title: "We just considered it  to be over there" : A qualitative study exploring urban perspectives for disease introduction

abstract: Rift Valley fever virus (RVFV) is a zoonotic arbovirus that is also transmitted to humans from fluids and tissues of infected livestock. Urban areas in Kenya have the hosts, dense vector distributions, and source livestock (often from high-risk locations to meet the demand for animal protein ) , yet there has never been a documented urban outbreak of RVFV. To understand the likely risk of RVFV introduction in urban communities and guide future initiatives, we conducted Focus Group Discussions with slaughterhouse workers, slaughterhouse animal product traders, and dairy livestock owners in Kisumu City and Ukunda Town in Kenya. For added perspective and data triangulation, in-depth interviews were conducted one-on-one with meat inspector veterinarians from selected slaughterhouses. Themes on benefits of livestock in the urban setting were highlighted, including business opportunities, social status, and availability of fresh milk in the household. Urban slaughterhouses have formalized meat trading, which , in turn , has resulted in regulation for meat inspection and reduction in local livestock theft. High-risk groups have moderate knowledge about zoonotic diseases and consensus was towards lower personal risk in the urban setting compared to rural areas. Risk assessment was focused on hand hygiene rather than the slaughtering process. There was high reliance on veterinarians to confirm animal health and meat safety, yet veterinarians reported lack access to RVFV diagnostics. We also highlighted regulatory vulnerabilities relevant to RVFV transmission including corruption in meat certification outside of the slaughterhouse system, and blood collected during slaughter being used for food and medicine.  These factors, when compounded by urban vector abundance and dense human and animal populations could create ideal conditions for RVFV to emerge in endemic regions and establish an urban transmission cycle. Here, we present a qualitative study that provides context for urban RVFV introduction risks and insight for adapting current prevention and control measures.


title: "Does a respiratory virus have an ecological niche, and if so, can it be mapped?" Yes and yes.

abstract: Although the utility of Ecological Niche models (ENM) and Species Distribution models (SDM) has been demonstrated in many ecological applications, their suitability for modelling epidemics or pandemics, such as SARS-Cov-2, has been questioned. In this paper, contrary to this viewpoint, we show that ENMs and SDMs can be created that can describe the evolution of pandemics, both in space and time. As an illustrative use case, we create models for predicting confirmed cases of COVID-19, viewed as our target "species", in Mexico through 2020 and 2021, showing that the models are predictive in both space and time. In order to achieve this, we extend a recently developed Bayesian framework for niche modelling, to include: i) dynamic, non-equilibrium "species" distributions; ii) a wider set of habitat variables, including behavioural, socio-economic and socio-demographic variables, as well as standard climatic variables; iii) distinct models and associated niches for different species characteristics, showing how the niche, as deduced through presence-absence data, can differ from that deduced from abundance data. We show that the niche associated with those places with the highest abundance of cases has been highly conserved throughout the pandemic, while the inferred niche associated with presence of cases has been changing. Finally, we show how causal chains can be inferred and confounding identified by showing that behavioural and social factors are much more predictive than climate and that, further, the latter is confounded by the former.

category: epidemiology


title: Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

abstract:
ObjectivesThis study aimed to assess contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people in the United Kingdom as they are an understudied genetic ancestry group with high rates of parental relatedness and disproportionate disease burden.

MethodsFive genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by low/mid whole exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency <5%. Variants were filtered and annotated. Variants associated with a phenotype or predicted to be likely pathogenic (LP) underwent protein structure and modelling analysis.

ResultsOut of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were heterozygous. 90 were novel and unique to this cohort and not previously reported in the GnomAD database. Of those novel variants, 22 were considered LP and 9 pathogenic. We identified variants associated with gallstone disease (n=31), intrahepatic cholestasis of pregnancy (ICP, n=16), cholangiocarcinoma and cirrhosis (n=2). Fourteen heterozygous novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. A total of 73 variants underwent protein modelling. The study identified 10 variants that resulted in predicted significant structural damage at a protein level, of which 4 were unique to this cohort.

ConclusionsThis study identified novel LP and pathogenic variants. We provide further insight into rare variants associated with ICP, cholangiocarcinoma, and gallstone disease. This study highlights the importance of studying diverse ancestry groups in genomic research.

WHAT IS KNOWNCholestatic liver diseases encompass a broad range of conditions.

Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disease.

Genetic and environmental factors contribute to the aetiology of cholestatic disease.

South Asian populations are disproportionally affected.

WHAT IS NEW HEREExome sequencing analysis in a British South Asian population discovered new genetic mutations.

Pathogenic variants were identified that increase risk to cholestatic liver disease.

Novel variants that contribute to ICP were identified.

category: gastroenterology


title: Construction of a short version of the Montreal Cognitive Assessment (MoCA) rating scale using Partial Least Squares analysis

abstract:
BackgroundThe Montreal Cognitive Assessment (MoCA) rating scale is frequently used to assess cognitive impairments in amnestic mild cognitive impairment (aMCI) and Alzheimers disease (AD).

ObjectivesThe aims of this study are to a) evaluate the construct validity of the MoCA and its subdomains or whether the MoCA can be improved by feature reduction, and b) develop a short version of the MoCA (MoCA-Brief).

MethodsWe recruited 181 participants, divided into 60 healthy controls, 61 aMCI, and 60 AD patients.

ResultsThe construct reliability of the original MoCA was not optimal and could be improved by deleting one subdomain (Naming) and five items, namely Clock Circle, Lion, Digit Forward, Repeat 2nd Sentence, and Place, which showed inadequate loadings on the extracted latent vectors. To construct the MoCA-Brief, the reduced model underwent further reduction and feature selection based on model quality data of the outer models. We produced a MoCA-Brief rating scale comprising five items, namely Clock Time, Subtract 7, Fluency, Month, and Year. The first latent vector extracted from these five indicators showed adequate construct validity with an Average Variance Extracted of 0.599, composite reliability of 0.822, Cronbachs alpha of 0.832 and rho_A of 0.833. The MoCA-Brief factor score showed a strong correlation with the total MoCA score (r=0.98, p<0.001) and shows adequate concurrent, test-retest, and inter-rater validity.

ConclusionThe construct validity of the MoCA may be improved by deleting five items. The new MoCA-Brief rating scale deserves validation in independent samples and especially in other countries.

category: psychiatry and clinical psychology


title: Reporting Rates for VAERS Death Reports Following COVID-19 Vaccination, December 14, 2020-November 17, 2021

abstract:
BackgroundDespite widely available safety information for the COVID-19 vaccines, vaccine hesitancy remains a challenge. In some cases, vaccine hesitancy may be related to concerns about the number of reports of death to the Vaccine Adverse Event Reporting System (VAERS).

ObjectiveTo provide information and context about reports of death to VAERS following COVID-19 vaccination.

DesignDescriptive study; reporting rates for VAERS death reports.

SettingUnited States; December 14, 2020, to November 17, 2021.

ParticipantsCOVID-19 vaccine recipients.

MeasurementsReporting rates for death events per million persons vaccinated; adverse event counts; data mining signals of disproportionate reporting.

Results9,201 death events were reported for COVID-19 vaccine recipients aged five years and older (or age unknown). Reporting rates for death events increased with increasing age, and males generally had higher reporting rates than females. For death events within seven days and 42 days of vaccination, respectively, observed reporting rates were lower than the expected all-cause death rates. Reporting rates for Ad26.COV2.S vaccine were generally higher than for mRNA COVID-19 vaccines, but still lower than the expected all-cause death rates. Reported adverse events were non-specific or reflected the known leading causes of death.

LimitationsVAERS data are subject to several limitations such as reporting bias (underreporting and stimulated reporting), missing or inaccurate information, and lack of a control group. Reported diagnoses, including deaths, are not causally verified diagnoses.

ConclusionReporting rates for death events were lower than the expected all-cause mortality rates. Trends in reporting rates reflected known trends in background mortality rates. These findings do not suggest an association between vaccination and overall increased mortality.

Funding SourceNo external sources of funding were used.

category: public and global health


title: Altered Lateralization of the Cingulum in Deployment-Related Traumatic Brain Injury: An ENIGMA Military-Relevant Brain Injury Study

abstract:
Traumatic brain injury (TBI), a significant concern in military populations, is associated with alterations in brain structure and function, cognition, as well as physical and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) is particularly sensitive to changes in brain structure following TBI, as alterations in white matter (WM) microstructure are common. However, dMRI studies in mild TBI (mTBI) are conflicting, likely due to relatively small samples, sample heterogeneity (demographics, pre- and comorbidities) and injury characteristics (mechanism; chronicity). Furthermore, few studies account for brain asymmetry, which may impact cognitive functions subserved by WM tracts. Examining brain asymmetry in large samples may increase sensitivity to detect heterogeneous areas of subtle WM alteration in mTBI.

Through the Enhancing Neuroimaging and Genetics through Meta-analysis (ENIGMA) Military-Relevant Brain Injury working group, we conducted a mega-analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n=2,598; 2,321 males/277 females; age 19-85 years). 1,080 reported a deployment-related TBI, 480 had a history of only non-military-related TBI, 823 reported no history of TBI, and 215 did not differentiate between military and non-military TBI. dMRI data were processed in a harmonized manner along with harmonized demographic, injury, psychiatric, and cognitive measures. Hemispheric asymmetry of fractional anisotropy (FA, a common proxy for myelin organization) was calculated for 19 WM tracts and compared between those with and without TBI history.

FA in the cingulum showed greater asymmetry in individuals with a history of deployment-related TBI; this effect was driven by greater left lateralization in the group with TBI. There was a trend towards lower FA of the right cingulum in the TBI group. These results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness and were driven primarily by individuals who had sustained their worst TBI before age 40. We further found that alterations in the cingulum were associated with slower processing speed and poorer set shifting.

The results indicate an enhancement of the previously reported natural left laterality, possibly due to vulnerability of the non-dominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI.

category: neurology


title: Tanycytes are degraded in Alzheimer Disease, disrupting the brain-to-blood efflux of Tau

abstract: The accumulation of pathological Tau in the brain and cerebrospinal fluid (CSF) and its eventual increase in the blood are hallmarks of Alzheimers disease (AD). However, the mechanisms of Tau clearance from the brain to the periphery are not clear. We show here, using animal and cellular models as well as patient blood samples and post mortem brains, that hypothalamic tanycytes, whose cell bodies line the ventricular wall and send long processes to the underlying pituitary portal capillary bed, take up and transport Tau from the CSF and release it into these capillaries, whence it travels to the pituitary and eventually the systemic circulation. Specifically blocking tanycytic vesicular transport leads to an accumulation of exogenous fluorescent Tau in the CSF of mice. In AD and frontotemporal dementia, tanycytic morphology is altered, with a dramatic fragmentation of the secondary cytoskeleton in the former but not the latter, accounting for reduced CSF Tau clearance in AD. Both the implication of tanycytic degradation in the pathophysiology of a human disease and the evidence for the existence of a brain-to-blood tanycytic shuttle are unprecedented, and raise important questions regarding the role of tanycytes in physiological clearance mechanisms and the development of neurodegenerative disorders.


title: A Genome-Wide Association Study of Survival in Patients with Sepsis

abstract:
BackgroundSepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units (ICUs). Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis.

MethodsThis study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1,362 European Americans and 701 African Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p<5.0x10-8. Whole-blood transcriptomic and functional annotations were evaluated on the identified genes and variants.

FindingsWe identified three independent variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval]=1.64 [1.37-6.78], p=4.92x10-8). SAMD9 encodes a mediator of the inflammatory response to tissue injury that is overexpressed in peripheral blood of non-surviving sepsis patients compared to those surviving (p=2.18x10-3).

InterpretationWe performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Our findings could allow the identification of novel targets for sepsis treatment and patient risk stratification.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSepsis is defined as a life-threatening clinical syndrome of physiological, pathological, and biochemical abnormalities caused by a dysregulated host response to an infection, and with long-term physical, psychological, and cognitive disabilities. Many genetic studies have focused on identifying genetic risk factors associated with sepsis development and severity, but only four genome-wide association studies (GWAS) have been published to date. Three of them focused on sepsis mortality. The first study identified that common genetic variation in the FER gene associated with a reduced risk of death. The second study found variants associated with an increased risk of death in VPS13A, which is key in autophagic degradation. In the last study, variants of the CISH gene, involved in cytokine regulation, were associated with the risk of death. Nevertheless, there is a lack of GWAS focused on sepsis survival, which takes into account the probability estimates of death for each patient over time.

Added value of this studyTo the best of our knowledge, we provide the results of the first GWAS of 28-day sepsis survival conducted to date. In this two-staged study, we identified three novel loci associated with reduced 28-day survival among sepsis patients. We identified one missense variant in SAMD9, which encodes a critical regulator in the inflammatory response and apoptosis. A significant upregulation of SAMD9 gene expression in whole blood was observed among non-surviving sepsis patients compared to those surviving. Associations were also found for one intergenic variant to SLC5A12\FIBIN and an intergenic variant to two non-coding RNAs (LINC00378\MIR3169).

Implications of all the available evidenceThe identification of effective prognostic genetic markers in sepsis is a promising instrument for clinical practice. This study identified three novel genetic factors of fatal outcomes, all having interesting and important biological plausibly that could serve as novel targets for sepsis treatment. This knowledge is important to propose effective sepsis treatments and will be central in the development of personalized medicine approaches.

category: genetic and genomic medicine


title: Acetylation of Adenine Nucleotide Translocase, Fuel Selection, and Metabolic Flexibility in Human Skeletal Muscle

abstract: Introduction: Healthy, resting skeletal muscle primarily oxidizes lipid, but insulin resistant muscle oxidizes carbohydrate and shows metabolic inflexibility during hyperinsulinemia. It is unclear whether fuel selection and metabolic flexibility are dependent on insulin sensitivity in skeletal muscle performing mild exercise. Research Design and Methods: Sedentary volunteers underwent a cycle exercise protocol using stepwise increments in power output (15, 30, and 45 watts) and indirect calorimetry to estimate fuel oxidation in working muscle. Euglycemic clamps, indirect calorimetry and muscle biopsies were used to measure insulin sensitivity and acetylation and content of Adenine Nucleotide Translocase 1 (ANT1), which might be involved in fuel selection via acetylation of lysine 23, which was quantified using mass spectrometry. Results: Mild exercise produced predicted rates of oxygen consumption (11-12 ml O2/min), with low and stable blood lactate, allowing use of indirect calorimetry to calculate a respiratory exchange ratio in working muscle (RERm). ANT1 acetylation varied from 0.6 to 21% (10.3 +/- 1.2%). Exercising muscle mainly oxidized carbohydrate (45 +/- 9, 62 +/- 6, and 70 +/1 5% of total at 15, 30, and 45watts). Multiple linear regression showed that RERm rose with increasing power output (P < 0.001) and was lower with greater protein content of ANT1 (P < 0.001). Insulin-stimulated glucose disposal, ANT acetylation, and VO2peak were not predictors of RERm. Conclusions: Mildly exercising muscle in sedentary people prefers to oxidize carbohydrate independent of insulin sensitivity but depending on ANT1 protein content. The ability to oxidize lipid may be regulated by higher ANT1 content due to either higher mitochondrial abundance or greater ANT content per mitochondrial mass.

category: endocrinology


title: Aggressive Antipyretics in CNS Malaria: Study Protocol of a Randomized-Controlled Trial Assessing Antipyretic Efficacy and Parasite Clearance Effects (Malaria FEVER Study)

abstract: Background : Despite ongoing eradication efforts, malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neurodisability. Evidence indicates that among children with CNS malaria, a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted, at least among children with complicated malaria who are at substantial risk of brain injury. Previous clinical trials conducted primarily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management using dual therapies. In this clinical trial of aggressive antipyretic therapy, children hospitalized with CNS malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature greater than or equal to 38.5 degrees Celsius vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours. This proof-of-concept study will determine whether aggressive antipyretic therapy results in a lower mean maximum temperature relative to usual care. Methods : We will enroll 284 participants from three settings at Queen Elizabeth Central Hospital in Blantyre, Malawi; at the University Teaching Hospitals Children's Hospital in Lusaka, Zambia and at Chipata Central Hospital, Chipata, Zambia. Parents or guardians must provide written informed consent. Eligible participants are 2-11 years with evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test with CNS symptoms associated with malaria. Eligible children will receive treatment allocation as determined by randomization and will be assigned to treatment groups with 1:1 allocation using blocked randomization. Discussion : The clinical trial proposed here seeks to challenge the practice paradigm of limited fever treatment based upon hyperpyrexia by evaluating the fever-reduction efficacy of more aggressive antipyretic use involving two antipyretics and prophylactic administration while also taking advantage of a relatively new method for quantifying total parasite burden (HRP2 quantification) to further characterize malaria severity and elucidate the impact of antipyretics on parasite sequestration and clearance. If aggressive antipyretic therapy is shown to safely reduce the maximum temperature during CNS malaria, a clinical trial evaluating the neuroprotective effects of temperature reduction in CNS malaria is warranted.


title: Behavioral Effects in Disorders of Consciousness Following Transcranial Direct Current Stimulation: A Systematic Review and Individual Patient Data Meta-analysis of Randomized Clinical Trials

abstract: Background: In patients with Disorders of Consciousness (DoC), transcranial direct current stimulation (tDCS) was a promising intervention for it. However, uncertainties remain about the treatment effect and the optimal treatment strategy of the tDCS in the DoC. Objective: In this meta-analysis of individual patient data (IPD), we assess whether utilizing tDCS as a treatment in DoC could improve patients' behavioral performance and whether patient characteristics or tDCS protocol could modify the treatment effect. Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials through April 7, 2022, using the terms 'persistent vegetative state,' 'minimally conscious state,' 'disorder of consciousness,' or 'unresponsive wakefulness syndrome,' and 'transcranial direct current stimulation' to identify Randomized Controlled Trials (RCTs) in English-language publication. Studies were eligible for inclusion if they reported pre- and post-tDCS Coma Recovery Scale-Revised (CRS-R) scores. From the included studies, any patients who had incomplete data were excluded. We performed a meta-analysis to assess the treatment effect of the tDCS compared with sham control. Additionally, a subgroup analysis was performed to determine whether patients' baseline characteristics could modify the treatment effect and the optimal tDCS protocol. Results: We identified 145 papers, eight trials (including 181 patients) were finally included in the analysis, and one individual data were excluded because of incompletion. Our meta-analysis demonstrated a mean difference change in the CRS-R score of 0.89 (95% CI, 0.17-1.61) between tDCS and sham-control, favoring tDCS. The subgroup analysis showed that patients who were male or in minimally conscious state (MCS) were associated with a greater improvement in CRS-R score and that adopting 5 or more sessions of tDCS protocol might have a better treatment effect than just one session. Conclusion: tDCS can improve the behavioral performance of DoC patients. However, heterogeneity existed within the patients' baseline condition and the stimulation protocol. There should be more exploration of the optimal tDCS protocol and the most beneficial patient group based on the mechanism of tDCS in the future.


title: Associations of Midlife Diet Quality with Incident Dementia and Brain Structure: Findings from the UK Biobank Study

abstract: Objective: To investigate the associations of midlife diet quality with incident dementia and brain structure. Design: Population-based prospective study and cross-sectional study. Setting: UK Biobank. Participants: In total, 187,783 participants (mean age 56.8 years, 54.9% women) who completed the 24-hour recall dietary questionnaire were included in the prospective study. A subgroup of 25,380 participants (mean age 55.7 years, 52.9% women) with brain structure data were included in the cross-sectional study. Main exposure and outcome measures: Cox proportional hazards models and linear regression models were used to examine the associations of seven diet quality scores, i.e., hPDI (Healthful Plant-based Diet index), MDS (Mediterranean Diet score), aMED (alternate Mediterranean diet), RFS (Recommended Food Score), DASH (Dietary Approaches to Stop Hypertension), MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay diet) and AHEI-2010 (the Alternative Healthy Eating Index-2010), with incident dementia and brain structure (estimated using magnetic resonance imaging), respectively. Results: During a total follow-up of 1,969,993 person-years, 1,363 (0.73%) participants developed dementia. Higher diet quality scores (except for hPDI) were consistently associated with a lower incidence risk of dementia (all P for trend<0.001). For instance, for RFS, the hazard ratios of the intermediate tertile group and the highest tertile group relative to the lowest tertile group were 0.85 (95% confidence interval [95%CI]=0.75 to 0.97) and 0.70 (95%CI=0.61 to 0.81), respectively. Moreover, higher diet quality scores were significantly associated with larger regional brain volumes including volumes of grey matter (GM) in the parietal and temporal cortex and volumes of the hippocampus and thalamus. For instance, higher RFS was associated with larger volumes of GM in the postcentral gyrus (Beta=16.05, SD=4.08, P<0.001) and the hippocampus (Beta=5.87,SD=1.26, P<0.001). A series of sensitivity analyses confirmed the main results. Conclusion: Greater adherence to MDS, aMED, RFS, DASH, MIND, and AHEI-2010 were individually associated with lower risk of incident dementia and larger brain volumes in specific regions. This study shows a comprehensive picture of the consistent associations of midlife diet quality with dementia risk and brain health, providing mechanistic insights into the role of healthy diet in the prevention of dementia.

category: nutrition


title: Substance abuse and the risk of severe COVID-19: Mendelian randomization confirms the causal role of opioids but hints a negative causal effect for cannabinoids.

abstract: Since the start of the COVID-19 global pandemic, our understanding of the underlying disease mechanism and factors associated with the disease severity has dramatically increased. A recent report investigated the relationship between substance use disorders (SUD) and the risk of severe COVID-19 in the United States and concluded that the risk of hospitalization and death due to COVID-19 is directly correlated with substance abuse, including opioid use disorder (OUD) and cannabis use disorder (CUD). While we found this analysis fascinating, we believe this observation may be biased due to comorbidities (such as hypertension, diabetes, and cardiovascular disease) confounding the direct impact of SUD on severe COVID-19 illness. To objectively answer this question, we sought to investigate the causal relationship between substance abuse and medication-taking history (as a proxy trait for comorbidities) with the risk of COVID-19 adverse outcomes. Our Mendelian randomization analysis confirms the causal relationship between SUD and severe COVID-19 illness but hints at a negative causal effect for cannabinoids. Given that a great deal of COVID-19 mortality is attributed to disturbed immune regulation, the possible modulatory impact of cannabinoids in alleviating cytokine storms merits further investigation.


title: Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron Variant of Concern

abstract: Background Recent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting SARS-CoV-2 varies according to the Variant of Concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC. Methods The MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with early COVID-19. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was COVID-19 progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions. Results Overall, 319 patients were included. Among 141 patients infected with Delta, no disease progression was recorded and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.895). Among 170 patients infected with Omicron (80.6% BA.1, 19.4% BA.1.1), two disease progressions were recorded in the bamlanivimab/etesevimab group and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared to bamlanivimab/etesevimab and casirivimab/imdevimab (HR 0.526 and HR 0.451, 95% CI 0.359 - 0.77 and 95% CI 0.303 - 0.669, p 0.001 and 0.0001, respectively). Conclusions These results confirm the in-vitro data of superiority of sotrovimab versus casirivimab/imdevimab and bamlanivimab/etesivamab in reducing the time to recovery in patients infected with Omicron BA.1 and BA.1.1, while no difference was detected in Delta infections. Casirivimab/imdevimab seems to maintain a role in preventing severe COVID-19 in the Omicron population. Adaptive clinical trials comparing mAbs by VOC should be pursued to promptly inform clinical recommendations.

category: infectious diseases


title: Clinical and Virological Features of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in Vaccinated and Unvaccinated Patients in Mexico City

abstract: Background: Coronavirus disease 2019 (COVID-19) vaccines are very effective at protecting against severe disease and death. However, the impact of the vaccine used, viral variants, and host factors on disease severity in vaccinated individuals remain poorly understood. Here we compared COVID-19 clinical presentations and outcomes in vaccinated and unvaccinated patients in a tertiary hospital in Mexico City. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants were also determined to study their potential impact on disease severity. Methods: From March to September 2021, clinical and demographic characteristics were obtained from 1,014 individuals with a documented SARS-CoV-2 infection, and viral variants were identified in a subset of 386 patients. We compared three groups of patients: 1) unvaccinated, 2) partially vaccinated, and 3) fully vaccinated, stratifying by age groups (<30 years, 31-60 years, and > 61 years) on the clinical outcomes, and including in-hospital mortality. We fitted different multivariate statistical models to evaluate the impact of vaccination status, SARS-CoV-2 lineages, vaccine types, and clinical parameters. Results: 1,014 patients were included, with 11% being outpatients and 88% hospitalized. Most hospitalized patients were unvaccinated. In patients over 61 years old, mortality was significantly higher in unvaccinated compared to fully vaccinated individuals. In patients aged 31 to 60 years, vaccinated patients were more likely to be outpatients (46%) than unvaccinated individuals (6.1%). The percentage of critical patients over 61 years was higher in unvaccinated than vaccinated individuals (75% vs. 56%, p < 0.001). We found immune disease (OR: 3.12, 95% CI: 1.09-8.34, p = 0.02) and age above 61 years old (OR: 3.51, 95% CI: 2.3-5.2, p = 5.9e-10) as risk factors. While fully vaccination was found as the most protective factor against in-hospital death (OR: 0.25, 95% CI: 0.12-0.46, p = 2.89e-05). Conclusions: This study suggests that vaccination and particularly full vaccination is essential to reduce mortality in a comorbid population such as that of Mexico. When analyzing the presence of comorbidities and advanced ages as risk factors, complete vaccination was the most significant protective factor against death by COVID-19. We found no strong association between SARS-CoV-2 lineages or vaccine type and disease severity.


title: How to improve access to TB care for the nomads? Review of barriers and enablers for Sahel nomadic populations

abstract: Background Tuberculosis (TB) control in nomadic populations represents a major public health problem in sub Saharan Africa. Methods Barriers and enablers of TB care for nomads were identified through a literature review and survey conducted among the National TB Programs (NTPs) of six Sahelian countries: Burkina Faso, Chad, Niger, Mali, Mauritania and Senegal. A conceptual framework was developed. Data retrieved from twenty-eight peer-reviewed papers or collected through the survey were regrouped in 5 categories: health system related factors, socioeconomic factors, cultural, political and environmental factors. Results The large distance between nomadic camps and health care facilities and the absence of TB-specific programmatic interventions for nomads were the main barriers identified. The establishment of a multi-ministerial national committee in charge of nomadic populations, the mapping of nomadic transhumance roads, the identification of gaps in health service provision and community engagement for defining fit for purpose solutions are key elements to improve TB control in nomadic population. Conclusion Some countries in the region successfully implemented interventions to overcome the barriers to TB care. These interventions should be more widely shared to inform other countries for the development of appropriate strategies for which community engagement is essential.


title: Measuring the impact of nonpharmaceutical interventions on the SARS-CoV-2 pandemic at a city level: An agent-based computational modeling study of the City of Natal.

abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic hit almost all cities in Brazil in early 2020 and lasted for several months. Despite the effort of local state and municipal governments, an inhomogeneous nationwide response resulted in a death toll amongst the highest recorded globally. To evaluate the impact of the nonpharmaceutical governmental interventions applied by different cities -- such as the closure of schools and business in general -- in the evolution and epidemic spread of SARS-CoV-2, we constructed a full-sized agent-based epidemiological model adjusted to the singularities of particular cities. The model incorporates detailed demographic information, mobility networks segregated by economic segments, and restricting bills enacted during the pandemic period. As a case study, we analyzed the early response of the City of Natal -- a midsized state capital -- to the pandemic. Although our results indicate that the governmental response could be improved, the restrictive mobility acts saved many lives. The simulations show that a detailed analysis of alternative scenarios can inform policymakers about the most relevant measures for similar pandemic surges and help developing future response protocols.


title: Neighborhood distribution of availability of newer tobacco products: A four-site study, 2021

abstract: Background: Audits of tobacco retail stores can identify marketing patterns as newer tobacco products are introduced in the US. Our study examined store and neighborhood correlates of availability of nicotine pouches and disposable e-cigarettes in four US sites. Methods: We conducted standardized store audits of n=242 tobacco retailers in 2021 in different states: New Jersey, Kentucky, North Carolina, and New York. Store audits focused on availability of nicotine pouches and disposable e-cigarettes. We geocoded stores linking them with census tract demographics. We conducted unadjusted and adjusted Poisson regression of availability of each product with correlates of the proportion of Non-Hispanic White residents, households under poverty, proximity to schools, site, and store type. Results: Nicotine pouches and disposable e-cigarettes were each available in around half the stores, but availability differed across sites. In adjusted analyses, nicotine pouches were less likely to be available in each store type vs. chain convenience and more likely in stores in census tracts with more non-Hispanic White residents. In contrast, disposable e-cigarettes were more likely to be available in tobacco store/vape shops than convenience stores and less likely in non-specialty store types like groceries. Conclusions: The availability of newer tobacco products like nicotine pouches and disposable e-cigarettes were widely available in stores across sites, but retail marketing patterns appear to differ. As these product types become subject to increased regulation as they go through the FDA pre-market authorization process, understanding changes in their retail environment is critical to inform potential policies regulating their sale and marketing.


title: Partial and Radical cystectomy Provides Equivalent Oncologic Outcomes in T2 Bladder Cancer: a Population-Based Study

abstract: Purpose: To compare the oncologic outcomes of T2 bladder cancer (BCa) patients after partial cystectomy (PC) or radical cystectomy (RC). Materials and Methods: Relevant data of T2 BCa patients diagnosed between 2004 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database. After propensity score matching, the oncologic outcomes after PC or RC were compared in patients who underwent lymph node dissection (LND) or not. Additionally, the benefits of different LND strategies were also explored. Results: Eventually, 3834 T2 BCa cases were enrolled in the analysis, including 724 (18.9%) received PC cases and 3110 (81.1%) RC cases. The PC and RC groups presented entirely different profiles in clinical parameters such as age, number of lymph nodes (LNs) removed, and adjuvant therapy. Particularly, LNDs were performed in 92.0% of RC cases, while only in 45.4% of PC cases. After propensity score matching, PC and RC present similar oncologic outcomes regardless of the LND strategies. Further exploration found that LND could improve the prognosis of patients and the benefit is associated with the number of LNs removed. Conclusion: PC and RC could provide equivalent oncologic outcomes in T2 BCa. LND is essential in curative surgery and could significantly affect the prognosis, but it was frequently neglected, especially in PC. The criteria for PC in T2 BCa need further exploration in future studies.

category: oncology


title: Validation of a transcriptome-based assay for classifying cancers of unknown primary origin

abstract: Cancers assume a variety of distinct histologies and may originate from a myriad of sites including solid organs, hematopoietic cells, and connective tissue. Clinical decision making based on consensus guidelines such as NCCN is often predicated on a specific histologic and anatomic diagnosis, supported by clinical features and pathologist interpretation of morphology and immunohistochemical (IHC) staining patterns. However, in patients with nonspecific morphologic and IHC findings - in addition to ambiguous clinical presentations such as recurrence versus new primary - a definitive diagnosis may not be possible, resulting in the patient being categorized as having a cancer of unknown primary (CUP). Therapeutic options and clinical outcomes are poor for CUP patients, with a median survival of 8-11 months. Here we describe and validate the Tempus Tumor Origin (Tempus TO) assay, an RNA-seq-based machine learning classifier capable of discriminating between 68 clinically relevant cancer subtypes. We show that the Tempus TO model is 91% accurate when assessed on retrospectively and prospectively held out cohorts of containing 9,210 samples with known diagnoses. When evaluated on a cohort of CUPs, the model recapitulated established associations between genomic alterations and cancer subtype. Combining diagnostic prediction tests (e.g., Tempus TO) with sequencing-based variant reporting (e.g., Tempus xT) may expand therapeutic options for patients with cancers of unknown primary or uncertain histology.


title: Accuracy and Glycemic Efficacy of Continuous Glucose Monitors in Critically Ill COVID-19 Patients: a Retrospective Study

abstract: Background: Continuous Glucose Monitoring (CGM) is approved for insulin dosing decisions in the ambulatory setting, but not currently for inpatients. CGM has the capacity to reduce patient-provider contact in inpatients with coronavirus disease 2019 (COVID-19), thus potentially reducing in hospital virus transmission. However, there are sparse data on the accuracy and efficacy of CGM to titrate insulin doses in inpatients. Methods: Under an emergency use protocol, CGM (Dexcom G6) was used alongside standard point-of-care (POC) glucose measurements in patients critically ill from complications of COVID-19 requiring intravenous (IV) insulin. Glycemic control during IV insulin therapy was retrospectively assessed comparing periods with and without adjunctive CGM use. Accuracy metrics were computed and Clarke Error Grid analysis performed comparing CGM glucose values with POC measurements. Results: 24 critically ill patients who met criteria for emergency use of CGM resulted in 47333 CGM and 5677 POC glucose values. During IV insulin therapy, individuals' glycemic control improved when CGM was used (mean difference -30.2 mg/dL). Among 2194 matched CGM:POC glucose pairs a high degree of concordance was observed with a MARD of 14.8% and 99.5% of CGM:POC pairs falling in Zones A and B of the Clarke Error Grid. Conclusions: CGM use in critically ill COVID-19 patients improved glycemic control during IV insulin therapy. CGM glucose data were highly concordant with POC glucose during IV insulin therapy in critically ill patients suggesting that CGM could substitute for POC measurements in inpatients thus reducing patient-provider contact and mitigating infection transmission.


title: Routine Saliva Testing for SARS-CoV-2 in Children: Partnering with Childcare Centers in the Greater New Haven Community

abstract: Background: While considerable attention was placed on SARS-CoV-2 testing and surveillance programs in the K-12 setting, younger age groups in childcare centers were largely overlooked. Childcare facilities are vital to communities, allowing parents/guardians to remain at work and providing safe environments for both children and staff. Therefore, early in the COVID-19 pandemic, we established a PCR-based COVID-19 surveillance program in childcare facilities, testing children and staff with the goal of collecting actionable public health data and aiding communities in the progressive resumption of standard operations and ways of life. In this study we describe the development of a weekly saliva testing program and provide early results from our experience implementing this in childcare centers. Methods: We enrolled children (aged 6 months to 7 years) and staff at 8 childcare facilities and trained participants in saliva collection using video chat technology. Weekly surveys were sent out to assess exposures, symptoms, and vaccination status changes. Participants submitted weekly saliva samples at school. Samples were transported to a partnering clinical laboratory for RT-PCR testing using SalivaDirect and results were uploaded to each participant's online patient portal within 24 hours. Results: This study fostered a cooperative partnership with participating childcare centers, parents/guardians, and staff with the goal of mitigating COVID-19 transmission in childcare centers. Age-related challenges in saliva collection were overcome by working with parents/guardians to conceptualize new collection strategies and by offering parents/guardians continued virtual guidance and support. Conclusion: SARS-CoV-2 screening and routine testing programs have focused less on the childcare population, resulting in knowledge gaps in this critical age group, especially as many are still ineligible for vaccination. SalivaDirect testing for SARS-CoV-2 provides a feasible method of asymptomatic screening and symptomatic testing for children and childcare center staff. Given the relative aversion to nasal swabs in the childcare age group, especially as a routine surveillance tool, an at-home saliva collection method provides an attractive alternative. Results can be shared rapidly electronically through participants' private medical chart portals, and video chat technology allows for discussion and instruction between investigators and participants.