title: Autoantibodies linked to autoimmune diseases associate with COVID-19 outcomes

abstract: The SARS-CoV-2 infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a wide spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients, in a cohort of 248 individuals, of which171 were COVID-19 patients (74 with mild, 65 moderate, and 32 with severe disease) and 77were healthy controls. Dysregulated autoantibody serum levels, characterized mainly by elevated concentrations, occurred mostly in patients with moderate or severe COVID-19 infection, and was accompanied by a progressive disruption of physiologic IgG and IgA autoantibody signatures. A similar perturbation was found in patients with anosmia. Notably, autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations, being both indicated by random forest classification as strong predictors of COVID-19 outcome, together with age. Moreover, higher levels of autoantibodies (mainly IgGs) were seen in the elderly with severe disease compared with young COVID-19 patients with severe disease. These findings suggest that the SARS-CoV-2 infection induces a broader loss of self-tolerance than previously thought, providing new ideas for therapeutic interventions.


title: Shared Decision Making for Patients Hospitalized with Acute Myocardial Infarction. A Randomized Trial

abstract:
ObjectiveAdherence to guideline-recommended medications after acute myocardial infarction (AMI) is suboptimal. Patient fidelity to treatment regimens may be related to their knowledge of the risk of death following AMI, the pros and cons of medications, and to their involvement in treatment decisions. Shared decision making may improve both patients knowledge and involvement in treatment decisions.

MethodsIn a pilot trial, patients hospitalized with AMI were randomized to the use of the AMI Choice conversation tool or to usual care. AMI Choice includes a pictogram of the patients estimated risk of mortality at 6 months with and without guideline-recommended medications, i.e., aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors. Primary outcomes were patient knowledge and conflict with the decision made assessed via post-encounter surveys. Secondary outcomes were patient involvement in the decision-making process (observer-based OPTION12 scale) and 6-month medication adherence.

ResultsPatient knowledge of the expected survival benefit from taking medications was significantly higher (62% vs. 16%, p<0.0001) in the AMI Choice group (n=53) compared to the usual care group (n=53). Both groups reported similarly low levels of conflict with the decision to start the medications (13 (SD 24.2) vs. 16 (SD 22) out of 100; p=.16). The extent to which clinicians in the AMI Choice group involved their patients in the decision-making process was high (OPTION12 score 53 out of 100, SD 12). Medication adherence at 6-months was relatively high in both groups and not different between groups.

ConclusionsThe AMI Choice conversation tool improved patients knowledge of their estimated risk of short-term mortality after an AMI and the pros and cons of treatments to reduce this risk. The effect on patient fidelity to recommended medications of using this SDM tool and of SDM in general should be tested in larger trials enrolling patients at high risk for nonadherence.

Trial registration numberNCT00888537

category: cardiovascular medicine


title: Immune system and blood-brain barrier-wide biomarker analyses provide causal evidence for autoimmunity in dementia

abstract: Immune system and blood brain barrier (BBB) dysfunction are implicated in the development of Alzheimers disease and other dementias, but their causal role remains unknown. We performed Mendelian randomization (MR) for over 43,643 immune system and BBB-related biomarkers and identified 126 potential causal risk factors for dementias. A phenome-wide analysis using MR-based polygenic risk score in FinnGen study (N=339,233) for these risk factors revealed a common genetic background for dementias and autoimmune diseases which was supported by further HLA analyses. Pathway analyses linked the 126 proteins to amyloid-{beta}, tau and -synuclein pathways, increased inflammatory responses, and altered self-tolerance mechanisms. In inverse-probability-weighted analyses simulating randomized controlled drug trials in observational data, anti-inflammatory and immunosuppressive medications were associated with reduced dementia risk (p<0.01 for methotrexate and TNF- inhibitors). These converging results from different research lines suggest that autoimmunity is a modifiable component in diseases causing dementia.

category: epidemiology


title: Timeliness of reporting of SARS-CoV-2 seroprevalence results and their utility for infectious disease surveillance

abstract:
Seroprevalence studies have been used throughout the COVID-19 pandemic to monitor infection and immunity. These studies are often reported in peer-reviewed journals, but the academic writing and publishing process can delay reporting and thereby public health action. Seroprevalence estimates have been reported faster in preprints and media, but with concerns about data quality. We aimed to (i) describe the timeliness of SARS-CoV-2 serosurveillance reporting by publication venue and study characteristics and (ii) identify relationships between timeliness, data validity, and representativeness to guide recommendations for serosurveillance efforts.

We included seroprevalence studies published between January 1, 2020 and December 31, 2021 from the ongoing SeroTracker living systematic review. For each study, we calculated timeliness as the time elapsed between the end of sampling and the first public report. We evaluated data validity based on serological test performance and correction for sampling error, and representativeness based on use of a representative sample frame and adequate sample coverages. We examined how timeliness varied with study characteristics, representativeness, and data validity using univariate and multivariate Cox regression.

We analyzed 1,844 studies. Median time to publication was 154 days (IQR 64-255), varying by publication venue (journal articles: 212 days, preprints: 101 days, institutional reports: 18 days, and media: 12 days). Multivariate analysis confirmed the relationship between timeliness and publication venue and showed that general population studies were published faster than special population or health care worker studies; there was no relationship between timeliness and study geographic scope, geographic region, representativeness, or serological test performance.

Seroprevalence studies in peer-reviewed articles and preprints are published slowly, highlighting the limitations of using the academic literature to report seroprevalence during a health crisis. More timely reporting of seroprevalence estimates can improve their usefulness for surveillance, enabling more effective responses during health emergencies.


title: Quantifying the health benefits of physical activity due to active commuting in a French transition scenario : a health impact assessment of the negaWatt scenario

abstract:
BackgroundEnergy transition scenarios are prospective outlooks describing combinations of changes in socio-economic systems that are compatible with climate targets. These changes could have important short-term health co-benefits. We aimed to quantify the health benefits of physical activity caused by active transportation on all-cause mortality in the French negaWatt energy transition scenario over the 2021-2050 period.

MethodsWe conducted a heath impact assessment of increased walking, cycling and E-biking projected in the negaWatt scenario. Time-varying mileage of walking and cycling projected by the scenario were distributed across the French population according to various hypotheses up to 2050. We quantified the number of premature death and years of life lost (YLL) prevented by increased physical activity. Health benefits were monetised based on the value of statistical year of life.

ResultsThe negaWatt scenario assumes increases of walking and cycling volumes of +11% and +612%, respectively, over the study period. As compared to a scenario with no volume increase, we quantified that the negaWatt scenario would prevent 9,797 annual premature deaths in 2045 and generate {euro}34 billion of economic benefits from 2045 onwards; cumulatively over the study period, it would prevent 215,000 premature deaths and generate {euro}696 billion of benefits. In 2045, health benefits would translate into a 3-month increase of life expectancy in the general population.

ConclusionsIncreased physical activity implied in the negaWatt transition scenario would generate substantial public health benefits, which are comparable to the gain expected by large scale health prevention interventions.

category: public and global health


title: A systematic review of previous MRI studies demonstrating the relationship between season and brain volume

abstract:
IntroductionSpecific diseases such as Alzheimers, schizophrenia and multiple sclerosis have been associated with environmental changes, including changes in season. The relationship between changes in season or photoperiod and brain volume has been widely studied in animals. However, the relationship between changes in season and brain volume in humans is not yet well established. Here, we aim to provide a comprehensive and systematic review of magnetic resonance imaging (MRI) studies examining the effects of changes in season or photoperiod on brain volume.

MethodsWe used a systematic review approach to study reports on the relationship between changes in season or photoperiod and brain volume using MRI. PubMed database and Google Scholar search engines were used to locate appropriate. PRISMA was used in selection of appropriate studies on season or photoperiod and brain volume using MRI.

ResultsFive studies were included in the current review: three examined the relationship between changes in photoperiod and brain volumes while two studies examined the relationship between changes in season and brain volume.

ConclusionWhen studying other variables like changes in temperature and humidity on how they affect brain volume, no effect was observed. It was, however, observed from studies that hydration status changed brain volumes when measured using MRI. Overall, we found evidence demonstrating differences in human brain volumes across different seasons. We suggest future longitudinal research to prove changes in brain volume across different seasons.

category: radiology and imaging


title: Effect of mHealth interventions on psychological issues experienced by women diagnosed with breast cancer receiving chemotherapy: A systematic review and meta-analysis

abstract:
BackgroundA range of psychological issues often accompany breast cancer chemotherapy. Owing to their ubiquity, mobile phones have been used to deliver supportive interventions that address these issues. However, we currently lack sufficient evidence to guide the design of such interventions.

AimTo analyse and synthesise available evidence on the effectiveness of mobile-phone-based (mHealth) interventions in alleviating the psychological issues experienced by women receiving chemotherapy for breast cancer.

MethodsA systematic literature search was conducted from 14 relevant databases. Revman 5.4 was used to pool the quantitative results from comparable studies for statistical meta-analysis. For clinically heterogeneous studies where statistical pooling of results was not possible, a narrative summary was used to present the findings.

ResultsThe review included ten published studies which covered 1,548 patients. The meta-analysis results indicated a significant improvement in the quality of life (standardised mean difference [SMD] = 0.32, 95% confidence interval [CI] [0.07, 0.58], p = .01, I2 = 17%). No significant effects were found for anxiety (SMD = -0.01, 95% CI [-0.26, 0.25], p = 0.96, I2 = 53%) and depression (SMD = 0.02, 95% CI [-0.17, 0.20], p = .87, I2 = 0%). Individual studies suggest reduced symptom prevalence (p = .033, d =.27), symptom distress (p = .004, d = .004), symptom interference (p = .02, d = .51), supportive care needs (p < .05, d = 2.43); improved self-efficacy (p = .03, d = 0.53), self-esteem (p <.001, d = 0.87) and emotional functioning (p = .008, d = .30). The methodological quality ranged from low to moderate.

ConclusionmHealth interventions might be helpful in addressing certain psychological issues experienced by this population, although the evidence is still being gathered and not yet conclusive. More rigorous trials are hereby warranted to confirm the suitable duration while addressing the methodological flaws found in previous studies

PROSPERO registration numberCRD42021224307

category: oncology


title: Clinical and Non-clinical Proof of Concept Supporting the Development of RJX As an Adjunct to Standard of Care Against Severe COVID-19

abstract:
BackgroundThe identification of effective strategies capable of reducing the case mortality rate of high-risk COVID-19 is an urgent and unmet medical need. We recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). Here we report data from a pilot clinical study (RPI-015) which examined the safety, tolerability, and feasibility of using RJX in combination with clinical standard of care (SOC) in hospitalized COVID-19 patients with pneumonia (ClinicalTrials.gov Identifier: NCT04708340). In addition to our early clinical proof of concept (POC) data, we also present non-clinical POC from a mouse model of CRS and ARDS that informed the design of the reported clinical study.

Methods13 patients, who were hospitalized with COVID-19 pneumonia and abnormally elevated serum inflammatory biomarkers markers [≥]3 months prior to the identification of the first confirmed U.S case of the Omicron variant, were treated with IV RJX (daily x 7 days) plus SOC. Non-clinical POC study examined the ability of RJX plus dexamethasone (DEX) to improve the survival outcome in the lipopolysaccharide (LPS)-Galactosamine (GalN) mouse model of fatal cytokine release syndrome (CRS), sepsis and acute respiratory distress syndrome (ARDS).

FindingsIn the Phase 1 clinical study, none of the 13 patients developed a treatment-related DLT, SAE, or Grade 3-5 AEs. Nine (9) of the 12 evaluable patients, including 3 patients with hypoxemic respiratory failure, showed rapid clinical recovery. In the non-clinical POC study in LPS-GalN challenged mice, the combination of RJX plus DEX was more effective than RJX alone or DEX alone, reversed the CRS as well as inflammatory tissue damage in the lungs and liver, and improved the survival outcome. Taken together, these findings provide the early clinical and non-clinical POC for the development of RJX as an adjunct to the SOC in the multi-modality management of high-risk COVID-19.

category: pharmacology and therapeutics


title: The level of liver and renal function biomarker abnormalities among hospitalized COVID-19 patients in Ethiopia

abstract:
BackgroundCOVID-19 pandemic is unprecedented public health emergency and added burden to developing countries. The pandemic cause multi organ failures (MOF) predominantly affects lung, cardiac, renal and liver organs as severity of the disease exacerbates. That is the rationale to execute this study with the aim to determine the magnitude of abnormal organ function test parameters and its association between markers of organ failure and disease severity in patients infected with COVID-19 admitted at Millennium COVID-19 Care Center (CCC).

MethodsA cross-sectional study was conducted among COVID-19 patients admitted at Millennium COVID-19 Care and Treatment Center (MCCTC) from May 2021 up to Oct 2021. In this study 500 participants information were collected from the laboratory database of Millennium COVID-19 care center. Data were analyzed using SPSS version 25. P-value <0.05 was considered significantly associated.

ResultThe median age of the 500 study participants was 55.6{+/-}7.7 years, and from these 67.6% of patients were males. Liver function parameters Aspartae transferase (AST),) alanine aminotransferase (ALT) and Alakaline phosphatase (ALP) the mean value of overall patients were elevated and three of these parameters were highly elevated among critical patients (56.9{+/-}57.7, 58.5{+/-}6, and 114.6{+/-}6) respectively. All study participants had an elevated Creatinine. 66.8% males, 65% Intensive care unit (ICU), had an elevated serum value of ALT and AST respectively. Troponin was found elevated among males (54%) and 59% among ICU (critical) patients.

ConclusionLiver and renal function test biomarkers such as creatine kinase muscle-brain isoenzymes (CK-MB), troponin, AST, ALT and Creatinine serum value was found elevated among ICU than non ICU patients. Organ function biomarkers are a candidate for predicting COVID-19 disease severity in order to guide clinical care.


title: Antibiotic utilization pattern in burn patients admitted at tertiary hospital: A retrospective study

abstract:
Burn patients are at high risk for nosocomial infection. Antibiotics are the key drugs for the treatment of infections. Overuse and inappropriate use of antibiotics increase both bacterial resistance and the cost of treatment. The introduction of correct and rational use of antibiotics appears to be impossible without having the knowledge of the current situation of antibiotic consumption. So, the study was conducted to know the current situation of antibiotic utilization pattern in burn patients.

MethodsA Retrospective review of medical records was done to analyze the utilization pattern of antibiotics. The data were collected from Kirtipur hospital from June 2018 to May 2019. All the admitted patients irrespective of age, gender who were prescribed antibiotics and presented within three days of burn were included in the study. Patients admitted for less than 24hrs of a time were excluded from the study.

ResultsA total of 249 reviewed case records came under inclusion criteria. Among them 51.8% were female and 48.2% were male. Mostly affected age group was 15-29 years (34.5%). Flame burn (51.8%) was the main cause of the burn. The majority had second-degree burn and 36.90% had 0-10% burn. Third-generation cephalosporin, ceftriaxone had the highest DDD/100BD (19.05). The most frequently used antibiotics were ceftriaxone, cefazolin, and piperacillin+tazobactam. DU90% comprises 12 antibiotics out of 30 antibiotics. The average number of antibiotics prescribed was 2.12 with a range of 1 to 7.

ConclusionsThis study revealed the trend of antibiotic utilization pattern in burn patients. Third-generation cephalosporin, ceftriaxone was the most prescribed antibiotic. Regular antibiotic consumption using DDD methodology is needed for regular monitoring of antibiotic consumption so that timely intervention can be made and this study can be used as a baseline study.


title: The effects of COVID-19 on European healthcare provision for people with major depressive disorder: a scoping review protocol

abstract: Even before the pandemic, the treatment gaps in depression care were substantial, with issues ranging from rates of depression detection and intervention to a lack of follow-up after treatment initiation and access to secondary care services. The COVID-19 pandemic, which has had major effects on global healthcare systems, is almost certain to have impacted the MDD care pathway, though it is unclear what changes have manifested and what opportunities have arisen in response to COVID-19. The extent to which patients receive best-practice care is likely closely linked to clinical outcomes (and therefore disability burden) and as such, it is important to examine treatment gaps on the MDD care pathway during the pandemic. Here, we outline a protocol for a scoping review that investigates this broad topic, focusing on continuity of care and novel methods (e.g. digital approaches) used to mitigate care disruption. This scoping review protocol was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) standards and will culminate in a narrative synthesis of evidence.

category: psychiatry and clinical psychology


title: The combination of autism and exceptional cognitive ability increases risk for suicidal ideation

abstract: Autism with co-occurring exceptional cognitive ability is often accompanied by severe internalizing symptoms and feelings of inadequacy. Whether cognitive ability also translates into greater risk for suicidal ideation is unclear. To investigate this urgent question, we examined two samples of high-ability individuals with autism for factors that were predictive of suicidal ideation. In the first sample (N=1,074 individuals seen at a clinic specializing in gifted/talented youth), we observed a striking excess of parent-reported suicidal ideation in autistic individuals with IQ[≥]120 (OR=5.9, p = 0.0007). In separate sample of N=1,983 SPARK participants, we confirmed higher rates of suicidal thoughts compared to non-autistic children from the ABCD cohort (OR=6.8, p < 2.2 x 10-16), and further that autistic children with suicidal thoughts had significantly higher cognitive ability (p < 2.2 x 10-16) than those without. Elevated polygenic scores (PGS) for cognitive performance were associated with increased suicidal thoughts (Z = 2.16, p = 0.03), with PGS for educational attainment trending in the same direction (Z = 1.4, p = 0.17). Notably, similar results were found in parents of these autistic youth, where higher PGS for educational attainment was associated with increasing thoughts of suicide (Z=2.28, p=0.02). Taken together, these results suggest that on a phenotypic and genetic level, increasing cognitive ability is an unexpected risk factor for suicidal ideation in individuals diagnosed with, or at risk for autism.


title: Wastewater-based detection of an influenza outbreak

abstract: Traditional influenza surveillance informs control strategies but can lag behind outbreak onset and undercount cases, while wastewater surveillance is effective for monitoring near real-time dynamics of outbreaks but has not been attempted for influenza. We quantified Influenza A virus RNA in wastewater during an active outbreak. RNA concentrations were strongly associated with reported clinical cases and reflected the outbreak pattern and magnitude, suggesting this approach could aid in early detection.


title: Can a greenhouse gas emissions tax on food also be healthy and equitable? A systematized review and modelling study from Aotearoa New Zealand

abstract:
IntroductionPolicies to mitigate climate change are essential. The objective of this paper was to estimate the impact of greenhouse gas (GHG) food taxes and assess whether such a tax could also have health benefits and reduce ethnic inequalities in health in Aotearoa NZ.

MethodsWe undertook a systemised review on GHG food taxes to inform four tax scenarios, including one combined with a subsidy. These scenarios were modelled to estimate lifetime impacts on quality adjusted health years (QALY), health inequities by ethnicity, GHG emissions, health system costs and food costs to the individual.

Results28 modelling studies on food tax policies were identified. Taxes resulted in decreased consumption of the targeted foods (e.g., -15.4% in beef/ruminant consumption, N=12 studies) and an average decrease of 8.3% in GHG emissions (N=19 studies). Using this review, we conceptualized four scenarios: a GHG weighted tax on all foods; a GHG weighted tax on food groups with the highest 50% of emissions ( high emitters); A GHG weighted tax on  high emitters combined with a fruit and vegetable subsidy; A 20% tax on  high emitters.

The  GHG weighted tax on all foods scenario had the largest health gains and costs savings (455,800 QALYs and NZ$8.8 billion), followed by the tax-subsidy scenario (410,400 QALYs and NZ$6.4 billion). All scenarios were associated with reduced GHG emissions (between 4.2% and 7.0% of the baseline GHG emissions from food). Age standardised per capita QALYs were between 1.6 and 2.1 times higher for M[a]ori than non-M[a]ori.

ConclusionApplying taxes that target foods with high GHG emissions has the potential to be effective for reducing GHG emissions and to result in co-benefits for population health. Combining a GHG food tax with a fruit and vegetable subsidy may help reduce the negative effects on household food expenditure of such a tax.

Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSModelling studies investigating the impact of food taxes have shown taxes aimed at high GHG emitting foods reduce consumption of ruminant meats and GHG emissions. No reviews of modelling studies of GHG motivated food taxes have been published.

What this study addsModelling studies are reviewed and summarised and used to inform modelling of four GHG motivated tax scenarios. Modelled results identify a tax/subsidy with positive impacts on population health (410,400 total or 93.2 quality adjusted life years per 1000 people over their lifetime), health system costs (NZD 6.4 billion savings), ethnic health equity (health gains were 1.6 times higher for NZs indigenous population, M[a]ori than non-M[a]ori), GHG emissions (-4.2%) and cost of diets (-0.5%).

How this study might affect research, practice or policyPolicymakers can use these findings in designing a food tax to benefit both climate and population health, utilising these detailed results on factors that affect population wellbeing.


title: Should COVID-specific arrangements for abortion continue? The views of women experiencing abortion in Britain during the pandemic.

abstract:
BackgroundDuring the COVID-19 pandemic, the British governments issued temporary approvals enabling the use of both pills for medical abortion at home. This permitted the introduction of a fully telemedical model of abortion care with consultations taking place via phone or video call and medications delivered to womens homes. The approvals in England and Wales will expire at the end of March 2022, while that in Scotland remains under consultation.

MethodsWe interviewed 30 women who had undergone an abortion in England, Scotland or Wales between August and December 2021. We explored their views on the changes in abortion service configuration during the pandemic and whether abortion via telemedicine and use of abortion medications at home should continue.

ResultsSupport for continuation of the permission to use mifepristone and misoprostol at home was overwhelmingly positive. Reasons cited included convenience, comfort, reduced stigma, privacy, and respect for autonomy. A telemedical model was also highly regarded for similar reasons but for some its necessity was linked to safety measures during the pandemic and an option to have an in-person interaction with a health professional at some point in the care pathway was endorsed.

ConclusionsThe approval to use abortion pills at home via telemedicine are supported by women having abortions in Great Britain. The respective governments in England, Scotland, and Wales, should be responsive to the patient voice and move to make permanent these important advances in abortion care.

What is already known on this topicDuring the COVID-pandemic, specific permission to use both pills for medical abortion at home was granted in England, Scotland and Wales leading to the widespread implementation of a telemedical model with direct-to-patient delivery of medications. The safety, effectiveness, and acceptability of this model of care had been well-documented prior to and during the pandemic.

What this study addsThis study adds the voices of women undergoing abortion during the pandemic regarding the specific changes that led to the transformation of medical abortion care in Britain. Amongst 30 women interviewed, there was endorsement for the continuation of permissions to use medical abortion pills at home via telemedicine.

How this study might affect research, practice, or policyThe UK governments vision of health provision puts patients and the public first, where "no decision about me, without me" is the norm. Our findings support law and policy makers in applying this principle to recent developments in abortion care by making the permissions permanent.

category: sexual and reproductive health


title: Forensic Alcohol Calculations in transgender individuals undergoing gender-affirming hormonal treatment

abstract:
There are an increasing number of individuals undergoing gender-affirming hormonal treatment (GAHT) to treat gender dysphoria. Forensic alcohol calculations require knowledge of the sex of the individual but this may disadvantage trans people as research has demonstrated that there are physiological changes in individuals who are undergoing GAHT.

Using previously published studies on total body water (TBW) in cis individuals and the known changes in lean body mass and hematocrit in trans individuals, it is possible to revise the rubric for the estimation of TBW in trans individuals. We propose these revised equations are used for transgender individuals. When using these revised rubrics, we determined that for trans women the use of the cis male (sex at birth) anthropometric TBW equation only gives a small underestimation of TBW (0.9%) compared to the underestimation (-17.7%) of TBW using the cis female (affirmed gender) TBW equation. For trans men the use of gender at birth (cis female) TBW equation gives the largest disadvantage, underestimating TBW by -10.8 % compared to the affirmed gender (cis male) TBW equation that over estimates TBW by 6.6 %. For this reason, we recommend that if the sex at birth of an individual is not known or disclosed, any forensic alcohol calculations in the report are made assuming that the gender declared by the individual is their sex at birth.

HIGHLIGHTSO_LILarge number of people taking gender-affirming hormonal treatment (GAHT) around the world
C_LIO_LITotal body water is altered in individuals taking GAHT
C_LIO_LIForensic alcohol calculation results are affected by GAHT
C_LIO_LIRecommended that in an individual undergoing GAHT revised Watson equation used
C_LIO_LIForensic alcohol reports state assumption that individual is cis (unless sex at birth is known)
C_LI

category: toxicology


title: How hostile is prolonged brain death for donor organs in transplantation? A time course analysis using clinical samples

abstract: Organ donation after brain death (DBD) is an important source of transplanted organs, as chronic undersupply means many patients die whilst awaiting transplant. Improving organ quality and graft survival is key to reducing waiting lists: the interval between brain death (BD) confirmation and organ procurement offers an opportunity to reduce injury or encourage repair, yet data are lacking. Here, we developed a novel method of studying time-course changes in serum proteins in a DBD cohort from a UK biobank. Individual donor trajectories were combined into a mathematical model to allow us to determine changes in pro-inflammatory (TNF-alpha, IL-6, Complement) mediators and markers of central nervous injury (NSE, GFAP) after BD. Surprisingly, we found no evidence of a rise of TNF-alpha, NSE, IL-6 or C5a with prolonged BD, questioning the consensus view of progressively pro-inflammatory environment, and identified complement as a potential target for therapeutic intervention to improve organ quality.

category: transplantation


title: Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression in the VA Health Care System

abstract:
BackgroundSerious mental illnesses, including schizophrenia, bipolar disorder and depression are heritable, highly multifactorial disorders and major causes of disability worldwide. Polygenic risk scores (PRS) aggregate variants identified from genome-wide association studies (GWAS) into individual-level estimates of liability, and are a promising tool for clinical risk stratification.

MethodsBy leveraging the VAs extensive electronic health record (EHR) and a cohort of 9,378 individuals with confirmed diagnoses of schizophrenia or bipolar I disorder, we validated automated case-control assignments based on ICD-9/10 codes, and benchmarked the performance of current PRS for schizophrenia, bipolar disorder, and major depression in 400,000 Million Veteran Program (MVP) participants. We explored broader relationships between PRS and 1,650 disease categories via phenome-wide association studies (PheWAS). Finally, we applied genomic structural equation modeling (gSEM) to derive novel PRS indexing common and disorder-specific latent genetic factors.

FindingsAmong 3,953 and 5,425 individuals with diagnoses of schizophrenia or bipolar disorder type I that were confirmed by structured clinical interviews, 95% were correctly identified using ICD-9/10 codes (2 or more). Current PRS were robustly associated with case status in European (p<10-254) and African (p<10-5) participants and were higher among more frequently hospitalized patients (p<10-4). PheWAS confirmed previous associations among higher neuropsychiatric PRS and elevated risk for psychiatric and physical health problems and extended these findings to African Americans.

InterpretationUsing diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRS, we demonstrated the validity of an EHR-based phenotyping approach in US veterans, highlighting the potential of PRS for disentangling biological and mediated pleiotropy.

FundingDepartment of Veterans Affairs Cooperative Studies Program (CSP) #572; Million Veteran Program (MVP-000, MVP-006); Office of Research and Development, Department of Veterans Affairs.

category: genetic and genomic medicine


title: Mismatches in gene deletions and kidney-related proteins are novel histocompatibility factors in kidney transplantation

abstract:
BackgroundThe genomic mismatch level between donor and recipient is associated with the risk of acute rejection and long-term graft survival. In the present study, we determined the association of genome-level matching with acute rejection in a single-center kidney transplantation cohort.

MethodsAltogether, 1025 pairs of deceased donors and kidney transplant recipients transplanted in 2007-2017 were genotyped. The associations between the sums of whole genome missense variant mismatches and missense mismatches in transmembrane, secretory, and kidney-related proteins, with acute rejection were estimated using Cox proportional hazards model. Additionally, we analyzed 40 common deletion-tagging variants using Cox model.

ResultsThe increasing mismatch sum in kidney-related proteins associated with acute rejection with an unadjusted HR of 1.15 (95% CI, 1.01-1.30; P=0.029) when dividing the sum into quartiles. The sums of other mismatches were not associated with acute rejection. In deletion analysis, a mismatch in rs7542235 (NC_000001.11:g.196854483A>G), genotype GG tagging a homozygous deletion at the complement Factor H-related (CFHR) proteins locus, predisposed to acute rejection with adjusted HR of 2.97 (95% CI, 1.46-6.05; P=0.003).

ConclusionsThe present study supports that mismatches in gene deletions and kidney-related proteins are novel histocompatibility factors in kidney transplantation. The relative importance of different gene deletions varies between populations, as we found evidence for CFH-related gene deletion but not for the previously reported LIMS1 deletion.

SIGNIFICANCE STATEMENTThe first genome-wide association studies have not identified strong candidate genes for complication risks of kidney transplantation whereas matching of non-HLA genes may be promising. The current study determined the association of genome-level matching with acute rejection among 1025 kidney transplant pairs. The increasing mismatch sum in kidney-related proteins was associated with acute allograft rejection. Also, an association between acute allograft rejection and rs7542235 genotype GG, tagging a homozygous deletion at the complement factor H-related (CFHR) loci on chr 1 was found. The present study suggests that mismatches in gene deletions and kidney-related proteins are important novel histocompatibility factors in kidney transplantation.


title: Examining the Impact of Chronic Pain on Information Processing Behavior: An Exploratory Eye-tracking Study

abstract: Chronic pain is a multifaceted complex experience that is often captured with self-reported measures. While subjective self-reported measures capture pain from a patients point of view, they are limited in information richness. Collecting eye movements when completing self-reported subjective pain measures provides valuable insight about information processing and decision behavior. This information can improve the information richness of self-reported pain measures by providing a broader view of an individuals pain experience. How people process information and make decisions when completing pain measures can also help to investigate the cognitive-evaluative aspects of chronic pain, which in turn can provide insight for developing eye-tracking biomarkers of chronic pain, and by doing so help develop smart clinician support technologies. Our preliminary results show that people with chronic pain expended significantly more cognitive effort than their pain-free counterparts when completing three self-reported pain measures that are widely used in clinical settings. These results are promising because they suggest that eye movements may serve as valuable information to accompany self-reported pain scores and thus enable effective assessment and management of chronic pain. The results also suggest that eye movements may serve as suitable biomarkers of chronic pain.

category: health informatics


title: Narratives of the convalescent plasma donor in a Peruvian social security hospital: motivations, fears, expectations and experiences

abstract:
ObjectivesTo know and explore from convalescent plasma donators voices the experience in the blood donation process at a Peruvian social security hospital.

MethodsQualitative study with a phenomenological design. The investigation was carried out in 01 hospitals of the social security of Peru. Semi-structured interviews were carried out.

ResultsEleven donors of convalescent plasma were interviewed. The main motivations for donating were being able to contribute to national research and supporting patients affected by COVID-19. Fears focus on the possible risk of contagion within the hospital. Donors emphasised the attention and support of health personnel alongside the donation procedure. The main expectations and suggestions point towards greater dissemination of donation campaigns with special emphasis on safety. Likewise, an improvement in the time of the donation procedure (from enrolment to the extraction of convalescent plasma), and the implementation of friendly spaces to encourage future blood donation campaigns were highlighted.

ConclusionsThe experience of the convalescent plasma donors was positive. However, improvements must be made in terms of processes and infrastructure to ensure future successful blood donation campaigns.

category: hematology


title: Performance of three rapid antigen tests against the SARS-CoV-2 Omicron variant

abstract: Rapid antigen detection tests (RADTs) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now in widespread use in the United States. RADTs play an important role in maintaining an open society but require periodic reassessment to ensure test performance remains intact as the virus evolves. The nucleocapsid (N) protein is the target for the majority of RADTs and the SARS-CoV-2 Omicron variant has several N protein mutations that are previously uncharacterized. We sought to assess the impact of these mutations by testing 30 Omicron variant samples across a wide range of viral loads on three widely used RADTs: the iHealth COVID-19 Antigen Rapid Test, the ACON Laboratories FlowFlex COVID-19 Antigen Home Test, and the Abbott BinaxNOW COVID-19 Antigen Card, using 30 Delta variant samples as a comparator. We found no change in the analytic sensitivity of all three RADTs for detection of Omicron versus Delta, but noted differences in performance between assays. No RADT was able to detect samples with a cycle threshold (Ct) value of [≥]27.5 for the envelope gene target on the Roche cobas RT-PCR assay. Epidemiologic studies are necessary to correlate these findings with their real-world performance.

category: infectious diseases


title: Performance of an artificial intelligence-based smartphone app for guided reading of SARS-CoV-2 lateral-flow immunoassays

abstract:
ObjectivesTo evaluate an artificial intelligence-based smartphone application to automatically and objectively read rapid diagnostic test (RDT) results and assess its impact on COVID-19 pandemic management.

MethodsOverall, 252 human sera from individuals with PCR-positive SARS-CoV-2 infection were used to inoculate a total of 1165 RDTs for training and validation purposes. We then conducted two field studies to assess the performance on real-world scenarios by testing 172 antibody RDTs at two nursing homes and 92 antigen RDTs at one hospital emergency department.

ResultsField studies demonstrated high levels of sensitivity (100%) and specificity (94.4%, CI 92.8-96.1%) for reading IgG band of COVID-19 antibodies RDTs compared to visual readings from health workers. Sensitivity of detecting IgM test bands was 100% and specificity was 95.8%, CI 94.3-97.3%. All COVID-19 antigen RDTs were correctly read by the app.

ConclusionsThe proposed reading system is automatic, reducing variability and uncertainty associated with RDTs interpretation and can be used to read different RDTs brands. The platform can serve as a real time epidemiological tracking tool and facilitate reporting of positive RDTs to relevant health authorities.


title: Genomically informed clinical comparison of three epidemic waves of COVID-19 in Malawi

abstract:
BackgroundCompared to the abundance of clinical, molecular, and genomic information available on patients hospitalised with COVID-19 disease from high-income countries, there is a paucity of data from low-income countries.

MethodsWe enrolled 245 hospitalised patients with PCR confirmed COVID-19 disease at Queen Elizabeth Central Hospital, the main hospital for southern Malawi, between July 2020 and September 2021. The recruitment period covered three waves of SARS-CoV-2 infections in Malawi. Clinical and diagnostic data were collected using the ISARIC clinical characterization protocol for COVID-19. The viral material from PCR-positive swabs was amplified with a tiling PCR scheme and sequenced using the MinION sequencer in Malawi. Consensus genomes were generated using the ARTIC pipeline and lineage assignment was performed using Pangolin.

ResultsSequencing data showed that wave one was predominantly B.1 (8/11 samples), wave two consisted entirely of Beta variant of concern (VOC) (6/6), and wave three was predominantly Delta VOC (25/26). Patients recruited during the second and third waves had progressively fewer underlying chronic conditions, and in the third wave had a shorter time to presentation (2 days vs 5 in the original wave). Multivariable logistic regression demonstrated increased mortality in wave three, dominated by the Delta VOC, compared to previous waves (OR 6.6 [CI 1.1-38.8]).

ConclusionsPatients hospitalised with COVID-19 disease and who were recruited to the ISARIC cohort, in Blantyre during the Delta wave had more acute symptom onset; fewer underlying conditions; and were more likely to die. Whilst we demonstrate the value of linking virus sequence data with clinical outcome data in a low-income setting, this study also highlights the considerable barriers to establishing sequencing capacity in a setting heavily affected by disruptions in supply chain and inequity of resource distribution.


title: Clinical severity of Omicron sub-lineage BA.2 compared to BA.1 in South Africa

abstract: Early data indicated that infection with Omicron BA.1 sub-lineage was associated with a lower risk of hospitalisation and severe illness, compared to Delta infection. Recently, the BA.2 sub-lineage has increased in many areas globally. We aimed to assess the severity of BA.2 infections compared to BA.1 in South Africa. We performed data linkages for (i) national COVID-19 case data, (ii) SARS-CoV-2 laboratory test data, and (iii) COVID-19 hospitalisations data, nationally. For cases identified using TaqPath COVID-19 PCR, infections were designated as S-gene target failure (SGTF, proxy for BA.1) or S-gene positive (proxy for BA.2). Disease severity was assessed using multivariable logistic regression models comparing individuals with S-gene positive infection to SGTF-infected individuals diagnosed between 1 December 2021 to 20 January 2022. From week 49 (starting 5 December 2021) through week 4 (ending 29 January 2022), the proportion of S-gene positive infections increased from 3% (931/31,271) to 80% (2,425/3,031). The odds of being admitted to hospital did not differ between individuals with S-gene positive (BA.2 proxy) infection compared to SGTF (BA.1 proxy) infection (adjusted odds ratio (aOR) 0.96, 95% confidence interval (CI) 0.85-1.09). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ for individuals with S-gene positive infection compared to SGTF infection (aOR 0.91, 95%CI 0.68-1.22). These data suggest that while BA.2 may have a competitive advantage over BA.1 in some settings, the clinical profile of illness remains similar.


title: Characterizing SARS-CoV-2 transcription of subgenomic and genomic RNAs during early human infection using multiplexed ddPCR

abstract: Control of SARS-CoV-2 (SCV-2) transmission is a major priority that requires understanding SCV-2 replication dynamics. We developed and validated novel droplet digital PCR (ddPCR) assays to quantify SCV-2 subgenomic RNAs (sgRNAs), which are only produced during active viral replication, and discriminate them from full-length genomic RNAs (gRNAs) in a multiplexed format. We applied this multiplex ddPCR assay to 144 cross-sectional nasopharyngeal samples. sgRNAs were quantifiable across a range of qPCR cycle threshold (Ct) values and correlated with Ct values. The ratio of sgRNA:gRNA was remarkably stable across a wide range of Ct values, whereas adjusted amounts of N sgRNA to a human housekeeping gene declined with higher Ct values. Interestingly, adjusted sgRNA and gRNA amounts were quantifiable in culture-negative samples, although levels were significantly lower than in culture-positive samples. Longitudinal daily testing of 6 persons for up to 14 days revealed that sgRNA is concordant with culture results during the first week of infection but may be discordant with culture later in infection. Further, sgRNA:gRNA is constant during infection despite changes in viral culture. These data indicate stable viral transcription during infection. More work is needed to understand why cultures are negative despite persistence of viral RNAs.


title: Steroid Treatment Balance According To The Lymphocyte / White Blood Cells Ratio In COVID-19 Patients, A Retrospective Cohort Analysis

abstract:
ObjectivesProgressive respiratory failure is the main cause of clinical worsening in Coronavirus disease (COVID-19) patients. The decision to intubate during the follow-up of COVID-19 patients is critical because of high mortality rates.

MethodsWe analyzed the COVID-19 related intubation and in-hospital mortality risk factors of patients admitted to two tertiary hospitals.

ResultsOf the 275 patients included in the study, 44 (16%) were intubated, while 30 of them were patients (53%, 30/56) who had previously received steroid therapy. In 23 patients (77%) who received steroid therapy and were intubated, antiviral therapy was started in the first 6 days and Lymphocyte / White blood cells (LYM/WBC) ratios were lower than 0.18. The LYM/WBC ratio was found to be less than 0.12 in 14 patients who were intubated but did not receive steroid treatment before. 30(11%) of the patients included in the study died. While the number of deaths among those who did not receive steroid treatment was 10 (5%), it was 20 (36%) among the patients who did. Among in these 20 patients, it was observed that all 9 people who started antiviral treatment before 3 days, who were over 57 years old and whose oxygen saturation result was moderate or severe, died.

ConclusionsWe think that the use of steroids in early period may be detrimental in rapidly progressive patients with lymphopenia that may be an independent marker of immune dysregulation.

Box-ED SectionO_ST_ABSWhat is already known on the study topic?C_ST_ABSProgressive respiratory failure is the main cause of clinical worsening in COV[I]D-19 patients. Corticosteroid treatment has remarkable favourable effect on the prognosis.

What is the conflict on the issue? Has it importance for readers?Corticosteroids is immunosupresive drug that have also nonspesific antienflammatory effect. Clinicians must consider multiple parameters such as patient status, disease period and existence of bacterial superinfection when to start corticosteroid treatment at bedside.

How is this study structured?We conducted a retrospective study to analyze risk factors COVID-19 related intubation two cohorts. This study included patients diagnosed with COVID-19 induced pneumonia from March 21 to Apr 23,2020, at two university hospitals located on distinct sides of Istanbul province in Turkey.

What does this study tell us?We think that the use of steroids in early period may be detrimental in rapidly progressive patients with lymphopenia that may be an independent marker of immune dysregulation


title: Real-time monitoring of the effectiveness of six COVID-19 vaccines in Hungary in 2021 using the screening method

abstract: Several studies have reported a waning of the effectiveness of COVID-19 vaccines. We report real-life vaccine effectiveness in Hungary, estimated with the screening method, in 2021, i.e., covering the dominance of both the Alpha and the Delta variant, and including the booster roll-out. Hungary is in the unique position to use six different vaccines (including the Sputnik V and Sinopharm vaccines, for which limited evidence was available prior to the present study) in the same, relatively homogeneous population. All vaccines provided high level of protection initially which declined over time. While the picture is different in each age group, the waning of immunity is apparent for all vaccines and especially in the younger age groups and the Sinopharm, Sputnik-V and AstraZeneca vaccines, which performed similarly. This is clearly reversed by booster doses, more prominent for those vaccines, where recipients were more likely to take the booster dose (which were the aforementioned three vaccines). Booster doses were almost exclusively mRNA vaccines. Overall, two vaccines, Pfizer/BioNTech and Moderna tend to produce the best results in all age groups, and even with waning taken into account.


title: Host and microbiome features of secondary infections in lethal covid-19

abstract: Secondary infections contribute significantly to covid-19 mortality but host and microbial factors driving this sequel remain poorly understood. We performed an autopsy study of 20 covid-19 cases and 14 controls from the first pandemic wave. Autopsies combined with microbial cultivation and deep RNA sequencing (RNAseq) allowed us to define major organ pathologies and specify secondary infections. Lethal covid-19 segregated into two main death causes separating cases with either dominant diffuse alveolar damage (DAD) or secondary infections of lungs. Lung microbiome changes were profound in covid-19 showing a reduced biodiversity and increased presence of prototypical bacterial and fungal pathogens in cases with secondary infections. Deep RNAseq of lung tissues distinctly mirrored death causes and cellular deconvolution stratified DAD cases into subgroups with different cellular compositions. Myeloid cells, including macrophages, and complement C1q activation were found to be strong stratifying factors suggesting a pathophysiological link possibly leading to tolerance in DAD subgroups. Moreover, several signs of immune-impairment were evident in covid-19 lungs including strong induction of inhibitory immune-checkpoints. Thus, our study highlights profound alterations of the local immunity in covid-19, wherein immune-impairment leads to reduced antimicrobial defense favoring the development of secondary infections on top of SARS-CoV-2 infection.

category: pathology


title: Global prevalence of antidepressant utilization in the community: A protocol for a systematic review

abstract:
BackgroundAntidepressant drugs are the most frequently prescribed medication for mental disorders. They are also used off-label and for non-psychiatric indications. Prescriptions of antidepressants have increased in the last decades, but no systematic review exists on the extent of their use in the community.

Methods and analysisWe will conduct a systematic review to estimate the prevalence of antidepressant use in the community. We will search for studies published from 2010 in the Embase and MEDLINE databases. Study selection (by title/abstract and full-text screening) and data extraction for included studies will be independently conducted by pairs of reviewers. We will then synthesize the data on the prevalence of antidepressant use in individuals living in the community. If possible, we will perform a meta-analysis to generate prevalence-pooled estimates. If the data allows it, we will conduct subgroup analyses by antidepressant class, age, sex, country or other sociodemographics. We will evaluate the risk of bias for each included study through a quality assessment using the Joanna Briggs Institute Critical Appraisal tool: Checklist for Studies Reporting Prevalence Data. DistillerSR software will be used for the management of this review.

Ethics and disseminationEthical approval is not required for this review as it will not involve human or animal subjects. The findings of our systematic review will be disseminated through publications in peer-reviewed journals, the Qualaxia Network (https://qualaxia.org), presentations to international conferences on mental health and pharmacoepidemiology, as well as general public events.

PROSPERO registration detailsCRD42021247423


title: Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

abstract:
BACKGROUNDTreatment-resistant schizophrenia (TRS) affects [~]30% of individuals with the disorder. Clozapine is the medication of choice in TRS but optimizing administration and dose titration are complex. The identification of predictive factors that influence clozapine prescription and response, including genetics, is of clinical interest in a precision psychiatry framework. We aimed to determine if a polygenic risk score (PRS) for schizophrenia is associated with the highest drug dose an individual received during clozapine treatment.

METHODSWe used generalized linear regression models accounting for demographic, pharmacological, and clinical covariates to determine the relationship between PRS and highest daily dose of clozapine. We used two independent multi-ancestry samples of individuals from the UK from a clozapine monitoring system, CLOZUK2 (N= 3133) and CLOZUK3 (N= 909). Schizophrenia PRS were calculated using the latest available GWAS summary statistics from the Psychiatric Genomics Consortium. In a secondary analysis of the two merged cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRS and clozapine doses classified as low, standard, or high (>600 mg/day).

RESULTSAfter controlling for relevant available covariates, schizophrenia PRS were correlated with the highest clozapine dose ever prescribed, in both CLOZUK2 ({beta}= 12.217, s.e= 3.776, P= 0.001) and CLOZUK3 ({beta}= 12.730, s.e= 5.987, P= 0.034). In the secondary analysis, the schizophrenia PRS was specifically associated with taking a clozapine dose greater than 600 mg/day (OR= 1.279, P= 0.006).

CONCLUSIONSSchizophrenia PRS is associated with the highest clozapine dose ever prescribed in two independent multi-ancestry samples from the UK, suggesting that the genetic liability to schizophrenia might index factors associated with therapeutic decisions in TRS cohorts.


title: Combined treatment of nightmares with targeted memory reactivation and imagery rehearsal therapy: a randomized controlled trial

abstract:
BackgroundNightmare disorder (ND) is characterized by dreams with strong negative emotions occurring during rapid-eye movement (REM) sleep. ND is mainly treated by imagery rehearsal therapy (IRT), where the patients are asked to change the negative story line of their nightmare to a more positive one.

MethodsWe used targeted memory reactivation (TMR) during REM sleep to strengthen IRT-related memories and accelerate remission of ND. Thirty-six patients (27 women) with ND were asked to perform an initial IRT session and, while they generated a positive outcome of their recurrent nightmare, half of the patients were exposed to a sound (TMR group), while no such pairing with a sound took place for the other half (control group). During the next two weeks, all patients performed IRT every evening at home, and were exposed to the sound during REM sleep with a wireless headband, which automatically detected sleep stages. The frequency of nightmares per week at 2 weeks and at a three-month follow-up was used as primary outcome measure.

ResultsWe found that the patients of the TMR group had less frequent nightmares (p=.026, Cohens d=1.05) and more positive dream emotions (p=.004, Cohens d=1.06) than patients of the control group after two weeks of IRT, and a sustained decrease of nightmares after 3 months (p=.006, Cohens d=1.45).

ConclusionsBy demonstrating the effectiveness of TMR during sleep to potentiate therapy, these results have clinical implications for the management of ND, with plausible relevance for learning-based therapies in other psychiatric diseases. Additionally, these findings show that TMR applied during REM sleep can modulate emotions in dreams.

Clinical trial registrationClinicalTrials.gov identifier NCT05237778


title: Using agent-based modeling to compare corrective actions for Listeria contamination in produce packinghouses

abstract: The complex environment of a produce packinghouse can facilitate the spread of pathogens such as Listeria monocytogenes in unexpected ways. This can lead to finished product contamination and potential foodborne disease cases. There is a need for simulation-based decision support tools that can test different corrective actions and are able to account for a facilitys interior cross-contamination dynamics. Thus, we developed agent-based models of Listeria contamination dynamics for two produce packinghouse facilities; agents in the models represented equipment surfaces and employees, and models were parameterized using observations, values from published literature and expert opinion. Once validated with historical data from Listeria environmental sampling, each models baseline conditions were investigated and used to determine the effectiveness of corrective actions in reducing prevalence of agents contaminated with Listeria and concentration of Listeria on contaminated agents. Evaluated corrective actions included reducing incoming Listeria, modifying cleaning and sanitation strategies, and reducing transmission pathways, and combinations thereof. Analysis of Listeria contamination predictions revealed differences between the facilities despite their functional similarities, highlighting that one-size-fits-all approaches may not always be the most effective means for selection of corrective actions in fresh produce packinghouses. Corrective actions targeting Listeria introduced in the facility on raw materials, implementing risk-based cleaning and sanitation, and modifying equipment connectivity were shown to be most effective in reducing Listeria contamination prevalence. Overall, our results suggest that a well-designed cleaning and sanitation schedule, coupled with good manufacturing practices can be effective in controlling contamination, even if incoming Listeria spp. on raw materials cannot be reduced. The presence of water within specific areas was also shown to influence corrective action performance. Our findings support that agent-based models can serve as effective decision support tools in identifying Listeria-specific vulnerabilities within individual packinghouses and hence may help reduce risks of food contamination and potential human exposure.


title: Plasma p217+tau vs NAV4694 amyloid and MK6240 tau PET across the Alzheimer continuum.

abstract:
INTRODUCTIONWe evaluated a new Simoa plasma assay for phosphorylated tau at aa217 enhanced by additional ptau sites (p217+tau).

METHODSPlasma p217+tau levels were compared to 18F-NAV4694 amyloid-beta (A{beta}) PET and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants.

RESULTSCompared to A{beta}-CU, the plasma levels of p217+tau increased two-fold in A{beta}+ CU and 3.5-fold in A{beta}+ CI. In A{beta}-the p217+tau levels did not significantly differ between CU, MCI or dementia. P217+tau correlated with A{beta} centiloids {rho}=0.67 (CI 0.64; CU 0.45) and tau SUVRMT {rho}=0.63 (CI 0.69; CU 0.34). Area under curve (AUC) for AD vs A{beta}-CU was 0.94, for AD vs other dementia was 0.93, for A{beta}+ vs A{beta}- PET was 0.89 and for tau+ vs tau-PET was 0.89.

DISCUSSIONPlasma p217+tau levels elevate early in the AD continuum and correlate well with A{beta} and tau PET.

Research in ContextO_LISystematic review: The authors reviewed the literature using PubMed, meeting abstracts and presentations. Plasma phospho-tau measures compare well to PET and post-mortem across the continuum of AD but accuracy varies across ptau target sites and assay methods. There are no reports comparing PET to plasma assays targeting multiple sites of tau phosphorylation as typically found in AD. The p217+tau assay targets p217 with binding enhanced by phosphorylation at additional sites such as aa212.
C_LIO_LIInterpretation: Plasma p217+tau elevates early and correlates with both A{beta} and tau as measured by PET indicating that tau phosphorylation is an early event in AD and occurs with A{beta} deposition. Plasma p217+tau measurement should assist both selection for trials and diagnosis of AD.
C_LIO_LIFuture directions: Further validation studies, head-to-head comparison to other assays, assessing the influence of co-morbidities and the ability to measure change in brain A{beta} and tau levels are required.
C_LI

category: neurology


title: Resting-state EEG distinguishes depression in Parkinson's disease

abstract:
IntroductionDepression is a non-motor symptom of Parkinsons disease (PD). PD-related depression is hard to diagnose and the neurophysiological basis is poorly understood. Depression can markedly affect cortical function, which suggests that scalp electroencephalography (EEG) may be able to distinguish depression in PD.

MethodsWe recruited 18 PD patients, 18 PD patients with depression, and 12 demographically-similar non-PD patients with clinical depression. All patients were on their usual medications. We collected resting-state EEG in all patients and compared cortical brain signal features between patients with and without depression. We used a machine-learning algorithm that harnesses the entire power spectrum (linear predictive coding of EEG Algorithm for PD: LEAPD), to distinguish between groups.

ResultWe found differences between PD patients with and without depression in the alpha band (8-13 Hz) globally and in the beta (13-30 Hz) and gamma (30-80 Hz) bands in the central electrodes. From two minutes of resting-state EEG we found that LEAPD-based machine learning could robustly distinguish between PD patients with and without depression with 97% accuracy, and between PD patients with depression and non-PD patients with depression with 100% accuracy. We verified the robustness of our finding by confirming that the classification accuracy declines gracefully as data are truncated.

ConclusionsWe demonstrated the efficacy of the LEAPD algorithm in identifying PD patients with depression from PD patients without depression and controls with depression. Our data provide insight into cortical mechanisms of depression and could lead to novel neurophysiologically-based biomarkers for non-motor symptoms of PD.

HIGHLIGHTSO_LIWe used EEG to analyze depression in Parkinsons disease.
C_LIO_LIDepressed Parkinsons patients had distinct spectral EEG features.
C_LIO_LIMachine-learning algorithms could accurately distinguish depression in Parkinsons disease.
C_LI


title: Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high grade serous carcinoma

abstract:
BACKGROUNDOvarian carcinosarcoma (OCS) is an uncommon, biphasic and highly aggressive ovarian cancer type, which has received relatively little research attention.

METHODSWe curated the largest pathologically-confirmed OCS cohort to date, performing detailed histopathological characterisation, analysis of features associated with survival, and comparison against high grade serous ovarian carcinoma (HGSOC).

RESULTS82 OCS patients were identified; overall survival was poor (median 12.7 months). 79% demonstrated epithelial components of high grade serous (HGS) type, while 21% were endometrioid. Heterologous elements were common (chondrosarcoma in 32%, rhabdomyosarcoma in 21%, liposarcoma in 2%); chondrosarcoma was more frequent in OCS with carcinomatous components of endometrioid type. Earlier stage, complete surgical resection, and treatment with platinum-containing chemotherapy were associated with prolonged survival; however, risk of relapse and mortality was high across all patient groups. Histological subclassification did not identify subgroups with distinct survival. Compared to HGSOC, OCS patients were older at diagnosis (P<0.0001), more likely to be FIGO stage I (P=0.025), demonstrated lower chemotherapy response rate (P=0.001) and had significantly poorer survival (P<0.0001).

CONCLUSIONOCS represents a distinct, highly lethal form of ovarian cancer for which new treatment strategies are urgently needed. Aggressive adjuvant chemotherapy should be considered for all patients, including those with early stage disease.


title: Multi-cohort transcriptomic subtyping of B-cell acute lymphoblastic leukemia

abstract: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and comprises multiple genetically distinguishable subtypes. To detect subtypes, current pipelines include fusion calling, polymorphisms, candidate gene copy numbers and cytogenetics but these approaches have limitations. RNA-seq provides a functional genome-wide snapshot that enables classification of ALL subtypes, however, typical mRNA-seq clustering analyses lack the rigor of quantitative modelling. Furthermore, high-dimensional gene expression data across cohorts and countries contain biases that previous transcriptomics studies have not addressed. Our aim was to integrate easy-to-interpret reliable transcriptome-wide biomarkers into subtyping pipelines. We analyzed 2,046 samples from two continents, carefully adjusted for biases and applied a rigorous machine learning design with independent replication. Six ALL subtypes that covered 32% of patients were robustly detected by mRNA-seq (PPV [≥] 87%). Five other frequent subtypes were distinguishable in 40% of patients, although overlapping transcriptional profiles led to lower accuracy (52% [≤] PPV [≤] 73%). Based on these findings, we developed the Allspice tool that predicts ALL subtypes and driver genes from unadjusted mRNA-seq read counts as encountered in real-world settings. Allspice also includes quantitative classification and safety metrics to help determine the most plausible genetic drivers for cases where other findings are inconclusive.


title: Evolutionary Trajectories of SARS-CoV-2 Alpha and Delta Variants in White-Tailed Deer in Pennsylvania

abstract: Introductory paragraphThe SARS-CoV-2 pandemic likely began by spillover from bats to humans1-3; today multiple animal species are known to be susceptible to infection4-8. White-tailed deer, Odocoileus virginianus are infected in the United States at substantial levels9-11, raising concerns about the formation of a new animal reservoir and potential of spill-back of new variants into humans12. Here we characterize SARS CoV-2 in deer from Pennsylvania (PA) sampled during fall and winter 2021. Of 93 nasal swab samples analyzed by RT-qPCR, 18 (19.3%) were positive for SARS-CoV-2. Seven whole-genome sequences were obtained, which were annotated as alpha and delta variants, the first reported observations of these lineages in deer, documenting multiple new jumps from humans to deer. The alpha lineage persisted in deer after its displacement by delta in humans, and deer-derived alpha variants diverged significantly from those in humans, consistent with a distinctive evolutionary trajectory in deer.


title: Risk of SARS-CoV-2 reinfection 18 months after primary infection: population-level observational study.

abstract: Current data suggest that SARS-CoV-2 reinfections are rare, but uncertainties remain on the duration of the natural immunity, its protection against Omicron variant, finally the impact of vaccination to reduce reinfection rates. In this retrospective cohort analysis of the entire population of an Italian Region, we followed 1,293,941 subjects from the beginning of the pandemic to the current scenario of Omicron predominance (up to mid-January 2022). After an average of 334 days, we recorded 260 reinfections among 84,907 previously infected subjects (overall rate: 0.31%), two hospitalizations (2.4 x100,000), and one death. Importantly, the incidence of reinfection did not vary substantially over time: after 18-22 months from the primary infection, the reinfection rate was still 0.32%, suggesting that protection conferred by natural immunity may last beyond 12 months. The risk of reinfection was significantly higher among the unvaccinated subjects, and during the Omicron wave.


title: Pan-cancer detection and typing by mining patterns in large genome-wide cell-free DNA sequencing datasets

abstract:
BackgroundCell-free DNA (cfDNA) analysis holds great promise for non-invasive cancer screening, diagnosis and monitoring. We hypothesized that mining the patterns of big datasets of shallow whole genome sequencing cfDNA from cancer patients could improve cancer detection.

MethodsBy applying unsupervised clustering and supervised machine learning on large shallow whole-genome sequencing cfDNA datasets from healthy individuals (n=367), patients with different hematological (n=238) and solid malignancies (n=320), we identify cfDNA signatures that enable cancer detection and typing.

ResultsUnsupervised clustering revealed cancer-type-specific sub-grouping. Classification using supervised machine learning model yielded an overall accuracy of 81.62% in discriminating malignant from control samples. The accuracy of disease type prediction was 85% and 70% for the hematological and solid cancers, respectively. We demonstrate the clinical utility of our approach by classifying benign from invasive and borderline adnexal masses with an AUC of 0.8656 and 0.7388, respectively.

ConclusionsThis approach provides a generic and cost-effective strategy for non-invasive pan-cancer detection.


title: The impact of theta-burst stimulation on cortical GABA and glutamate in treatment-resistant depression: A surface-based MRSI analysis approach

abstract:
BackgroundTheta burst stimulation (TBS) belongs to one of the biological antidepressant treatment options. When applied bilaterally, excitatory intermittent TBS (iTBS) is commonly targeted to the left and inhibitory continuous TBS (cTBS) to the right dorsolateral prefrontal cortex. TBS was shown to influence neurotransmitter systems, while iTBS is thought to interfere with glutamatergic circuits and cTBS to mediate GABAergic neurotransmission.

ObjectivesWe aimed to expand insights in the therapeutic effects of TBS on the GABAergic and glutamatergic system utilizing 3D-multivxovel magnetic resonance spectroscopy imaging (MRSI) in combination with a novel surface-based MRSI analysis approach to investigate changes of cortical neurotransmitter levels in patients with treatment resistant depression (TRD).

MethodsTwelve TRD patients (5 female, mean age{+/-}SD=35{+/-}11 years) completed paired MRSI measurements, using a GABA-edited 3D-multivoxel MEGA-LASER sequence, before and after three weeks of bilateral TBS treatment. Changes in cortical distributions of GABA+/tNAA (GABA+macromolecules relative to total N-acetylaspartate) and Glx/tNAA (Glx=mixed signal of glutamate and glutamine), were investigated in a surface-based region-of-interest (ROI) analysis approach.

ResultsANCOVAs revealed a significant increase in Glx/tNAA ratios in the left caudal middle frontal area (pcorr.=0.046, F=13.292), an area targeted by iTBS treatment. Whereas, contralateral treatment with cTBS evoked no alterations in glutamate or GABA concentrations.

ConclusionThis study demonstrates surface-based adaptions in the stimulation area to the glutamate metabolism after excitatory iTBS but not after cTBS, using a novel surface-based analysis of 3D-MRSI data. The reported impact of facilitatory iTBS on glutamatergic neurotransmission provides further insight into the neurobiological effects of TBS in TRD.


title: Neural Dysregulation in Post-Covid Fatigue

abstract:
Following infection from SARS-CoV-2, a substantial minority of people develop lingering after-effects known as  long COVID. Fatigue is a common complaint with substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear.

We recruited 37 volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems.

In comparison to age and sex matched volunteers without fatigue (n=52), we show underactivity in specific cortical circuits, dysregulation of autonomic function, and myopathic change in skeletal muscle. Cluster analysis revealed no sub-groupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. Based on our analysis we were also able to exclude dysregulation in sensory feedback circuits and descending neuromodulatory control.

These abnormalities on objective tests may indicate novel avenues for principled therapeutic intervention, and could act as fast and reliable biomarkers for diagnosing and monitoring the progression of fatigue over time.


title: A Human Skin Model for Assessing the Arboviral Infections

abstract: Arboviruses such as flaviviruses and alphaviruses cause a significant human healthcare burden on the global scale. Transmission of these viruses occurs during human blood feeding at the mosquito-skin interface. Not only do pathogen immune evasion strategies influence the initial infection and replication of pathogens delivered, but arthropod salivary factors also influence transmission foci. In-vitro cell cultures do not provide an adequate environment to study complex interactions between viral, mosquito, and host factors. To address this need for a whole tissue system, we describe a proof-of-concept model for arbovirus infection using adult human skin ex vivo with Zika virus (flavivirus) and Mayaro virus (alphavirus). Replication of these viruses in human skin was observed up to 4 days post-infection. Egressed viruses could be detected in the culture media as well. Antiviral and pro-inflammatory genes, including chemoattractant chemokines, were expressed in infected tissue. Immunohistochemical analysis showed the presence of virus in the skin tissue at 4 days post-infection. This model will be useful to further investigate: 1) the immediate molecular mechanisms of arbovirus infection in human skin, and 2) the influence of arthropod salivary molecules during initial infection of arboviruses in a more physiologically relevant system.


title: Anti-SARS-CoV-2 IgG antibodies after recovery from COVID-19 or vaccination in Libyan population: comparison of four vaccines

abstract:
Measurement of strength and durability of SARS-COV-2 antibody response is important to understand the waning dynamics of immune response to both vaccines and infection. The study aimed to evaluate the level of IgG antibodies against SARS-CoV-2 and their persistence in recovered, naive and vaccinated individuals. We randomly investigate Anti-spike RBD IgG antibody responses in 10,000 individuals, both following infection with SARS-CoV-2 and immunization with SARS-COV-2 adenoviral-vector and killed vaccines. Overall, antibody titres in recovered vaccinated individuals and naive vaccinee persists beyond 20 weeks. The mean levels of anti-spike IgG antibodies were higher in vaccinated participants with prior COVID-19 infections than in individuals without prior infection. Decline for IgG antibodies were faster in vaccinated individuals without previous COVID-19 infection compared to those with previous COVID-19 infection. Vaccination with adenoviral-vector vaccines generates higher antibody titers than for killed virus vaccine. Slightly over half of asymptomatic unvaccinated individuals develops antibody response. Previous COVID-19 infection elicited robust and sustained levels of SARS-CoV-2 antibodies in vaccinated individuals. A single dose of the vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with prior SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals. This study also underlines that asymptomatic infection equally generates antibodies as symptomatic infection. Those vaccinated with inactivated vaccine may require more frequent boosters than those vaccinated with an adenoviral vaccine. These findings are important for formulating public health vaccination strategies during COVID-19 pandemic.

ImportanceMeasurement of strength and durability of SARS-COV-2 antibody response is important to understand the waning dynamics of immune response to both vaccines and infection. We randomly surveyed 10,000 people for SARS-COV-2 antibodies. One vaccine dose with prior infection generated stronger immune response than two vaccine doses. Overall, antibody titres in recovered vaccinated individuals and naive vaccinee persists beyond 20 weeks. Vaccination with adenoviral-vector vaccines generates higher antibody titers than for killed virus vaccine slightly over half of asymptomatic unvaccinated individuals develops antibody response. This study emphasise on the benefit of vaccination in inducing strong immune response. These findings are important for formulating public health vaccination strategies during COVID-19 pandemic.


title: Immunity post-COVID-19 recovery boosts the antibody immune response to SARS-CoV-2 vaccination


title: Quantitative Radiomic Features from Computed Tomography Can Predict Pancreatic Cancer up to 36 Months Before Diagnosis

abstract:
ObjectivesPancreatic cancer (PC) is the 3rd leading cause of cancer deaths. We aimed to detect early changes on computed tomography (CT) images associated with pancreatic ductal adenocarcinoma (PDAC) based on quantitative imaging features (QIF).

MethodsAdults 18+ years of age diagnosed with PDAC in 2008-2018 were identified. Their CT scans 3 months-3 years prior to the diagnosis date were matched to up to two scans of controls. Pancreas was automatically segmented using a previously developed algorithm. 111 QIF were extracted. The dataset was randomly split for training/validation. Neighborhood and principal component analyses were applied to select the most important features. Conditional support vector machine was used to develop prediction algorithms. The computer labels were compared with manually reviewed CT images 2-3 years prior to the index date in 19 cases and 19 controls.

Results227 scans from cases (stages: 35% I-II, 44% III-IV, 21% unknown) and 554 matched scans of healthy controls were included (average age 71 years; 51% females). In the validation dataset, accuracy measures were 94%-95%, and area under the curve (AUC) measures were 0.98-0.99. Sensitivity, specificity, positive predictive value, and negative predictive values were in the ranges of 88-91%, 96-98%, 91-95%, and 94-96%. QIF on CT examinations within 2-3 years prior to index date also had very high predictive accuracy (accuracy 95-98%; AUC 0.99-1.00). The QIF-based algorithm outperformed manual re-review of images for determination of PDAC-risk.

ConclusionsQIF can accurately predict PDAC on CT imaging and represent promising biomarkers for early detection of pancreatic cancer.

WHAT IS KNOWNO_LIPancreatic cancer is the 3rd leading cause of cancer deaths.
C_LIO_LIEarly detection of pancreatic ductal adenocarcinoma (PDAC) is difficult owing to lack of specific symptoms or established screening.
C_LI

WHAT IS NEW HEREO_LIQuantitative imaging features (QIF) of pre-diagnostic CT scans can accurately predict PDAC in 3-36 months prior to diagnosis (accuracy 94-95% and AUC 0.98-0.99).
C_LIO_LIQIF on CT examinations within 2-3 years prior to cancer diagnosis also had very high predictive accuracy (accuracy 95-98%; AUC 0.99-1.00).
C_LIO_LIThe QIF-based algorithm outperformed manual re-review of images for determination of PDAC risk.
C_LI

category: gastroenterology


title: Factors Associated with Food Insecurity among Pregnant Women in Gedeo Zone Public Hospitals, Southern Ethiopia

abstract:
BackgroundFood insecurity refers to a lack of consistent access to sufficient food for active, better health. Around two billion people worldwide suffer from food insecurity and hidden hunger. Food insecurity and associated factors among pregnant women in Gedeo Zone Public Hospitals, Southern Ethiopia, are the focus of this study.

MethodFrom May to June 2021 G.C. institutional-based cross-sectional study was conducted among pregnant women in Gedeo zone public hospitals. A sample of 506 women has been used, and a multistage cluster sampling technique was used. An adjusted odds ratio (AOR) and their 95% confidence intervals (CI) were calculated to determine the association between various factors and outcomes. A p-value of less than 0.05 was considered significant in multivariable regression.

ResultsFood insecurity was found to be prevalent in 67.4% of pregnant mothers. The results of a multivariable logistic regression revealed that pregnant women from rural areas [AOR=0.532, 95 % CI: 0.285, 0.994], married [AOR=0.232, 95% CI: 0.072, 0.750], have a secondary education [AOR=0.356, 95%CI: 0.154, 0.822], and be employed [AOR=0.453, 95% CI: 0.236, 0.872], income between 1000 and 2000 [AOR=0.163, 95% CI: 0.066, 0.399], and income greater than 2000 [AOR=0.125, 95% CI: 0.053,0.293], the wealth index middle and rich [AOR=0.441, 95% CI: 0.246, 0.793] were significant predictors of food insecurity among pregnant mothers [AOR=0.24, 95 % CI: 0.128, 0.449].

ConclusionThe study area had a high prevalence of food insecurity. Food insecurity was reduced in those who lived in rural areas, were married, had a secondary education, earned between 1000 and 2000 ETB and more than 2000 ETB, and had a wealth index of middle and rich.


title: Can we see gender through the microscope? The research output using menstrual blood cells has much to say.

abstract: Despite proven scientific quality of menstrual blood mesenchymal cells, research and science output using those cells is still incipient and considered taboo. This study analyzes the literature of the menstrual blood mesenchymal stromal/stem cells (mbMSC) at PubMed database between (2008 - 2020) and the social attention it received on Twitter. A comparative analysis showed that mbMSC has a very small space within mesenchymal cells research (0.25%). Most first authors are women (53.2%), whereas most last authors are men (63.74%). Menstrual blood tends to be less used in experiments and its scientific value tends to be underestimated, which brings gender bias to a technical and molecular level. Although women are more positive in the mbMSC debate on Twitter, communication efforts toward visibility and public interest in menstrual cells has room to grow.


title: Knowledge, Attitude and Perceptions Regarding Male Infertility among the Medical Students and Healthcare Professionals of Bangladesh

abstract:
BackgroundPeople worldwide have many misconceptions regarding reproductive health and fertility because infertility is still a taboo subject. The general public seek medical and psychological counsel and assistance from health experts about male infertility. Therefore, this study aimed to explore the knowledge, attitude, and behavior regarding male infertility among medical students and health care workers of Bangladesh.

MethodThis cross-sectional study used quota sampling to assure equal participation from each of the eight divisions of Bangladesh and convenience. 46 structured questions were used to assess respondents knowledge, attitudes, and perceptions (34-items for knowledge, 5-items for attitudes, and 7-items for perceptions).Two scoring systems were employed with the mean scores as cut-off value for good knowledge and positive attitude. The mean knowledge and attitude scores were then correlated with sociodemographic factors using chi-square and two-independent sample t-tests. Finally, we performed binary logistic regression to explore predictors of good knowledge and positive attitude.

ResultAmong the participant, 49.82% did not have a good male infertility knowledge and nearly 60.79% had negative attitudes regarding male infertility. Young (23-26 years) healthcare professionals and medical students were more likely to have good knowledge than others (OR: 1.81; 95% CI: 1.099 to 2.988). Surprisingly, females were more likely to have positive attitude (OR=1.48; 95%CI: 1.002 and 2.19, p=0.049) compared to males. Among all the professions, MBBS doctors were most likely to have good knowledge and positive attitude regarding male infertility. Good knowledge of male infertility predicted positive attitude (OR=1.61; 95% CI: 1.105 and 2.346, p=0.013) and vice versa.

ConclusionOur research found that despite favourable opinions, healthcare professionals and medical students in Bangladesh had inadequate knowledge and negative attitudes regarding male infertility. This emphasizes the need for interdisciplinary training programs, standardization of healthcare worker guidelines, and curricular adjustments for medical students.


title: Resurgence of malaria in Uganda despite sustained indoor residual spraying and repeated long lasting insecticidal net distributions

abstract: Five years of sustained indoor residual spraying (IRS) of insecticide from 2014 to 2019, first using a carbamate followed by an organophosphate, was associated with a marked reduction in the burden of malaria in five districts of Uganda. We assessed malaria burden over an additional 21 months, corresponding to a change in IRS formulations using clothianidin with and without deltamethrin and the start of the COVID-19 pandemic. We document an unprecedented resurgence in malaria burden: in years 4-5 of sustained IRS cases were 84% lower than the pre-IRS period, in year 6 this increased to a 43% reduction, and in the first 9 months of year 7, cases were 39% higher than pre-IRS levels. The timing of this resurgence corresponded to a change of active ingredient to clothianidin, a new IRS active ingredient. Further research is needed to determine mechanisms leading to this resurgence.


title: Post-COVID-19 tele-survey for persistent symptoms in a single center hospital cohort in India along with a parallel country-wide web-survey

abstract:
IntroductionA major concern amidst the ongoing coronavirus pandemic has been the longer term persistence of morbidities in individuals recovering from COVID-19 disease, called  long COVID. We aimed at documenting the prevalence and key associations of post-COVID symptoms (PCS) in India in telephonic survey among recovered patients in a single hospital in eastern India as well as a parallel web-survey covering a wider population of the country.

MethodsSelf-reported PCS, ranging up to one year since the original COVID-19 diagnosis, were documented in a telephonic survey of subjects (analyzed N=986), treated for acute COVID-19 in Infectious Diseases and Beleghata General Hospital, Kolkata, between April 1, 2020 and April 13, 2021. In parallel, we ran a web-based survey (analyzed N=580), to evaluate concordance.

ResultsShortness of breath, fatigue and insomnia were identified to be the most commonly reported PCS in both the surveys, with higher prevalence in females. In the telephonic survey, a 3.65% post-discharge mortality was registered within a median of 39 days since COVID diagnosis. Intensive care during acute disease and hypertension were more often associated with PCS, while fatigue was more often reported by the 20-40 years age-group. The web-survey revealed a gradual decline in PCS with time since COVID-19 diagnosis and type 2 diabetes to be associated with higher prevalence of these symptoms.

ConclusionsWe assessed the predominant PCS among Indian COVID-19 patients and identified key demographic and clinical associations in our surveys, which warrants deeper epidemiological and mechanistic studies for guiding management of long-COVID in the country.


title: Clinical activity of MAPK targeted therapies in patients with non-V600 BRAF mutant tumors

abstract:
PurposeNon-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers in a wide array of cancer types and can be classified into three Classes according to molecular characteristics. Consensus treatment strategies for Class 2 and 3 BRAF mutations have not yet been established.

MethodsWe performed a systematic review and meta-analysis of individual patient data to assess treatment outcomes with FDA-approved mitogen activated protein kinase pathway (MAPK) targeted therapy according to BRAF Class, cancer type and MAPK targeted therapy type. A search was conducted on literature from 2010-2021. Individual patient data was collected and analyzed from published reports of patients with cancer harboring Class 2 or 3 BRAF mutations and who received MAPK targeted therapy with available treatment response data. Co-primary outcomes were response rate (RR) and progression-free survival (PFS).

Results18167 studies were screened, identifying 80 studies with 238 patients that met inclusion criteria. This included 167 patients with Class 2 and 71 patients with Class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, RR and PFS were higher among patients with Class 2 compared to Class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK +/- BRAF inhibitors demonstrated greater clinical activity in Class 2 compared to Class 3 BRAF mutant tumors than BRAF or EGFR inhibitors.

ConclusionsThis meta-analysis suggests that MAPK targeted therapies have clinical activity in some Class 2 and 3 BRAF mutant cancers. BRAF Class may dictate responsiveness to current and emerging treatment strategies, particularly in metastatic melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made based on a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.


title: Functional and structural impairment of small nerve fibers in patients suffering from hypermobile Ehlers Danlos Syndrome/Hypermobility Spectrum Disorder

abstract:
Ehlers Danlos syndromes (EDS) are heritable connective tissue disorders. The hypermobile form (hEDS) is the most frequent, yet the only one without an identified genetic mutation. Patients suffering from symptomatic joint hypermobility, yet not fulfilling the hEDS criteria, enter the Hypermobility Spectrum Disorder (HSD) category. In addition to musculoskeletal pain affecting joints, hEDS/HSD patients often describe painful sensations, hypoesthesia, and autonomic symptoms suggesting a neuropathic component. Small fiber neuropathy (SFN) refers to the dysfunction or damage of A-{delta} and C-fibers, which relay thermal and nociceptive information as well as mediating autonomic function. SFN has been suggested by prior studies in hEDS but these early findings (case series N[≤]20) with sole reliance on intraepidermal nerve fiber density (IENFD) called for a larger sample combined with functional testing.

In this retrospective chart extraction from 79 hEDS/HSD patients referred to a pain center due to neuropathic pain or dysautonomia, both functional (Quantitative Sensory Testing (QST), N=79) and structural (IENFD, N=69) evaluations of small nerve fibers were analyzed in combination with clinical data and standardized questionnaires.

All the patients reported moderate to severe pain interfering with daily life. A decreased thermal detection (QST) was shown in 55/79 patients (70%) and a decreased IENFD in 54/69 patients (78%). Hence a small fiber neuropathy (both abnormal IENFD and QST) was definite in 40/69 patients (58%), possible in 23/69 patients (33%) and excluded in only 6/69 patients (9%).

These results add strong evidence for a peripheral neuropathic contribution to pain symptoms in hEDS/HSD, in addition to the known nociceptive and central sensitization components. Such neuropathic contribution could raise the hypothesis of a neurological cause of hEDS, the only EDS syndrome still without a known genetic cause. Hence, our data is leading the way to a better stratification of this very heterogeneous population, which could improve symptommanagement and expand pathophysiological research.

category: pain medicine


title: Characterization of small fiber neuropathy in hypermobile Ehlers Danlos Syndrome


title: SPECIFICATIONS OF THE ACMG/AMP VARIANT CURATION GUIDELINES FOR MYOCILIN: RECOMMENDATIONS FROM THE CLINGEN GLAUCOMA EXPERT PANEL

abstract: The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation guidelines. The Glaucoma VCEP was created to develop rule specifications for genes associated with primary glaucoma, including myocilin (MYOC), the most common cause of Mendelian glaucoma. Of the 28 ACMG/AMP criteria, the Glaucoma VCEP adapted 15 rules to MYOC, and deemed 13 rules not applicable. Key specifications included determining minor allele frequency thresholds, developing an approach to counting probands and segregations, and reviewed functional assays. The rules were piloted on 81 variants and led to a change in classification in 38% of those that were classified in ClinVar with functional evidence influencing the classification of 18 variants. The standardized variant curation guidelines for MYOC provide a framework for the consistent application of the rules between laboratories, to improve MYOC genetic testing in the management of glaucoma.