title: Adaptive design methods in dialysis clinical trials - a systematic review

abstract:
BackgroundAdaptive design methods are intended to improve efficiency of clinical trials and are relevant to evaluating interventions in dialysis populations. We sought to quantify the use of adaptive designs in dialysis clinical trials.

MethodsWe completed a full text systematic review and adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Our review utilised a machine learning classifier and a novel full text systematic review method. We searched MEDLINE (Pubmed) and performed a detailed data extraction of trial characteristics and a completed a narrative synthesis of the data.

Results50 studies, available as 66 articles, were included after full text review. 31 studies were conducted in a dialysis population and 19 studies had renal replacement therapy as a primary or secondary outcome. While the absolute number of adaptive design methods is increasing over time, the relative use of adaptive design methods in dialysis trials is decreasing over time (6.1% in 2009 to 0.3% in 2019). Adaptive design methods impacted 52% of dialysis trials they were used in. Group sequential designs were the most common type of adaptive design method used. Acute Kidney Injury (AKI) was studied in 27 trails (54%), End Stage Kidney Disease (ESKD) was studied in 22 trials (44%) and Chronic Kidney Disease (CKD) was studied in 1 trial (2%). 26 studies (52%) were supported by public funding. 41 studies (82%) did not report their adaptive design method in the title or abstract and would not be detected by a standard systematic.

ConclusionsAdaptive design methods are employed in dialysis trials, but there has been a decline in their relative use over time.

Registration NumberPROSPERO: CRD42020163946

Significance statementO_ST_ABSWhat was previously known about the specific topic of the manuscript?C_ST_ABSThe use of adaptive designs methods in dialysis trials is unquantified.

What were the most important findings? If studies are animals, this should be specifiedAlthough absolute numbers of adaptive design trials have increased over time, the proportion of dialysis trials using an adaptive design has reduced. Among trials that employed an adaptive design, 52% of dialysis trials were revised due to the adaptive criteria. Group sequential designs were the most common type of adaptive design method used in dialysis randomized clinical trials. Acute Kidney Injury (AKI) was studied in 54% of trials and End Stage Kidney Disease (ESKD) was studied in 44% of trials, which used an adaptive design.

How does the new information advance a new understanding of the kidney and its diseases?Adaptive design methods are effective in dialysis trials, but their relative use has declined over time.

category: nephrology


title: Lipidomic profiling of human serum enables detection of pancreatic cancer

abstract: Pancreatic cancer has the worst prognosis among all cancers1. Cancer screening programs based on the analysis of body fluids can improve the survival time of patients, who are often diagnosed too late at an incurable stage2. Several studies have reported the dysregulation of lipid metabolism in tumor cells and tissues3, suggesting that the changes of blood lipidome may accompany tumor growth and progression. Analytical methods based on mass spectrometry (MS) using either direct infusion or chromatographic separation4 are convenient for high-throughput lipidomic profiling. Here we show that the comprehensive quantitation of a wide range of serum lipids reveals statistically significant differences between pancreatic cancer patients and healthy controls visualized by multivariate data analysis. Initial results for 364 human serum samples in the discovery phase were subsequently verified in the qualification phase on 554 samples measured by three independent laboratories, and finally on 830 samples from four blood collection sites in the verification phase. Concentrations suggestive of dysregulation of some very long chain sphingomyelins (SM 42:1, SM 41:1, SM 39:1, and SM 40:1), ceramides (Cer 41:1, and Cer 42:1), and (lyso)phosphatidylcholines (LPC 18:2) were recorded. Some lipid species indicated a potential as biomarkers of survival. The sensitivity and specificity to diagnose pancreatic cancer is over 90%, which outperforms CA 19-9, especially in early stage, and is comparable to established imaging diagnostic methods. The accuracy of lipidomic approach is not influenced by the cancer stage, analytical method, or blood collection site.

category: oncology


title: Identification of novel biomarkers for pyridoxine-dependent epilepsy using untargeted metabolomics and infrared ion spectroscopy - biochemical insights and clinical implications

abstract: Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of -aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important co-factor pyridoxal-5-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but despite this treatment, intellectual disability may occur. Early diagnosis and treatment, preferably based on newborn screening, potentially optimize long-term clinical outcome. However, the currently known diagnostic PDE-ALDH7A1 biomarkers are incompatible with newborn screening procedures. Using a combination of the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, we have been able to discover novel biomarkers for PDE-ALDH7A1: 2S,6S-and 2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) and 6-oxopiperidine-2-carboxylic acid (6-oxoPIP). We demonstrate the applicability of 2-OPP as a PDE-ALDH7A1 biomarker in newborn screening. Additionally, we show that 2-OPP accumulates in brain tissue of patients and Aldh7a1 knock-out mice, and induces epilepsy-like behavior in a zebrafish model system. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.

category: genetic and genomic medicine


title: Role of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 in severity of COVID-19 infection: from GWAS hit to therapeutic hypothesis

abstract:
Coronaviruses remodel intracellular membranes to form specialized viral replication compartments, such as double-membrane vesicles where viral RNA genome replication takes place. Understanding the factors affecting host response is instrumental to design of therapeutics to prevent or ameliorate the course of infection.

As part of explorative tests in hospitalized patients with confirmed COVID-19 infection participating in ODYSSEY trial, we obtained samples for whole genome sequencing analysis as well as for viral genome sequencing. Based on our data, we confirm one of the strongest severity susceptibility locus thus far reported in association with severe COVID-19: 3p21.31 locus with lead variant rs73064425. We further examine the associated region. Interestingly based on LD analysis we report 3 coding mutations within one gene in the region of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1). We specifically focus on the role of FYCO1 modifiers and gain-of-function variants. We report the associations between the region and clinical characteristics in this severe set of COVID-19 patients.

We next analyzed expression profiles of FYCO1 across all 466 compounds tested. We selected only those results that showed a significant reduction of expression of FYCO1. The most significant candidate was indomethacin - an anti-inflammatory that could potentially downregulate FYCO1. We hypothesize that via its direct effects on efficiency of viral egress, it may serve as a potent therapeutic decreasing the replication and infectivity of the virus. Clinical studies will be needed to examine the therapeutic utility of indomethacin and other compounds downregulating FYCO1 in COVID-19 infection and other strains of betacoronaviruses.


title: Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24

abstract: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Genotypic data were obtained from PRACTICAL consortium for 6,253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with performance of PHS46+African. A calibration factor (CF) was formulated using estimated Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our dataset with 1000 Genomes, we identified statistically significant associations between continental and calibration groupings. In conclusion, we identified PCs within 8q24 SNP window that were strongly associated with performance of PHS46+African. Further research to improve clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry


title: Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants

abstract:
BackgroundHypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.

MethodsWe compared outcomes and cardiovascular phenotypes in UK Biobank participants with whole exome sequencing stratified by sarcomere-encoding variant status.

ResultsThe prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), of which 0.24% (n=474, 1 in 423) were pathogenic or likely pathogenic variants (SARC-P/LP). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.68, 95% CI 1.37-2.06, p<0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p<0.001) and arrhythmia (HR 1.55, 95% CI 1.18-2.03, p=0.002). In 21,322 participants with cardiac magnetic resonance imaging, SARC-P/LP were associated with increased left ventricular maximum wall thickness (10.9{+/-}2.7 vs 9.4{+/-}1.6 mm, p<0.001) and concentric remodelling (mass/volume ratio: 0.63{+/-}0.12 vs 0.58{+/-}0.09 g/mL, p<0.001), but hypertrophy ([≥]13mm) was only present in 16% (n=7/43, 95% CI 7-31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5{+/-}1.7 vs 9.4{+/-}1.6 mm, p=0.002) with no combined excess cardiovascular risk (HR 1.00 95% CI 0.92-1.08, p=0.9).

ConclusionsIn the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and a sub-clinical cardiomyopathic phenotype. In contrast, rare sarcomeric variants that do not meet criteria to be classified as P/LP appear to have minimal clinical impact.


title: Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

abstract: ABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboring DYRK1A variants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specific DYRK1A clinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurring de novo.


title: Development and validation of gradient boosting decision tree models for predicting care needs using a long-term care database in Japan

abstract:
ObjectiveThe purpose of the study was to develop machine learning models using data from long-term care (LTC) insurance claims and care needs certifications to predict the individualized future care needs of each older adult.

MethodsWe collected LTC insurance-related data in the form of claims and care needs certification surveys from a municipality of Kanagawa Prefecture from 2009 to 2018. We used care needs certificate applications for model generation and the validation sample to build gradient boosting decision tree (GBDT) models to classify if 1) the insureds care needs either remained stable or decreased or 2) the insureds care needs increased after three years. The predictive model was trained and evaluated via k-fold cross-validation. The performance of the predictive model was observed in its accuracy, precision, recall, F1 score, area under the receiver-operator curve, and confusion matrix.

ResultsLong-term care certificate applications and claim data from 2009-2018 were associated with 92,239 insureds with a mean age of 86.1 years old at the time of application, of whom 67% were female. The classifications of increase in care needs after three years were predicted with AUC of 0.80.

ConclusionsMachine learning is a valuable tool for predicting care needs increases in Japans LTC insurance system, which can be used to develop more targeted and efficient interventions to proactively reduce or prevent further functional deterioration, thereby helping older adults maintain a better quality of life.

category: health informatics


title: Validation of Kiswahili Version of WHOQOLHIVBREF questionnaire among people living with HIV/AIDS in Tanzania: a cross-sectional study.

abstract:
BackgroundQuality of life is an important element of surveillance in people living with HIV/AIDS. WHO has developed an HIV specific quality of life tool (WHOQOLHIV-Bref) for assessing Quality of life of HIV individuals. This tool takes into account the different cultural variations that exist worldwide and hence enable assessment of the quality of life across different cultures. Despite its preliminary sound validity and reliability from several studies, the developers recommend it to be validated in different cultures to fully assess its psychometric properties before its adaptation.

ObjectivesTo evaluate the validity and reliability of WHOQOLHIV-Bref questionnaire in Tanzanian culture among people living with HIV/AIDS.

MethodsThis was a cross-sectional study of 103 participants interviewed using a Kiswahili WHOQOLHIV-BREF questionnaire. Of, these participants 47 participants were enrolled to repeat an interview two weeks later. Internal consistency and test-retest reliability were analyzed. Validity was assessed through analysis of translational, concurrent, convergent and discriminant validity while the model performance was assessed by Exploratory and confirmatory factor analysis.

ResultsThe mean age of the participants was 40.5 {+/-} 9.702 years. Translation validity was assessed through the WHO translational protocol and was found to be good. The internal consistency and test-retest reliability of the Kiswahili version of WHOQOL-HIV BREF were excellent: Cronbachs alpha values of 0.89-0.90, and ICC of 0.92 p < 0.01 respectively. Concurrent valid was excellent, significant correlations were noted across all domains (correlation coefficient r > 0.3) except for physical and spiritual domains. Confirmatory factor analysis found that the six domain produced an acceptable fit to the data. The convergent and divergent validities were satisfactory.

ConclusionKiswahili WHOQOLHIV-Bref was found to be reliable and valid questionnaire among Tanzanian people living with HIV/AIDS. These findings provide support for the use of this tool in assessing the quality of life in Tanzania.

category: hiv aids


title: A High-throughput Microsphere-based Immunoassay of Anti-SARS-CoV-2 IgM Testing for COVID-19 Diagnostics

abstract: The pandemic of novel coronavirus disease COVID-19 is rapidly expanding across the world. A positive result of antibody tests suggests that the individual has potentially been exposed to SARS-CoV-2, thus allowing to identify asymptomatic infections and determine the seroprevalence in a given population. The aim of this study was to evaluate the performances of a newly developed high throughput immunoassay for anti-SARS-CoV-2 IgM antibody detection on the Luminex MAGPIX platform. Clinical agreement studies were performed in 42 COVID-19 patient serum samples and 162 negative donor serum/plasma samples. Positive percent agreement (PPA) was 42.86% (95% CI: 9.90% to 81.59%), 71.43% (95% CI: 29.04% to 96.33%), and 28.57% (95% CI: 13.22% to 48.67%) for samples collected on 0-7 days, 8-14 days, and 2-8 weeks from symptom onset, respectively. Negative Percent Agreement (NPA) was 97.53% (95% CI: 93.80% to 99.32%). There was no cross-reactivity with the SARS-CoV-2 IgG antibody Hemoglobin (200 mg/dL), bilirubin (2 mg/dL), triglyceride (250 mg/dL) and EDTA (10 mM) showed no significant interfering effect on this assay. In conclusion, an anti-SARS-CoV-2 IgM antibody assay with high sensitivity and specificity has been developed. With the high throughput, this assay will speed up the anti-SARS-CoV-2 IgM testing.

category: infectious diseases


title: Strategic Treatment Optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C

abstract:
BackgroundThe WHO has identified the need for a better understanding of which patients can be cured with ultrashort course hepatitis C (HCV) therapy

Methods202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks sofosbuvir/ledipasvir/ribavirin. Primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment.

ResultsAll evaluable participants achieved SVR12 overall (197/197, 100%[95%CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95%CI -3.8%,+3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91%[86%-97%] (92/101) for fixed-duration vs 48%[39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall first-line SVR12 was 72%[65%-78%] (70/101) without ribavirin and 68%[61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01).

ConclusionsUnsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy.

RegistrationISRCTN 37915093.

FundingNational Institutes of Health Research.


title: The longest persistence of viable SARS-CoV-2 with recurrence of viremia and relapsing symptomatic COVID-19 in an immunocompromised patient - a case study

abstract:
BackgroundImmunocompromised patients show prolonged shedding of SARS-CoV-2 in nasopharyngeal swabs. We report a case of a prolonged persistence of viable SARS-CoV-2 associated with clinical relapses of COVID-19 in a lymphoma patient.

MethodsNasopharyngeal swabs and blood samples were tested for SARS-CoV-2 by Real time-PCR (RT-PCR). On five positive nasopharyngeal swabs, we performed viral culture and next generation sequencing. We analysed the patients adaptive and innate immunity to characterize T and NK cell subsets.

FindingsSARS-CoV-2 RT-PCR on nasopharyngeal swabs samples remained positive with cycle threshold mean values of 22 {+/-} 1{middle dot}3 for over 8 months. All five performed viral cultures were positive and genomic analysis confirmed a persistent infection with the same strain. Viremia resulted positive in three out of four COVID-19 clinical relapses and cleared each time after remdesivir treatment. T and NK cells dynamic was different in aviremic and viremic samples and no SARS-CoV-2 specific antibodies were detected throughout the disease course.

InterpretationIn our patient, SARS-CoV-2 persisted with proven infectivity for over eight months. Viremia was associated with COVID-19 relapses and remdesivir treatment was effective in viremia clearance and symptoms remission, although it was unable to clear the virus from the upper respiratory airways. During the viremic phase, we observed a low frequency of terminal effector CD8+ T lymphocytes in peripheral blood that are probably recruited in inflammatory tissue for viral eradication. In addition we found a high level of NK cells repertoire perturbation with a relevant involvement during SARS-CoV-2 viremia.

FundingNone.


title: Evaluation of a Commercial Culture-free Neutralization Antibody Detection Kit for Severe Acute Respiratory Syndrome-Related Coronavirus-2 and Comparison with an Anti-RBD ELISA Assay

abstract:
BackgroundSARS-CoV-2 surrogate neutralization assays that obviate the need for viral culture offer substantial advantages regarding throughput and cost. The cPass SARS-CoV-2 Neutralization Antibody Detection Kit (Genscript) is the first such commercially available assay, detecting antibodies that block RBD/ACE-2 interaction. We aimed to evaluate cPass to inform its use and assess its added value compared to anti-RBD ELISA assays.

MethodsSerum reference panels comprising 205 specimens were used to compare cPass to plaque-reduction neutralization test (PRNT) and a pseudotyped lentiviral neutralization (PLV) assay for detection of neutralizing antibodies. We assessed the correlation of cPass with an ELISA detecting anti-RBD IgG, IgM, and IgA antibodies at a single timepoint and across intervals from onset of symptoms of SARS-CoV-2 infection.

ResultsCompared to PRNT-50, cPass sensitivity ranged from 77% - 100% and specificity was 95% - 100%. Sensitivity was also high compared to the pseudotyped lentiviral neutralization assay (93% [95%CI 85-97]), but specificity was lower (58% [95%CI 48-67]). Highest agreement between cPass and ELISA was for anti-RBD IgG (r=0.823). Against the pseudotyped lentiviral neutralization assay, anti-RBD IgG sensitivity (99% [95%CI 94-100]) was very similar to that of cPass, but overall specificity was lower (37% [95%CI 28-47]). Against PRNT-50, results of cPass and anti-RBD IgG were nearly identical.

ConclusionsThe added value of cPass compared to an IgG anti-RBD ELISA was modest.


title: Seroprevalence and attainment of herd immunity against SARS CoV-2: A modelling study

abstract:
ObjectiveThe present study is aims to predict the likelihood of and likely time required to attain herd immunity against COVID-19 in New Delhi due to natural infection.

MethodAn ODE based mathematical model was constructed by extending the classical SEIR model to predict the seroprevalence rate in Delhi. We estimated the parameter values for Delhi using available data (reported cases and the seroprevalence rate) and used them for future prediction. We also attempted to capture the changes in the seroprevalence rate with different possibilities of reinfection.

ResultsMaximum seroprevalence rate obtained through our model is 31.65% and also a reduction in the seroprevalence rate was observed for the upcoming one month (month of January, 2021) due to the reduced transmission rate. After increasing the transmission rate to the value same as the third wave in New Delhi, we obtained a maximum value of 54.96%. This maximum value significantly decreased with the reduction in the reinfection possibilities. Also, a little impact of the duration of persistence of antibodies, 180 vs 105 days, was observed on the maximum seroprevalence.

ConclusionThis modelling study suggests that natural infection alone, as gauged by serial sero-surveys, will not result in attainment of herd immunity in the state of Delhi.


title: ACoRE: Accurate SARS-CoV-2 genome reconstruction for the characterization of intra-host and inter-host viral diversity in clinical samples and for the evaluation of re-infections

abstract: We report Accurate SARS-CoV-2 genome Reconstruction (ACoRE), an amplicon-based viral genome sequencing workflow for the complete and accurate reconstruction of SARS-CoV-2 sequences from clinical samples, including suboptimal ones that would usually be excluded even if unique and irreplaceable. We demonstrated the utility of the approach by achieving complete genome reconstruction and the identification of false-positive variants in >170 clinical samples, thus avoiding the generation of inaccurate and/or incomplete sequences. Most importantly, ACoRE was crucial to identify the correct viral strain responsible of a relapse case, that would be otherwise mis-classified as a re-infection due to missing or incorrect variant identification by a standard workflow.


title: Extraction of Viral Nucleic Acids with Carbon Nanotubes Increases SARS-CoV-2 RT-qPCR Detection Sensitivity

abstract:
The global SARS-CoV-2 coronavirus pandemic has led to a surging demand for rapid and efficient viral infection diagnostic tests, generating a supply shortage in diagnostic test consumables including nucleic acid extraction kits. Here, we develop a modular method for high-yield extraction of viral single-stranded nucleic acids by using  capture ssDNA sequences attached to carbon nanotubes. Target SARS-CoV-2 viral RNA can be captured by ssDNA-nanotube constructs via hybridization and separated from the liquid phase in a single-tube system with minimal chemical reagents, for downstream quantitative reverse transcription polymerase chain reaction (RT-qPCR) detection. This nanotube-based extraction method enables 100% extraction yield of target SARS-CoV-2 RNA from phosphate buffered saline in comparison to [~]20% extraction yield when instead using a commercial silica-column kit. Notably, carbon nanotubes enable extraction of nucleic acids directly from 50% human saliva, bypassing the need for further biofluid purification and avoiding the use of DNA/RNA extraction kits. Carbon nanotube-based extraction of viral nucleic acids facilitates high-yield and high-sensitivity identification of viral nucleic acids such as the SARS-CoV-2 viral genome with reduced reliance on reagents affected by supply chain obstacles.

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title: Oral ulcers of COVID-19 patients: a scoping review protocol

abstract:
ObjectiveThis scoping review aims to systematically identify the types, characteristics, and possible pathophysiologic etiologies of the oral ulcers that emerge in COVID-19 patients.

IntroductionThe oral cavity is a vulnerable niche for the most diverse microbial ecosystem in the human body; therefore, it presents a wide array of mucocutaneous complications that could indicate various acute and chronic conditions. The COVID-19-related oral conditions, including oral ulcers, had been widely debated as direct manifestations or indirect complications of the SARS-CoV-2 infection. According to a preliminary search of PROSPERO, MEDLINE, the Cochrane Database of Systematic Reviews and the JBI Evidence Synthesis, there is no published nor registered scoping review concerned with the oral ulcers of COVID-19 patients.

Inclusion criteriaThe review will include studies included COVID-19 patients whose infection had been confirmed by RT-PCR testing regardless of infection severity and clinical course. Only the studies that reported COVID-19 patients with oral ulcers.

MethodsA three-phase search strategy will be carried out: an initial limited search, a full electronic search, and hand search using the reference lists of all included records. The main bibliographic databases of published literature will include MEDLINE(R) (Ovid), EMBASE (Elsevier), and Cochrane COVID-19 Study Register. All identified records will be managed using EndNote 9.2, and the titles and abstracts will be screened against the inclusion criteria before the full text of all potentially relevant studies will be examined. The data will be presented in tabular form, rating maps, and narrative summary.

RegistrationThis protocol had been pre-registered in Open Science Framework (OSF) Registries.[1]

category: dentistry and oral medicine


title: Analysis of the number of deaths in Brazil between 2003 and 2020 and possible inferences about the COVID-19 pandemic and history of other diseases

abstract: This work explores data on the number of deaths in Brazil since the beginning of the historical series of IBGE, 2003, together with data for the period 2015-2020 of the Transparency Portal. The graphs for total deaths, deaths from violence and deaths in hospitals are discussed. The relationship between them leads to conclusions about the real dimension of the effect of COVID-19 in Brazilian society during the year 2020 and its relative importance to other diseases that had a lesser impact. Hypotheses are also made about the number of deaths in future years.

category: epidemiology


title: Projected spread of COVID-19's second wave in South Africa under different levels of lockdown

abstract: South Africa is currently experiencing a second wave of resurgence in COVID-19 infection. In this modelling study, we use a Bayesian compartmental model to project possible spread of the second wave of COVID-19 in South Africa under various levels of lockdown restrictions. Our model suggests that strict lockdown restrictions will have to be in place up to the end of March 2021 before cases can drop to levels observed, in September to early November 2020, after the first wave. On the one hand, extended lockdown restrictions have negative consequences - albeit effective, they are not sustainable over extended periods. On the other hand, short lockdown restrictions over a few weeks will not have a lasting effect on the spread of the disease. Lockdown restrictions need to be supplemented with increased rapid testing, palliative support for the vulnerable, and implementations of other non-pharmaceutical interventions (NPIs) such as mask mandate. These multifaceted approaches could help keep cases under control until vaccines are widely available.


title: Cohort Profile: The Birhan Health and Demographic Surveillance System

abstract:
The Birhan health and demographic surveillance system (HDSS) was established to determine the magnitude and causes of morbidity and mortality in Ethiopia among pregnant and postpartum women and children. Located in the North Shewa Zone of the Amhara Region, the site includes 16 kebeles (villages) and spans two woredas (districts), Angolela Tera and Kewet/Shewa Robit. The initial census was conducted in May 2018, and core demographic and health events are updated every three months. The site has 18,933 households and a population of 77,766. Over 82.6% of the population is rural.

During the baseline census, all households were geocoded; household members were enumerated; and data were collected on sociodemographic status, housing construction material, economics and asset ownership, care seeking behaviors, and water and sanitation access. During each subsequent round, data on key demographic events such as births, deaths, marital status changes, in-migration, or out-migration were collected for all enumerated household members. Pregnancy surveillance was conducted among married women of reproductive age 15-49 using a pregnancy screening questionnaire and confirmed by urine pregnancy tests. Morbidity and immunization status data for children aged under two years were collected during each round.


title: Estimating COVID-19 Cases on University Campuses Prior To Semester

abstract: For many institutions of higher learning, the beginning of each semester is marked by a significant migration of young adults into the area. In the midst of the COVID19 pandemic, this presents an opportunity for active cases to be introduced into a community. Prior to the Fall 2020 semester, Colorado State University researchers combined student home locations with recent case counts compiled by the New York Times to assign a probability to each individual of arriving with COVID19. These probabilities were combined to estimate that there would be 7.8 new cases among the on-campus population. Comprehensive testing of arriving students revealed 7 new cases, which validated the approach. The procedure was repeated to explore what could happen if students had returned to campus after Fall break. The estimate of 48 cases corroborated the Universitys early decision to transition to fully remote learning after break.


title: Agreement between state registry, health record, and self-report of influenza vaccination.

abstract:
BackgroundDocumentation of influenza vaccination, including the specific product received, is critical to estimate annual vaccine effectiveness (VE).

MethodsWe assessed performance of the Michigan Care Improvement Registry (MCIR) in defining influenza vaccination status relative to documentation by provider records or self-report among subjects enrolled in a study of influenza VE from 2011 through 2019.

ResultsThe specificity and positive predictive value of MCIR were high; however, >10% of vaccinations were identified only by other sources each season. The proportion of records captured by MCIR increased from a low of 67% in 2013-2014 to a high of 89% in 2018-2019, largely driven by increased capture of vaccination among adults.

ConclusionsState vaccine registries, such as MCIR, are important tools for documenting influenza vaccination, including the specific product received. However, incomplete capture suggests that documentation from other sources and self-report should be used in combination with registries to reduce misclassification.


title: Epidemic Overdispersion Strengthens the Effectiveness of Mobility Restrictions

abstract:
Human mobility is the fuel of global pandemics. In this simulation study, we analyze how mobility restrictions mitigate epidemic processes and how this mitigation is influenced by the epidemics degree of dispersion.

We find that (even imperfect) mobility restrictions are generally efficient in mitigating epidemic spreading. Notably, the effectiveness strongly depends on the dispersion of the offspring distribution associated with the epidemic. We also find that mobility restrictions are useful even when the pathogen is already prevalent in the whole population. However, also a delayed implementation is more efficient in the presence of overdispersion. Conclusively, this means that implementing green zones is easier for epidemics with overdispersed transmission dynamics (e.g., COVID-19). To study these relationships at an appropriate level of abstraction, we propose a spatial branching process model combining the flexibility of stochastic branching processes with an agent-based approach allowing a conceptualization of locality, saturation, and interaction structure.


title: Exploring domains, clinical implications and environmental associations of a deep learning marker of biological ageing

abstract:
Deep Neural Networks (DNN) have been recently developed for the estimation of Biological Age (BA), the hypothetical underlying age of an organism, which can differ from its chronological age (CA). Although promising, these population-specific algorithms warrant further characterization and validation, since their biological, clinical and environmental correlates remain largely unexplored.

Here, an accurate DNN was trained to compute BA based on 36 circulating biomarkers in an Italian population (N=23,858; age[≥]35 years; 51.7% women). This estimate was heavily influenced by markers of metabolic, heart, kidney and liver function. The resulting {Delta}age (BA-CA) significantly predicted mortality and hospitalization risk for all and specific causes. Slowed biological aging ({Delta}age<0) was associated with higher physical and mental wellbeing, healthy lifestyles (e.g. adherence to Mediterranean diet) and higher socioeconomic status (educational attainment, household income and occupational status), while accelerated aging ({Delta}age>0) was associated with smoking and obesity. Together, lifestyles and socioeconomic variables explained {square}48% of the total variance in {Delta}age, potentially suggesting the existence of a genetic basis.

These findings validate blood-based biological aging as a marker of public health in adult Italians and provide a robust body of knowledge on its biological architecture, clinical implications and potential environmental influences.


title: Assessing the lockdown effect from excess mortalities

abstract:
Background and AimsThe reported case numbers of COVID-19 are often used to estimate the growth rate of infections. We use the excess mortality instead to show the effect of most restrictive non-pharmaceutical interventions (mrNPIs) as compared to less restrictive NPIs (lrNPIs) concerning growth rate and death counts.

MethodsWe estimate the COVID-19 growth rate for Austria, France, Germany, Italy, Netherlands, South Korea, Spain, Sweden, UK and USA from the excess mortality. We use the average growth rate obtained for Sweden and South Korea, the only countries with lrNPIs only, to estimate additional death numbers in the other countries, had mrNPIs not been applied.

ResultsThe growth rate estimated from excess mortality decreased faster for countries with mrNPIs than for Sweden and South Korea, suggesting that the mrNPIs do have a non-negligible effect. Implementing lrNPIs instead of mrNPIs results in up to 3 times higher death numbers. This is not visible when the growth rate is calculated using the reported case numbers of COVID-19 instead of the excess mortality.

ConclusionThe conclusion for the spreading of COVID-19 obtained from reported COVID-19 cases in previous studies are most likely biased. Using our method, a more realistic estimate of the growth rate is obtained. Conclusions made for the reproduction number derived from the reported case numbers, such as the apparent insignificance of mrNPIs (lockdowns), might therefore be wrong and will have to be reevaluated using the growth rates obtained with our method.


title: Myelin pathology in ataxia-telangiectasia is the cell-intrinsic consequence of ATM deficiency in the oligodendrocytes

abstract: Ataxia-telangiectasia (A-T) is a rare genetic disease caused by mutations in the gene encoding the ATM (Ataxia-telangiectasia mutated) protein. Although neuronal degeneration in the cerebellum remains the most prominent sign in A-T, neuroimaging studies reveal myelin abnormalities as early comorbidities. We hypothesize that these myelin defects are the direct consequence of ATM deficiencies in the oligodendrocytes (OL) lineage. We examined samples from ten A-T brains in which the ATM mutations had been mapped by targeted genomic sequencing as well as samples from Atm-/- mice. In healthy human and wild type mouse cerebellum we confirmed the presence of ATM in white matter OLs. In A-T but not age-matched controls, a significant reduction in OL density was coupled with a massive astrogliosis. We found that the extent of this OL pathology was particularly strong in cases with frameshifts or premature termination ATM mutations. Similar pathologies were also found in Atm-/- mice in an age- and gene dose-dependent fashion. In vitro, DNA damage induced by etoposide-induced DSBs or blockade of ATM activity with KU-60019 differentially jeopardized cell cycle control in OL progenitors and mature OLs. Turning to structural analysis in silico, we identified likely interactions between ATM and myelin basic protein as well as myelin regulatory factor and confirm this by immunoprecipitation. These novel OL-specific functions of the ATM protein affect all stages of the OL lineage. They thus provide a cell biological basis for a direct role for ATM in central nervous system myelination and illustrate how the myelin pathology found in A-T is at least in part independent of neuronal degeneration.

category: pathology


title: Improving executive, behavioural and socio-emotional competences in very preterm young adolescents through a mindfulness-based intervention: study protocol and feasibility

abstract:
Background(VPT) children and adolescents exhibit executive, behavioural and socio-emotional difficulties that persists into adulthood. Previous research suggests that mindfulness-based intervention (MBI) may specifically target the development of theses competences. The objective of the current study is to describe the study protocol and to evaluate the feasibility of a clinical trial on a MBI program to enhance executive, behavioural and socio-emotional competences in a cohort of VPT young adolescents.

Methods164 VPT young adolescents from 10 to 14 years old, born before 32 gestational weeks, were invited to participate in an MBI program of 8 weekly sessions in groups of up to 8 participants, lasting 1h30. Participant were enrolled in a randomised controlled trial (RCT) or in a pre-post intervention designs depending of their availability. Satisfaction and attendance measures of the MBI were collected using self-reported questionnaires and registration of attendance.

ResultsOf the 63 participants who were enrolled in the study (38.2% of families invited to participate), 52 (82.5%) completed all assessments. Once enrolled, acceptability was high as shown by the high attendance rate in the sessions and the feedback evaluation questionnaire.

DiscussionTo our knowledge, this is the first study to investigate the feasibility of an MBI study in VPT born young adolescents. Our findings suggest that an MBI study is feasible and show a high acceptability among participants. The use of an RCT design in our study constitutes the gold standard for testing the efficacy of such intervention in VPT young adolescents. If effective, the MBI program could potentially be a valuable tool for improving executive, behaviour and socio-emotional competences in the vulnerable VPT population.

Trial registrationClinicalTrials, NCT04638101. Registered 19 November 2020 - Retrospectively registered, https://clinicaltrials.gov/show/NCT04638101.

category: pediatrics


title: Chest wall abnormalities in Swiss childhood cancer survivors

abstract:
BackgroundChest wall abnormalities are a poorly studied complication after treatment for childhood cancer. Chest wall abnormalities are not well described in the literature, and little is known on the impact on daily life of survivors.

MethodsWe investigated chest wall abnormalities in the nationwide, population-based cohort study (Swiss Childhood Cancer Survivor Study) with a questionnaire survey to describe prevalence and risk factors. We then interviewed a nested sample of survivors to understand types of chest wall abnormalities and their impact on daily life of survivors.

Results48 of 2,382 (95%CI 2%-3%) survivors reported a chest wall abnormality. Risk factors were older age at cancer diagnosis (16-20 years; OR 2.5, 95%CI 1.0- 6.1), lymphoma (OR 3.8, 95%CI 1.2-11.4), and central nervous system tumors (OR 9.5, 95%CI 3.0-30.1) as underlying disease, and treatment with thoracic radiotherapy (OR 2.0, 95%CI 1.0-4.2), surgery to the chest (OR 4.5, 95%CI 1.8-11.5), or chemotherapy (OR 2.9, 95%CI 1.0-8.1) .The nature of the chest wall abnormalities varied and included thoracic wall deformities (30%), deformations of the spine (5%) or both (55%), and scars (10%). Chest wall abnormalities affected the daily life in two thirds (13/20) of those who reported these problems, and 15 (75%) had required chest wall abnormalities-related medical attention.

ConclusionIt is important that during follow-up care physicians pay attention to chest wall abnormalities, which are rare late-effect of cancer treatment, but can considerably affect well-being of cancer survivors.


title: Preliminary Evidence on Long COVID in children

abstract:
There is increasing evidence that adult patients diagnosed with acute COVID-19 suffer from Long COVID initially described in Italy.

To date, data on Long COVID in children are lacking.

We assessed persistent symptoms in pediatric patients previously diagnosed with COVID-19. More than a half reported at least one persisting symptom even after 120 days since COVID-19, with 42.6% being impaired by these symptoms during daily activities. Symptoms like fatigue, muscle and joint pain, headache, insomnia, respiratory problems and palpitations were particularly frequent, as also described in adults.

The evidence that COVID-19 can have long-term impact children as well, including those with asymptomatic/paucisymptomatic COVID-19, highlight the need for pediatricians, mental health experts and policy makers of implementing measures to reduce impact of the pandemic on childs health.


title: Attention Deficit and Hyperactivity Disorder and Enuresis co-occurrence in the pediatric population: a systematic review and meta-analysis

abstract:
BackgroundAttention Deficit and Hyperactivity/Impulsivity Disorder (ADHD) and Enuresis are common behavioral disorders in childhood, impacting in adolescence and adult life.

ObjectiveWe systematically search the literature to verify the relationship between ADHD and enuresis and how these conditions can modify each other during development.

MethodUsing PRISMA guidelines, we tried to answer the following question: How frequent is ADHD and Enuresis comorbidity?

ResultsTwenty-five studies were fully read and show similar rates of ADHD in the Enuretic group than the frequency of Enuresis in the ADHD group. There is a two-times higher risk to have both conditions simultaneously.

ConclusionEnuresis and ADHD seems to happen as a continuous of the same spectrum. Further studies are necessary to evaluate if gender, age, course and presence of comorbidities are similar in patients with both conditions in comparison to those with only one of these conditions.


title: Validation of the short Mood and Feelings Questionnaire in young adulthood

abstract:
BackgroundDepression often onsets in adolescence and is associated with recurrence in adulthood. There is a need to identify and monitor depression symptoms across adolescence and into young adulthood. The short Mood and Feelings Questionnaire (sMFQ) is commonly used to measure depression symptoms in adolescence but has yet to be validated in young adulthood. This study aimed to (1) examine whether the sMFQ is a valid assessment of depression in young adults, and (2) identify cut-points that best capture a DSM-5 diagnosis of depression at age 25.

MethodsThe sample included young people who took part in the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 25 (n=4098). Receiver Operating Characteristic analyses were used to examine how well the self-rated sMFQ discriminates between cases and non-cases of DSM-5 Major Depressive Disorder (MDD) classified using the self-rated Development and Well Being Assessment. Sensitivity and specificity values were used to identify cut-points on the sMFQ.

ResultsThe sMFQ had high accuracy for discriminating MDD cases from non-cases at age 25. The commonly used cut-point in adolescence ([≥]12) performed well at this age, best balancing sensitivity and specificity. However, a lower cut-point ([≥]10) may be appropriate in some contexts, e.g. for screening, when sensitivity is favoured over specificity.

LimitationsALSPAC is a longitudinal population cohort that suffers from non-random attrition.

ConclusionsThe sMFQ is a valid measure of depression in young adults in the general population. It can be used to screen for and monitor depression across adolescence and early adulthood.

category: psychiatry and clinical psychology


title: Patients with Asthma and Chronic Obstructive Pulmonary Disease (COPD) have increased levels of plasma inflammatory mediators upregulated in severe COVID-19

abstract:
BackgroundChronic obstructive pulmonary disease (COPD) is associated with increased risk of severe COVID-19, but the mechanisms are unclear. Besides, patients with severe COVID-19 have been reported to have increased levels of several immune mediators.

ObjectiveTo perform an immunoproteomic profiling of dysregulated plasma proteins in patients with asthma and COPD and to evaluate their relationship with biomarkers of severe COVID-19.

MethodsNinety-two proteins were quantified in 315 plasma samples from adult subjects (age 40-90 years) including 118 asthmatics, 99 COPD patients and 98 healthy controls, that have been recruited in two reference pneumology clinics in Colombia before the beginning of the COVID-19 pandemic. Protein levels were compared between each disease group and healthy controls.

Significant proteins were compared to the gene signatures of SARS-CoV-2 infection reported in the "COVID-19 Drug and Gene Set Library" and with known protein biomarkers of severe COVID-19.

ResultsForty-one plasma proteins showed differences between patients and controls. Asthmatic patients have increased levels in IL-6 while COPD patients have a broader systemic inflammatory dysregulation driven by HGF, OPG, and several chemokines (CXCL9, CXCL10, CXCL11, CX3CL1, CXCL1, MCP-3, MCP-4, CCL3, CCL4 and CCL11). These proteins are involved in chemokine signaling pathways related with response to viral infections and some, were found up-regulated upon SARS-CoV-2 experimental infection of Calu-3 cells as reported in the COVID-19 Related Gene Sets database. An increase of HPG, CXCL9, CXCL10, IL-6, MCP-3, TNF and EN-RAGE has also been found in patients with severe COVID-19.

ConclusionsCOPD patients have altered levels of plasma proteins that have been reported increased in patients with severe COVID-19. Our study suggests that COPD patients have a systemic dysregulation in chemokine networks (including HGF and CXCL9) that could make them more susceptible to severe COVID-19. Our study also suggest that IL-6 levels are increased in some asthmatics and this may influence their immune response to COVID-19.

category: respiratory medicine


title: Barriers and facilitators to cross-sector workforce competency assessment in the care of older people residing in care homes

abstract: In recent years, transformation in care delivery towards cross-sector models has occurred with the aim of providing safe, efficient care for older people with complex needs, including those living in care homes. Effective workforce competency development and assessment across sectors is integral to these models. However, there is much evidence to suggest a distinct lack of cross-sector alignment with regard to competency development and assessment, which could lead to variations in practice and affect outcomes for older people. This qualitative study explored the barriers and facilitators to cross-sector workforce competency assessment in the care of older people residing in care homes. Twenty nine staff with responsibility for staff learning and development participated. Data were analysed using Braun and Clarkes (2006) six phase thematic analysis approach. Findings indicate that a significant challenge to the development of a competent workforce is evidencing competency, due to difficulties in finding appropriate assessors and inconsistencies in the assessment process. Findings also indicate potential solutions including: a system-wide, standardised framework and strategy for assessment of competence; policy for the  sign-off of competencies that is recognised across organisational boundaries; and adopting practice-based approaches to competence development and assessment.

category: medical education


title: Longevity of SARS-CoV-2 immune responses in haemodialysis patients and protection against reinfection

abstract:
BackgroundPatients with end stage kidney disease (ESKD) receiving in-centre haemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. Following infection, ICHD patients frequently develop serological evidence of infection, even with asymptomatic disease. The aim of this study is to investigate the durability and functionality of immune responses to SARS-CoV-2 infection in ICHD patients.

MethodsThree hundred and fifty-six ICHD patients were longitudinally screened for SARS-CoV-2 antibodies and underwent routine PCR-testing for symptomatic and asymptomatic infection. Patients were screened for nucleocapsid protein (anti-NP) and receptor binding domain (anti-RBD) antibodies. Patients who became seronegative at 6 months were investigated for SARS-CoV-2 specific T-cell responses.

ResultsOne hundred and twenty-nine (36.2%) patients had detectable antibody to anti-NP at Time 0, of which 127 (98.4%) also had detectable anti-RBD. At 6 months, of 111 patients tested, 71(64.0%) and 97 (87.4%) remained anti-NP and anti-RBD seropositive respectively, p<0.001. For patients who retained antibody, both anti-NP and anti-RBD levels reduced significantly after 6 months. Ten patients who were anti-NP and anti-RBD seropositive at Time 0, had no detectable antibody at 6 months; of which 8 were found to have SARS-CoV-2 antigen specific T cell responses.

Independent of antibody status at 6 months, patients with baseline positive SARS-CoV-2 serology were significantly less likely to have PCR confirmed infection over the following 6 months.

ConclusionsICHD patients mount durable immune responses 6 months post SARS-CoV-2 infection, with <3% of patients showing no evidence of humoral or cellular immunity. These immune responses are associated with a reduced risk of subsequent reinfection.

SIGNIFICANCE STATEMENTFollowing infection with SARS-CoV-2, patients with end stage kidney disease (ESKD) frequently develop serological evidence of infection, even with asymptomatic disease. Patients with ESKD receiving in-centre haemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. What is not known is how durable the serological responses in ESKD patients are or whether evidence of prior immune responses protect patients from reinfection. In this study of 356 ICHD patients, at 6 months following the detection of SARS-CoV-2 antibodies, fewer than 3% of patients lacked evidence of either humoral or cellular immunity. Furthermore, patients with serological evidence of infection had a significantly lower risk of being diagnosed with subsequent infection or  reinfection, suggesting functional immune protection.


title: A Genetic Risk Score for Glioblastoma Multiforme Based on Copy Number Variations.

abstract:
Glioblastoma multiforme is the most common form of brain cancer. Several lines of evidence suggest that glioblastoma multiforme has a genetic basis. A genetic test that could identify people who are at high risk of developing glioblastoma multiforme could improve our understanding of this form of brain cancer.

Using the Cancer Genome Atlas (TCGA) dataset, we found common germ line DNA copy number variations in the TCGA population. We tested whether different sets of these germ line DNA copy number variations could effectively distinguish patients with glioblastoma multiforme from others in the TCGA dataset. We used a gradient boosting machine, a machine learning classification algorithm, to classify TCGA patients solely based on a set of germline DNA copy number variations.

We found that this machine learning algorithm could classify TCGA glioblastoma multiforme patients from the other TCGA patients with an area under the curve (AUC) of the receiver operating characteristic curve (AUC=0.875). Grouped into quintiles, the highest ranked quintile by the machine learning algorithm had an odds ratio of 3.78 (95% CI 3.25-4.40) higher than the average odds ratio and about 40 (95% CI 20-70) times higher than the lowest quintile.

The identification of an effective germ line genetic test to stratify risk of developing glioblastoma multiforme should lead to a better understanding of how this cancer forms. This result might ultimately lead to better treatments of glioblastoma multiforme.


title: S-ketamine in patient-controlled analgesia with oxycodone improves analgesia in a dose-dependent manner after major lumbar fusion surgery: a randomized, double-blind, placebo-controlled clinical trial

abstract:
BACKGROUNDSpinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown.

METHODSWe randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery.

RESULTSOf the 100 patients analyzed, patients receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml-1 (74.7 mg) or 0.25 mg ml-1 (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013-0.32, P = 0.033). The occurrence of adverse events was similar among the groups.

CONCLUSIONSOxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects.

category: pain medicine


title: S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: a randomized, double-blind, placebo-controlled clinical trial


title: Genetic overlap between Alzheimer's disease and depression mapped onto the brain

abstract:
BackgroundAlzheimers disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterizing their genetic overlap may provide etiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects.

MethodsWe applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD (n=79,145) and depression (n=450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (mean age 57.21 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data.

ResultsMiXer estimated 98 causal genetic variants overlapping between the two disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD (B=-0.002, p=9.1x10-4) and depression (B=0.007, p=3.2x10-9) in the UK Biobank. This SNP was also associated with several regions of the corpus callosum volume anterior (B>0.024, p<8.6x10-4), third ventricle volume ventricle (B=-0.025, p=5.0x10-6), and inferior temporal gyrus surface area (B=0.017, p=5.3x10-4).

DiscussionOur results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders.


title: Counterfactual inference for single-cell gene expression analysis

abstract: Finding a causal gene is a fundamental problem in genomic medicine. We present a causal inference framework that prioritizes disease genes by adjusting confounders without prior knowledge of control variables. We demonstrate that our method substantially improves statistical power in simulations and real-world data analysis of 70k brain cells collected for dissecting Alzheimers disease. We identified that 215 causal genes are differentially regulated by the disease in various cell types, including highly relevant genes with a proper cell type context. Genes found in different types enrich distinctive pathways, implicating the importance of cell types in understanding multifaceted disease mechanisms.


title: Single nuclei profiling identifies cell specific markers of skeletal muscle aging, sarcopenia and senescence

abstract: Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia include inflammation, muscle stem cell depletion, mitochondrial dysfunction and loss of motor neurons, but whether there are key drivers of sarcopenia is not yet known. To gain deeper insights into age-related sarcopenia, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, old and sarcopenic subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed novel changes in gene expression that occur with age and sarcopenia in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in old muscle. We validated key genes in fixed human muscle tissue using digital spatial profiling. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21-driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related sarcopenia.

category: geriatric medicine


title: Why is the Vaccination Rate Low in India?

abstract: Why does the vaccination rate remain low, even in countries where long-established immunization programs exist, and vaccines are provided for free? We study this lower vaccination paradox in the context of India--which contributes to the largest pool of under-vaccinated children in the world and about one-third of all vaccine-preventable deaths globally. We explore the importance of historical events shaping current vaccination practices. Combining historical records with survey datasets, we examine the Indian governments forced sterilization policy implemented in 1976-77 and find that greater exposure to forced sterilization has had a large negative effect on the current vaccination completion rate. We explore the mechanism for this practice and find that institutional delivery and antenatal care are low in states where policy exposure was high. Finally, we examine the consequence of lower vaccination, suggesting that child mortality is currently high in states with greater sterilization exposure. Together, the evidence suggests that government policies implemented in the past could have persistent impacts on adverse demand for health-seeking behavior, even if the burden is exceedingly high.

category: health economics


title: Assessment of the knowledge, preferences and concern regarding the prospective COVID- 19 vaccine among adults residing in New Delhi, India-A cross-sectional study.

abstract:
BackgroundUnderstanding the perception and concerns of people about COVID-19 vaccine in developing and populous country like India will help in understanding demand for the vaccine and further tailoring out public health information and education activities before the launch of the vaccine. The study was carried out to assess the present state of knowledge people have about the probable vaccine for COVID-19, to know the preferences of respondents about this vaccine and to learn the expectations and apprehensions of people about features of this prospective COVID-19 vaccine residing in the capital city of India.

MethodsThis cross-sectional study was conducted amongst the residents of Delhi, India from July-October 2020. Both offline and online interview method was used to collect date from 513 participants representing various occupational strata. Data was collected on socio demographic variable, vaccine acceptance and concerns regarding COVID-19 vaccine.

ResultsAmong the study population 79.5% said they will take the vaccine while 8.8% said they were not going to take the vaccine and remaining 11.7% had not yet decided about it. Most of them(78.8%),believed that vaccine would be available to public next year but at the same time half(50.1%) of them believe that it may not be in sufficient amount for everyone to get. More than 50% were willing to pay for the vaccine and 72% felt vaccine should first be given to health workers and high risk group.

ConclusionThe following study has helped to understand the percentage of people who are hesitant to take the vaccine and also the concerns regarding the vaccine. Also since half of the population is willing to pay for the vaccine, a strategical approach considering the various economical classes of people could be applied in a developing country like India.


title: Identification of COVID-19 Subtypes Based on Immunogenomic Profiling

abstract: Although previous studies have shown that the host immune response is crucial in determining clinical outcomes in COVID-19 patients, the association between host immune signatures and COVID-19 patient outcomes remains unclear. Based on the enrichment levels of 11 immune signatures (eight immune-inciting and three immune-inhibiting signatures) in leukocytes of 100 COVID-19 patients, we identified three COVID-19 subtypes: Im-C1, Im-C2, and Im-C3, by clustering analysis. Im-C1 had the lowest immune-inciting signatures and high immune-inhibiting signatures. Im-C2 had medium immune-inciting signatures and high immune-inhibiting signatures. Im-C3 had the highest immune-inciting signatures while the lowest immune-inhibiting signatures. Im-C3 and Im-C1 displayed the best and worst clinical outcomes, respectively, suggesting that antiviral immune responses alleviated the severity of COVID-19 patients. We further demonstrated that the adaptive immune response had a stronger impact on COVID-19 outcomes than the innate immune response. The patients in Im-C3 were younger than those in Im-C1, indicating that younger persons have stronger antiviral immune responses than older persons. Nevertheless, we did not observe a significant association between sex and immune responses in COVID-19 patients. In addition, we found that the type II IFN response signature was an adverse prognostic factor for COVID-19. Our identification of COVID-19 immune subtypes has potential clinical implications for the management of COVID-19 patients.


title: TCA cycle remodeling is associated with IL-1β-mediated proinflammatory eicosanoid signaling in humans with pulmonary tuberculosis

abstract:
The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1{beta}-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the pro-inflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1{beta} were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates are important drivers of IL-1{beta}-mediated proinflammatory eicosanoid signaling in humans with pulmonary TB disease. Host-directed therapies that mitigate such metabolic reprograming have potential to limit pulmonary inflammation and tissue damage.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/21250380v2_ufig1.gif" ALT="Figure 1">
View larger version (25K):
org.highwire.dtl.DTLVardef@1ee7e7dorg.highwire.dtl.DTLVardef@b247b0org.highwire.dtl.DTLVardef@8086a2org.highwire.dtl.DTLVardef@7109b_HPS_FORMAT_FIGEXP  M_FIG C_FIG One Sentence SummaryRemodeling of the tricarboxylic acid cycle, characterized by increases in the proinflammatory metabolite succinate and decreased itaconate, mediates proinflammatory eicosanoids signaling in humans with pulmonary tuberculosis through induction of IL-1{beta}.


title: TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis


title: Pooled Sample Testing for SARS-CoV-2

abstract: We tested an operationally efficient way to pool samples on a rapid, point-of-care PCR device and examined the limit of detection of SARS-CoV-2 for various pool sizes. Pooled testing maintained testing performance similar to individual sample PCR testing, offering the potential for scalable rapid testing at lower cost with less supplies.


title: CovidArray: a microarray-based assay with high sensitivity for the detection of SARS-CoV-2 in nasopharyngeal swabs

abstract:
BackgroundA new coronavirus (SARS-CoV-2) caused the current Covid-19 epidemic. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is used as the gold standard for clinical detection of SARS-CoV-2. Under ideal conditions RT-qPCR Covid-19 assays have analytical sensitivity and specificity greater than 95%. However, when the sample panel is enlarged including asymptomatic individuals, the sensitivity decreases and false-negative are reported. Moreover, RT-qPCR requires up to 3-6 hours with most of the time involved in RNA extraction from swab samples.

MethodsWe introduce CovidArray, a microarray-based assay, to detect SARS-CoV-2 markers N1 and N2 in the nasopharyngeal swabs. The method is based on solid phase hybridization of fluorescently labelled amplicons upon RNA extraction and reverse transcription. This approach combines the physical-optical properties of the silicon substrate with the surface chemistry used to coat the substrate to obtain a diagnostic tool of great sensitivity. Furthermore, we used an innovative approach, RNAGEM, to extract and purify viral RNA in less than 15 minutes. To validate the CovidArray results, we exploited the high sensitivity of the droplet digital PCR (ddPCR) technique.

ResultWe correctly assigned 12 nasopharyngeal swabs, previously analyzed by RT-qPCR. Thanks to the CovidArray sensitivity that matches that of the ddPCR, we were able to identify a false-negative sample.

ConclusionsCovidArray is the first DNA microarray-based assay to detect viral genes in the swabs. Its high sensitivity and the innovative viral RNA extraction by RNAGEM allows to reduce both the amount of false negative results and the total analysis time to about 2 hours.


title: Chinese medicine (Q-14) in the Treatment of Patients with Coronavirus Disease 2019 (COVID-19): A Single-center, Open label, Randomised Controlled Trial

abstract:
OBJECTIVETo evaluate the efficacy and safety of Chinese medicine (Q-14) plus standard care compared with standard care alone in adult with coronavirus disease 2019 (COVID-19).

Study DESIGNSingle-center, open label, randomised controlled trial.

SETTINGWuhan Jinyintan Hospital, Wuhan, China, February 27 to March 27, 2020.

PARTICIPANTS204 patients with laboratory confirmed COVID-19 were randomised in to treatment group and control group, which was 102 patients each group.

INTERVENTIONSIn treatment group, Q-14 was administrated at 10g (granules), twice daily for 14 days and plus standard care. In control group, patients were given standard care alone for 14 days.

MAIN OUTCOME MEASUREThe primary outcome was conversion time of SARS-CoV-2 viral assay. Adverse events were analyzed in the safety population.

RESULTSAmong 204 patients, 195 were analyzed according to the intention to treat principle. There were 149 patients (71 vs. 78 in treatment group and control group respectively) turning to negative via SARS-CoV-2 viral assay. No statistically significance showed in conversion time between treatment group and control group (FAS: Median (IQR): 10.00 (9.00-11.00) vs. 10.00 (9.00-11.00); Mean rank: 67.92 vs. 81.44; P=0.051.). Time to recovery of fever was shorter in treatment group as compared in control group. The disappearance rate of symptom in cough, fatigue, chest discomfort was significantly higher in treatment group. In chest computed tomography (Chest CT) examinations, overall evaluation of chest CT examination after treatment compared with baseline showed more patients improved in treatment group .There were no significant differences in the other outcomes.

CONCLUSIONAdministration of Q-14 on standard care for COVID-19 was useful for improvement of symptoms (such as fever, cough, fatigue and chest discomfort), while did not result in a significantly higher probability of negative conversion of SARS-CoV-2 viral assay. No serious adverse events were reported.

TRIAL REGISTRATIONChiCTR2000030288


title: Two original observations concerning bacterial infections in COVID-19 patients hospitalized in intensive care units during the first wave of the epidemic in France

abstract: Among 197 COVID-19 patients hospitalized in ICU, 88 (44.7%) experienced at least one bacterial infection, with pneumonia (39.1%) and bloodstream infections (15,7%) being the most frequent. Unusual findings include frequent suspicion of bacterial translocations originating from the digestive tract as well as bacterial persistence in the lungs despite adequate therapy.


title: Ultrasensitive measurement of both SARS-CoV2 RNA and serology from saliva

abstract: Tests for COVID-19 generally measure SARS-CoV2 viral RNA from nasal swabs or antibodies against the virus from blood. It has been shown, however, that both viral particles and antibodies against those particles are present in saliva, which is more accessible than both swabs and blood. We present methods for highly sensitive measurements of both viral RNA and serology from the same saliva sample. We developed an efficient saliva RNA extraction method and combined it with an ultrasensitive serology test based on Single Molecule Array (Simoa) technology. We apply our test to the saliva of patients who presented to the hospital with COVID-19 symptoms, some of whom tested positive with a conventional RT-qPCR nasopharyngeal swab test. We demonstrate that combining viral RNA detection by RT-qPCR with serology identifies more patients as infected than either method alone. Our results suggest the utility of combining viral RNA and serology testing from saliva, a single easily accessible biofluid.


title: SARS-CoV-2 RNA screening in routine pathology specimens

abstract:
Virus detection methods are important to cope with the SARS-CoV-2 pandemics. Apart from the lung, SARS-CoV-2 was detected in multiple organs in severe cases. Less is known on organ tropism in patients developing mild or no symptoms, and some of such patients might be missed in symptom-indicated swab testing.

Here we tested and validated several approaches and selected the most reliable RT-PCR protocol for the detection of SARS-CoV-2 RNA in patients routine diagnostic formalin-fixed and paraffin-embedded (FFPE) specimens available in pathology, to assess a) organ tropism in samples from COVID-19-positive patients, b) unrecognized cases in selected tissues from negative or not-tested patients during a pandemic peak, and c) retrospectively, pre-pandemic lung samples.

We identified SARS-CoV-2 RNA in four samples from confirmed COVID-19 patients, in two gastric biopsies, one colon resection, and one pleural effusion specimen, while all other specimens, particularly from patients with mild COVID-19 disease course, were negative. In the pandemic peak cohort, we identified one previously unrecognized COVID-19 case in tonsillectomy samples. All pre-pandemic lung samples were negative.

In conclusion, SARS-CoV-2 RNA detection in FFPE pathology specimens can potentially improve surveillance of COVID-19, allow retrospective studies, and advance our understanding of SARS-CoV-2 organ tropism and effects.


title: Genomic Epidemiology of SARS-CoV-2 in Esteio, Rio Grande do Sul, Brazil

abstract: Brazil is the third country most affected by Covid-19 pandemic. In spite of this, viral evolution in municipality resolution is poorly understood in Brazil and it is crucial to understand the epidemiology of viral spread. We identified four main circulating lineages in Esteio (Southern Brazil) and their relationship with global, national and regional lineages using phylogenetics and phylodynamics inferences from 21 SARS-CoV-2 genome sequences. We provided a comprehensive view of viral mutations from a time- and age-representative sampling from May to October 2020, in Esteio (RS, Brazil), highlighting two frequent mutations in Spike glycoprotein (D614G and V1176F), an emergent mutation (E484K) in Spike Receptor Binding Domain (RBD) characteristic of the South African lineage B.1.351, and the adjacent replacement of 2 amino acids in Nucleocapsid phosphoprotein (R203K and G204R). A significant viral diversity was evidenced with the identification of 80 different SNPs. The E484K replacement was found in two genomes (9.5%) from samples obtained in mid-October, which is to our best knowledge the earliest description of E484K harboring SARS-CoV-2 in South Brazil. This mutation identified in a small municipality from the RS state demonstrates that it was probably widely distributed in the Brazilian territory, but went unnoticed so far by the lack of genomic surveillance in Brazil. The introduction of E484K mutants shows temporal correlation with later increases in new cases in our state. Importantly, since it has been associated with immune evasion and enhanced interaction with hACE-2, lineages containing this substitution must be the subject of intense surveillance. Our date demonstrates multiple introductions of the most prevalent lineages (B.1.1.33 and B.1.1.248) and the major role of community transmission in viral spreading and the establishment of Brazilian lineages. This represents an important contribution to the epidemiology of SARS-CoV-2.


title: Personalized and dynamic antibiograms-an exploration in seven infectious syndromes

abstract: To prevent antimicrobial resistance and inform better, antibiograms should distinguish different biomedical situations. It is also desirable that new antibiograms provide in vivo, temporal, and patient-specific immunological information. Here, the informative ability of a pattern recognition-based method was explored with data collected from patients that experienced seven infectious syndromes (pneumonia, endocarditis, tuberculosis, syphilis, as well as skin and soft tissue, intra-abdominal, and/or urinary tract infections associated with meningitis). Interactions among seven dimensions (7D) were investigated: (i) space, (ii) time, (iii) temporal data directionality, (iv) immunological multicellularity, (v) antibiotics, (vi) immunomodulation, and (vii) personalized data. Omissions and ambiguity (confounding different biological situations) occurred when static metrics were used in isolation, such as leukocyte percentages. In contrast, hidden information was uncovered when complexity and dynamics were assessed. The 7D approach grouped together observations that displayed similar immune profiles and identified antibiotics that modulated specific leukocytes. For instance, in tuberculosis, blood monocytes were modulated by isoniazid-related antimicrobials. In spite of the diverse syndromes analyzed, this proof-of-concept discriminated. It is suggested that the simultaneously exploration of numerous dimensions associated with complexity may be biologically interpretable, prevent ambiguity, promote research, expand machine learning-oriented methods, and support personalized medicine.


title: Magnitude and timing of the antiviral response determine SARS-CoV-2 replication early in infection

abstract: The interferon response is a potent antiviral defense mechanism, but its effectiveness depends on its timing relative to viral replication. Here, we report viral replication and host response kinetics in patients at the start of SARS-CoV-2 infection and explore the impact of these kinetics experimentally. In both longitudinal patient nasopharyngeal samples and airway epithelial organoids, we found that SARS-CoV-2 initially replicated exponentially with a doubling time of [~]6hr, and induced interferon stimulated genes (ISGs) with delayed timing relative to viral replication. Prior exposure to rhinovirus increased ISG levels and blocked SARS-CoV-2 replication. Conversely, inhibiting ISG induction abrogated interference by rhinovirus and enhanced SARS-CoV-2 replication rate. These results demonstrate the importance of initial interferon-mediated defenses in determining the extent to which SARS-CoV-2 can replicate at the start of infection and indicate that biological variables that alter the airway interferon response, including heterologous induction of innate immunity by other viruses, could profoundly impact SARS-CoV-2 susceptibility and transmission.


title: Dynamic change and clinical relevance of post-infectious SARS-CoV-2 antibody responses.

abstract:
BackgroundAlthough reports suggest that most individuals with COVID-19 develop detectable antibodies post infection, the kinetics, durability, and relative differences between IgM and IgG responses beyond the first few weeks after symptom onset remain poorly understood.

MethodsWithin a large, well-phenotyped, diverse, prospective cohort of subjects with and without SARS-CoV-2 PCR-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity and specificity, relationship with disease severity and mapped the kinetics of antibody responses over time using generalised additive models.

ResultsWe analysed 1,001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1-47.1%) early (<10 days) after symptom onset but increased to >80% after 10 days. IgM positivity increased earlier than IgG-targeted assays but positivity peaked between day 32 and 38 post onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analysed, with more rapid decline observed with IgM. Early (<10 days) IgM but not IgG levels were significantly higher in those who subsequently developed severe disease (signal / cut-off 4.20 (0.75-17.93) versus 1.07 (0.21-5.46), P=0.048).

ConclusionsThis study suggests that post-infectious antibody responses in those with confirmed COVID-19 begin to decline relatively early post infection and suggests a potential role for higher IgM levels early in infection predicting subsequent disease severity.


title: Hydroxychloroquine and azithromycin: As a double edge sword for COVID-19?

abstract:
BackgroundHydroxychloroquine with or without azithromycin was one of the common therapies at the beginning of the COVID-19 pandemic. They can prolong QT interval, cause Torsade de pointes, and lead to sudden cardiac death. We aimed to assess QT interval prolongation and its risk factors in patients who received hydroxychloroquine with or without azithromycin.

MethodsThis was a retrospective cohort study. 172 patients with COVID-19 included, hospitalized at hospitals of Babol University of Medical Sciences between March 5, 2020, and April 3, 2020. Patients were divided into two groups: hydroxychloroquine alone and hydroxychloroquine with azithromycin. Electrocardiograms were used for outcome assessment.

Results83.1% of patients received hydroxychloroquine plus azithromycin vs 16.9% of patients who received only hydroxychloroquine. The mean age of patients was 59.2 {+/-} 15.4. The mean of post-treatment QTc interval in the monotherapy group was shorter than the mean of post-treatment QTc interval in the combination therapy group but it had no significant statistical difference (462.5 {+/-} 43.1 milliseconds vs 464.3 {+/-} 59.1 milliseconds; P = 0.488). Generally, 22.1% of patients had a prolonged QTc interval after treatment. Male gender, or baseline QTc [≥] 450 milliseconds, or high-risk Tisdale score increased the likelihood of prolonged QTc interval. Due to QTc prolongation, 14 patients did not continue therapy after 4 days.

ConclusionHospitalized patients treated with hydroxychloroquine with or without azithromycin, had no significant difference in prolongation of QT interval and outcome. But the number of patients with prolonged QT intervals in this study emphasizes careful cardiac monitoring during therapy; especially in high-risk patients.

category: cardiovascular medicine


title: A Reproducible Protocol to Assess Arrhythmia Vulnerability in Silico: Pacing at the End of the Effective Refractory Period

abstract: In both clinical and computational studies, different pacing protocols are used to induce arrhythmia and non-inducibility is often considered as the endpoint of treatment. The need for a standardized methodology is urgent since the choice of the protocol used to induce arrhythmia could lead to contrasting results, e.g., in assessing atrial fibrillation (AF) vulnerabilty. Therefore, we propose a novel method - pacing at the end of the effective refractory period (PEERP) - and compare it to state-of-the-art protocols such as phase singularity distribution (PSD) and rapid pacing (RP) in a computational study. All methods were tested by pacing from 227 evenly distributed endocardial points in a bi-atrial geometry. 6 different atrial models were implemented: 4 cases without specific AF-induced remodelling but with decreasing global conduction velocity and 2 persistent AF cases with an increasing amount of fibrosis resembling different substrate remodeling stages. Compared with PSD and RP, PEERP induced a larger variety of arrhythmia complexity requiring, on average, only 2.7 extra-stimuli and 3 s of simulation time to initiate reentry. Moreover, PEERP and PSD were the protocols which unveiled a larger number of areas vulnerable to sustain stable long living reentries compared to RP. Finally, PEERP can foster standardization and reproducibility, since, in contrast to the other protocols, it is a parameter-free method. Furthermore, we discuss its clinical applicability. We conclude that the choice of the inducing protocol has an influence on both initiation and maintenance of AF and we propose and provide PEERP as a reproducible method to assess arrhythmia vulnerability.


title: Assessment of The Relationship of REMS and MEWS Scores with Prognosis in Patients Diagnosed with Covid-19 Admitted to the Emergency Department

abstract:
AimWith the rapid and global increase in COVID-19 cases, it is becoming important to identify patients with a risk of mortality and patients that need hospitalization. The aim of this study is to try to predict the mortality rate of COVID patients admitted to the emergency department with rapid scoring systems such as REMS and MEWS and their clinical termination in the emergency department at the end of the first month.

MethodWe have designed this study to be a single-centered, prospective and an observational study. A total of 392 patients diagnosed with COVID-19, who were admitted to the emergency department in a 1-month period, were included in the study. REMS and MEWS scores were calculated for each case. Demographic data of patients, clinical outcomes such as discharge, service hospitalization, ICU hospitalization, and first-month mortality were analysed based on these scores. ROC curves were analysed to determine the cut-off value with the help of which REMS and MEWS scores can predict 1-month mortality and hospitalization.

ResultsOut of the 392 patients included in the study, the 43.4% (n=170) were female and 56.6% (n=222) were male. The average age of our patients was 48.98{+/-}19.49 years. The 1-month mortality rate of our patients was 4.3% (n=17). At the end of the first month, the mortality of patients with a comorbid disease was higher than those who did not (p<0.01). The average of the REMS score was higher in patients with an average mortality of (7.24{+/-}3.77) than in patients without it (2.87{+/-}3.09), and there was a statistically significant difference between them (p<0.01). Similarly, the average of the MEWS score was higher in patients with an average mortality of (2.76{+/-}1.86) than in patients without it (1.65{+/-}1.35), and there was a statistically significant difference (p<0.01). The REMS score of patients admitted to the service was higher than that of patients discharged (p<0.01). When the REMS score was determined as 3 cut-off value in ROC analysis, service hospitalization was 5 times higher in patients with a REMS score of 3 and above than in those who were discharged (OR: 1:5.022 95% CI: 3.088-8.168)). REMS and MEWS scores were also higher in ICU patients than in discharged patients (p<0.01).

ConclusionIn predicting the 1-month mortality of ER patients diagnosed with COVID-19, REMS and MEWS scoring systems can be useful and guiding in determining the patients who need hospitalization for emergency physicians. The use of these scoring systems in emergency departments can help predict the clinical outcomes of patients at the time of the initial evaluation, and can also be a practical method of predicting the prognosis of the patients.

category: emergency medicine


title: Prevalence of Iron Deficiency, Iron Deficiency Anaemia and General Anaemia in Male Gambian Blood Donors Residing in Greater Banjul Region

abstract:
ObjectiveThe objective of this study is to determine the prevalence of iron deficiency (ID) and iron deficiency anaemia (IDA) as well as general anaemia in male blood donors and their association with ageing process.

Methodology and ResultsA total of two hundred and one (201) serum samples were analysed for ferritin in male Gambian blood donors. The ferritin measurement was achieved with COBAS(R) INTEGRA 400 plus. At the same time, haemoglobin values were retrospectively obtained from the archived haematological full blood count result in the GARIS database. IDA was defined as (Haemoglobin <13.0g/dL+ Ferritin<15ng/ml) whilst ID was defined as (Haemoglobin [≥]13.0g/dL+ Ferritin<15ng/ml) and general anaemia was defined as haemoglobin <13.0g/dL in males. The prevalence of anaemia (20%, n=41), ID (22%, n=44) and IDA (10%, n=21), were recorded in male donors. The results show no relationship between ferritin and haemoglobin among the blood donors (collection coefficient (r) = 0.04). Besides, no linear association of having anaemia and ID with ageing was reported among the blood donor population.

Conclusion and potential application of findingsID and IDA as well as general anaemia are highly prevalent among blood donors in the Gambia. Besides, no predisposition to ID and anaemia was observed in term of age, thus all blood donors from 18-60 should be considered for blood donation without any age preference.


title: Data Resource Profile: thousands of circulating RNA profiles of pre-clinical samples from the Janus Serum Bank Cohort

abstract: There is justified optimism regarding the use of miRNAs as early detection biomarkers of cancer. They are well characterized and are involved in all the hallmarks of cancer. Less is known about the role of most other non-coding RNA (ncRNAs) classes in normal physiology and tumorigenesis. The JanusRNA dataset consist of circulating RNA profiles of pre-clinical samples from 1631 cancer patients and 673 cancer-free controls. We studied eight cancer types including cancer of the: lung, colon, rectum, prostate, breast, testis, ovaries and gallbladder. JanusRNA has its origin from the large population-based Janus Serum Bank Cohort which consists of 318 628 Norwegians. The dataset combines information from the complete nationwide cancer registry, RNA sequencing profiles from 1631 cancer patients and 673 cancer-free controls, as well as data on lifestyle, anthropometry and biochemical measurements from national health surveys. The Janus Serum Bank is specifically suited for studies of early detection and risk biomarkers of cancer, since samples are collected nationwide over a large time span, pre-clinically and cancer occurs at different points in time after blood draw. We used a nested case-control design, selecting both cases and controls among the Janus cohort members. We restricted our selection to cases with at least one sample collected within 10 years prior to cancer diagnosis. We selected 673 cancer-free Janus participants for comparison of RNA levels with the cancer cases. The controls were frequency matched to the case group on sex, age at blood donation and date of blood donation. The JanusRNA dataset has been used to investigate the natural variation of circulating RNAs in cancer-free individuals. This data resource was also used in a study of variation in RNA expression associated with common traits like age, sex, smoking, BMI and physical activity in cancer-free individuals. RNA dynamics in lung and testicular carcinogenesis throughout a 10-year follow-up has also been studied.


title: Interpretable machine learning prediction of all-cause mortality

abstract: Prior studies on all-cause mortality traditionally use linear models; however, growing field of explainable artificial intelligence (XAI) can improve prediction accuracy over traditional linear models using complex machine learning (ML) models while still revealing novel insights. We propose the IMPACT (Interpretable Machine learning Prediction of All-Cause morTality) framework that implements and explains complex, non-linear ML models by combining a tree ensemble mortality prediction model and a principled XAI technique. We apply IMPACT to the NHANES (1999-2014) dataset, which enables us to understand different subpopulations according to shorter or longer term mortality and younger and older individuals. Our IMPACT models have higher predictive accuracy than popular pre-existing mortality risk scores and biological ages. Using individualized feature importance scores, we discover novel risk predictors (e.g., arm circumference) and interactions between risk predictors (e.g., serum chloride with age and/or gender). Furthermore, IMPACT provides a novel perspective of reference intervals and may suggest that the widely accepted reference intervals for serum albumin, mean cell volume and platelet count may in fact be sub-optimal for health. Finally, in order to ensure that our models are useful to as broad of a community as possible, we develop and publish a variety of explainable risk scores usable by individuals with and without medical expertise. The predictive accuracy of IMPACT combined with the capability of discovering mortality risk predictors and complex relationships demonstrates the value and utility of XAI in epidemiologic study design.