KAIMRC Innovations - Issue 10

DECEMBER 2021 - Issue No.10

ISSN 7901-2398 innovations.kaimrc.med.sa

A DY NAMIC DUO TO FIGHT MERS Experiments suggest that a two-antibody cocktail could prevent MERS-CoV infection

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RE VIE W ING R APID COVID-19 TES T S Point-of-care tests offer speed and practicality over lab-based PCR testing— with some caveats

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THE PSYCHOLOGICAL IMPACT OF COVID-19 T HE PA NDE MIC H A S BROUGH T A NE W F OUND A P P R E CI AT ION OF T HE T OL L T HE C ORON AV IRU S I S TA K ING ON ME N TA L HE A LT H P. 4 4

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

COVE R I M AG E : JACK I E NI A M / I S TOCK / G E T T Y I M AG E S P LU S

TABLE OF CONTENTS

P.8 A PROTEIN WITH POWER OVER BLOOD VESSELS

P.10 GENOMIC TESTS TO HELP SAUDIS P.11 FINDING LINKS BETWEEN WITH HEALTHY BIRTHS GENES AND DISEASES

Insights into an ion channel protein in blood vessels could lead to better understanding of vascular disease

A new screening service offers the country’s first prenatal and preimplantation genetic tests

Genetic sequencing and disease diagnosis databases help to identify new links

P.12 SAFER, EFFECTIVE CHEMOTHERAPY VIA NANOPARTICLE CARRIERS

P.14 TINY CARRIERS TO FAST-TRACK CANCER VACCINE DELIVERY

P.16 ROOM FOR IMPROVEMENT IN LUNG CANCER TREATMENT

Porous magnetic nanoparticles could carry cancer drugs directly into tumours while avoiding damage to healthy cells

Smaller, smarter cancer vaccines

The diversity in treatment practices and outcomes in stage III lung cancer patients in low- and middle-income countries

P.18 GENETIC CLUES TO BETTER TACKLE SARS-COV-2

P.20 A LOOK AT COVID- 19-RELATED ETHICS

Spike protein gene sequences could help control the novel coronavirus epidemic

Exploring the ethical challenges posed by the pandemic for healthcare providers and medical researchers across KSA

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P.21 REVIEWING RAPID COVID-19 TESTS

P.22 LINK BETWEEN COVID-19 AND GENETIC VARIATIONS EXAMINED

Point-of-care tests offer speed and practicality over labbased PCR testing—with some caveats

An international collaboration between biobanks has challenged a previous finding on a potential genetic basis for COVID-19 severity

P.24 HYDROXYCHLOROQUINE AND CHLOROQUINE ARE INEFFECTIVE AGAINST COVID-19 AND POSSIBLY HARMFUL

P.25 ADULT VACCINATION TO TACKLE BACTERIAL DISEASES

A meta-analysis of clinical trial results shows that hydroxychloroquine and chloroquine are of no benefit to COVID-19 patients

Pediatric vaccination programmes in the region have drastically reduced preventable diseases, but adult programmes lag behind

DIABETES IN FOCUS

P.26 DIABETES IN THE SPOTLIGHT Patients with diabetes could potentially experience serious complications if they contract COVID-19, leading researchers to focus closely on the lifelong condition, its prevention and promising avenues to better control type 1 diabetes 4

December 2021

TABLE OF CONTENTS

FEATURE

DIABETES IN FOCUS

FEATURE

FEATURE

P.28 EXPLORING THE LINK BETWEEN DIABETES AND COVID-19

P.32 PREVENTING DIABETES

P.36 NEW TYPE 1 DIABETES TREATMENT TARGETS

SARS-CoV-2 infections in diabetic patients reveals a complex relationship between the virus and metabolic glucose

Predicting a person’s risk of developing diabetes could save lives and conserve valuable medical resources

New avenues are opening for better control of type 1 diabetes, with some now showing promise in clinical trials

MENTAL HEALTH

P.40 THE HIDDEN CHALLENGE As scientists race to develop vaccines and drugs to combat the SARS-CoV-2 virus, the ongoing pandemic is taking its toll on our mental health. Researchers take stock of the impact of COVID-19 on the emotional well-being of patients, healthcare workers and their families

FEATURE

FEATURE

FEATURE

P.42 THE MENTAL HEALTH LANDSCAPE IN SAUDI ARABIA

P.44 THE PSYCHOLOGICAL IMPACT OF COVID-19

P.48 A PANDEMIC FOR ALL AGES

Promoting and improving wellbeing during the COVID-19 pandemic, while reducing the stigma of mental illness

Research from across the globe is now providing insights into its psychological toll

Research shows the impact of the global pandemic on families whose members suffer from childhood PTSD and autism

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P.52 NEW MODEL PREDICTS THE RISK OF BLOOD THINNERS FOR ARABS

P.54 A DYNAMIC DUO TO FIGHT MERS

A novel model that predicts bleeding risk in Arab patients taking direct oral anticoagulants shows good sensitivity and specificity

Experiments in mice suggest a two-antibody cocktail could prevent infection with the Middle East respiratory syndrome coronavirus

P.56 IMMUNE CHECKPOINT INHIBITORS CAUSE MILD TO SEVERE SIDE EFFECTS

P.58 ANTICOAGULANT SATISFACTION SURVEY TRANSLATED INTO ARABIC

A small Saudi study shows that the cancer therapy commonly causes mild side effects but sometimes result in more severe ones

The quality of life of Arab patients on long-term anticoagulant drugs can be assessed by an Arabic satisfaction scale

P.60 EXISTING DRUGS MAY HELP WITH COVID-19 TREATMENT

P.62 COMBINED THERAPY BOOSTS KIDNEY CANCER SURVIVAL RATES

Computational screening of SARS-CoV-2 genomes finds several proteins which could be targeted by existing drugs

A global phase 3 clinical trial demonstrates the efficacy of a novel combined therapy for advanced kidney cancer

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P.64 PROMISING NANO-PARTICLE CARRIER FOR CHEMO DRUG

P.65 TRIAL BEGINS ON ANTIVIRAL DRUG FOR COVID-19

Using nanoparticles to deliver the existing chemotherapy drug epirubicin could improve its efficacy and safety

A clinical trial in Saudi Arabia will examine the efficacy of an existing antiviral in treating mild COVID-19

P.66 OPTIMISING TREATMENT REGIMENS FOR CHILDHOOD ACUTE LYMPHOBLASTIC LEUKAEMIA A multinational study shows that radiotherapy with chemotherapy before hematopoietic stem cell transplantation improves the survival of children with acute lymphoblastic leukaemia compared with multi-agent chemotherapy

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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Cell membranes are a complex part of the cell which controls the movement of substances in and out of the cell and is selectively permeable to ions and organic molecules.

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A protein with power over blood vessels

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olecular details of the role of a specific protein that is part of a channel in cell membranes offer new insights into the function of blood vessels in health and disease. The findings may be relevant to several medical conditions, including high blood pressure, diet-induced type 2 diabetes, and vascular problems associated with obesity.

Dr. Ahmad Alghanem at King Saud bin Abdulaziz University for Health Sciences, together with colleagues at several research centres in the US, have been investigating the role of the LRRC8A (SWELL1) protein.

They had previously shown that the protein is an essential part of the Volume-Regulated Anion Channel (VRAC), which controls the flow of negatively charged ions (anions) through cell membranes.

The team has now performed further studies using endothelial cells from the veins of human umbilical cord tissue.

Human Umbilical Vein Endothelial Cells (HUVECs) are widely studied to investigate the activity of the endothelium, a single layer of cells that lines the interior of regions of the body including all blood vessels. It plays an important role in regulating blood pressure, blood flow, and the contractile activity of muscle cells surrounding blood vessels. Endothelial cells are also crucial to the formation of new blood vessels, known as angiogenesis.

innovations.kaimrc.med.sa

The new research has uncovered proteins that LRRC8A interacts with and molecular signalling pathways that it controls. The results suggest that LRRC8A plays a wide and multi-faceted in the normal functioning of blood vessels, including the maintenance of healthy blood pressure. Impairments in the activity of LRRC8A could be linked to problems with insulin signalling associated with the insulin resistance found in type 2 diabetes.

The research also revealed what the authors describe as “curious observations” that suggest there is more to learn about LRRC8A and its role in the vascular system. One possibility requiring further investigation is whether the protein and the VRAC channel as a whole may be involved in sensing fluid flow and fluid pressure within blood vessels. This mechanoresponsive activity may be a significant aspect of blood pressure control, which could be of major significance for many patients.

While the work is fundamental research, rather than applied science, the new insights into the control of blood vessel activity could eventually lead to a better understanding of vascular diseases and possible new avenues towards treatments.

Alghanem, A. F. et al. The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function. eLife 10:e61313 (2021).

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JUA N G A ER T N ER /S C I EN C E P H OTO LI B R A RY / G ET T Y I M AG ES

Insights into an ion channel protein in blood vessels could lead to better understanding of vascular disease

Genomic tests to help Saudis with healthy births

A new screening service offers the country’s first prenatal and pre-implantation genetic tests to pregnant women, and couples undergoing IVF

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KAIMRC laboratory is the first in Saudi Arabia to offer prenatal and pre-implantation screening tests for chromosome abnormalities. The genetic resource will help women who are pregnant or those struggling with infertility to make more informed choices about their family planning in ways that are safe, accurate and minimally invasive.

“Our main goal is really to help more families have healthy children,” says KAIMRC deputy executive director Majid

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Alfadhel, the pediatric geneticist who heads the lab.

Alfadhel and his colleagues outlined their experience implementing the diagnostic service in two reports published this year. In both papers, the researchers focused on detecting an abnormal number of chromosomes, a condition known as aneuploidy that can reduce fertility by causing miscarriages and may also result in neurodevelopmental disorders in babies. However, each study aimed to detect aneuploidy

in a different clinical context. The first centred around testing in vitro fertilization (IVF)-created embryos before they are implanted in the uterus,1 a process known as pre-implantation genetic testing for aneuploidy (PGT-A). In the second, researchers analysed foetal DNA found in blood samples from pregnant women,2 a method known as non-invasive prenatal testing (NIPT). The KAIMRC team began offering both diagnostic services in late 2019 in partnership with the Department of Pathology and Laboratory Medicine at King Abdulaziz Medical City in Riyadh.

The researchers carried out PGT-A tests on embryos created for 36 Saudi couples who had either experienced prolonged infertility or had had trouble getting IVF-generated embryos to implant successfully. The majority of the 200 embryos tested were not deemed suitable for transfer—120 had chromosome anomalies and 34 were of low quality overall. However, 46 embryos with normal chromosome counts were recommended for transfer, and many yielded successful pregnancies.

“It’s a good tool for improving implantation rates,” says Yusra Alyafee, team leader for prenatal and pre-implantation screening at KAIMRC and the first author of the two new reports.

The researchers were similarly successful with NIPT. Of the first 200 tests run, 13 revealed a high risk for aneuploidy, only one of which later proved to be a false positive when examined with more invasive screening techniques. All 187 negative tests accurately foretold the birth of healthy babies without chromosome defects.

The lab has since performed around 1,000 NIPT tests for Saudi women. As Abeer Al Tuwaijri, a co-author on the new studies, points out: “It’s getting more popular over time.”

1. Alyafee, Y. et al. Next-generation sequencing-based pre-implantation genetic testing for aneuploidy (PGTA): First report from Saudi Arabia. Genes 12, 461 (2021).

2. Alyafee, Y. et al. Next generation sequencing based non-invasive prenatal testing (NIPT): First report from Saudi Arabia. Frontiers in Genetics 12, 630787 (2021).

P R OS TOCK-S T U DI O / A L A M Y S TOCK P HOTO

KAIMRC's new screening tests can identify chromo­ some abnormalities in pregnant women.

Finding links between genes and diseases

Genetic sequencing and disease diagnosis databases help to identify new links

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ix previously unknown associations between specific diseases and genes have been identified by analysing databases containing the output of two genetic sequencing approaches. The research was carried out by an international group comprising members from ten medical institutes in Saudi Arabia, including KAIMRC. The authors reveal that “more than half of patients with genetic diseases remain undiagnosed,” highlighting the importance of finding new ways to establish links between genes and specific diseases. They say that genetic labs should be encouraged to pursue the type of database analysis they have used “for the benefit of undiagnosed patients and their families.” innovations.kaimrc.med.sa

The researchers analysed information from two different genetic sequencing approaches, exome and genome sequencing. Exome sequencing is a more targeted approach, determining the sequence of only the regions of DNA that are known to code for proteins. Genome sequencing, by contrast, covers the entire genome. The protein-coding exome comprises less than 2% of the genome.

The results from a genetic analysis of 38 patients suggest a clear association between variants in six genes and particular neurodevelopmental conditions or intellectual disability. Data from other patients suggests possible links between a further 31 gene variants and other diseases, including

neurodevelopmental disorders, intellectual disability, oral–facial–digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia.

The authors explain that it is often difficult to definitively identify genes as causing or having some role in specific diseases.

This challenge is complicated by the rarity of many genetic diseases, resulting in very low numbers of patients available for investigation.

A third compounding factor is that even when a gene is identified as being linked to a disease, the function of the gene may not be known.

“Our work shows the benefits of performing extended exome sequencing/ genome sequencing analyses in patients with no genetic diagnosis, combined with further data repository mining,” the authors conclude. They suggest that this type of analysis become a more routine part of the work of genetic analysis laboratories rather than relying on specialised research teams.

Bertoli-Avella, M.A. et al. Combining exome/genome sequencing with data repository analysis reveals

novel gene–disease associations for a wide range of genetic disorders. Genetics in Medicine 23, 1551– 1568 (2021).

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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

Genome sequencing machines can help identify new links to diseases.

Delivering safer and more effective chemotherapy via nanoparticle drug carriers Porous magnetic nanoparticles could carry cancer drugs directly into tumours while avoiding damage to healthy cells

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anotechnology shows great potential to improve cancer treatments, providing tiny vessels that can carry drugs to tumour sites and release them gradually. Now, KAIMRC researchers Rizwan Ali and Mohamed Boudjelal, working with Kheireddine El-Boubbou at King Saud bin Abdulaziz University for Health Sciences, have developed magnetic nanostructures that can deliver the chemotherapy drug Doxorubicin (Dox) directly into cancer cells without harming healthy cells.

“Controlled drug delivery systems are a hot topic due to their promising ability to enhance the therapeutic efficacy of drugs,” says Boudjelal. “Our new iron oxide mesoporous magnetic nanoparticles (IO-MMNPs) are particularly attractive, due to their drug entrapment capabilities, low toxicity, and stability within the body.”

Producing nanoparticles of the perfect size and porosity requires meticulous laboratory work. “Controlling the physiochemical properties for effective therapeutic drug delivery is very challenging,” explains Ali. The team used an acid preparation technique to produce silica spheres with uniform pores.

They then impregnated the spheres with iron nitrate, which fills the pores with iron. The silica was removed using a hot alkaline treatment, leaving porous iron oxide nanoparticles with large surface areas that can soak up and store Dox or other drugs.

“Our fabrication approach provided uniform spherical morphologies, high surface

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areas and large, controllable pore structures,” says Boudjelal.

The team performed in vitro experiments, treating cell cultures with either free Dox, Dox-infused IO-MMNPs, or ‘bare’ IO-MMNPs. These revealed that Dox was tightly held within the IO-MMNPs by electrostatic interactions, meaning that negligible amounts of the drug were released in the neutral pH environment of healthy cells.

However, acidic environments such as those found in tumours caused more than half of the Dox to be released over a 24 to 48-hour period.

The researchers’ microscope images showed IO-MMNPs gradually being enveloped within the cell cytoplasm, effectively delivering Dox to kill colon and breast cancer cells but not healthy cells. This indicates that nanoparticle treatments could greatly reduce the side effects caused by chemotherapy drugs.

Eventually, the team hope that their IO-MMNPs could be injected and guided towards tumour sites using magnetic fields.

“Magnetic fields have excellent penetration in biological tissues,” explains Ali. “However, the delivery of nanoparticles using a magnetic field is still in its development phase. Before that, our immediate goal is to test our IO-MMNPs in live mouse models to evaluate their selective cytotoxic effect on different cancer types.”

El-Boubbou, K. et al. Iron Oxide Mesoporous Magnetic Nano-

structures with High Surface Area for Enhanced and Selective Drug Delivery to Metastatic Cancer Cells. Pharmaceutics 13, 553 (2021).

Magnetic nanoparticles can deliver cancer drugs to the site of disease during chemotherapy treatment.

GR E E N SH O O TS CO M M U N IC AT I O N S / A L A M Y S TO C K P HO TO

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Polymeric nanoparticles are used for drug encapsulation and faster tracking.

Tiny carriers to fast-track cancer vaccine delivery Smaller, smarter cancer vaccines

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such as the human papilloma virus, most cancer vaccines are used to treat patients who are already affected by the disease.

These therapeutic vaccines, which are usually antigens derived from patient cancer cells, trigger an immune response that results in an attack on cancer cells.

Cancer vaccines are highly effective but difficult to introduce into target organs and cells because they comprise negatively charged nucleic acids with high molecular weights. Vaccine formulation and storage also affect their performance and safety.

Beg, S. et al. Lipid/polymer-based nanocomplexes in nucleic acid delivery as cancer vaccines. Drug Discov-

ery Today (2021). Advance online publication, 18 February 2021.

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N A N O C LU ST E R I N G / 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

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nti-cancer strategies could soon become more selective and less toxic thanks to nanomaterials.

A survey by researchers from Saudi Arabia including at KAIMRC in collaboration with the Jamia Hamdard centre in New Delhi, India, shows that tiny self-assembled lipid and polymer-based objects, or nanocarriers, could aid therapeutics by making cancer vaccines easier to deliver to specific sites in the body.

Although some vaccines, known as prophylactic vaccines, can prevent cancers caused by viruses in healthy people,

There are several methods available for targeted cancer vaccine delivery.

First-generation vaccines relied on viruses, such as herpes simplex viruses and adenoviruses, to carry the cancer cell-specific antigens. However, this approach increases the risks of mutagenesis, carcinogenesis, and unexpected immune reactions.

Nanocarriers such as liposomes and nanoparticles are promising substitutes for viral carriers. Easy to manufacture and modify using a variety of functional groups, they provide multiple ways to encapsulate nucleic acids and release them at the desired sites. Specifically, lipid- and polymer-based nanocarriers can readily penetrate cell membranes and expedite the transfection process. These carriers are electrostatic complexes between positively charged lipids or polymers and negatively charged nucleic acids.

Vaccine delivery using lipid-based complexes hinges on the hydrophobic domain of the lipids, which mediates the transmembrane transport of the nucleic acids and shields them from enzymes present in target cells. After cell entry, the complexes can directly release their cargo into the cytoplasm. Polymer-based complexes require an additive to help rupture the endosomes formed during cell entry.

Highly branched polymers usually form smaller particles than their linear analogues, which boost their performance.

Nanocarriers have been used for two decades in genetic vaccine delivery against various cancers, including breast, colon, and cervical cancer. In particular, poly(ethyleneimine) complexes effectively transfected a small RNA antigen targeting breast cancer, inhibiting tumor growth. Albumin-contained liposomes used to deliver the drug vinblastine with a gene–prodrug mixture showed a synergistic antitumor effect against mammary adenocarcinoma cells.

The researchers are now developing new nanocarrier-based formulations to allow cancer vaccines to reach their full potential.

Room for improvement in lung cancer treatment A large multinational study reveals the diversity in treatment practices and outcomes in stage III non-small-cell lung cancer patients in low- and middle-income countries

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of each treatment regimen, and the reasons for changing or ending treatment.

They found more than 25 treatment approaches, suggesting that only a limited number of cases followed international guidelines. “It was surprising to find that the adherence to treatment guidelines varies and is low, which very likely leads to different outcomes in patients,” says Jazieh.

The relapse rates in patients with resected and unresectable disease were high: 62% and 79%, respectively. The treatments associated with longer survival were surgery, concurrent

Jazieh, A.R. et al. Real-World Treatment Patterns and

Clinical Outcomes in Patients With Stage III NSCLC:

Results of KINDLE, a Multicountry Observational Study.

J Thorac Oncol. Epub ahead of print 26 May 2021.

B S I P SA / A L A M Y STO CK P H OTO

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ountries in the Middle East and Africa need to provide better therapies and care for lung cancer patients, according to a new study from KAIMRC. Lung cancer remains one of the deadliest forms; about half of people diagnosed with lung cancer die within one year.

Non-small-cell lung cancer (NSCLC) accounts for almost 85% of lung cancer cases, and up to 30% of these patients are diagnosed with locally advanced (stage III) NSCLC. These patients are treated with a range of therapies, including surgery, radiation, chemotherapy, and, more recently, immunotherapy and targeted therapies.

Abdul Rahman Jazieh, a former KAIMRC researcher who is now at Cincinnati Cancer Advisors in the USA, led the KINDLE study of more than 3,000 stage III NSCLC patients from 19 countries across Asia, the Middle East, Africa, and Latin America. “Until now, there were no or very limited data available on the treatment regimens and outcomes of these patients in low- and middle-income countries,” he says.

The study included patients who were diagnosed between January 2013 and December 2017 with at least 9 months of follow-up, before the approval of the immunotherapeutic agent durvalumab, which has significantly reduced the risk of death of patients with stage III NSCLC. The authors examined the type of treatment the patients received, the duration

chemoradiation, and triple therapy (surgery and chemoradiation), yet only a minority of patients (<40%) with unresectable disease received concurrent chemoradiation as an initial therapy.

The survival rates of stage III NSCLC patients in the Middle-East and Africa were worse than in the global cohort, highlighting the need for new therapies and quality care in this area. “There is a definite gap in optimal selection and sequencing of various treatment approaches,” Jazieh says.

Jazieh and his colleagues in Saudi Arabia have published updated guidelines for the management of stage III NSCLC and are working to improve physician education and patient access to new medicines.

Over the coming months, they will carry out in-depth regional and country-level specific analyses to improve the provision of lung cancer care.

“The study provides a benchmark for understanding the existing treatment landscape and will serve as a basis for comparison of newer therapies in this population,” says Jazieh.

Lung cancer remains one of the deadliest forms of cancer around the world.

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

Rising COVID-19 infections have resulted in genetic modifications of the virus.

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Genetic clues to better tackle SARS-CoV-2

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olecular level insight into the evo- outbreak and from bat SARS-like coronaviruses lutionary pathways and structure of collected between 2011 and 2017 in Yunnan provSARS-CoV-2, the virus responsible for ince and elsewhere in China. They discovered seven COVID-19, could help manage present mutations resulting from positive evolutionary and future coronavirus-related epidemics, suggest pressure on the SARS-CoV-2 spike protein. Five of researchers at King Saud University. these alter amino acids in protein domains responSARS-CoV-2 has spread exponentially, causing a sible for receptor binding. These mutations could global pandemic that continues to affect millions of enhance the receptor’s affinity and consequently people worldwide. The novel coronavirus is genet- the transmissibility of the virus, as observed in the ically similar to other human viruses that cause SARS-CoV-2 variant B.1.1.7, known as Alpha. severe acute respiratory Despite the strong oversyndromes, such as SARSall resemblance between “Spike proteins play a crucial SA R S - C o V- 2 a n d b a t CoV and MERS-CoV, as well as bat coronaviruses, sugSARS-like coronavirus, role in infection, enabling gesting that it originated their spike proteins had the binding of virus particles several variations in their from a bat-borne virus.

The ongoing rise in infecindividual constituent and fusion with host cells.“ tions has resulted in genetic chains. The researchers modifications, producing found that the SARS-CoV-2 multiple variants of the virus that have made the spike protein has a more open configuration and epidemic difficult to control. multiple polysaccharides that could facilitate viral Led by Saleh Eifan, the team has now devised a entry into host cells and provide a potential target gene sequencing approach to better understand for antibodies. Furthermore, the subunit responsithe emergence of these variants. The researchers ble for transmembrane fusion contained a site that identified the selection pressures that have driven can be cleaved by proteases and can thus be investichanges in the gene sequence encoding the spike gated as a potential target for antiviral drugs. proteins. Spike proteins dot the SARS-CoV-2 surThe researchers are currently exploring ways to face and play a crucial role in infection by enabling use these findings to develop therapeutic and prethe initial binding of virus particles and their fusion ventative approaches against coronaviruses. with host cells.

The researchers compared three SARS-CoV-2 Nour, I., Alenazi, O.I., Hanif, A. & Eifan, S. Molecular adaptive evolution spike protein sequences from Saudi Arabia to of SARS-COV-2 spike protein in Saudi Arabia. Saudi Journal of Biothose from SARS-CoV that caused the recent SARS logical Sciences 28, 3325–3332 (2021).

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

Spike protein gene sequences could help control the novel coronavirus epidemic

“Pandemic restrictions and policies raise ethical questions related to personal freedoms, beneficence, autonomy and justice.“ Travel bans, and social distancing and mask mandates have been enforced across the world since the pandemic broke out in 2020.

A look at COVID19-related ethics A new study explores the ethical challenges posed by the pandemic for healthcare providers and medical researchers across the Kingdom

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he COVID-19 outbreak forced quarantines and many restrictions. To manage the crisis, protect vulnerable communities, and curb the exponential spread of the virus, regional and local governments across the globe enforced tough measures for disease control and prevention, including lockdowns, curfews, travel bans and mask mandates.

Some of these restrictions and policies raise ethical questions related to personal freedoms, beneficence, autonomy and justice, and they also raise practical issues and contemplative questions regarding data sharing and tracking, privacy, and confidentiality, as well as challenges of preventing inequity, stigma, discrimination, and implementing the ethics of research practices.

A study published this year by KAIMRC explored how the Kingdom’s researchers and hospital workers feel about these challenges, which issues they prioritise and how they have dealt with them.

Between May and September 2020, the researchers interviewed 24 frontline healthcare providers along with COVID19 researchers and experts from different backgrounds working in Riyadh, at the King Abdul Aziz Medical City, including

Alahmad’s research confirmed that even though countries rely on different health infrastructures and navigate different cultural norms, the ethical challenges facing doctors and healthcare workers in response to COVID-19 seem to be universal. “ The people here share the same concerns, though there are some different points of view with regard to some issues, especially related to confidentiality, and using software to track people,” he explains. Alahmad adds that while some were vehemently against any compromise regarding sensitive health data, privacy, or confidentiality, others believe that public health interests should prevail.

However, Alahmad notes that the scope of this study, as well as the data collected, remain limited. “Some very important issues have not been discussed yet, such as problems relating to the vaccination [process] itself, manufacturing the vaccine and distributing it, as well as the idea of forcing people to take the vaccine. But we are working on that,” says Alahmad.

While this survey focused on people working in the treatment and management of COVID-19, Alahmad is also planning to survey patients and their families.

Alahmad, G., et al. Ethical Challenges Related to the Novel Coronavirus (COVID-19) Outbreak: Interviews with Professionals from Saudi Arabia. Front. Med. (2021).

FAY E Z NU R E L DI NE / A FP VI A G E T T Y I M AG E S

King Abdullah Specialized Hospital, and also the King Saud bin Abdulaziz University for Health Sciences and KAIMRC. Ghiath Alahmad, bioethicist and scientist at KAIMRC, says that the scarcity of this type of research in the Arab world prompted him and his peers to create their own survey.

Reviewing rapid COVID-19 tests

A N DR EW DUK E / A L A M Y S TOC K P H OTO

Point-of-care tests offer speed and practicality over labbased PCR testing, with some caveats

Lateral flow tests provide faster results.

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aboratory PCR testing for COVID-19 is highly accurate but requires specialist equipment, trained personnel, time, and infrastructure to produce and report results. In recent months, antigen pointof-care tests,’or AgPOCTs, have hit the European market with the promise of offering fast, cheap, and accessible testing. A research collaboration from Germany tested a selection of these new devices and found that they have the potential to inform novel public health decisions and provide a new tool for clinicians.

AgPOCTs are small, cheap, portable medical devices that detect a SARSCoV-2 protein in a patient sample. To use an AgPOCT, a patient sample is placed at one end of a test strip and is wicked to the other end via capillary action. If the sample contains a detectable SARS-CoV-2 protein, a positive result is indicated via the appearance of a line on the device, similar to a pregnancy test.

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However, AgPOCTs don’t match the gold standard of lab-based RT-PCR testing in two important measures: sensitivity and specificity. Sensitivity is the ability of a test to correctly identify those with COVID-19, while specificity is its ability to correctly identify healthy individuals — a test with high specificity would have few false positives.

Christian Drosten, of Charité – Universitätsmedizin Berlin, led a collaboration across several German institutes which performed a comparative analysis of the sensitivities and specificities of seven AgPOCTs that had recently become available on the European market. The tests were pitted against a variety of samples, including SARS-CoV-2 protein, respiratory samples known to have SARS-CoV-2 viruses, and samples containing other coronaviruses and respiratory pathogens.

The team found that the AgPOCTs have limits in sensitivity, and noted in their paper that the tests lack the power to provide a definitive diagnosis, especially in

very early or later-phase infections. The team noted that most tests showed acceptable specificities, with all but two having a false-positive rate of less than 3%.

Despite falling short of the sensitivity offered by RT-PCR, the sensitivities of most tested AgPOCTs overlapped with the viral loads typically seen in infectious patients, suggesting that AgPOCTs could provide a quick, snapshot assessment of a patient’s infectivity.

The availability of a fast and cheap tool to measure a patient’s infectivity could offer a powerful tool to inform public health decisions, such as having individuals quarantine based on infectivity rather than merely infection. The authors also state that AgPOCTs may find use in hospital environments, for example by enabling clinicians to decide which patients to isolate.

Corman, V. M., et al. Comparison of seven commercial

SARS-CoV-2 rapid point-of-care antigen tests: a single-centre laboratory evaluation study. Lancet

Microbe (2021).

Issue No.10

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Link between COVID-19 and genetic variations examined

An international collaboration between biobanks has challenged a previous finding on a potential genetic basis for COVID-19 severity

Research must use rigorous study design principles and properly control for ancestry differences as these greatly impact the frequency of gene variants.

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December 2021

I

n October 2020, a large, multinational research study led by Qian Zhang, of New York’s Rockefeller University, showed that some severe COVID-19 cases could be explained by hereditary mutations in genes that modulate important immune system pathways. Another large collaboration which used data from four independent COVID-19 biobanks from across the world sought to replicate these findings, but found that the original study’s results did not hold up. The new analysis found no link between severe COVID-19 and

mutations in the genes identified in the earlier study.

Type I IFNs are polypeptides secreted by infected cells that modulate different elements of immunity. Inherited mutations in genes encoding proteins or polypeptides, such as those involved in type I IFN immunity, can result in non-functional proteins.

In their study, Zhang et al. identified 13 variations in type I IFN-related genes that were predicted to cause a loss of function, and they assessed that as many as 3.5% of severe COVID-19 cases could be associated with changes in these 13 genes.

Following this, 52 researchers across six countries pooled data on 1,864 participants with COVID-19—713 severe cases and 1,151 mild cases—and 15,033 healthy controls. The genome and exome data were obtained from biobanks in the United States, Canada, Saudi Arabia, and Qatar.

The researchers found just one instance of one of the 13 previously identified predicted loss-of-function variants in this data, and they saw no greater incidence of the predicted loss-of-function variants in severe COVID-19 cases compared to mild cases or uninfected people. innovations.kaimrc.med.sa

In the May 2021 study, results are corroborated by another analysis performed on data obtained from the UK Biobank, in which a comparison of 1,184 COVID-19 cases and 422,318 controls “showed no association between [predicted loss-offunction] variants in these genes.”

KAIMRC’s Manal Alaamery, who worked on the study, says that “the beauty of this paper is really the power of collaboration,” both on a national level within Saudi Arabia and internationally. In their paper, the team conclude that research along these lines must use rigorous study

design principles and properly control for ancestry differences, as these greatly impact the frequency of gene variants.

Further research projects will continue to investigate links between COVID-19 and genetics and could reveal potential therapeutic targets.

Povysil, G., et al. Rare loss-of-function variants in type I IFN

immunity genes are not associated 1 with severe COVID19. Journal of Clinical Investigation 131, e147834 (2021).

Zhang Q et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 370, eabd4570 (2020)

Issue No.10

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D E S I GN C E L L S/ IS TO C K / G ET T Y I M AGE S P LU S

As researchers race to identify predictors of COVID-19 severity and potential avenues for treatment, one study’s newly identified link between genetic variations and COVID-19 outcomes has been contested by a more recent finding.

Hydroxychloroquine has not been shown to have any benefits for COVID-19 patients.

Hydroxychloroquine and chloroquine are ineffective against COVID-19 and possibly harmful A meta-analysis of clinical trial results shows that hydroxychloroquine and chloroquine are of no benefit to COVID-19 patients

A

n international team, including Yaseen Arabi of KAIMRC, has confirmed that treatment with hydroxychloroquine (HCQ) is associated with higher mortality in patients with COVID-19 and that there is no benefit to using chloroquine (CQ) to treat the disease. All COVID-19 clinical trials involving the two drugs have been stopped.

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December 2021

“These two drugs are used for the treatment of malaria and rheumatic disorders, and scientists had been hopeful of their potential as treatments for COVID19 thanks to their antiviral and immunomodulatory activity,” says Arabi. He served as the COVID-19 Antiviral Therapy Domain Chair of the REMAP-CAP trial, an ongoing international trial that

Axfors, C. et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Nature Communications 12: 2349 (2021)

L I L I BOAS / I S TOCK / G E T T Y I M AG E S P LU S

tested HCQ, and is currently testing other therapeutics against community-acquired pneumonia and COVID-19.

HCQ and CQ became a focus of multiple clinical trials as the COVID-19 pandemic took hold in early 2020. In several countries including the US and China, both drugs were listed as treatment options for patients in March and April 2020, even though they were known to cause potentially severe side effects. By June 2020, the FDA had revoked the emergency use authorisation of the drug, following data emerging from two high-profile trials, the RECOVERY and WHO Solidarity trials.

Arabi, along with many other scientists around the globe, contributed data from their own trials to the meta-analysis project to definitively determine the efficacy of the two treatments. The meta-analysis included data from 28 ongoing, completed, or discontinued randomized clinical trials, including the REMAP-CAP trial, that used either or both drugs to treat COVID-19. The team analysed data from more than 10,000 patients.

“By including data from multiple RCTs, meta-analysis increases the power to detect differences in outcome related to individual therapies,” says Arabi. “In this case, it showed that HCQ and CQ were associated with poor outcomes.”

Treatment with HCQ was associated with a longer hospitalisation and a higher risk of progression to invasive ventilation and/or death. Variation in the dosage did not alter these findings, and no clinical benefit was found for CQ either, although data was limited for this particular treatment.

“The analysis provides conclusive proof that neither drug should be used for COVID-19, and all trials pertaining to these treatments have stopped,” says Arabi. “Thanks to the rapid, collaborative efforts made by scientists around the world, any further harm linked to HCQ use in COVID-19 treatment has been prevented.”

Adult vaccination to tackle bacterial diseases

While pediatric vaccination programmes in the MENA region have drastically reduced preventable diseases, adult vaccination programmes lag behind

innovations.kaimrc.med.sa

“Adult vaccination efforts in the Middle East must be prioritised to reduce the burden of preventable diseases.“ in place in some countries, such as Saudi Arabia, where many Hajj pilgrims are required to have meningococcal vaccinations. However, the introduction of comprehensive adult vaccination strategies across the region is significantly hindered by the lack of access to affordable vaccines.

There is also a “disappointing” lack of epidemiological data or public

Bizri, A. R., Althaqafi, A., Kaabi, N., Obeidat, N., Al Akoury, N. et al. The Burden of Invasive Vaccine-Preventable Dis-

eases in Adults in the Middle East and North Africa (MENA) Region. Infectious Diseases and Therapy 10,

663-685 (2021).

AH M A D SA LE M / B LO O M B E RG VI A G ET T Y I M AG ES

I

nvasive bacterial diseases pose a significant threat to people in countries in the Middle East and North Africa (MENA), many of which lack sufficient public health surveillance and robust access to vaccines. International aid programmes are working to improve access to affordable vaccines, but these efforts focus on children. In a recent review of scientific literature, a team from across the Middle East reports that adult vaccination efforts must be prioritised to reduce the burden of preventable diseases, but significant hurdles stand in the way.

Vaccines are already available for the three most common bacterial pathogens behind invasive bacterial diseases — Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. These three bacteria are associated with deadly diseases such as meningitis, pneumonia, and blood infections. In the modern era, they tend to cause death primarily in aging populations and those with comorbidities. Despite this and the continuing preventable disease burden in adults, few vaccine strategies across the globe prioritize adult populations.

Abdul Rahman Bizri, from the American University of Beirut Medical Center, and a team from Lebanon, Saudi Arabia, United Arab Emirates and Jordan, performed a review of 39 papers found in the biomedical literature database PubMed. The researchers report that no countries within the MENA region currently have routine adult [invasive meningococcal disease] vaccination policies. Vaccination policies for high-risk individuals are

health surveillance on vaccines, say the researchers. This surveillance is important to identify new pathogen strains, as well as for implementing and evaluating prophylaxis or treatment strategies.

The researchers say it is crucial that the lack of adult vaccination programmes is addressed. This would not only addresses the burden of preventable diseases in adults, but also the critical issue of antimicrobial resistance, since disease prevention would reduce antimicrobial use.

The researchers make several recommendations in their review, such as implementing surveillance mandates, using electronic medical records, and putting knowledge and information management systems in place. In addition, they highlight the value of training medical personnel effectively regarding the importance of surveillance. Through commitments from and cooperation between governments, the private sector, and international organizations, the researchers argue, preventative disease levels in the MENA region can be reduced significantly.

The lack of comprehensive vaccine strategies in the MENA region is failing to address the issue of preventable disease burden in adults. A recent literature review discusses potential ways forward.

Issue No.10

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DIABETES IN FOCUS

Diabetes In The Spotlight Patients with diabetes could potentially experience serious complications if they contract COVID-19, leading researchers to focus closely on the lifelong condition, its prevention and promising avenues to better control type 1 diabetes.

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innovations.kaimrc.med.sa

Issue No.10

27 B I LL H EI N S OH N / A L A M Y S TOCK P HOTO

DIABETES IN FOCUS

Patients with diabetes are more likely to suffer serious complications from COVID-19.

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Exploring the link between diabetes and COVID-19

P

atients with diabetes are more likely to suffer serious complications from COVID-19, and scientists are trying to understand why the novel coronavirus is worse for diabetic patients and how to reduce risk.

A study in Diabetes Care, authored by Justin Gregory of the Ian M. Burr division of pediatric endocrinology and diabetes at Vanderbilt University School of Medicine, Nashville, and colleagues, found that COVID-19 severity is tripled among diabetic patients.¹ Elevated blood glucose enables the novel coronavirus to infiltrate cells and eventually bind to ACE2, a protein on the surface of many cells and a receptor for SARSCoV-2. Recent studies also show that people with diabetes have chronic lowgrade inflammation which contributes to the severity of illness. Other studies suggest that the number of T-cells is dramatically reduced among severe COVID-19 patients, eventually causing immune system dysfunction. Innate

innovations.kaimrc.med.sa

immune defences can also be impaired in diabetic patients.

Despite these findings, a full understanding of why diabetics have a worse prognosis remains elusive. “What I suspect is that people with diabetes, whether you’re talking about type 1, or type 2, have this condition called endothelial dysfunction, and it’s also pretty well known that people with diabetes have blood vessel disease,” says Gregory.

He explains that the blood vessels of people with diabetes are more prone to inflammation, from those that supply the backs of the eyes, retina, kidneys, or nerves to the large vessels that lead to the coronary artery. “Take someone who already has a propensity for blood vessel disease and then you stack COVID-19 on top, and it doesn’t take much to have those clots that are so problematic or for those capillaries to become leaky, and let fluid into the lungs.”

According to Gregory, there’s enough evidence to suggest that COVID-19 gets into a cell through ACE2, which Issue No.10

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B I L L HE I N S OH N / A L A M Y S TOC K P H OTO

Studying how SARS-CoV-2 infections affect diabetic patients reveals a complex relationship between the virus and metabolic glucose

DIABETES IN FOCUS

To date there is no evidence to suggest that meformin can prevent infection with COVID-19.

endothelial cells typically highly express.

“This is a key point at which SARS-CoV-2 is attacking the cell, and so I think the key vulnerability for people who have diabetes is the lining of those blood vessels.” Gregory is investigating the increase in endothelial dysfunction in diabetes patients immediately after they contract COVID-19.

So far, it’s unclear if there’s a major difference in risk between type 1 or type 2 diabetes, but the data suggests that both types are hit in similar ways. “It really depends on how you analyse the data.

That was one of the driving forces behind our research,” says Gregory. “What we found is that both type 1 and type 2 diabetes patients have about a three- or four-fold higher risk of severe COVID19 compared to people who don’t have diabetes at all.”

In their assessment, Gregory and his colleagues also adjusted for other risk factors. “If you walk into an ICU in a city with a lot of COVID-19 cases, you might think most of the people who really are sick with COVID-19 have type 2. It’s not because people with type 1 are at less risk. It’s because there’s fewer of them and because they are often younger as a group.”

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December 2021

Metformin: old drug, new insights

New studies are revealing that diabetic patients who take metformin, the firstline medication for the treatment of type 2 diabetes, show better prognosis when infected with COVID-19.

“Metformin was used in the early 20th century to treat influenza,” says Abdallah Al-Salameh of the department of endocrinology, diabetes mellitus and nutrition at Amiens University Hospital in France who led a study on metformin published in Diabetes Metab. Al-Salameh explains that metformin has some antimicrobial, anti-inflammatory, immunosuppressive, and antifibrotic properties.² “All of these issues are important in COVID-19 because it is a microbial disease with a cytokine storm,” While metformin users fare better post-infection, it’s still too early to extrapolate beyond a correlation between metformin use and the alleviation of some severe COVID-19 symptoms. It is also unlikely that giving metformin to patients who hadn’t taken the drug before hospitalization would have confer any benefits or result in noticeable improvement.

“What we know is that metformin is useful in people with diabetes to improve

the severity of COVID-19, but if we give a patient metformin in the acute phase of COVID-19, will it be useful? We need a controlled randomised study to answer this question. All we have so far are observational studies.” Al-Salameh adds that there’s no evidence to suggest that metformin can prevent infection.

Scientists are also trying to establish whether there is a link between COVID19 and metabolic glucose disturbances.

An international group of diabetes researchers created CoviDIAB, a global registry of patients with COVID-19-related diabetes, which at a later stage will incorporate pre-existing diabetics who present with severe acute metabolic disturbance. Through the registry, the researchers plan to explore the extent and phenotype of new-onset diabetes to investigate the “pathogenesis of COVID-19-related diabetes and to gain clues regarding appropriate care for patients during and after the course of COVID19,” according to a letter published in the New England Journal of Medicine.³ Despite all the questions about the strong relationship between high blood glucose and COVID-19, Gregory points out that one tool that seems to work to preemptively lower the risk of infection is vaccines. “Despite the fact that people with diabetes have a higher risk of getting severe illness, the vaccine is just as efficacious for people with diabetes,” he says.

1. Gregory J.M., et al. COVID-19 Severity Is Tripled in the Diabetes Community: A Prospective Analysis of the Pan-

demic’s Impact in Type 1 and Type 2 Diabetes. Diabetes

Care. 44(2):526-532 (2021).

2. Lalau J.D., Al-Salameh A., et al. Metformin use is asso-

ciated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19. Diabetes Metab.

10;47(5):101216. (2020)

3. Correspondence: New-Onset Diabetes in Covid19, NEJM.

N I A I D/N I H /F LI C K R

“Diabetic patients who take metformin show better prognosis when infected with COVID-19.“

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

DIABETES IN FOCUS

Preventing diabetes

A

diagnosis of diabetes brings a lifetime of medication, lifestyle alterations, careful management of blood glucose levels, and the long-term risk of life-threatening complications.

But for many, this disease is preventable and, importantly, predictable. Pre-diabetics can use lifestyle interventions to alter the course of their progression to avoid developing diabetes. Armed with better predictions on who to target, health authorities and clinicians can focus their limited resources on those in the greatest need.

A lifelong disorder

Diabetes is a complex, lifelong disease resulting in an inability to maintain a normal blood glucose level. This is characterised by a propensity for hyperglycemia (high blood sugar) or hypoglycemia (low blood sugar). The disease is categorized into two main types. Type 1 diabetes, mediated by autoimmunity against the insulin-producing beta cells, normally develops in childhood, whereas type 2 diabetes develops in adulthood.

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Type 2 diabetes is much more common than type 1, comprising around 90% of diabetes cases worldwide. While there are many risk factors for type 2 diabetes, including genetics, the disease is heav-

“Researchers are looking into ways to categorise and predict groups of people who are on a trajectory to develop diabetes.“ ily associated with obesity and physical inactivity. Maintaining a healthy body weight, regular exercise and good nutrition are ways to avert or delay type 2 diabetes. With 422 million people suffering from diabetes in 2014, type 2 diabetes constitutes a large-scale public health concern.

Researchers are now looking into ways to categorise and predict groups of people who are on a trajectory to develop diabetes. They are using an arsenal of technological advances, such as machine learning, to carry out investigations to identify prodromes of the disease.

Doing more with less

One research project, published in Scientific Reports, aims to develop a public health tool for Qataris to gauge their personal risk of diabetes.¹ Laith Abu-Raddad of Weill Cornell Medicine Qatar, is leading an international research collaboration that uses mathematical modelling to simulate a cohort of Qataris and builds on this to develop a public health risk factor score that can predict individuals’ diabetes risk.

Abu-Raddad says that the increase in computational power afforded by technological advances means that more countries can avail themselves of the benefits of data. In wealthy countries such as the United States, he says, primary data is more easily accessible. The US conducts epidemiological surveys on diabetes once every two years, providing a wealth of data to fuel the development of a national diabetes risk score tool that takes into account how predictive variables change over time.

This isn’t an option for many countries. Less wealthy nations may have more infrequent surveys or use different

S O U T H WE S T I MAG ES S C OT L A N D / A L A M Y S TOC K P H OTO

Predicting a person’s risk of developing diabetes could save lives and conserve valuable medical resources for those in the greatest need

Public health tools gauging risk of diabetes could help diagnoses and conserve valuable medical resources for those in greatest need. innovations.kaimrc.med.sa

Issue No.10

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DIABETES IN FOCUS

More than just glucose

Another international team, led by Robert Wagner of the University of Tübingen, Germany, says that we need to fundamentally change the definition of what we classify as pre-diabetes to better predict the risk of diabetes. “The current definition of pre-diabetes is only glucose-based,” explains Wagner. In his team’s paper, published in Nature Medicine, they describe how pre-diabetes’ current definition doesn’t reflect future metabolic trajectories, nor many of the variables that truly predict how an individual’s health might progress from healthy to diabetic.² Wagner says that in order to understand the pathophysiology of diabetes, we must investigate before the disease takes hold.

“By the time diabetes manifests, there are often lots of metabolic derangements, which makes the analysis of the picture biased,” he says. Wagner adds that the development of diabetes is a long process, and without looking at pre-diabetes it can 34

December 2021

be difficult to know whether high blood sugar is cause or consequence of some of the metabolic derangements associated with diabetes.

“By the time diabetes manifests, there are often lots of metabolic derangements, making the analysis biased.”

Wagner and his team classified a cohort of people at increased diabetes risk into groups based on clusters of health metrics associated with the disease. Out of six groups, only three were found to have increased blood glucose levels, and only two had imminent diabetes risk. One group had moderate diabetes risk, but notably increased risk of kidney disease and all-cause mortality.

“We know that glucose is not the whole story,” says Wagner.

Methods such as machine learning and advanced modelling enable researchers to make sense of the masses of data available to them, says Wagner. Technology such as

continuous glucose monitoring devices, which sit under the skin and continuously measure interstitial fluid glucose levels as a proxy for blood glucose, has the potential to deliver so much data that insights would be lost without state-of-the-art analysis techniques.

With so many people living with diabetes worldwide and such a high disease burden on individuals and health authorities, there is a wealth of research into recognizing the warning signs as early as possible. By using the latest technologies, scientists can make sense of the available data and develop systems to categorize those at the highest risk. In addition to indicating when an individual needs to be tested for diabetes, this enables health authorities and clinicians to focus costly and resource-intense interventions on those who need them.

1. Awad, S. F., et al. A diabetes risk score for Qatar utilizing a novel mathematical modeling approach to iden-

tify individuals at high risk for diabetes. Scientific Reports 11, 1811 (2021).

2. Wagner, R. et al. Pathophysiology-based subpheno-

typing of individuals at elevated risk for type 2 diabetes.

Nature Medicine 27, 49-57 (2021).

S O UT H WE S T I M AGE S S C O T L A N D / A L A M Y S TO CK P HO TO

methodologies that make the collection of empirical data difficult. In this sense, the rise of mathematical modelling has made good science more accessible. “Technology provides us a very inexpensive tool that negates the need for surveys,” says Abu-Raddad.

And the technology works. When Abu-Raddad’s team compared the scores of their simulated data to those of the primary data collected from Qatari subjects, the scores aligned “very well,” he says.

Abu-Raddad goes on to say that a primary goal of predicting diabetes risk is to build public awareness around what individuals can do to reduce their chances of developing diabetes. “It’s about building self-awareness and the need to change behavior,” he says. In countries like the United States and the United Kingdom, online tools exist where anyone can plug in very simple metrics, and instantly retrieve their personal diabetes risk score.

“This is what we plan to do in Qatar,” he says. “It empowers people at an individual level to know their risks, which will hopefully lead to a change in behavior and create more awareness about diabetes.”

For many, a lifetime of diabetes and its complications can be avoided. Research is providing early warning systems so that health organisations can target those at risk with early interventions.

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

DIABETES IN FOCUS

New Type 1 diabetes treatment targets New avenues are opening for better control of type 1 diabetes, with some now showing promise in clinical trials

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Insulin regulates the metabolism of carbohydrates, proteins and fats. Disruption of insulin function can lead to diabetes.

T

ype 1 diabetes is an autoimmune disease which attacks and depletes the β-cells of the pancreas responsible for secreting the hormone insulin, which mediates the uptake of glucose by cells. For years the standard treatment has been regular administration of insulin, but this only manages the symptoms rather than preventing or reversing the progress of the disease. innovations.kaimrc.med.sa

Many patients cannot achieve longterm effective control of their blood glucose using insulin. They remain at risk from ketosis, the generation of ketones when fat is used as an energy source, and can also experience erratic fluctuations in blood glucose levels, including damaging episodes of low blood sugar, or hypoglycemia. The long-term effects of these issues can include vascular problems

causing serious damage to the eyes, kidneys, and feet.

Researchers are exploring several avenues for novel therapies that might offer a more convenient treatment, a reduction in the complications and limitations of long-term insulin administration, and the possibility of detecting the disease in its early stages and limiting its impact.

One option uses transplanted donor cells, including stem cells, to try to generate a new population of healthy β-cells.

However, while it shows some promise, this approach has been hampered by considerable challenges in obtaining suitable cells for transplantation and getting them to integrate and flourish in their new environment.

Two recent clinical trials have demonstrated the potential of alternative approaches based on modulating auto-immune attack or biochemically improving blood glucose control, possibly through improved β-cell survival and function.

In one of these approaches, researchers at the University of North Carolina, USA and the company vTv Therapeutics in North Carolina conducted a Phase 1b/2 adaptive trial of a drug that activates an enzyme in the liver.1 The drug, known as TTP399, binds to and activates the enzyme glucokinase, which adds phosphate groups to glucose. This enzyme has attracted the attention of researchers because mutations in the gene that encodes it are associated with changes in blood glucose and insulin balance. In a trial involving fewer than 100 subjects, the drug effectively and safely counteracted hypoglycemia in people with type 1 diabetes. The treatment was not tested as an alternative to insulin therapy but as an additional or ‘adjunct’ treatment that might improve blood glucose control and reduce the complications associated with insulin treatment alone.

Issue No.10

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J UA N GA E RT N E R / SC I E N C E P HO TO LI B R A RY / G ET T Y I M AG ES

One option uses transplanted donor cells, including stem cells, to try to generate a new population of healthy -cells.

DIABETES IN FOCUS The frequency of severe hypoglycemic attacks was reduced by as much as 40% in treated patients compared with those receiving only their usual insulin treatment plus placebo. Their ketone levels, detected by excretion in urine, were also significantly reduced.

The authors say their results suggest that the treatment improves the control of blood sugar levels in a way that “to our knowledge is unique.” They add that by preventing complications associated with other treatments, “it would be a substantial advance in the treatment of type 1 diabetes.”

In recognition of its promise, the US Food and Drug Administration (FDA) has granted this approach a “Breakthrough Therapy” designation. This opens access to greater financial support for vTv, the company developing the treatment, as well as the possibility of facilitating FDA development and expediting the review process leading towards approval for clinical use.

The second approach also recently underwent a phase 2 clinical trial. A large international research team tested a combination therapy based on an antibody designed to modulate the immune attack on β-cells together with the drug liraglutide, which is more commonly used to treat type 2 diabetes.2

The antibody, known as anti-interleukin-21 (IL-21), is designed to bind to and inhibit the action of interleukin-21, a natural signalling protein implicated in promoting the progression of type 1 diabetes in animal models. Liraglutide is a large synthetic molecule known to improve the function and survival of β-cells.

The trial concluded that the combination therapy could preserve β-cell function in young adults who have been recently diagnosed with type 1 diabetes.

While its efficacy appears to be similar to existing treatments, the trial data suggest that it has a better safety profile. The researchers feel that these results are sufficiently encouraging to move into third phase of clinical trials, involving a much larger group of subjects.

“Disease-modifying therapeutic interventions in type 1 diabetes will become the new standard in newly diagnosed patients,” says Thomas Pieber of the Medical University of Graz in Austria, the corresponding author of the research paper reporting the results.

Pieber says the Phase 3 trials will expand the research to children, who are one of the groups most likely to benefit in the long term from a new intervention that can control the disease in its earliest stages.

There are also several promising developments in early stage laboratory work that has not yet reached clinical trials.

Researchers in Germany, for example, have discovered a novel cell membrane receptor involved in insulin signaling which is more active in people with type 1 diabetes. Early work with mice suggests that inhibiting this receptor holds the potential to prevent the depletion of β-cells or even support their regeneration.3 In a recent review article, researchers at Sidra Medicine in Qatar discussed why they believe type 1 diabetes is a very promising candidate for a personalised medicine approach, which aims to apply “the right therapy at the right time, to the right patient.”They review a wide range of initiatives, from gene therapy to new drugs to changes in nutrition, which they say might herald a new dawn in treatments targeted to the specific needs of each individual.4 A personalized approach might bring significant benefits since the onset and progress of the disease, as well as the response to therapy, can vary widely among different individuals.

The outlook for improved control, reversal or prevention of type-1 diabetes therefore seems promising on several fronts. However, all of these hopes are subject to the familiar caveats in translating laboratory research to early clinical trials, followed by confirmation in wider trials and eventually extended clinical practice.

1. Klein, K. R., et al. The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes. Dia-

betes Care 44 960-968 (2021).

and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised,

double-blind, placebo-controlled, phase 2 trial. The Lan-

cet Diabetes & Endocrinology 9 212-224 (2021).

3. Jain, A. C., et al. Inceptor counteracts insulin signalling

in β-cells to control glycaemia. 590 326-331 Nature, 590 326-331 (2021).

4. Akil, A. A-S., et al. Diagnosis and treatment of type 1

A combination therapy could preserve β-cell function in young adults recently diagnosed with type 1 diabetes.

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diabetes at the dawn of the personalized medicine era.

Journal of Translational Medicine 19 Article No. 137 (2021).

P I KSE L / I S TO C K / G E T T Y IM AGE S P LU S

2. von Herrath, M., et al. Anti-interleukin-21 antibody

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

MENTAL HEALTH

The Hidden Challenge

While scientists race to develop vaccines and drugs to combat the SARS-CoV-2 virus, the ongoing pandemic is taking its toll on our mental health. Researchers are now taking stock of the impact that COVID-19 continues to have on the emotional well-being of patients, healthcare workers and their families.

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Issue No.10

41 AG SA N DR EW / I S TOC K / G E T T Y I M AG E S P LU S

MENTAL HEALTH

The mental health landscape in Saudi Arabia Promoting and improving wellbeing during the COVID-19 pandemic, while reducing the stigma of mental illness

T

he COVID-19 pandemic has been an unprecedented global crisis.

Uncertainty, loss of loved ones, social distancing, and economic insecurity have had a marked effect on mental health and exacerbated problems for those already suffering from mental disorders. How are Saudis coping with psychological distress, and how is the country dealing with this demanding situation? A few recent studies and surveys have offered an overview of the services, attitudes and challenges related to mental healthcare and wellbeing in the Kingdom.

Mental healthcare by the numbers

There were only two psychiatric hospitals in Saudi Arabia in the early 1980s, but mental health research and treatment have been made a greater priority and an urgent concern in past decades. The Kingdom’s General Department for Mental and Social Health, created in 1983, focused on allocating funding to mental healthcare, developing modern infrastructure, and training staff. Furthermore, in line with Saudi Vision 2030, the Ministry of Health aims to develop 42

December 2021

a new patient-centred healthcare system that takes into account social, mental, and physical wellbeing.1 The number of counselling clinics that provide primary mental healthcare has grown to 55.2 Saudi Arabia devotes 4% of its healthcare budget to mental health disorders, above the world average (<2%) but still behind other high-income countries (6%).3,4 With 19.4 mental health professionals per 100,000 citizens, the Kingdom’s rate is higher than the global average (6.6 per 100,000) but much lower than the world’s wealthiest countries (64.3 per 100,000).

While depression and anxiety disorders were some of the most prevalent mental illnesses even before COVID-19, the crisis has taken a toll on the mental health of a larger segment of the population. Researchers at King Saud University set up a social media survey to monitor mental health symptoms during the pandemic. They have reported that around 21% of the participants experienced moderate to very severe depression, 17.5% anxiety, and 12.6% stress.5 In keeping with findings from China, Italy and Spain, young adults, women, and people with a history of mental illness were more likely to suffer from severe symptoms.6,7 “This research is important to recognize the effect of COVID-19 and devise strategies for prevention and treatment,” says Ahmad N. AlHadi, an associate professor at King Saud University who led the study.5 He also emphasises the need for further studies and prevention and treatment programmes for other mental health issues, such as bullying, behavioural addictions (online gaming and social media), and burnout.

Providing counselling and focusing on prevention

Traditionally, studies on mental health carried out in the Kingdom have focused on specific diseases or populations, such as patients in hospitals. The first comprehensive scientific survey was conducted between 2011 and 2016, when Saudi Arabia became the first Gulf Cooperation Council state to join the World Mental Health Survey Initiative. The Saudi National Mental Health Survey (SNMHS), launched in 2010, which included 4,004 male and female

participants between the ages of 15 and 65, found that approximately one in three Saudis are diagnosed with a mental health condition at some point in their lifetime.

These results are comparable with data collected in France and the Netherlands.8,9 A number of initiatives have been organised in the Kingdom to help prevent or overcome the psychological distress caused by COVID-19. For example, the National Center for Mental Health launched the ‘Labayh Al Amal’ initiative in 2020 to provide confidential psychological counselling through a free smartphone app, as well as engaging public sector employees through the ‘Promoting Mental Health in the Work Environment’ programme to enhance their efficiency and productivity at work.10 Furthermore, the Saudi Center for Disease Prevention and Control published a ‘Preventive Guide for Mental and Social Health’, which recommends some best practices for mental health during the COVID-19 pandemic.11 For example, the guide highlights the importance of physical exercise, because integrating mental and physical health is considered an important prevention strategy. Saudi Arabia has the highest rate of physical inactivity among the Gulf Cooperation Council countries, and a recent Saudi survey found that moderate aerobic physical activity is associated with lower depression among male participants, leading to fewer symptoms of anxiety and depression.12

Open challenges: stigma and community perception toward mental health

The SNMHS survey also revealed that 80% of Saudis with severe mental health disorders do not seek any treatment, and around 9% of the population consult religious or non-medical healers.9 Stigma and other social barriers prevent people from visiting mental health experts, adhering to treatments, or even taking part in surveys related to mental health.13 As a result, vulnerable individuals delay medical treatments, making their condition become harder to treat.

The high prevalence rate of untreated mental disorders in the Kingdom, together

cross-sectional study.” BMC psychiatry 21.1 (2021): 1-13.

6. Mazza C, Ricci E, Biondi S, Colasanti M, Ferracuti S, Napoli C, et al. A Nationwide survey of psychological distress

among Italian people during the COVID-19 pandemic:

immediate psychological responses and associated fac-

tors. Int J Environ Res Public Health. 2020;17(9):3165. https://doi.org/10.3390/ijerph17093165.

7. González-Sanguino C, Ausín B, Castellanos MÁ, Saiz J,

López-Gómez A, Ugidos C, et al. Mental health conse-

quences during the initial stage of the 2020 coronavirus pandemic (COVID-19) in Spain. Brain Behav Immun. 2020; 87:172–6. https://doi.org/10.1016/j.bbi.2020.05.040.

8. http://www.healthandstress.org.sa/Publications/ Articles/Al-Subaie%20et.%20al%202020%20-%20 Mental%20Health%20Survey.pdf

9. Saudi National Mental Health Survey - Technical

Globally, the COVID-19 pandemic has had a detrimental effect on mental health and exacerbated problems for those already suffering from mental disorders.

with the negative perception and experience in mental health hospitals, highlight some of the unsolved challenges facing the country.14 Several studies also point to the need to invest in more research on mental health in women, migrants, the elderly, and young people, as well as the need for more support facilities tailored to them.

“Despite various attempts to address mental illness, this area of study is still in its early stages in Saudi Arabia,” explains Adel F Almutairi, a population health expert at KAIMRC and the King Saud Bin Abdulaziz University for Health Sciences.15 “Further research on women’s mental illness, societal barriers to getting assistance, stigmatization and adherence to treatments are all needed to control the rising risk of adverse mental health in the country.”

Promoting conversations around mental health can break taboos, encourage a positive attitude toward people with mental illness, and improve wellbeing.16 Researchers at Sulaiman Al Rajhi University found that a large majority of medical students had positive attitudes towards the mentally ill, and those who were more exposed to mental illness or were planning to specialise in psychiatry were also more willing to share a room with, or even marry someone with mental illness. This suggests that experience with mental illness and an interest in studying it reduce stigma, and promote inclusive and supportive behaviour.17 innovations.kaimrc.med.sa

“Stigmatization of people with mental illness is an evident public health obstacle,” says Osama Zitoun, who led the study.

“Further efforts should be needed to assess the situation and possibly propose interventions to tackle stigmatization of mental illness among the general population.”.

Awareness of mental health issues, especially among youths, has been boosted by international celebrities opening up about their personal struggles with mental illness during COVID-19. While this is a heartening development, the data show that more can and should be done to address the stigma around mental illness and provide support for those who need it.

Report:

http://www.healthandstress.org.sa/Publica-

tions/Articles/Al-Subaie%20et.%20al%202020%20

-%20Overview%20of%20the%20Saudi%20National%20 Mental%20Health%20Survey.pdf

10. Hassounah, Marwah, Hafsa Raheel, and Mohammed Alhefzi. “Digital response during the COVID-19 pandemic in Saudi Arabia.” Journal of Medical Internet

Research 22.9 (2020): e19338. Journal of Medical Inter-

net Research - Digital Response During the COVID-19 Pandemic in Saudi Arabia (jmir.org)

11. https://covid19.cdc.gov.sa/wp-content/uploads/2020/04/ EN_Preventive-Guide-for-Mental-and-Social-Health.pdf and https://covid19.cdc.gov.sa/community-public/mental-health/

12. Althumiri, Nora A., Mada H. Basyouni, and Nasser F.

BinDhim. “Exploring the Association Between Physical Activity and Risk of Mental Health Disorders in Saudi Arabian Adults: Cross-sectional Study.” JMIR Public

Health and Surveillance 7.4 (2021): e25438.

13. Alissa, Nawal A. “Social barriers as a challenge in seeking mental health among Saudi Arabians.” Journal of Edu-

1. https://europepmc.org/article/MED/33245612

cation and Health Promotion 10.1 (2021): 143. https://

vision2030.aspx

14. Al Mousa, Yaqoub, et al. “Saudi service users’ per-

2. https://www.moh.gov.sa/en/Ministry/nehs/Pages/ 3 . Al-Subaie, Abdullah S., AbdulHameed Al-Habeeb, and

Yasmin A. Altwaijri. “Overview of the Saudi National

Mental Health Survey.” International Journal of Methods

in Psychiatric Research 29.3 (2020): e1835. https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC7507437/

4. World Health Organization. (2018a). Mental health

atlas 2017. Geneva, Switzerland: World Health Organi-

zation. https://cdn.who.int/media/docs/default-source/ mental-health/mental-health-atlas-2017-country-

profiles/sau.pdf?sfvrsn=f82734c1_1&download=true

5. AlHadi, Ahmad N., Mohammed A. Alarabi, and Khulood M.

AlMansoor. “Mental health and its association with coping

strategies and intolerance of uncertainty during the COVID-

19 pandemic among the general population in Saudi Arabia:

www.ncbi.nlm.nih.gov/pmc/articles/PMC8224481/

ceptions and experiences of the quality of their mental

health care provision in the Kingdom of Saudi Arabia

(KSA): A qualitative inquiry.” International journal of men-

tal health nursing 30.1 (2021): 300-316.

15. Almutairi, Adel F. “Mental illness in Saudi Arabia: an overview.” Psychology research and behavior manage-

ment 8 (2015): 47.

16. Dawood, Eman, and Omar Modayfer. “Public attitude

towards mental illness and mental health services in Riyadh, Saudi Arabia.” Res Hum Soc Sci 6 (2016): 63-75.

17. Zitoun, Osama A., et al. “Attitudes of medical stu-

dents in Saudi Arabia towards mental illness and their beliefs regarding its causes and treatability.” Asian Jour-

nal of Psychiatry 56 (2021): 102515.

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Overview%20of%20the%20Saudi%20National%20

MENTAL HEALTH

Lockdowns, self-isolations and quarantines have taken their toll on people’s mental health around the world.

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The psychological impact of COVID-19

“

I’ll tell you an interesting story,” says Nasser BinDhim. “We have a mental health assessment tool on our website and one day, in April 2020, our servers went down. When I looked into it, I found a flood of people trying to access the tool–on average 10,000 per second.” BinDhim, an accomplished researcher and business leader, was witnessing the intense focus on mental health driven by the coronavirus pandemic.

Now entering its third year, COVID-19 continues to sweep the planet. The pandemic’s psychological toll became apparent shortly after its devastating physical effects. Many found themselves beset by fear of serious illness, compounded by sudden and long-lasting periods of government-enforced social isolation.

This stark threat to mental wellbeing is driving scientists to investigate the impact of the pandemic on mental health more broadly. Following the deluge of interest in their online assessment, BinDhim and a Saudi research team set out to create a national mental health surveillance system–one of the first of its kind in Saudi Arabia. With ongoing funding from the Sharik Association for Health Research, which BinDhim founded in 2015, he and his team of volunteer scientists now conduct regular phone and app-based mental health interviews across Saudi Arabia, feeding the data to a dashboard hosted by the country’s National Center for Mental Health Promotion.

Between May and August 2020, BinDhim and his team conducted monthly interviews via a random phone list, canvassing

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B A R A N OZDEM I R / E+ / G ET T Y I M AG ES

The pandemic has brought a newfound appreciation of the importance of mental health. Research from across the globe is now providing insights into its psychological toll

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Caring for healthcare

It is vital to also consider the needs of healthcare providers. Frontline healthcare is a notoriously high-stress profession, and this has been exacerbated by the pandemic. Khizra Sultana, a clinical research coordinator at KAIMRC, and a team from Saudi Arabia and India investigated the impact of COVID-19 and lockdowns on healthcare workers within the Kingdom.

“Our main aim was to protect the mental health of our healthcare workers,” says Sultana. She remembers how, during the outbreak of MERS, 75% of respondents to one study reported suffering from psychological problems. However, after a survey of healthcare workers in 2020 across the Kingdom, the team found relatively low levels of adverse mental health amongst respondents.² Approximately 77% of their 1,130 participants exhibited a level of depression from “normal to mild.” A similar percentage experienced “minimal to mild” anxiety, and approximately 86% experienced “absence to subthreshold” levels of insomnia.

These results were initially quite surprising to Sultana, who expected less positive findings. However, as corroborating studies around the globe were published, including from China and Italy during the height of their infections, the team proposed explanations of how healthcare workers are coping so well.

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One theory is preparedness. Sultana says that lessons were definitely learned in Saudi Arabia from the MERS outbreak.

When COVID-19 hit the country, the government and healthcare organizations made swift decisions that saved lives and protected the wellbeing of the population. This included access to PPE, vaccinations, and psychological services for healthcare workers.

Sultana also suggests that despite the bleak context, coronavirus lockdowns can offer a silver lining in the form of greater time with family. While this is anecdotal, formal research is being conducted into the prevalence of coping strategies and their importance.

Syed Sameer Aga, from King Saud bin Abdulaziz University for Health Sciences, led a Saudi-Indian research team that studied global mental health and coping strategies among the general population in the age of COVID-19.³ They revealed a less optimistic picture than Sultana’s investigation into healthcare workers, with a “significant level of depression and anxiety” in their participants. Aga and his team identified a range of coping strategies people use to try to maintain their wellbeing, including watching TV, social networking, spending time with family, cooking, sleeping, and listening to music.

The findings highlight the importance of widespread provision of psychological services to offset the stressors of these unusual times. COVID-19 has placed the concept of mental health at the forefront of many peoples’ minds. There’s a clear consensus amongst researchers that mental health support needs to be a priority. Logistically, however, these services have obstacles, as social distancing forces healthcare providers to offer services remotely. Future research will explore the impact of mental health support on those afflicted by COVID-19, providing data to inform governmental and healthcare bodies on how to effectively fight the wide-ranging impacts of the disease.

1. BinDhim, N. F., Althumiri, N. A., Basyouni, M. H., Alageel, A. A, Alghnam, S. et al. Saudi Arabia Mental Health Surveillance System (MHSS): mental health trends amid COVID-

19 and comparison with pre-COVID-19 trends. European

Journal of Psychotraumatology 12, 1875642 (2021).

2. Al Ammari, M., Sultana, K., Thomas, A., Al Swaidan, L., Al Harthi, N. Health Outcomes Amongst Health Care

Workers During COVID 19 Pandemic in Saudi Arabia.

Frontiers in Psychiatry 11, 619540 (2021).

3. Sameer, A. S., Khan, M. A., Nissar, S., Banday, M. Z.

Assessment of Mental Health and Various Coping Strategies among general population living Under Imposed COVID-Lockdown Across world: A Cross-Sectional Study.

Ethics, Medicine and Public Health 15, 100571 (2020).

J UA N M O N I N O / I S TO C K / G E T T Y I M AG E S P LU S

the thoughts and feelings of more than 16,000 adults in Saudi Arabia. They found that participants had a “relatively high” risk of developing major depressive disorder (MDD) and generalised anxiety disorder (GAD).¹ When they compared their findings with data from a national study conducted in 2018, they found the risk of depression in Saudi Arabia had increased by 71.2%. In a related research project, BinDhim and his team also found a correlation between vaccination status and mental health severity—fully vaccinated people had less anxiety, depression, and insomnia than those who had received only one vaccine dose, who in turn had less adverse mental health than unvaccinated people.

Frontline healthcare workers have borne the brunt of the pandemic, many of whom run a “relatively high” risk of developing depression and anxiety disorders.

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

MENTAL HEALTH

A pandemic for all ages New research shows the impact of the global pandemic on families whose members suffer from childhood PTSD and autism

I

t is established that the most damaging physical effects of COVID-19 are usually in elderly people. Now, evidence is demonstrating the extent to which children and adolescents suffer psychologically from the ongoing crisis.

Researchers looking into the interplay of COVID-19 and significant childhood mental afflictions have revealed the difficulties faced by affected children and their families.

A study published in PLOS ONE showed that COVID-19 can create “intense psychological problems … especially in the vulnerable.”¹ Before then, no research had investigated the emotional impact of the pandemic on Saudi children. The team led by Moustafa Hegazi, of Saudi Arabia’s King Abdulaziz University and Egypt’s Mansoura University Children’s Hospital, approached Saudi and non-Saudi families randomly via social media between

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Researchers looking into the interplay of COVID-19 and childhood mental afflictions have revealed the dif­ficulties faced by affected children and their families.

March and June 2020 to carry out a survey tailored to identify post-traumatic stress disorder (PTSD) symptoms associated with the COVID-19 pandemic. The screening tool was originally developed by the University of California, Los Angeles. Older adolescents can take the survey themselves or it can be administered

to younger children by their caregivers.

With a total of 537 responses, as many as 71.5% of surveyed children showed at least some PTSD symptoms, and 13% ranking in the most at-risk bracket of “potential PTSD.” Many factors, such as age, gender, and school performance proved to have no impact on how likely

JU S T I N PAG ET / DI G I TA LVI S I ON / G ET T Y I M AG ES

One test detected a correlation between PTSD symptoms in children and having a close relative working in proximity to the SARS-CoV-2 virus. innovations.kaimrc.med.sa

a child was to exhibit PTSD symptoms in relation to the COVID-19 pandemic. The researchers noted that one test detected a correlation between PTSD symptoms and having a close relative working in proximity to the SARS-CoV-2 virus; however, this association was not seen in another test that evaluated multiple

variables. It was observed that children of Saudi nationals had a significantly lower PTSD risk than the children of resident immigrants.

The researchers noted that studies involving infection-related PTSD tend to focus on the experiences of clinicians, with few investigations conducted on Issue No.10

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MENTAL HEALTH

COVID-19 has the capacity to worsen the mental health of children and their parents, recently published research reveals.

children. However, “critically developing children/adolescents are more vulnerable to psychological disturbances, owing to their less mature cognitive abilities and adaptive capacities.” As the data indicate a likelihood of PTSD prevalence amongst Saudi Arabia’s juvenile population, the researchers suggest that a link between childhood PTSD and COVID-19 “should not be overlooked.”

These findings put pressure on governmental and healthcare organisations to recognise the prevalence of PTSD in children and adolescents, and to provide preventative and ameliorative therapies.

Another study, conducted solely by King Abdulaziz University’s Youssef Althiabi, sought to discern the impact of the pandemic on vulnerable families — particularly, the impact of COVID19 affected the parents of children with autism spectrum disorder (ASD).² Children with ASD often have behavioral and communication difficulties that can result in depression and anxiety in their parents. COVID-19 forced many countries, including Saudi Arabia, to adopt online learning, and the resulting disruption to the routine of a child with ASD could lead to a worsening of behavioral 50

December 2021

“There is pressure on governmental and healthcare organisations to recognise the prevalence of PTSD in children and adolescents.” problems. Combined with the pandemic’s direct stressors on parents, such as work troubles, COVID-19 thus has a significant potential to exacerbate the suffering of parents of children with ASD. To explore this, 211 mothers and fathers of children with ASD across Saudi Arabia were surveyed online for their attitudes towards parenthood, anxiety, mental health, and perceived mental health care needs. Notable conclusions were that parents’ anxiety levels were significantly worse mid-pandemic than they were before it. Althiabi suggests that this could potentially be due to the impact of raising children with ASD in the context of reduced essential services, school services, and professional support.

This study showed that during the pandemic, parents of children with ASD found solace in consulting with teachers, family members, and therapists in order

to maintain their mental health. In particular, the data show that young mothers were especially negatively affected by the impact of COVID-19. When parents were asked what support they most needed, psychological and financial support were in the most demand. Remote training, online counseling and advice on how to deal with adverse child behavior were also requested.

While there are activities that parents can use to more effectively manage children with ASD, Althiabi’s study reveals the importance of accessible support for children with ASD and their parents, especially in the context of a global crisis.

Accumulating data show that recovery from COVID-19 requires a holistic approach and proactive, accessible support for afflicted families.

1. Sayed, M.H., Hegazi, M.A., El-Baz, M.S., Alahmadi, T.

S., Zubairi, N.A. et al. COVID-19 related posttraumatic

stress disorder in children and adolescents in Saudi Arabia. PLOS ONE 16, e0255440 (2021).

2. Althiabi, Y. Attitude, anxiety and perceived mental

health care needs among parents of children with Autism Spectrum Disorder (ASD) in Saudi Arabia during COVID-19 pandemic. Research in Developmental Disa-

bilities 111, 103873 (2021).

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

New model predicts the risk of blood thinners for Arabs

A novel model that predicts bleeding risk in Arab patients taking direct oral anticoagulants shows good sensitivity and specificity

T

aking blood thinning drugs for long periods can increase the risk of internal bleeding in some patients. Now, scientists at KAIMRC have developed a new model for predicting the risk of bleeding

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in Arab patients taking direct oral anticoagulants (DOACs).

Existing bleeding risk models developed in other countries are not directly transferrable to Arab populations. Along with co-workers across Saudi Arabia,

Maha Al Ammari and Khizra Sultana at KAIMRC have developed a new model called the GAMA RLSTC score based on 15 variables. They validated it using data from a cohort of 1722 patients with non-valvular atrial fibrillation who were

receiving DOACs in hospitals and clinics in Riyadh.

“Most previous studies assessing bleeding risk used models like HAS-BLED score, which was originally validated in patients using warfarin, but not in patients using the newer anticoagulants,” says Sultana. “Our new model is necessary for the Arab population because factors such as eating habits, family relationships, and lifestyle are very different to Western cultures. Many of these factors are proven to be associated with diseases that lead to the use of DOACs.” DOACs can limit strokes and blood clots in patients with non-valvular atrial fibrillation, with some DOACs showing superior action to warfarin. Bleeding risk can innovations.kaimrc.med.sa

vary with physiological factors such as age, gender, ethnicity, comorbidities and uncontrolled blood pressure, alongside lifestyle choices. The team determined the best-fit parameters for their model using a resampling approach and a five-fold cross validation process. This analysis helped them fit the model to accurately predict bleeding risk in an Arab population.

The GAMARLSTC model is encoded in an Excel score calculator with a simple interface where users can enter patient data and produce an instant risk score—a green colour code indicates the use of DOACs is safe in that patient, yellow indicates a moderate or borderline risk, and red indicates a high risk of bleeding. This means physicians get an instant notification of an individual’s

risk score.“The score applies to people who do not consume alcohol,” says Sultana. “The model works from easily measured and inputted variables and does not require genetic details or laboratory data.”

The team aims to use this model widely in the Saudi population to confirm that it works on a wider scale. “This will give us valuable feedback to improve the model if required, and we hope that this model will also be validated in other Arab populations,” says Sultana.

AlAmmari, M., et al. The development and validation

of a multivariable model to predict the bleeding risk score for patients with non-valvular atrial fibrillation using direct oral anticoagulants in the Arab population.

PLOS One (2021)

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A new, easy-to-use model developed and validated by KAIMRC researchers can accurately predict the risk of internal bleeding in Arab patients using direct oral anticoagulants.

A dynamic duo to fight MERS

Experiments in mice suggest that a two-antibody cocktail could prevent infection with the Middle East respiratory syndrome coronavirus

T

he Middle East respiratory syndrome coronavirus (MERS-CoV) currently poses a relatively minor threat to human health, but more dangerous strains could emerge through natural mutation. Researchers at Regeneron Pharmaceuticals have demonstrated that treatment with a pair of virus-binding antibodies could confer potent protection against infection with MERS-CoV, even when administered after exposure to the virus.

MERS-CoV has about 34% mortality rate in humans, but the spread of this virus has been limited, with only about 2,600 cases reported, almost all in the Arabian Peninsula. But the virus continues to circulate widely in camels throughout the Middle East, and as COVID19 has demonstrated, new coronavirus variants can emerge that readily jump from animals to humans.

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MERS-CoV currently poses a minor threat to human health, but more dangerous strains could emerge through natural mutation.

Sivapalasingam, S. et al. Human Monoclonal Antibody Cocktail for the Treatment or

Prophylaxis of Middle East Respiratory Syndrome Coronavirus. Journal of Infectious

Diseases. Published online 28 January 2021.

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“All coronaviruses mutate as they replicate, and the resulting mutant virus always has the chance of gaining increased fitness,” says Matthew Frieman, a microbiologist at the University of Maryland.

Our bodies can naturally fend off infection by producing virus-specific antibodies, and Regeneron has been exploring the possibility of bolstering this protection through treatment with engineered antiviral antibodies. Regeneron researchers, in collaboration with Frieman’s lab, developed a pair of promising antibodies for MERS-CoV in 2015, and the two groups recently teamed up again to test how well these can control infection.

They first tested in the preclinical study the antibody combination in a ‘humanised’ mouse model that is susceptible to MERS-CoV infection. Whereas virus levels surged within two days post-infection in control animals, pre-treatment with the two antibodies effectively quashed viral replication in the lungs.

Importantly, the antibodies were equally effective when administered one day after infection. “This gives some confidence that treatment in humans before infection isn’t required,” says Frieman, adding that this would be valuable in terms of enabling prompt intervention when the earliest signs of disease appear.

The researchers also conducted an initial safety test in healthy adults subjects in the following phase 1 study, and demonstrated that the antibody cocktail was stable in the bloodstream and generally well tolerated.

Further testing in MERS-endemic regions will be needed to determine the protective power of these antibodies in humans, but Frieman is encouraged by these preliminary results. “We should be preparing for the time when MERS-CoV evolves to a more problematic virus and have therapies ready,” he says.

And as the scientific community continues to improve its understanding of the immune response to SARS-CoV-2 that determines the ultimate severity of infection, Frieman sees exciting potential in working towards developing broadly-protective ‘pan-coronavirus’ antibodies.

Immune checkpoint inhibitors cause mild to severe side effects A small Saudi study shows that the cancer therapy commonly causes mild side effects but can sometimes result in more severe ones

ICIs improve the overall survival rates and prognosis of cancer patients. In this immunofluorescence IHC image of immunotherapy treatment, tumor cells in blue are attacked by the immune system T cells lymphocytes in green.

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were related to gastrointestinal disorders, such as colitis and diarrhoea. Pneumonitis occurred in 7.5% of the patients, skin reactions in 15%, and infections in 62.2%.

Some patients also suffered from thyroid, renal, and liver issues.

“After the beginning of the ICIs treatment, most patients experienced mild and manageable side effects. However, there were also a few severe and life-threatening cases of colitis and pneumonitis,” says Mohammed Al Nuhait of the National Pharmacovigilance and Drug Safety Center at SFDA, who is currently affiliated with Umm Al-Qura University.

Overall, one-third of patients had to discontinue the treatment due to adverse events: 12 (32.4%) patients on nivolumab, 6 (60%) on atezolizumab, and 1 (16.6%) on pembrolizumab. A total of 17 patients required steroids to manage the adverse effects of immunotherapy.

“This is the first study in the Middle East that looks at the effect of ICIs in our population. We seem to have a higher rate of discontinuation and adverse events compared to other ICIs studies. However, we need to collect more data from all of the specialised hospitals in the Kingdom to confirm our findings,” says Al Nuhait. “In the future, we are planning to analyse ICIs related adverse events reported to the Saudi National Pharmacovigilance Center.”

Al Nuhait, Mohammed, et al. “Real-world safety experience with immune checkpoint inhibitors in Saudi Arabia.”

Science Progress 104.1 (2021): 0036850421997302.

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esearchers in the Kingdom of Saudi Arabia have assessed safety and tolerability of three commonly used cancer therapeutics that belong to a new class of drugs known as immune checkpoint inhibitors (ICIs). While most of the reported side effects were mild, one-third of the patients (19 out of 53) had to discontinue the treatment.

First introduced in Saudi Arabia in 2015, ICIs are a new and rapidly growing class of anti-cancer drugs. By blocking specific immune checkpoint proteins, they make cancer cells vulnerable to the immune system. Although ICIs improve the overall survival rates and prognosis of cancer patients, they are also known to trigger immune-related adverse effects.

Researchers from the Saudi Food and Drug Authority (SFDA), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City (KAMC) and King Abdullah Medical City analysed the medical records of 53 adult cancer patients who received ICIs treatment in KAMC between 2016 and 2018. The patients had received one of three immunotherapy drugs: 37 had been given nivolumab, 10 had been treated with atezolizumab and 6 had received pembrolizumab.

The patients visited the emergency room an average of three times after the start of treatment. Around 41% of the patients suffered from joint pain (arthralgia), and 79% experienced general fatigue. Other frequent side effects

Anticoagulant satisfaction survey translated into Arabic

T

he health-related quality of life of patients on long-term medications is an important aspect of treatment regimens because people are less likely to stick with taking drugs that negatively impact their daily lives. The international Duke Anticoagulation Satisfaction Scale (DASS) is used by medical professionals to monitor this in patients on long-term oral anticoagulant treatment.

Scientists at KAIMRC have now translated the DASS into Arabic for the first time and tested its efficacy on a patient cohort in Saudi Arabia.

Anticoagulants such as warfarin and apixaban help prevent blood clots and strokes in patients with atrial fibrillation and thromboembolic disorders. However, some patients experience significant side effects and are at higher risk of internal bleeding while taking these drugs. Adherence to these drugs can thus be poor, making a survey such as DASS a valuable tool.

Like any survey, DASS must be tailored to different cultures and translated into different languages while keeping the inherent meaning and implications of each question relevant. “Since each population group and setting is different, it is important to assess the reliability and validity of a specific tool, especially when it has been translated from another language,” says Khizra Sultana of KAIMRC’s Research Office.

“Once we had created the translated Arabic version, we wanted to ensure that it accurately measures patient satisfaction and give consistent results every time it is administered.”

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The team therefore asked 439 patients 18 years old and above at a large government facility in Saudi Arabia to complete the Arabic DASS. Their analysis of patient responses highlighted three questions that were less relevant for Arabs.

“The questions referred to alcohol intake, which is not relevant to Arab culture, and also to overthe-counter medications, which is not an element of our healthcare system and so would be confusing to patients in Saudi Arabia,” says Sultana. “It is important to note that while we have produced an Arabic language version of the DASS, it is up to individual Arabic-speaking nations to check that the survey fits their specific culture – our version is tailored for Saudi Arabia.”

The remaining questions showed high validity and provided a suitable tool for assessing patient satisfaction with both drugs. Similar to other cultures, the team found that males were more satisfied with the drugs than females, and that older patients tended to be happier with their treatment than younger people.

“We hope that, as awareness of this new Arabic DASS grows, healthcare professionals across Saudi Arabia will incorporate it into their support programme for patients on long-term anticoagulant treatment,” says Sultana.

AlAmmari, M., et al. Validation and psychometric properties of the Arabic version of the Duke Anticoagulation Satisfaction Scale (DASS). Fron-

tiers in Pharmacology 11: 587489 (2020)

S EB AS T I A N K AULI T ZK I / A L A M Y S TOC K P H OTO

The quality of life of Arab patients on long-term anticoagulant drugs can be comprehensively assessed by a translated version of an international satisfaction scale

Anticoagulants such as warfarin and apixaban help prevent blood clots and strokes in patients with atrial fibrillation and thromboembolic disorders.

innovations.kaimrc.med.sa

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Commercially available drugs that might prove effective against the strains of SARSCoV-2 circulating in Saudi Arabia can now be identified.

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Existing drugs may help with COVID-19 treatment

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xisting drugs designed to tackle viral infections could be repurposed to target the SARS-CoV-2 virus, cutting down the time and cost to develop a therapy. Now, an international team that included Pooi Ling Mok of Jouf University in Saudi Arabia and Suresh Kumar Subbiah at Bharath University in India, has used computational drug screening techniques to identify commercially available drugs that might prove effective against the strains of SARS-CoV-2 circulating in Saudi Arabia.

“Drug studies require costly and lengthy endeavours before new compounds can be used,” wrote the authors in their paper in the Saudi Journal of Biological Sciences. “[Computational drug discovery] utilizes bioinformatics processes and data mining on huge datasets to identify new drug targets and screen existing drugs for pharmaceutical research.”

Antiviral drugs often target essential proteins that are involved in viral replication. Despite the multiplicity of mutations in SARS-CoV-2 across the world, the key viral proteins – such as the viral replication proteins 3CLPRO and PLPRO – remain highly conserved across strains. Drugs developed to inhibit these in other viruses may therefore be effective against SARS-CoV-2.

The researchers screened 164 genomic sequences isolated from COVID-19 patients in Saudi Arabia. The isolates all had similar genomes with highly conserved proteins and elements from the original strain that first appeared in 2019. Base on this initial screening, they identified 73 similar viral therapeutic targets and matched these with existing approved drugs using the ZINC database.

The team then used a multiple sequence alignment approach to identify 29 viral orthologs (viral genes conserved from common ancestors) and matched them with high-affinity drug options.

“The main challenge was to narrow down the search for drug candidates,” says Mok. “We used multiple sequence alignment to identify closely related drug target sequences from other pathogens like SARS-CoV-1 and MERS-CoV. From there, we determined whether these candidates were possibly effective against SARS-CoV-2.”

The team found that a SARS-CoV-1 protein, the replicase polyprotein 1a (REP), is very similar to a replication protein in the SARS-CoV-2 Saudi isolates. A group of drugs based on tanshinones–bioactive compounds found in the dried root of Salvia miltiorrhiza, a plant used in traditional Chinese medicine–have strong binding affinity to REP and can inhibit the protein’s activity. Drugs containing tanshinones and their derivatives have already shown promise in clinical trials for other diseases and may prove potent against SARS-CoV-2.

“We hope to begin testing tanshinones in the laboratory to determine their effectiveness against SARS-CoV-2 infections,” says Subbiah.

Thereafter, the team members hope to combine their findings with their main research interests in stem cell treatments. “Drugs and stem cells are expected to complement each other in reducing severity in patients suffering from COVID-19.”

Mok, P.L., et al. Computational drug screening against the SARS-

CoV-2 Saudi Arabia isolates through a multiple-sequence alignment approach. Saudi Journal of Biological Sciences 28 (25022509) (2021)

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M I R R OR I M AG ES / A L A M Y S TOC K P H OTO

Computational screening of SARS-CoV-2 genomes identified several proteins which could be targeted by existing drugs to treat COVID-19

Combined therapy boosts kidney cancer survival rates A global phase 3 clinical trial demonstrates the efficacy of a novel combined therapy for advanced kidney cancer

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dvanced kidney cancer is challenging to treat, and many patients suffer relapse after developing resistance to existing treatments. Now, a global phase 3 clinical trial led by Robert Motzer at the Memorial Sloan Kettering Cancer Center in New York, US, has demonstrated the potential of therapies combining an antiangiogenic agent called lenvatinib with one of two other drugs, pembrolizumab (an immune checkpoint inhibitor) or everolimus (an immunosuppressant).

“Advanced kidney cancer is a highly lethal malignancy,” says Motzer. “This trial was inspired by the exceptional activity we saw in a recent phase 2 trial of lenvatinib plus pembrolizumab.”

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The researchers examined progression-free survival rates in a large, international patient cohort. They faced significant challenges to bring the trial together, having not only to co-ordinate it across 200 sites in 20 countries and meeting different regulatory requirements but also working against the backdrop of the

COVID-19 pandemic. The team compared the effectiveness of lenvatinib plus pembrolizumab or everolimus against the most common first-line drug for the disease, sunitinib. They randomly assigned a total of 1069 patients between 2016 and 2019 to one of the three drug options, then monitored survival rates and adverse side

The regimen showed the longest progression free survival we’ve recorded in a phase 3 trial for kidney cancer.” innovations.kaimrc.med.sa

effects. Lenvatinib plus pembrolizumab significantly outperformed the other two therapies, with 79.2% of patients in that group surviving to the two-year mark. This is an increase of almost 10% in survival rate compared to those on sunitinib alone.

“We were pleasantly surprised by the efficacy of the lenvatinib plus

pembrolizumab regimen, which showed the longest progression free survival we have yet recorded in a phase 3 trial for kidney cancer,” says Motzer. “Lenvatinib plus everolimus showed some benefit as well, but not to the same degree.”

There were side effects in almost every patient regardless of the drugs they were prescribed, with diarrhoea and hypertension being the two most common.

The team used accepted methods to limit toxicity, such as interrupting or reducing treatment doses over time, and these approaches worked to minimise adverse effects, allowing the patients to continue therapy.

The team have since started a fresh phase 3 trial to compare lenvatinib plus pembrolizumab with other possible therapies.

“We will study tumours from the patient cohort to determine the mechanism of response,” says Motzer. “Longer follow-up times will help us establish long-term survival chances and durability of response. Cost is an issue of high importance across many aspects of oncology and must be considered carefully, particularly given the extraordinary efficacy of this combined regimen.”

Motzer, R. et al. Lenvatinib plus Pembrolizumab or Everolimus for advanced renal cell carcinoma. The New

England Journal of Medicine 384 (14) (2021)

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S EB AS T I AN K AU L I T Z KI / A L AM Y STO C K P HOTO

A lenvatinibpembrolizumab regimen could offer hope for patients with kidney cancer.

G I R OS CI E NCE / A L A M Y S TOCK P HOTO

Promising nano­ particle carrier for chemo drug

Using nanoparticles to deliver the existing chemotherapy drug epirubicin could improve its efficacy and safety

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anoparticle carriers show great promise as drug delivery systems because they can be programmed to release their load when they reach a specific location or cell type. Now, researchers at KAIMRC have designed and developed a polymer nanoparticle capable of carrying the chemotherapy drug, epirubicin, safely and directly to breast cancer cells.

Epirubicin is less cardiotoxic than its widely used derivative, doxorubicin, and has proven effective against breast, lung, and liver cancer. However, epirubicin is currently administered as an intravenous solution, and in certain cases can cause serious side effects, such as damage to DNA and cellular membranes, the formation of secondary malignancies or even extravasation - the leakage of a fluid or medicine from the vein into the surrounding area. This is largely due to the drug interfering with healthy cells and tissues en route to the tumour.

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Polymeric nanoparticles can be effectively used for drug encapsulation to ensure better delivery.

Salam Massadeh and her colleagues prepared their novel nanoparticles using three different polymers. Each nanoparticle had a hydrophobic core covered in a hydrophilic outer layer, enabling them to carry both hydrophobic and hydrophilic drugs.

The team encapsulated epirubicin in the nanoparticles. The ‘EPI-NPs’ had an encapsulation efficiency of 82% thanks to the robust synthesis method. The researchers then analysed the stability of the EPI-NPs over time and under different environmental conditions. The EPI-NPs remained stable at different pH values and retained their spherical shape throughout all trials. Crucially, they did not form aggregates – a potential stumbling block for nanoparticle drug delivery systems, which can clump together to create a blockage in a capillary. The EPI-NPs also remained stable when stored at room temperature for over 30 days.

In a series of experiments on breast cancer cell cultures, Massadeh and co-workers monitored the way in which the carrier released the drug over time. They found a strong initial release of the drug within a few hours of the nanoparticles reaching their target followed by a steady, sustained release of the drug as the EPI-NPs gradually degraded. “Flow cytometry studies showed that the EPI-NPs have an apoptotic effect on MCF-7 breast cancer cells,” state the researchers in their paper, published in Polymers in 2021. “In addition, the high-content imaging studies revealed a gradual decrease in cancer cells number after treatment with EPI-NPs. […] Further in vivo studies are recommended as a next step to study the pharmacokinetics of the EPI-NPs in animal models.”

Alaamery, M. et al. Development of epirubicin-loaded

biocompatible polymer PLA–PEG–PLA nanoparticles:

Synthesis, characterization, stability, and in vitro anti-

cancerous assessment. Polymers 13 (1212) (2021)

Trial begins on antiviral drug for COVID-19 A clinical trial in Saudi Arabia will examine the efficacy of an existing antiviral in treating mild COVID-19

innovations.kaimrc.med.sa

hospitals and clinics in Saudi Arabia. “We are working closely with all sites involved to mitigate issues with regards to recruitment, and the trial is designed to take patient hesitancy into account,” says Bosaeed. The team aims to recruit more than 500 participants in total unless the Data and Safety Monitoring Board recommends an early termination for safety or efficacy reasons. The team monitors the clinical progression of the patients and tracks the time it takes for each patient to present a negative PCR test.

In previous trials, treatment with favipiravir has proven safe, although the drug can cause some side effects, such as diarrhoea. The researchers will carefully monitor the patients for adverse effects during the trial.

Bosaeed acknowledges that, along with the other unknowns in dealing with this novel coronovirus, it is unclear whether the efficacy of treatments (including antivirals) could be affected by future viral mutations.

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

M

aking use of existing, certified drugs cuts the time it takes to begin therapy in patients, and many clinical trials are examining the use of antiviral drugs to tackle COVID-19.

One such trial, underway in Saudi Arabia under the guidance of Mohammad Bosaeed, an associate director of Research Trial Services in KAIMRC, is examining favipiravir as a potential COVID-19 therapy. The antiviral medication has been shown to improve Ebola survival rates in non-human studies, as well as reducing viral load in influenza patients and speeding up their recovery.

“Early, effective antiviral therapy can help prevent COVID-19 progression to severe illness, especially for patients at high risk, with the additional benefit of decreasing the burden on the healthcare system,” says Bosaeed. “Taking antivirals can also reduce the number of viral particles shed by an individual, which limits the spread of the disease.”

Favipiravir is a potent inhibitor of viral RNA polymerase – the enzyme that kickstarts the replication of viral RNA in host cells. By blocking polymerase activity, the antiviral drug is a valuable tool against RNA viruses such as Ebola and coronaviruses, preventing their spread through the body.

Bosaeed and his team have begun their multi-centre, randomised double blinded clinical trial of favipiravir as a potential treatment for adults with mild COVID-19 symptoms. Around 230 patients have been enrolled so far from different

Bosaeed, M. et al. Multicentre randomised double-blinded placebo-controlled trial of favipiravir

in adults with mild COVID-19. BMJ Open 11 (e047495) (2021)

An existing antiviral drug, favipiravir, is being tested to treat mild COVID-19 patients in a clinical trial in Saudi Arabia.

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Children with acute lymphoblastic leukaemia could benefit from optimised treatment.

Optimising treatment regimens for childhood acute lymphoblastic leukaemia A multinational study shows that radiotherapy with chemotherapy before hematopoietic stem cell transplantation improves the survival of children with acute lymphoblastic leukaemia compared with multi-agent chemotherapy

A

cute lymphoblastic leukaemia (ALL) is the most common type of cancer in children. It is a white blood cell cancer that stops bone marrow from producing healthy blood cells, increasing the risk of infection. “Thanks to recent advances in chemo and immunotherapies, childhood ALL has an excellent prognosis,” says Mohammed Essa, a paediatric oncologist

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at King Abdullah Specialist Children Hospital. Although most children with ALL are cured, around 15-20% have a high risk of relapse, and Essa explains that hematopoietic stem cell transplantation (HSCT) greatly improves survival in patients who relapse or have suboptimal response to chemotherapy.

Prior to undergoing transplantation, patients receive a conditioning regimen

Peters, C. et al. Total Body Irradiation or Chemotherapy

Conditioning in Childhood ALL: A Multinational, Rand-

omized, Noninferiority Phase III Study. Journal of Clinical

Oncology 39, 295–307 (2021).

FATCA M E R A / E + / G E T T Y I M AG E S

that consists of either chemotherapy alone or chemotherapy combined with radiotherapy. The goal is to reduce the tumour burden and suppress the recipient’s immune system to allow the transplanted stem cells to make their way to the bone marrow and start making new blood cells.

Patients with ALL commonly receive total body irradiation (TBI) together with a chemotherapy drug called etoposide before undergoing HSCT. However, TBI-based conditioning can have lifelong adverse effects; it can impair growth and cognition, and increase the risk of secondary malignancies.

Essa took part in an international study led by Christina Peters at the University Vienna, Austria, which aimed to determine whether conditioning with chemotherapy (chemo-conditioning) could replace TBI in paediatric patients with high-risk ALL. The team followed the outcomes of more than 400 patients aged 18 and younger between 2013 and 2018. The patients were randomly assigned to TBI and etoposide or chemo-conditioning before HSCT. “TBI was the leader,” says Essa.

They found that patients who had received TBI had a significantly lower risk of relapse and treatment-related mortality after seven years compared with patients who received chemo-conditioning. “We hoped that the outcomes would be similar with both regimens so patients could avoid the adverse effects of radiotherapy,” Essa says, “but our results confirm those of previous retrospective studies showing that TBI is better in preventing relapse.”

The authors recommend conditioning with TBI plus etoposide for patients over four years old with high-risk ALL undergoing HSCT. However, chemo-conditioning remains an option in some cases.

“Although it may not be the first-choice treatment, chemo-conditioning is still a good option when TBI is not available or contraindicated,” Essa adds.

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