient metabolism and energy production. Most of these defects stem from single-gene mutations. For example, Wilson disease results from more than 700 mutations of a single gene, which hinders copper excretion and produces copper toxicity in the liver and central nervous

Umair, M. and Alfadhel, M. Genetic disorders associated with metal metabolism. Cells 8, 1598 (2019).

S C I EN C E P H OTO L I BR A RY / A L A M Y S TOCK P HOTO

system. However, recent next-generation sequencing studies contradict this ‘one gene–one enzyme’ concept.

Alfadhel and Muhammad Umair have surveyed the latest genetic research on various metal-related metabolic disorders. “We were able to highlight an ignored area of biomedical research, and focus on genes that may be key to develop targeted treatment,” says Alfadhel.

The researchers revealed that mutations in multiple genes may lead to the same phenotype. Specifically, different disorders associated with zinc imbalance, such as acrodermatitis enteropathica and transient neonatal zinc deficiency, involve several mutations of genes coding the same zinc transporter protein family, but show similar symptoms. Hereditary hemochromatosis, which causes severe iron accumulation in the liver and pancreas, is associated with mutations in five different genes involved in the production of hepcidin, a protein that regulates iron absorption in the intestinal track.

Individuals with hybrid phenotypes might show mutations in more than two genes that generate more than two phenotypes. This gives rise to complex genetic disorders that are difficult to diagnose and manage with a therapeutic plan. Specifically, inborn neurodegenerative disorders linked to brain iron accumulation arise from multiple genes, but only two of the identified genes control iron metabolism.

These inherited disorders also share analogous pathways with other neurodegenerative diseases, including Parkinson’s and Alzheimer’s. Similarly, selenium-related metabolic disorders are extremely complex and are associated with mutations in the genes encoding for selenoproteins, which mediate redox reactions, thyroid hormone metabolism, and iodine removal.

This insight into metal metabolism, regulation, and function could foster innovative therapeutic strategies.

“Reviewing the subject as a whole will open the horizon to connect the pieces and conduct more research that may help develop treatments,” the researchers say.

DNA sequencing can reveal mutations underlying a vitamin deficiency in newborns, but its rarity makes the value of populationscale testing unclear

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enetic testing of newborns can give doctors essential information about hereditary disorders that might be mitigated or even prevented if identified and treated early.

KAIMRC’s Majid Alfadhel and his colleagues demonstrated the feasibility of detecting mutations associated with a high-risk vitamin deficiency, although its incidence may be too low to justify widespread screening.

Children born with biotin-thiamine-responsive basal ganglia disease (BTBGD) carry mutations in both copies of a gene known as SLC19A3.

This gene encodes a transporter protein that manages the cellular uptake of thiamine, also known as vitamin B1.

The resulting deficiency leads to neurological symptoms such as seizures and cognitive and motor deficiency, which can become severe and even fatal over time. However, Alfadhel and colleagues found that prompt treatment with thiamine and another B vitamin, biotin, can prevent such outcomes and help healthy development. innovations.kaimrc.med.sa

C ULT UR A C R EAT I VE (R F ) / A L A M Y S TOC K PHOTO

Searching for signatures of a rare disease Genetic testing can reveal mutational insights to help treat hereditary disorders early on

Although generally rare, 50% of all reported cases of BTBGD came from the Saudi population. “Since we have the largest cohort of patients in the world, and this is a treatable condition, we decided to do a pilot study to know the incidence of this disease in Saudi Arabia,” says Alfadhel. In order to get a better handle on the disease’s prevalence in the country, Alfadhel and colleagues performed genetic analysis of the SLC19A3 gene in 3,000 healthy babies born at two Riyadhbased hospitals over a two-year period.

Six of these infants had a single copy of the disease-causing mutation, making them asymptomatic carriers. None of these were born into families with a reported history of this condition, and the researchers subsequently recommended that other relatives of the affected children also undergo genetic screening to assess their own risk of transmitting the mutation to their own children in the future.

These results revealed a 1 in 500 risk of carrying this particular SLC19A3 mutation, leading the researchers to estimate that 1 in a million children are born with BTBGD.

Although 37 other BTBGD-associated mutations have been described to date in the literature, none of these variants was observed in this particular cohort.

The Saudi newborn screening panel currently looks for 17 hereditary metabolic and endocrine disorders, encompassing conditions that occur with incidences ranging from roughly 1 in 7,000 newborns to just under 1 in 200,000. Given the apparent relative rarity of BTBGD, Alfadhel and colleagues advise against adding it to the panel at this time. “However, we certainly need to screen high-risk groups like first degree relatives, and do premarital screening for families screening from this disorder,” he says. They also note that the current cohort was limited in size, and suggest that additional studies in a larger population should be conducted before making a final recommendation.

Alfadhel, M., Umair, M., Almuzzaini, B., Alsaif, S., AlMo-

haimeed, S.A. et al. Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn

screening. Ann. Clin. Trans. Neurol. 6, 2097–2103 (2019).

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Scanning electron micrograph image of Salmonella Typhimurium (red), one of the most common types of bacteria that causes Salmonella infection in humans

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Salmonella in the spotlight

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KAIMRC-led study has identified S. Enteritidis and S. Typhimurium as the two most common Salmonella serotypes treated in a Riyadh hospital between 2015 and 2017. This observation aligns with global Salmonella serotype data.

The bacterial pathogen Salmonella is a leading cause of food-borne illness.

Eggs, chicken, fruit, vegetables, and processed foods can harbour the bacteria. An estimated 1.35 million cases of human infections are reported each year in the United States, resulting in 26,500 hospitalisations and 420 deaths. So far, data on the prevalence and type of Salmonella infections in Saudi Arabia has been scarce.

Now, researchers including Majed Alghoribi and Michel Doumith at KAIMRC’s Infectious Diseases Research Department (IDRD,) along with colleagues in Canada, have begun to address this knowledge gap.

“Our study1 is the first of its kind to examine the prevalence of Salmonella serotypes — groups of bacteria that share distinctive surface structures — associated with human infections in Saudi Arabia,” says corresponding author Taseen Desin at the University of Saskatchewan.

“Along with other work being done at the KAIMRC IDRD, our findings will lead to the development of better surveillance innovations.kaimrc.med.sa

and intervention measures in the country, which will result in lower human infections and a safer food supply.”

The team analysed 200 Salmonella clinical isolates collected between 2015 and 2017 at a hospital in Riyadh. The samples were taken from patients with symptoms ranging from gastrointestinal illness to whole-body (systemic) infection. Using a rapid testing kit called Check and Trace Salmonella™, they found that S. Enteritidis was the most prevalent at 40%, followed

by S. Typhimurium (13.5%) and three other serotypes called S. Livingstone (5%), S. Kentucky and S. Poona (both at 4.5%).

As S. Enteritidis and S. Typhimurium are the two most common serotypes in other parts of the world, including the US and Europe, Desin says the findings fit well with global Salmonella serotype data, although he cautions that further tests based on data collected nationally would be needed to confirm that this is the case.

Country-level disparities in the prevalence of less common serotypes could be accounted for by differences in eating habits, geographical location and climate, the researchers say.

The team tested for the presence of two virulence determinants considered to be hallmarks of Salmonella infection.

“The majority of strains we examined contained these determinants, called

SPI-1 and SPI-2,” explains Desin. “We found that SPI-2 was absent in some of the strains that did not cause systemic infection.” This observation aligns with previous studies pointing to SPI-2’s involvement in the systemic spread and survival of the bacteria in host organs.

The role of SPI-1 is less clear. It continues to be a topic of discussion following a study2, by Qinghua Hu and co-workers, that showed SPI-1 was absent from two strains isolated from an outbreak in Shenzhen, China, in 2002.

The fact that the study uncovered the presence of a multidrug-resistant S. Kentucky strain for the first time in Saudi Arabia is a concerning issue that poses challenges for physicians limited in their choice of treatment options. “Importantly, our work will enable us to develop a database of the antibiotic profiles of all Salmonella strains in the country along with their associated serotypes,” says Desin.

1. Alghoribi, M. F., Doumith, M., Alrodayyan, M., Al Zayer,

M., Köster, W. L. et al. , S. Enteritidis and S. Typhimurium harboring SPI-1 and SPI-2 are the predominant sero-

types associated with human salmonellosis in Saudi Arabia. Frontiers in Cellular and Infection Microbiology 9:187 (2019).

2. Hu, Q., Coburn, B., Deng, W., Li, Y., Shi, X., et al. Sal-

monella enterica serovar Senftenberg human clinical isolates lacking SPI-1. Journal of Clinical Microbiology 46, 1330–1336 (2008).

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C D C / J AM ES A R C H ER / A N T I B I OT I C R ES I S TA N C E C OOR DI N AT I ON A N D S T R AT EGY UN I T

Study investigating Salmonella serotypes in Saudi Arabia could lead to a reduction in food-borne illness, and the development of a vaccine

COVID-19

Upclose with COVID-19 From frontliners’ intimate knowledge and experience with COVID-19, to building on the kingdom’s knowledge of MERS-CoV, scientists and medical workers worldwide are getting to know the ins and outs of the virus and its potential treatments or vaccines

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COVID-19

Repurposing resources to take on COVID-19 KAIMRC is working hard to contribute to the search for an effective treatment for COVID-19

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Coronavirus is the subject of intense research in Saudi Arabia, and particularly at KAIMRC. You have announced progress in terms of isolating and sequencing the virus. What are some of the research trajectories KAIMRC is exploring?

There are several ways of repurposing medications for COVID19 and researchers use different technologies to search among thousands of existing compounds and medications. KAIMRC has a few of these technologies.

Can you give an example of these, and how they are helping researchers?

We use molecular modeling, medicinal chemistry and high-throughput drug screening of FDA approved drugs. This will give us an advantage to get the drug to market faster since these drugs already passed through Phase I (Safety and Toxicity) clinical trials.

Leading up to one of our clinical trials, for example, we’re using computational biology and bioinformatics to search among existing drugs molecules and see where they bind in the COVID19 virus or genome, to predict whether they can be used against the disease. Also, we have expressed one of the key enzymes of COVID-19 and testing FDA approved drugs. We are hopeful that we will repurpose a drug molecule through these efforts.

We look at the virus structure in three dimensions and try to see where the medication binds to the virus, and if it binds into a sensitive target of the virus, like envelop a protein, or an enzyme that might kill it. You need to target certain target proteins such as enzymes, genetic codes like RNA or lipids that envelop the virus, of which there are usually multiple, for the computer to try to match up with the drugs in question. That is being done now, and we are coming up with a number of compounds that will be validated in the laboratory, and in planned clinical trials.

Do you have enough Saudi patients for these types of trials?

We do. We’re collaborating with many hospitals in Saudi Arabia to reach as many patients and samples as possible. There are several major projects that are ongoing across the country and some of them are led by institutions other than KAIMRC. innovations.kaimrc.med.sa

You mentioned that you are trying to repurpose several medications for the treatment of COVID19 that have been pre-approved by the Saudi Food and Drug Administration (SFDA). Is there a specific medication or a combination of medications that is exceptionally promising?

We are participating in the international clinical trial led by the World Health Organization Solidarity, which tests Remdesivir, Chloroquine, Lopinavir with Ritonavir and Interferon β1b. This trial is enrolling patients in many countries, including in seven hospitals in Saudi Arabia. There is another national trial led by KAIMRC that uses Favipiravir, a medication that was developed

by Japanese company Fujifilm Toyama Chemical and approved for certain types of influenza in Japan. We have done a computational biology screening and we found Favipiravir a suitable candidate.

To follow up on Favipiravir, we have synthesised some analogs of Faviparavir which will be assayed in RNA dependent RNA polymerase (RdRP), a critical enzyme for replication of virus. We are trying Favipiravir in combination with Hydroxychloroquine, a medication that is typically used to prevent and treat malaria.

There is some skepticism about the world’s ability to fast-track a vaccine. We have had other types of coronaviruses such as SARS-CoV and MERS-CoV for years, and there are still no vaccines for either. Why would SARS-CoV-2 be any different?

The magnitude of the impact of COVID-19 on the world is much bigger than the others. The impact of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) was limited, and hence, the whole world was not as pressed to speed up the development of a vaccine. For MERS, there are three vaccines that have reached clinical trials worldwide. One of them is ours, in collaboration with Oxford University. This potential MERS vaccine is now in phase one clinical trial (and the research project kicked off in 2016). Considering the amount of time it takes to develop a vaccine, this is actually going faster than usual.

However, compared to the efforts to find a vaccine for COVID19, even this fast-tracked MERS trial is relatively slow. When it comes to COVID-19, the world is at the fastest that we’ve ever seen in terms of the amount of science that is being developed and shared. The whole world and its resources are just focused on this issue. That inspires hope.

With KAIMRC’s focus on the current pandemic, do you believe that COVID-19 research may be exhausting your funds or taking attention or resources from other important areas of research inside KAIMRC, such as cancer research, for instance? How do you think KAIMRC can strike a balance?

There will definitely be an impact on research areas other than COVID-19, financially and logistically, in terms of resources, and the ability to conduct research, even on the patients themselves.

This is definitely affecting everything, and other research will be affected for a while.

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hmed Alaskar, KAIMRC’s executive director, discusses the centre’s efforts in repurposing research labs and infrastructure to focus on SARS-CoV-2, the virus that causes COVID-19. Like many institutions around the world, KAIMRC is searching for ways to repurpose existing drugs, after isolating and sequencing the COVID-19 virus from a patient in Saudi Arabia. KAIMRC researchers are searching thousands of existing compounds and medications with the help of various cutting-edge technologies. In addition, using computational methods (modeling) we have generated new lead molecules. These new chemical entities (NCE) will be synthesised, and assayed in live virus assay.

COVID-19

Life on the COVID-19 frontline

Egyptian anesthetist in London speaks about the realities of COVID-19 for health workers

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s millions across the world quarantine at home, keeping a safe distance from a deadly virus, healthcare workers on the frontline of the pandemic are risking their lives every day. Moustafa Mortada, an anesthetist and intensive care unit (ICU) specialist in a hospital in Yorkshire, United Kingdom, speaks about the new normal for doctors and nurses around the world.

Speaking at a webinar held by Nature Middle East, the regional branch of Nature, Mortada shared his experience fighting a disease that killed more than 760,000 worldwide, and infected

Keeping calm and carrying on

All the beds in the hospital Mortada works for are now filled by people with COVID-19, as is the case in many ICUs around the world. innovations.kaimrc.med.sa

Patients admitted to the ICU are always in a serious condition, so this is a reality ICU workers are used to; but the unprecedented numbers being admitted in critical conditions are daunting. “We’re almost in a state of war; it is a huge burden on anyone to see large numbers of patients admitted at the same time, with the same diagnosis, and with high mortality rates,” says Mortada. “We’re trained to compartmentalize and separate work from personal response to deal with critical conditions.

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well over 20 million, including nearly 300,000 in Saudi Arabia by mid-August.

“I always left work behind when my shift was done, and I never carried work home with me. Now, the situation is different, it’s the first time my work affects my home, my family and my entire life,” says Mortada, who has 17 years of experience in the field.

COVID-19 different ways of coping, but second guessing themselves to assess whether they’ve done everything they could to save the patient remains a challenge.

In England, for instance, 5% of COVID19 cases require ICU care. Of those 165 patients admitted to the ICU in England, Wales and Northern Ireland throughout February and March, 79 died, according to data released by the Intensive Care National Audit and Research Center (ICNARC) on March 28.

In addition to feeling responsible for the cases he treats, Mortada explains that healthcare professionals also fear for their own lives and the safety of their families given COVID-19’s alarming contagion and fatality rates. Whereas a virus like MERSCoV, the virus causing the Middle East Respiratory Syndrome, has a fatality rate of 34%, since it was discovered in 2012, it has only affected 2,500 people around the world, according to figures from the World Health Organization (WHO). SARS-CoV-2, the virus causing COVID-19, has a lower mortality rate of an estimated 3.4% by early WHO estimates, to 6.5% when calculated based on the ratio between deaths and confirmed cases. SARS-CoV-2, however, has already affected 2.2 million around the world in four months. A single COVID-19 patient can infect 2 to 2.5 people, according to WHO, with some reports from the Center of Disease Control (CDC) estimating the transmission rate in the early days of the outbreak in Wuhan to be over five. A single influenza patient, by comparison, only transmits the disease to 1.3.

Its contagion and fatality rate, means that medical staff need to wear full protective gear, completely covering the eyes, nose and mouth. Regular surgical masks do not provide proper protection for medical professionals dealing with COVID-19 patients.

Some hospitals, including Mortada’s, had to triple the number of doctors in ICUs to deal with the volume of cases, and because a doctor can’t remain in the protective gear for more than 90 minutes at a time. The gear is tightly fit and can cause blisters, and is also difficult to communicate in, so ICU workers often have to rely on writing for communication inside the unit.

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“[These protective measures] keep us from being able to deal with patients as quickly as we are used to, and when a critical case arrives to the emergency room, we’re no longer able to tend to them immediately as we used to,” he explains. Now, first respondents have to wear the proper protective gear before they can tend to any suspected COVID19 case. It is not enough to take these precautions for confirmed cases alone, he says, because by the time they’re confirmed, a doctor or a nurse would have already become infected. One of Mortada’s patients, for instance, was tested negative three times before the fourth time finally came back positive for COVID-19.

Despite their best efforts, and rigidly

following hospital protocols, two of Mortada’s colleagues tested positive for the virus. “There are so many aspects about the virus that we still do not fully understand,” he adds.

Mortada’s key message to his fellow health workers is never to forsake their own safety, even if this goes against the instinct and training of emergency respondents who are used to rushing to deal with incoming cases. “There is no emergency in treatment with these cases, so don’t forsake your own health thinking this might save the patient. It is far more valuable for you, and for the sake of other patients you need to treat to take the proper procedures and wear your protective gear before dealing with a potential COVID-19 case,” he says.

Life in ICUs in numbers

Normal ICU

1 doctor per 8 beds

COVID-19 ICU

3 doctor per 8 beds

Transmission rate Transmission rate for Influenza for COVID-19 1 patient infects 1.3 others

Fatality

Fatality rate for Influenza: less than 1%

Fatality

Fatality rate for COVID-19: 3.4% to 6.5%.

Cases

1 patient infects 2.5 others

Cases

70% of ICU cases are 70% of ICU cases are overmen weight, obese or clinically obese

Medical staff can stay in protective gear for 90 minutes at a time

MEDICAL RESEARCH CORE FACILITIES & PLATFORMS They serve the MNG-HA scientific community’s needs for reagents, assays, samples and data analysis for the conduct of research projects as drug discovery and research areas as cancer, cardiovascular & rare diseases.

SERVICES • Cell Culture Facility • Biochemistry, Microbiology and Molecular Biology Lab • Lentivirus and Baculovirus Lab • Bio-Imaging Suite • Immunology and Flow-Cytometry Platform • Mass Spectrometry • Drug Discovery, Medicinal & Analytical Chemistry

KAIMRC-CORE@NGHA.MED.SA

COVID-19

SARS-CoV-2, the virus causing COVID-19

Sticking to the facts in the pandemic

Bombarded with news, advice, and pseudo-science presented as facts, it is time to debunk some of the misinformation around COVID-19 58

June 2020

Myth: Only old people need to worry about COVID-19

Elderly people are at greatest risk of severe disease or death from coronavirus infection. One recent study2 in Italy found that the median age of patients admitted to the intensive care unit (ICU) was 63 years old, and mortality rates were more than twice as high for those patients over 63. However, patients as young as 14 were hospitalised, and a report3 from the US Centers for Disease Control and Prevention found that 20% of American ICU patients were between the ages of 20 and 44. And as for the many young people who remain asymptomatic after infection, they are still contagious and can spread the disease, putting older family members, neighbours, and coworkers at considerable risk.

Myth: The COVID-19 coronavirus originated in a laboratory

The larger family of coronaviruses are well-known ‘zoonotic’ agents—meaning, pathogens that can make the leap from animal hosts to humans. In the past 20 years, the world has already seen multiple outbreaks from deadly coronaviruses that originated in species such as bats or camels, including the severe acute respiratory syndrome (SARS) outbreak of 2002–2003 and Middle East respiratory syndrome (MERS), which first emerged in 2012. All available evidence indicates that the SARS-CoV-2 virus responsible for COVID-19 is directly descended from a innovations.kaimrc.med.sa

natural bat-borne virus. In a recent study4 from Nature Medicine, a team of scientists from the US, Australia and the UK analysed the SARS-CoV-2 genome, and report that “our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.”

A report by the US Centers for Disease Control and Prevention found that 20% of American ICU patients were between the ages of 20 and 44.

Myth: COVID-19 is less dangerous than the flu

Seasonal and pandemic influenza are both major threats to health and life—Johns Hopkins estimates that flu virus infection is responsible for between 291,000 and 646,000 deaths worldwide each year. In contrast, COVID-19 has already caused upward of 480,000-plus deaths as of late June — just six months since the virus first appeared. It should also be noted that the COVID19 death toll is in spite of social distancing, surveillance, and infection control measures taken by many countries. Furthermore, both vaccines and therapeutics are available to mitigate influenza, whereas no such protection is currently available for COVID-19, creating the potential for a much deadlier situation if strong public health measures are not maintained. COVID-19 is also more contagious than the flu; and each COVID-19 patients infects between 2.2 to 2.5 others, whereas the rate in the flu is only 1.3. Flu mortality rate is also less than 1%, whereas early estimates of the World Health Organization puts the rate for COVID-19 at 3.4%.

Myth: A mask is sufficient to protect against catching COVID-19

In many countries, members of the public are being encouraged or even required to wear a surgical or cloth mask when in public during the pandemic. Masks can help reduce the spread of infection and are a good precaution, but should not be seen as complete protection. A report5 published in Nature found that individuals who wear homemade cotton masks or surgical masks are less likely to spread droplets containing the virus when they breathe or talk, and can thus help protect others in Issue No.7

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t is difficult to process the deluge of news about the coronavirus (SARS-CoV-2) responsible for the COVID-19 pandemic. Scientists, clinicians, and public health experts are still struggling to get a handle on this pathogen, which was completely unknown just six months ago. Myths and misconceptions can spread quickly in this environment, but there is information available to help the public to better protect themselves and their loved ones.

We are yet to understand various aspects of the SARS-CoV-2.

Research1 has concluded the virus stays in the air for up to three hours under the specific hospital settings because inserting breathing tubes in COVID-19 patients makes the virus spread, and stay in the air, more aggressively. Scientists, however, can still not say that the virus is airborne. Policymakers are still trying to determine whether mask use should be common advice.

Some facts about the respiratory virus that affected over 21 million around the world by mid-August, however, are well established.

COVID-19

COVID-19 myth busters

information that suggests that pets might be a source of infection for people with the coronavirus that causes COVID-19,” although they advise that patients with active infection should limit their contact with pets until they recover.

Myth: Warm spring and summer weather will slow the spread of COVID-19

Myth #1

Myth #2

Only the elderly should worry about COVID-19

Hot weather will halt the outbreak

Myth #3

Myth #4

It is laboratory made

Face masks provide full protection

Myth #5

Myth #6

COVID-19 is not more serious than the flu

Your pets can transmit the disease

In temperate climates, cold and flu season typically spans from late fall to spring. The reasons for this are not fully understood, but some experts6 believe that the airborne droplets that spread these viruses are more stable in the low-humidity winter air than in the damper summertime air. Our mucus membranes and immune systems may also be more vulnerable to infection in the winter. Although there is some evidence that COVID-19 is also somewhat hindered by warmer weather, many leading virologists see little reason to believe that summer will meaningfully hamper the pandemic’s spread, including Harvard researchers in a recent study7 published in Science. This is largely due to the novelty of the SARSCoV-2 virus; even if weakened by heat or humidity, human immune systems are illequipped to fend it off, relative to familiar foes like cold or flu viruses.

1. Doremalen, V. et al. Aerosol and Surface Stability of

SARS-CoV-2 as Compared with SARS-CoV-1. New Eng-

land Journal of Medicine. 382 (2020).

2. Grasselli G. et al. Baseline Characteristics and Out-

comes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy.

the community from infection. However, wearing a mask will not necessarily prevent contracting COVID-19 from unmasked individuals. It is essential that the mouth and nose are both fully covered, that the wearer refrains from touching either their face or the mask while in use, and that the mask is either immediately discarded afterward (for surgical masks) or washed before reuse (for fabric masks). And even with a mask, appropriate social distancing remains essential for maximum protection. It is also important to remember that the virus can also be caught through the eyes.

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June 2020

Myth: Pets can spread COVID-19

There have been a few reports of animals testing positive for infection with the SARS-CoV-2 virus. However, there is currently no evidence to suggest that animals carrying the virus can transmit it to humans. One laboratory study that is in preprint has demonstrated that cats can spread the virus to other cats in an experimental setting, but none of these animals developed disease, and it remains unclear whether similar spread between animals occurs in the real world. The American Veterinary Medical Association has announced that they “have no

JAMA. (2020).

3. Severe Outcomes Among Patients with Coronavirus

Disease 2019 (COVID-19) — United States, February

12–March 16, 2020. MMWR Morb Mortal Wkly Rep 69, 343-346 (2020).

4. Andersen, K.G., et al. The proximal origin of SARSCoV-2. Nat Med 26, 450–452 (2020).

5. Leung, N.H.L., et al. Respiratory virus shedding in

exhaled breath and efficacy of face masks. Nat Med (2020).

6. Shaman, J. et al. Absolute humidity and the seasonal onset of Influenza in the Continental United States.

PLoS Biol 8 (2) (2010).

7. Kissler, S. et al. Projecting the transmission

dynamics of SARS-CoV-2 through the postpandemic period. Science.

SAUDI BIOBANK

Is a national project; shepherded by (KAIMRC) and one of the important medical research projects in the Kingdom of Saudi Arabia that aims to:

SERVICES • Support a wide range of genetic and epidemiological research studies with focusing on improving preventive, diagnostic, and treatment of common and rare diseases • Increase the quality of patient care with implementing the highest standards of biological banking to provide outstanding clinical, medical, demographic and analytic data.

KAIMRC-BIOBANK@NGHA.MED.SA

COVID-19

The most discussed COVID-19 therapies

W

ith millions of people infected, and fatality numbers over 750,000 worldwide, an urgent search is underway for drugs to treat COVID-19 patients. Many treatments have been touted as potential cures, and now some are undergoing trials. Here’s an outline of the most talked about treatment options currently under study.

Convalescent plasma

Convalescent plasma (CP) therapy was developed and used as a therapy in the flu pandemic of 1918-19, the concept is straightforward: take blood plasma 62

June 2020

OV I D I U DUG UL A N / A L A M Y S TOC K P H OTO

While the world waits for a vaccine, there are several treatment options being considered for use on COVID-19 patients

containing neutralising antibodies from a person who has recovered, and transfuse it into patients with COVID-19.

Studies1 on patients in Wuhan, China, indicate the approach of preventing the SARS-CoV-2 from entering cells might work. Patients experiencing life-threatening respiratory distress showed some improvement, and the viral load levels in their bodies dropped. CP therapy was used to good effect in the previous SARS, MERS, and H1N1 outbreaks. A meta-analysis2 by John Mair-Jenkins and colleagues, published in 2014, showed that mortality rates were reduced after patients with severe acute respiratory

infections received various doses of convalescent plasma, with no adverse events or complications after treatment.

There are a number of efforts to investigate CP. The most advanced is in the United States, a national COVID-19 Convalescent Plasma Project run by Michigan State University, and the Mayo Clinic.

“The environment is conducive to moving the process forward,” says Priya Sampathkumar, a consultant at the Division of Infectious Diseases at the Mayo Clinic.

There are, however, problems with collecting sufficient quantities. A single donor yields only so many antibodies per draw, so a large pool of recovered donor

patients is required. Further tests are then needed to establish what levels of antibodies are effective, so that dosage can be established. Work is progressing, and a neutralising antibody test should soon be available onsite at the Mayo Clinic, Sampathkumar adds.

There are several clinical trials underway, some due for completion by the end of this year, including a phase III trial in Paris due for completion in August, and another in Beijing due for completion in June. Johns Hopkins is also starting a trial to assess whether convalescent plasma could be used as a prophylactic measure to confer passive immunity against COVID-19.

In the United States, immunologist Arturo Casadevall from Johns Hopkins is spearheading a nationwide effort to encourage plasma donation from recovered COVID-19 patients spans 40 US institutions, including Johns Hopkins University, and the Mayo Clinic. The UK’s National Health System (NHS) Blood and Transplant is also leading a programme across 23 blood centres to collect convalescent plasma for clinical trials. Saudi Arabia has also launched its own study into using convalescent plasma to treat COVID-19.

Several industry players, including Takeda, CSL Behring, Biotest, Bio Products Laboratory, LFB, Octapharma and Microsoft have collaborated to develop an unbranded polyclonal antibody product from a pool of donors.

Repurposed anti-virals

Using a familiar anti-viral drug may seem the quickest and safest approach, but scientists warn that this route is far from guaranteed.

Remdesivir is a nucleotide analogue anti-viral originally considered for Ebola. On April 29, Anthony Fauci, director of the US National Institute for Allergy and Infectious Diseases (NIAID) announced that a clinical trial in more than 1,000 people had showed that those taking remdesivir recovered in 11 days, compared with 15 days for those on a placebo. The U.S. Food and Drug Administration (USFDA) has innovations.kaimrc.med.sa

now authorised the use of remdesivir to treat COVID-19.

Data from the trial referred to by Fauci has not been placed in the public domain, and scientists, clinicians, and those in public health have not been able to analyse efficacy. To add to the confusion, it follows the publication of a study in The Lancet3 from a randomised double-blind trial in 237 severely ill patients in China which concluded the drug failed to have any clinical benefits.

Gilead Sciences, the US company that makes the drug, began increasing its production for clinical use from the end of March, before trial results were available, so that stocks would be immediately ready. Even if remdesivir is effective, is not taken orally as is not available in a capsule or tablet form, and must be injected, making wide-scale population treatment more difficult.

Joint research is underway into the nucleoside analogue, EIDD-2801, at the University of North Carolina, Emory University, and Vanderbilt University Medical Center. EIDD-2801 is an experimental antiviral drug that works by blocking RNA polymerase. The orally bioavailable drug was developed in 2018 in the search for a universal influenza vaccine, and with the outbreak of COVID-19, research turned to the SARS-CoV-2 virus. Data published in Science of Translational Medicine4 in early April shows promising activity against SARS-CoV-2 in cells and mice. But it’s a longer route to efficacy, and EIDD-2801 hasn’t gone through the safety screening that remdesivir has in human trials.

Unsuccessful antivirals

Another candidate that falls under the category of repurposed antivirals is chloroquine, the malaria drug, and its cousin, hydroxychloroquine, sometimes used in conjunction with the antibiotic azithromycin. Although sometimes touted as a potential treatment for COVID-19 , there has been no significant scientific evidence to back the claim.

The USFDA warned in a communication on April 24 that these drugs can cause dangerous abnormalities in heart

rhythm in coronavirus patients. The caution is based on a review of adverse events reported from multiple hospital and outpatient settings for treating or preventing COVID-19, the agency said, including rapid, irregular heartbeats, abnormal heart rates, delayed recharge by the heart muscle between beats, and in some cases, death.

Kaletra, a lopinavir-ritonavir therapy developed for HIV was also considered, but it lacks supporting data for in-vitro activity against SARS-CoV-2.

“Structurally, the HIV protease is quite different from the proteases, of which there’s more than one, in SARS-CoV-2.

It would be serendipity if it was active against the SARS-CoV-2 protease,” says Nick Matheson, principal investigator at the Cambridge Institute of Therapeutic Immunology and Infectious Diseases (CITIID) and honorary consultant in infectious disease at Addenbrooke’s Hospital, Cambridge.

Anti-inflammatories investigated

Existing anti-inflammatories are also being repurposed to potentially treat COVID-19.

There are also novel treatments such as tocilizumab, a humanised monoclonal antibody that works against the signalling chemical, interleukin-6, and has been used so far in the treatment of rheumatoid arthritis. Tocilizumab’s efficacy is being studied in phase III trials across sites in the United States, Europe, and Canada, but no significant findings have been yet published.

1. Duan, K. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proceedings of the

National Academy of Sciences. 117 (2020)

2. Mair-Jenkins, J. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiol-

ogy: A systematic review and exploratory meta-analysis.

The Journal of Infectious Diseases, 211 (201)

3.Wang, Y. et al. Rmedesivir in adults with severe COVID19: a randomised double-blind, placebo-controlled multicentre trial. Lancet. (2020)

4. Sheahan, T. An orally bioavailable broad-spectrum antibiral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.

Science Translational Medicine. 12 (2020)

Issue No.7

63

COVID-19

COVID-19 research efforts draw on Saudi Arabia’s MERS experience

KAIMRC is central to the kingdom’s efforts to slow COVID-19 as it builds on MERS research infrastructure and applies knowledge from previous coronavirus outbreaks

A

s the coronavirus disease ( C OV I D - 1 9 ) p a ndem ic spreads rapidly, KAIMRC has intensified its research efforts into the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)— the virus causing COVID-19—amid efforts to contain it. In addition to shutting schools, universities and suspending international flights and all public events, the government has announced a curfew and temporarily halted umrah.

Measures are gradually easing, but research efforts are still on track to find treatments and vaccinations.

As of August 15, Saudi Arabia had 64

June 2020

recorded 297,315 cases of the respiratory disease COVID-19, the largest number of infections reported in a single Arab country, as well as 3,369 deaths, according to the Saudi Ministry of Health . Most of the new cases were reported in Riyadh.

COVID-19 is potentially fatal for older people, and those with compromised immunity, underlying illnesses, or existing chronic conditions such as diabetes, or heart or lung disease. Its symptoms include fever, cough and shortness of breath, varying from mild to severe, and it can lead to pneumonia or organ failure.

MERS-CoV and SARS-CoV-2

While Saudi Arabia has had extensive experience with another member of the coronavirus family known as Middle East Respiratory Syndrome coronavirus (MERS-CoV), the level of disruption that SARS-CoV-2 has caused to the Saudi community, and the threat to public health, is unprecedented.

“The 2012 and 2015 MERS-CoV outbreaks in Saudi Arabia led to the shutdown of some hospitals. But, nothing at the time led to a shutdown of community and public places like what we’re experiencing now, because the ways in which novel coronaviruses spread are very

innovations.kaimrc.med.sa

more efficiently with the current outbreak. He warned, however, that the new mutated virus is not only crucially different than MERS-CoV, but it also comes with its own set of challenges.

MERS and COVID-19 manifest similarly, and have many symptoms in common. The pathogens responsible for the diseases probably originated in bats. Both viruses are contracted through close contact with an infected person, with transmission made worse by overcrowding. However, the new virus is more easily transmitted.

“Although MERS-CoV has the more severe impact on patients, with higher fatality rates, COVID-19 is spreading much

faster,” says Alaskar.

Projections on ICU bed availability across the kingdom vary, but Alaskar explains that a universal issue is that “the healthcare system will not cope with an entire community being sick at the same time.”

In a commentary published in February in the Journal of Epidemiology and Global Health1, Ziad A. Memish, senior consultant for adult infectious diseases at King Saud Medical City, warned that “it will be a huge challenge for healthcare workers to combat both viruses, MERSCoV and SARS-CoV-2.”

The Saudi Ministry of Health reported three more MERS-CoV infections on Issue No.7

65

W I T T HAYA P R AS O N G S IN / M O M EN T / GE T T Y I M AG ES

different,” says Ahmed Alaskar, KAIMRC’s executive director and associate professor of adult haematology.

Saudi Arabia was the site of the world’s most significant MERS-CoV outbreak, with 2,077 infections and around 773 fatalities, according to WHO. MERS-CoV was first identified in a pneumonic patient in the kingdom in 2012, and broke out again in 2015. Soon after, the kingdom prioritised research into MERS-CoV and poured resources into the study of its epidemiology, and into clinical trials of possible treatments and vaccines.

Alaskar explained that Saudi Arabia has leveraged its expertise with MERS to deal

March 20. Memish recommended that patients are now tested for both MERSCoV and SARS-CoV-2 simultaneously.

Experience matters

Saudi’s research experience with MERS might provide scientists with clues on the path to understanding the virus, how to contain it, and how to develop diagnostics and potential therapies.

“Prior knowledge of what triggers outbreaks is very important, and previous knowledge of SARS-CoV and MERS-CoV can help put us on the right path in our first steps to deal with this novel virus,” says Islam Hussein, formerly a virologist at the Massachusetts Institute of Technology (MIT), drug discovery researcher, and senior scientist at Microbiotix.

Hussein adds that this knowledge can help the research community build a picture of coronavirus transmission and how to deal with it effectively.

“Since we’re at a critical point, all the research that was previously done on preventive measures, the vaccines and antiviral drugs that were discovered and shelved but never been pushed to the markets are useful,” he explains.

WHO has announced on March 20 a large multi-country global trial, called Solidarity, that is expected to launch an aggressive, rapid search for drugs by testing four different drugs or combinations at once. Solidarity will also be looking at unapproved medications that showed promise against MERS and SARS during animal studies.

US biopharmaceutical company, Gilead Sciences, has also given several clinical trials access to the investigational broad-spectrum antiviral drug remdesivir — a medication originally developed for Ebola — for experimental use against COVID-19.

Meanwhile, KAIMRC has joined the global race for treatment and vaccines by scaling up research into the novel coronavirus, shifting some of its resources to scrutinising COVID-19.

Before the emergence of SARS-CoV-2 in Wuhan, China in December 2019, KAIMRC was already working to develop a new vaccine for MERS-CoV that has been tested successfully in camels, and had just been moved to human trials. These efforts are 66

June 2020

now providing the infrastructure needed by virologists, epidemiologists and infectious disease researchers at KAIMRC and across Saudi Arabia to build knowledge about COVID-19, including tools to study and handle the new virus safely.

“We’ve already started,” says Alaskar.

“The only challenge is that we have not yet got enough samples and patients, because we’re currently dealing with a smaller number of patients than those affected

by MERS-CoV.” According to Alaskar, researchers at KAIMRC have successfully isolated the new virus from patient clinical samples and sequenced its whole genome. “Whole genome sequencing would eventually lead to identification of certain targets for therapeutics and for tracking the virus,” he says. “The virus could develop resistance or transform. This way we would be able to track this.”

While international collaborations haven’t been formed, KAIMRC is on the hunt for partners in research within Saudi Arabia.

KAIMRC scientists are already coordinating efforts with other research centres in the country, according to Alaskar, so that clinical trials that were launched into MERS-CoV can be utilised for cases with COVID-19, and the data is shared.

This includes promising research into

monoclonal antibodies, synthetic proteins cloned from immune cells and used in drugs that enlist natural immune system functions to recognise and destroy a virus.

“We also have two rapid diagnostic tests that we’re working on,” says Alaskar.

“They’re still in the early phase. And we’re trying to validate these tests. Again, they were developed for MERS-CoV but we’re replicating them for COVID-19.”

Despite keen efforts, it is unlikely, however, that a treatment or a vaccine that could potentially turn the tide will emerge soon. It is also unclear whether Saudi Arabia will be further accelerating its research efforts, drug development, or testing of a fast-track vaccine.

“As we see now with this widespread and global pandemic of COVID-19, the whole world is basically trying to shortcut the research, and all government and scientific agencies are under pressure to approve the use of early data to approve vaccines and therapeutics. We have never seen a vaccine developed in four to six weeks, and with no or limited animal testing, and I would say this carries a risk,” says Alaskar. A vaccine typically takes a minimum of one year to be developed.

Memish, Z.A. et al. COVID-19 in the Shadows of MERSCoV in the Kingdom of Saudi Arabia. Journal of Epidemi-

ology and Global Health 10 (1): 1-3 (2020)

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