King Saud Medical City

The city of Wuhan in China is the focus of global attention due to an outbreak of a febrile respiratory illness due to a coronavirus 2019-nCoV. In December 2019, there was an outbreak of pneumonia of unknown cause in Wuhan, Hubei province in China, with an epidemiological link to the Huanan Seafood Wholesale Market where there was also sale of live animals. Notification of the WHO on 31 Dec 2019 by the Chinese Health Authorities has prompted health authorities in Hong Kong, Macau, and Taiwan to step up border surveillance, and generated concern and fears that it could mark the emergence of a novel and serious threat to public health (WHO, 2020a; Parr, 2020).

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.

RATIONALE: Corticosteroid therapy is commonly used among critically ill patients with Middle East Respiratory Syndrome (MERS), but its impact on outcomes is uncertain. Analyses of observational studies often do not account for patients' clinical condition at the time of corticosteroid therapy initiation. OBJECTIVES: To investigate the association of corticosteroid therapy on mortality and on MERS coronavirus RNA clearance in critically ill patients with MERS. METHODS: ICU patients with MERs were included from 14 Saudi Arabian centers between September 2012 and October 2015. We performed marginal structural modeling to account for baseline and time-varying confounders. MEASUREMENTS AND MAIN RESULTS: Of 309 patients, 151 received corticosteroids. Corticosteroids were initiated at a median of 3.0 days (quartile 1 [Q1]-Q3, 1.0-7.0) from ICU admission. Patients who received corticosteroids were more likely to receive invasive ventilation (141 of 151 [93.4%] vs. 121 of 158 [76.6%]; P < 0.0001) and had higher 90-day crude mortality (112 of 151 [74.2%] vs. 91 of 158 [57.6%]; P = 0.002). Using marginal structural modeling, corticosteroid therapy was not significantly associated with 90-day mortality (adjusted odds ratio, 0.75; 95% confidence interval, 0.52-1.07; P = 0.12) but was associated with delay in MERS coronavirus RNA clearance (adjusted hazard ratio, 0.35; 95% CI, 0.17-0.72; P = 0.005). CONCLUSIONS: Corticosteroid therapy in patients with MERS was not associated with a difference in mortality after adjustment for time-varying confounders but was associated with delayed MERS coronavirus RNA clearance. These findings highlight the challenges and importance of adjusting for baseline and time-varying confounders when estimating clinical effects of treatments using observational studies.

The covid-19 pandemic that was declared on 11 March 2020 has affected countries on all continents.1 Reported case numbers are certainly underestimates given the shortages or unavailability of test kits in many countries, a virus with a basic reproductive value (R) of 2.2, and evidence of viral shedding from asymptomatic infected people.1234 In addition to suspending travel and efforts to reduce crowds, countries are taking unprecedented measures, including wartime strategies to enhance production of medical supplies in the US, the use of the national guard to restrict movement of people, and suspension of exports of medical products from certain countries (Saudi Arabia, India).5678 Our challenge is to make the best use of available tools through systematic implementation by communities and countries to mitigate the exponential spread of covid-19. No specific drugs or vaccines are available, and health systems are overburdened everywhere. We have to rely on targeted, non-coercive, community interventions with sufficient transparency and public engagement and trust, and implement them urgently (box 1).91011 Such measures may help delay the exponential spread of the outbreak until drugs become available. Transparency and trust are …

BACKGROUND AND OBJECTIVES: Middle East Respiratory Syndrome Corona Virus (MERS-CoV) outbreak in 2014 was associated with high public anxiety in the affected countries. Media speculations may have increased this psychological distress. The healthcare community was the most distressed because they were at the highest risk of infection. This study is the first to explore MERS-CoV epidemic impact on medical students' perception and determinants of their psychological distress during this outbreak. METHODS: We randomly selected and surveyed 200 students from the College of Medicine at King Saud University, Riyadh, Saudi Arabia. A predesigned questionnaire was answered by participants, and the collected data were statistically analyzed. RESULTS: One hundred and seventy-four (87%) responded. Female students had a significantly higher mean stress level than males (P < 0.001). Participants had a mean GAD score of 2.7 ± 3.1 and a median of 2. Perceived sufficiency of information score was the highest mean and median (17.4 ± 4.2 and 18 respectively). College and hospital announcements were the most common source of information (25.4%). One hundred and thirty-four (77%) reported minimal anxiety, thirty-two (18.4%) reported mild anxiety, 8 (4.6%) reported moderate anxiety, and none of them reported severe anxiety (score >14). The stress level (as reported on 1-10 scale) shows significant correlation with Generalized Anxiety Disorder (GAD-7) score. We found in this study that significant predictors in our model, in terms of more significant to the least, were: an increased self-report on hygienic habits, self-reported social avoidance, the generalized anxiety score and finally being female gander while other variables including numbers of resources access, agreeing with public fear and knowledge score on MERS-CoV all were found to be non-significant. However, the number of accessed resources, as per students, has borderline significant correlation with higher self-reported anxiety from MERS-CoV. CONCLUSIONS: Medical students' psychological needs during the MERS-CoV outbreak should be addressed appropriately. Our results highlight the need to establish psychological support programs for medical students during an infectious disease outbreak.

OBJECTIVES: To report the experience with Middle East respiratory syndrome coronavirus (MERS-CoV) infection at a single center in Saudi Arabia. METHODS: Cases of laboratory-confirmed MERS-CoV occurring from October 1, 2012 to May 31, 2014 were reviewed retrospectively. Information sources included medical files, infection control outbreak investigations, and the preventive medicine database of MERS-CoV-infected patients. Data were collected on clinical and epidemiological aspects and outcomes. RESULTS: Seventy consecutive patients were included. Patients were mostly of older age (median 62 years), male (46, 65.7%), and had healthcare acquisition of infection (39, 55.7%). Fever (43, 61.4%), dyspnea (42, 60%), and cough (38, 54.3%) were the most common symptoms. The majority developed pneumonia (63, 90%) and required intensive care (49, 70%). Infection commonly occurred in clusters. Independent risk factors for severe infection requiring intensive care included concomitant infections (odds ratio (OR) 14.13, 95% confidence interval (CI) 1.58-126.09; p=0.018) and low albumin (OR 6.31, 95% CI 1.24-31.90; p=0.026). Mortality was high (42, 60%), and age ≥65 years was associated with increased mortality (OR 4.39, 95% CI 2.13-9.05; p<0.001). CONCLUSIONS: MERS-CoV can cause severe infection requiring intensive care and has a high mortality. Concomitant infections and low albumin were found to be predictors of severe infection, while age ≥65 years was the only predictor of increased mortality.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

DISCLAIMER: This is an updated guideline from the Extracorporeal Life Support Organization (ELSO) for the role of extracorporeal membrane oxygenation (ECMO) for patients with severe cardiopulmonary failure due to coronavirus disease 2019 (COVID-19). The great majority of COVID-19 patients (>90%) requiring ECMO have been supported using venovenous (V-V) ECMO for acute respiratory distress syndrome (ARDS). While COVID-19 ECMO run duration may be longer than in non-COVID-19 ECMO patients, published mortality appears to be similar between the two groups. However, data collection is ongoing, and there is a signal that overall mortality may be increasing. Conventional selection criteria for COVID-19-related ECMO should be used; however, when resources become more constrained during a pandemic, more stringent contraindications should be implemented. Formation of regional ECMO referral networks may facilitate communication, resource sharing, expedited patient referral, and mobile ECMO retrieval. There are no data to suggest deviation from conventional ECMO device or patient management when applying ECMO for COVID-19 patients. Rarely, children may require ECMO support for COVID-19-related ARDS, myocarditis, or multisystem inflammatory syndrome in children (MIS-C); conventional selection criteria and management practices should be the standard. We strongly encourage participation in data submission to investigate the optimal use of ECMO for COVID-19.

Abstract Rationale Response to positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome depends on recruitability. We propose a bedside approach to estimate recruitability accounting for the presence of complete airway closure. Objectives To validate a single-breath method for measuring recruited volume and test whether it differentiates patients with different responses to PEEP. Methods Patients with acute respiratory distress syndrome were ventilated at 15 and 5 cm H2O of PEEP. Multiple pressure–volume curves were compared with a single-breath technique. Abruptly releasing PEEP (from 15 to 5 cm H2O) increases expired volume: the difference between this volume and the volume predicted by compliance at low PEEP (or above airway opening pressure) estimated the recruited volume by PEEP. This recruited volume divided by the effective pressure change gave the compliance of the recruited lung; the ratio of this compliance to the compliance at low PEEP gave the recruitment-to-inflation ratio. Response to PEEP was compared between high and low recruiters based on this ratio. Measurements and Main Results Forty-five patients were enrolled. Four patients had airway closure higher than high PEEP, and thus recruitment could not be assessed. In others, recruited volume measured by the experimental and the reference methods were strongly correlated (R2 = 0.798; P < 0.0001) with small bias (−21 ml). The recruitment-to-inflation ratio (median, 0.5; range, 0–2.0) correlated with both oxygenation at low PEEP and the oxygenation response; at PEEP 15, high recruiters had better oxygenation (P = 0.004), whereas low recruiters experienced lower systolic arterial pressure (P = 0.008). Conclusions A single-breath method quantifies recruited volume. The recruitment-to-inflation ratio might help to characterize lung recruitability at the bedside. Clinical trial registered with www.clinicaltrials.gov (NCT02457741).

Background The triglyceride glucose (TyG) index is an easily accessible surrogate marker of insulin resistance, an important pathway in the development of type 2 diabetes and cardiovascular diseases. However, the association of the TyG index with cardiovascular diseases and mortality has mainly been investigated in Asia, with few data available from other regions of the world. We assessed the association of insulin resistance (as determined by the TyG index) with mortality and cardiovascular diseases in individuals from five continents at different levels of economic development, living in urban or rural areas. We also examined whether the associations differed according to the country's economical development. Methods We used the TyG index as a surrogate measure for insulin resistance. Fasting triglycerides and fasting plasma glucose were measured at the baseline visit in 141 243 individuals aged 35–70 years from 22 countries in the Prospective Urban Rural Epidemiology (PURE) study. The TyG index was calculated as Ln (fasting triglycerides [mg/dL] x fasting plasma glucose [mg/dL]/2). We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random effects to test the associations between the TyG index and risk of cardiovascular diseases and mortality. The primary outcome of this analysis was the composite of mortality or major cardiovascular events (defined as death from cardiovascular causes, and non-fatal myocardial infarction, or stroke). Secondary outcomes were non-cardiovascular mortality, cardiovascular mortality, all myocardial infarctions, stroke, and incident diabetes. We also did subgroup analyses to examine the magnitude of associations between insulin resistance (ie, the TyG index) and outcome events according to the income level of the countries. Findings During a median follow-up of 13·2 years (IQR 11·9–14·6), we recorded 6345 composite cardiovascular diseases events, 2030 cardiovascular deaths, 3038 cases of myocardial infarction, 3291 cases of stroke, and 5191 incident cases of type 2 diabetes. After adjusting for all other variables, the risk of developing cardiovascular diseases increased across tertiles of the baseline TyG index. Compared with the lowest tertile of the TyG index, the highest tertile (tertile 3) was associated with a greater incidence of the composite outcome (HR 1·21; 95% CI 1·13–1·30), myocardial infarction (1·24; 1·12–1·38), stroke (1·16; 1·05–1·28), and incident type 2 diabetes (1·99; 1·82–2·16). No significant association of the TyG index was seen with non-cardiovascular mortality. In low-income countries (LICs) and middle-income countries (MICs), the highest tertile of the TyG index was associated with increased hazards for the composite outcome (LICs: HR 1·31; 95% CI 1·12–1·54; MICs: 1·20; 1·11–1·31; p interaction =0·01), cardiovascular mortality (LICs: 1·44; 1·15–1·80; p interaction =0·01), myocardial infarction (LICs: 1·29; 1·06–1·56; MICs: 1·26; 1·10–1·45; p interaction =0·08), stroke (LICs: 1·35; 1·02–1·78; MICs: 1·17; 1·05–1·30; p interaction =0·19), and incident diabetes (LICs: 1·64; 1·38–1·94; MICs: 2·68; 2·40–2·99; p interaction <0·0001). In contrast, in high-income countries, higher TyG index tertiles were only associated with an increased hazard of incident diabetes (2·95; 2·25–3·87; p interaction <0·0001), but not of cardiovascular diseases or mortality. Interpretation The TyG index is significantly associated with future cardiovascular mortality, myocardial infarction, stroke, and type 2 diabetes, suggesting that insulin resistance plays a promoting role in the pathogenesis of cardiovascular and metabolic diseases. Potentially, the association between the TyG index and the higher risk of cardiovascular diseases and type 2 diabetes in LICs and MICs might be explained by an increased vulnerability of these populations to the presence of insulin resistance. Funding Full funding sources are listed at the end of the paper (see Acknowledgments).

During the COVID-19 pandemic, telemedicine has emerged worldwide as an indispensable resource to improve the surveillance of patients, curb the spread of disease, facilitate timely identification and management of ill people, but, most importantly, guarantee the continuity of care of frail patients with multiple chronic diseases. Although during COVID-19 telemedicine has thrived, and its adoption has moved forward in many countries, important gaps still remain. Major issues to be addressed to enable large scale implementation of telemedicine include: (1) establishing adequate policies to legislate telemedicine, license healthcare operators, protect patients' privacy, and implement reimbursement plans; (2) creating and disseminating practical guidelines for the routine clinical use of telemedicine in different contexts; (3) increasing in the level of integration of telemedicine with traditional healthcare services; (4) improving healthcare professionals' and patients' awareness of and willingness to use telemedicine; and (5) overcoming inequalities among countries and population subgroups due to technological, infrastructural, and economic barriers. If all these requirements are met in the near future, remote management of patients will become an indispensable resource for the healthcare systems worldwide and will ultimately improve the management of patients and the quality of care.

Effective management of breast cancer depends on early diagnosis and proper monitoring of patients' response to therapy. However, these goals are difficult to achieve because of the lack of sensitive and specific biomarkers for early detection and for disease monitoring. Accumulating evidence in the past several years has highlighted the potential use of peripheral blood circulating nucleic acids such as DNA, mRNA and micro (mi)RNA in breast cancer diagnosis, prognosis and for monitoring response to anticancer therapy. Among these, circulating miRNA is increasingly recognized as a promising biomarker, given the ease with which miRNAs can be isolated and their structural stability under different conditions of sample processing and isolation. In this review, we provide current state-of-the-art of miRNA biogenesis, function and discuss the advantages, limitations, as well as pitfalls of using circulating miRNAs as diagnostic, prognostic or predictive biomarkers in breast cancer management.

BACKGROUND: The global pandemic of coronavirus disease of 2019 (COVID-19) has led to unprecedented psychological stress on health workers (HCWs). We aimed to assess the psychological impact of COVID-19 on HCWs in comparison to the stress brought on by the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic in Saudi Arabia. METHOD: Between February 5th and 16th, 2020, 811 health-care workers (HCWs) of a tertiary care teaching hospital were invited to fill a questionnaire regarding concerns and worries about the novel coronavirus pandemic, along with Generalized Anxiety Disorder (GAD-7) Anxiety Severity screening tool. RESULTS: Out of 582 HCWs who completed the survey questionnaire (response rate of 71.8%), about 40% were exposed previously to MERS-CoV infected or suspected patients during a previous hospital outbreak. While there were no COVID-19 cases reported yet in Saudi Arabia at the time of data collection, still, the anxiety level from COVID-19 was significantly higher than that from MERS-CoV or seasonal influenza: 41.1% were more worried about COVID-19, 41.4% were similarly worried about both MERS-CoV and COVID-19, and 17.5% were more stressed by the previous MERS-CoV hospital outbreak. The most frequent concern was transmitting the infection to family and friends (2.71/5) than to themselves only (2.57/5). CONCLUSION: Pandemic and epidemic infectious diseases such as COVID-19 or MERS-CoV impose a significant level of anxiety and stress on healthcare workers who are caring of infected patients, with their main concern being the risk of transmitting the infection to their families or to acquire it themselves. Therefore, optimizing the compliance of healthcare workers with the proper infection prevention and control measures is paramount during the infectious disease outbreak, to ensure their safety, to decrease the likelihood of getting infected or transmitting the infection to others, and consequently to alleviate their psychological stress and anxiety.

OBJECTIVE: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomised controlled, adaptive, open label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS: . At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362085.

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous autosomal recessive immune disorder characterized by the occurrence of uncontrolled activation of lymphocytes and macrophages infiltrating multiple organs. Disease-causing mutations in the perforin (PRF1; also known as FHL2), Munc13-4 (UNC13D; also known as FHL3), and syntaxin-11 (STX11; also known as FHL4) genes have been identified in individuals with FHL. These genes all encode proteins involved in the cytotoxic activity of lymphocytes. Here, we show that the gene encoding syntaxin-binding protein 2 (Munc18-2; official gene symbol STXBP2) is mutated in another subset of patients with FHL (designated by us as "FHL5"). Lymphoblasts isolated from these patients had strongly decreased STXBP2 protein expression, and NK cells exhibited impaired cytotoxic granule exocytosis, a defect that could be overcome by ectopic expression of wild-type STXBP2. Furthermore, we provide evidence that syntaxin-11 is the main partner of STXBP2 in lymphocytes, as its expression required the presence of STXBP2. Our work shows that STXBP2 deficiency causes FHL5. These data indicate that STXBP2 is required at a late step of the secretory pathway for the release of cytotoxic granules by binding syntaxin 11, another component of the intracellular membrane fusion machinery.

Candida species present both as commensals and opportunistic pathogens of the oral cavity. For decades, it has enthralled the clinicians to investigate its pathogenicity and to improvise newer therapeutic regimens based on the updated molecular research. Candida is readily isolated from the oral cavity, but simple carriage does not predictably result in development of an infection. Whether it remains as a commensal, or transmutes into a pathogen, is usually determined by pre-existing or associated variations in the host immune system. The candida infections may range from non-life threatening superficial mucocutaneous disorders to invasive disseminated disease involving multiple organs. In fact, with the increase in number of AIDS cases, there is a resurgence of less common forms of oral candida infections. The treatment after confirmation of the diagnosis should include recognizing and eliminating the underlying causes such as ill-fitting oral appliances, history of medications (antibiotics, corticosteroids, etc.), immunological and endocrine disorders, nutritional deficiency states and prolonged hospitalization. Treatment with appropriate topical antifungal agents such as amphotericin, nystatin, or miconazole usually resolves the symptoms of superficial infection. Occasionally, administration of systemic antifungal agents may be necessary in immunocompromised patients, the selection of which should be based upon history of recent azole exposure, a history of intolerance to an antifungal agent, the dominant Candida species and current susceptibility data.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.

Background and Objectives: The novel coronavirus COVID-19 pandemic causes great public health and socioeconomic harms. Worldwide many countries implemented quarantine policies to minimize the spread of this highly contagious disease. The present study aim was to investigate the impact of quarantine on the medical students’ mental wellbeing and learning behaviors. Methods: In this descriptive study, we used a questionnaire with a Five-Point Likert Scale to collect the information. The questionnaire was distributed among 625 medical students through their emails with a response rate of 530 (84.8%), majority 294 (55.47%) being female. The survey questionnaire consisted of total 20 items; 12 items were related to psychological wellbeing and stress-allied queries and 08 items were about learning behaviors. Results: The findings encompass two important characteristics related to quarantine, psychological wellbeing, and learning behaviors. A combined cohort of 234 medical students, either female or male, (which was 44.1% of the total responders) showed a sense of being emotionally detached from family, friends and fellow students, 125/ 530 (23.5%) medical students felt disheartened. Both female and male medical students showed a marked decrease in their overall work performance. Moreover, 56.2% of the total students (61.5% of the females and 49.5% of the males) felt a decrease in the time they spent studying. Conclusions: Both female and male medical students have identified that quarantine has caused them to feel emotionally detached from family, fellows, and friends and decrease their overall work performance and study period. The findings also show that one-fourth of the medical students who participated in this study felt disheartened during the quarantine period. The long-term quarantine due to COVID-19 pandemic may causes further worsening in the psychological and learning behaviors of these medical students. doi: https://doi.org/10.12669/pjms.36.COVID19-S4.2809 How to cite this:Meo SA, Abukhalaf AA, Alomar AA, Sattar K, Klonoff DC. COVID-19 Pandemic: Impact of Quarantine on Medical Students’ Mental Wellbeing and Learning Behaviors. Pak J Med Sci. 2020;36(COVID19-S4):COVID19-S43-S48. doi: https://doi.org/10.12669/pjms.36.COVID19-S4.2809 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Recent advancements in the Internet of Health Things (IoHT) have ushered in the wide adoption of IoT devices in our daily health management. For IoHT data to be acceptable by stakeholders, applications that incorporate the IoHT must have a provision for data provenance, in addition to the accuracy, security, integrity, and quality of data. To protect the privacy and security of IoHT data, federated learning (FL) and differential privacy (DP) have been proposed, where private IoHT data can be trained at the owner's premises. Recent advancements in hardware GPUs even allow the FL process within smartphone or edge devices having the IoHT attached to their edge nodes. Although some of the privacy concerns of IoHT data are addressed by FL, fully decentralized FL is still a challenge due to the lack of training capability at all federated nodes, the scarcity of high-quality training datasets, the provenance of training data, and the authentication required for each FL node. In this paper, we present a lightweight hybrid FL framework in which blockchain smart contracts manage the edge training plan, trust management, and authentication of participating federated nodes, the distribution of global or locally trained models, the reputation of edge nodes and their uploaded datasets or models. The framework also supports the full encryption of a dataset, the model training, and the inferencing process. Each federated edge node performs additive encryption, while the blockchain uses multiplicative encryption to aggregate the updated model parameters. To support the full privacy and anonymization of the IoHT data, the framework supports lightweight DP. This framework was tested with several deep learning applications designed for clinical trials with COVID-19 patients. We present here the detailed design, implementation, and test results, which demonstrate strong potential for wider adoption of IoHT-based health management in a secure way.

BACKGROUND: The objective of this study was to evaluate the effect of ribavirin and recombinant interferon (RBV/rIFN) therapy on the outcomes of critically ill patients with Middle East respiratory syndrome (MERS), accounting for time-varying confounders. METHODS: This is a retrospective cohort study of critically ill patients with laboratory-confirmed MERS from 14 hospitals in Saudi Arabia diagnosed between September 2012 and January 2018. We evaluated the association of RBV/rIFN with 90-day mortality and MERS coronavirus (MERS-CoV) RNA clearance using marginal structural modeling to account for baseline and time-varying confounders. RESULTS: Of 349 MERS patients, 144 (41.3%) patients received RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a; none received rIFN-β1b). RBV/rIFN was initiated at a median of 2 days (Q1, Q3: 1, 3 days) from intensive care unit admission. Crude 90-day mortality was higher in patients with RBV/rIFN compared to no RBV/rIFN (106/144 [73.6%] vs 126/205 [61.5%]; P = .02]. After adjusting for baseline and time-varying confounders using a marginal structural model, RBV/rIFN was not associated with changes in 90-day mortality (adjusted odds ratio, 1.03 [95% confidence interval {CI}, .73-1.44]; P = .87) or with more rapid MERS-CoV RNA clearance (adjusted hazard ratio, 0.65 [95% CI, .30-1.44]; P = .29). CONCLUSIONS: In this observational study, RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a) therapy was commonly used in critically ill MERS patients but was not associated with reduction in 90-day mortality or in faster MERS-CoV RNA clearance.