title: Estimating the number of breakthrough COVID-19 deaths in the United States

abstract: While there is compelling evidence of the effectiveness of COVID-19 vaccines, increasing attention has also been paid to the fact that, like all vaccines, they are not 100% effective. Therefore, some fully vaccinated people have developed "breakthrough" cases of COVID-19, and some of these individuals have died as a result. The purpose of this study was to estimate the number of fully vaccinated or "breakthrough" deaths from COVID-19 in the United States. Data was compiled from state COVID-19 dashboards and various other sources for as many states as possible. As of March 27, 2022 based on data from 46 U.S. states and the District of Columbia, an estimated minimum of 57,617 breakthrough COVID-19 deaths had occurred in the United States. Furthermore, based on this incomplete data, a total of 12.8% of all COVID-19 deaths in the included regions and time periods were among fully vaccinated individuals (whether boosted or not). Extrapolating this data to the entire United States implies that the minimum total number of such deaths as of March 27, 2022 was 79,917. Data from a MMWR article, if similarly extrapolated to the entire country, implies a significantly larger number of breakthrough deaths throughout the United States: 99,152.


title: Linking cohort data and Welsh routine health records to investigate children at risk of delayed primary vaccination

abstract:
BackgroundDelayed primary vaccination is one of the strongest predictors of subsequent incomplete immunisation. Identifying children at risk of such delay may enable targeting of interventions, thus decreasing vaccine preventable illness.

ObjectivesTo explore socio-demographic factors associated with delayed receipt of the Diphtheria, Tetanus and Pertussis (DTP) vaccine.

MethodsWe included 1,782 children, born between 2000 and 2001, participating in the Millennium Cohort Study (MCS) and resident in Wales, whose parents gave consent for linkage to National Community Child Health Database records at the age seven years contact. We examined child, maternal, family and area characteristics associated with delayed receipt of the first dose of the DTP vaccine.

Results98.6% received the first dose of DTP. The majority, 79.6% (n=1,429) received it on time (between 8 and 12 weeks of age), 14.2% (n=251) received it early (prior to 8 weeks of age) and 4.8% (n=79) were delayed (after 12 weeks of age); 1.4% (n=23) never received it. Delayed primary vaccination was more likely among children with older natural siblings (risk ratio 3.82, 95% confidence interval (1.97, 7.38)), children admitted to special/intensive care (3.15, (1.65, 5.99)), those whose birth weight was >4Kg (2.02, (1.09, 3.73)) and boys (1.53, (1.01, 2.31)). There was a reduced risk of delayed vaccination with increasing maternal age (0.73, (0.53, 1.00) per 5 year increase) and for babies born to graduate mothers (0.27, (0.08, 0.90)).

ConclusionsAlthough the majority of infants were vaccinated in a timely manner, identification of infants at increased risk of early or delayed vaccination will enable targeting of interventions to facilitate timely immunisation. This is to our knowledge the first study exploring individual level socio-demographic factors associated with delayed primary vaccination in the UK and demonstrates the benefits of linking cohort data to routinely-collected child health data.

category: public and global health


title: Aberrant neurophysiological signaling underlies speech impairments in Parkinson's disease

abstract: Difficulty producing intelligible speech is a common and debilitating symptom of Parkinsons disease (PD). Yet, both the robust evaluation of speech impairments and the identification of the affected brain systems are challenging. We examine the spectral and spatial definitions of the functional neuropathology underlying reduced speech quality in patients with PD using a new approach to characterize speech impairments and a novel brain-imaging marker. We found that the interactive scoring of speech impairments in PD (N=59) is reliable across non-expert raters, and better related to the hallmark motor and cognitive impairments of PD than automatically-extracted acoustical features. By relating these speech impairment ratings to neurophysiological deviations from healthy adults (N=65), we show that articulation impairments in patients with PD are robustly predicted from aberrant activity in the left inferior frontal cortex, and that functional connectivity of this region with somatomotor cortices mediates the influence of cognitive decline on speech deficits.

category: neurology


title: Multimodal Hypersensitivity Derived from Quantitative Sensory Testing Predicts Long-Term Pelvic Pain Outcome

abstract: Multimodal hypersensitivity (MMH)--greater sensitivity across multiple sensory modalities (e.g., light, sound, temperature, pressure)--is hypothesized to be responsible for the development of chronic pain and pelvic pain. However, previous studies of MMH are restricted given their reliance on biased self-report questionnaires, limited use of multimodal quantitative sensory testing (QST), or limited follow-up. Therefore, we conducted multimodal QST on a cohort of 200 reproductive age women at elevated risk for developing or maintaining chronic pelvic pain conditions and pain-free controls. Pelvic pain self-report was examined over a four-year follow-up period. Multimodal QST was comprised of visual, auditory, bodily pressure, pelvic pressure, thermal, and bladder testing. A principal component analysis of QST measures resulted in three orthogonal factors that explained 43% of the variance: MMH, pressure stimulus-response, and bladder hypersensitivity. MMH and bladder hypersensitivity factors correlated with baseline self-reported menstrual pain, genitourinary symptoms, depression, anxiety, and health. Baseline self-report pain ratings were significant predictors of pelvic pain up to three years after assessment but decreased in their predictive ability of pelvic pain outcome over time. In contrast, MMH increased its predictive ability of pelvic pain outcome over time and was the only factor to predict outcome up to four years later. These results suggest that a "centralized" component of MMH is an important long-term risk factor for pelvic pain. Further research on the modifiability of MMH could provide options for future treatment avenues for chronic pain.

category: pain medicine


title: Assessment of Referral System on Maternal Services in Cagayan De Oro City, Philippines

abstract: A retrospective document analysis study aimed to assess the referral system on maternal services based on the referral forms of referred women of reproductive age from the referral facilities to the receiving hospital from January to December 2019. The specific objectives of the study were to describe the use of standard referral forms, compliance of the healthcare workers in using the standard form based on 14 criteria, and the utilization of relevant data related to maternal services based on 16 criteria. There were 3330 referral forms received by the receiving facility on different formats of forms during the study period. A random sampling of 384 referral forms was used as study population. Among 384 referral forms (random sampling), only 126 (31.8%) used the standard referral forms. The compliance of these referral forms using 14 criteria showed that 116 (92.06%) referral forms complied with only 51-75% of the criteria, and none of the referral forms complied with all the 14 criteria. On assessing the data entries among 384 referral forms with different formats, there were six data entries consistently used more than 60% by the healthcare providers which were not part of the printed form: last menstrual period (67.87%), expected date of confinement (64.84%), fundic height (63.04%), fetal heart beat (60.76%), birthweight (62.59%), and age of gestation (60%). Based on the 16 criteria, majority of referral forms (210) utilized 51-75% of the 16 criteria, 122 referral forms utilized 76-99%, 51 forms utilized 26-50%, and 1 form utilized less than 25% of the data entries. Several studies documented that referral forms and functional referral systems are vital to an improved maternal mortality rate (MMR) and infant mortality rate (IMR). Therefore, as part of a continued quality referral system, it is highly recommended that the required referral forms be re-assessed, revised, and regularly monitored on its form compliance and utilization.

category: health systems and quality improvement


title: Clinical Variables Correlate with Serum Neutralizing Antibody Titers after COVID-19 mRNA Vaccination in an Adult, US-based Population

abstract:
BackgroundWe studied whether comorbid conditions impact strength and duration of immune responses after SARS-CoV-2 mRNA vaccination in a US-based, adult population.

MethodsSera (pre-and-post-BNT162b2 vaccination) were tested serially up to 12 months after two doses of vaccine for SARS-CoV-2-anti-Spike neutralizing capacity by pseudotyping assay in 124 individuals; neutralizing titers were correlated to clinical variables with multivariate regression. Post-booster (third dose) effect was measured at 1 and 3 months in 72 and 88 subjects respectively.

ResultsAfter completion of primary vaccine series, neutralizing antibody IC50 values were high at one month (14-fold increase from pre-vaccination), declined at six months (3.3-fold increase), and increased at one month post-booster (41.5-fold increase). Three months post-booster, IC50 decreased in COVID-naive individuals (18-fold increase) and increased in prior COVID-19+ individuals (132-fold increase). Age >65 years ({beta}=-0.94, p=0.001) and malignancy ({beta}=-0.88, p=0.002) reduced strength of response at 1 month. Both strength and durability of response at 6 months, respectively, were negatively impacted by end-stage renal disease [({beta}=-1.10, p=0.004); ({beta}=-0.66, p=0.014)], diabetes mellitus [({beta}=-0.57, p=0.032); ({beta}=-0.44, p=0.028)], and systemic steroid use [({beta}=-0.066, p=0.032); ({beta}=-0.55, p=0.037)]. Post-booster IC50 was robust against WA-1 and B.1.617.2, but the immune response decreased with malignancy ({beta} =-0.68, p=0.03) and increased with prior COVID-19 (p-value < 0.0001).

ConclusionMultiple clinical factors impact the strength and duration of neutralization response post-primary series vaccination, but not the post-booster dose strength. Prior COVID-19 infection enhances the booster-dose response except in individuals with malignancy, suggesting a need for clinically guiding vaccine dosing regimens.

SummaryMultiple clinical factors impact the strength and duration of neutralization response post-primary series vaccination. All subjects, irrespective of prior COVID infection, benefited from a third dose. Malignancy decreased response following third dose, suggesting the importance of clinically guided vaccine regimens.

category: infectious diseases


title: A simple algorithm based on initial Ct values predicts the duration to SARS-CoV-2 negativity and allows more efficient test-to-release and return-to-work schedules

abstract:
Especially during global pandemics but also in the context of epidemic waves, the capacity for diagnostic qRT-PCRs rapidly becomes a limiting factor. Furthermore, excessive testing incurs high costs and can result in an overstrained work force in diagnostics departments. Obviously, people aim to shorten their isolation periods, hospitals need to discharge convalescent people, and re-employ staff members after infection. The aim of the study was to optimize retesting regimens for test-to-release from isolation and return-to-work applications. For this purpose, we investigated the association between Ct values at the first diagnosis of SARS-CoV-2 infection and the period until test negativity was reached, or at least until the Ct value exceeded 30, which is considered to indicate the transition to a non-infectious state. We included results from the testing of respiratory material samples for the detection of SARS-CoV-2 RNA, tested from 01 March 2020 to 31 January 2022.

Lower initial Ct values were associated with longer periods of SARS-CoV-2 RNA positivity. Starting with Ct values of <20, 20-25, 25-30, 30-35, and >35, it took median intervals of 20 (interval: 14-25), 16 (interval: 10-21), 12 (interval: 7-16), 7 (interval: 5-14), and 5 (interval: 2-7) days, respectively, until the person tested negative. Accordingly, a Ct threshold of 30 was surpassed after 13 (interval: 8-19), 9 (interval: 6-14), 7 (interval: 6-11), 6 (interval: 4-10), and 3 (interval: 1-6) days, respectively, in individuals with aforementioned start Ct values. Furthermore, the time to negativity was longer for adults versus children, wild-type SARS-CoV-2 variant versus other variants of concern, and in patients who were treated in the intensive care units.

Based on these data, we propose an adjusted retesting strategy according to the initial Ct value in order to optimize available PCR resources.


title: Priorities setting in mental health research: a scoping review

abstract:
ObjectiveResearch processes are opening to stakeholders beyond the scientific community. We analyse the user involvement in the definition of research priorities in the field of mental health. Mental disorders represent a significant disease burden at a global scale and their identification and treatment involves caregivers, patients and related social groups such as family and friends. Therefore it is an area conducive to the application of participatory methods in priority setting. We present a scoping review of participatory methods in mental health priority setting for the period 2010-2020 to shed light on their spread and characteristics, the types of groups involved and the link with the priorities identified.

MethodsFirst we describe the eligibility criteria for the scoping review. We selected peer-reviewed documents published between 2010 and 2020 using MEDLINE/PubMed, PsycINFO, the Core Collection of the Web of Science and Scopus, applying controlled terms of search. We initially identified 330 documents from which we selected seventy-four after further discarding studies that were not specifically addressing priority setting in mental disorders research. We noted and classified the interest groups participating in every study.

ResultsPriority setting partnerships are becoming the most frequent participatory instruments for priority setting in mental health. We identify regional differences in the extent to which such methods are being applied. When research beneficiaries participate in priority setting, prioritised research focuses on therapy, standards, education and psychology of mental disorders. When participation is limited to scientists, therapy, diagnosis, methods and standards, receive more attention.

category: psychiatry and clinical psychology


title: Thirteen-fold variation between states in clozapine prescriptions to United States Medicaid patients

abstract:
BackgroundClozapine was the first atypical antipsychotic for treating schizophrenia, with a long history of controversy over its usage. Guidelines currently recommend clozapine for patients diagnosed with refractory schizophrenia. However, this agent may be underutilized because of the costs associated with close monitoring of its adverse effects, particularly agranulocytosis. This is unfortunate because clozapine has demonstrated greater effectiveness compared with other antipsychotics. It is essential to examine clozapine usage to determine if it is being adequately utilized among United States (US) Medicaid patients.

MethodsMedicaid data, including the number of quarterly clozapine prescriptions and the number of Medicaid enrollees in each state from 2015-2019, was collected and used to evaluate clozapine use over time. Data-analysis and figures were prepared with Excel and GraphPad Prism. Exploratory correlations were completed between prescriptions per enrollee and other factors.

ResultsThe number of prescriptions, corrected for the number of enrollees in Medicaid, was generally consistent over time. However, average prescriptions per quarter were markedly lower in 2017 compared with other years, decreasing by 44.4% from 2016 average prescriptions per quarter. From 2015 to 2019, states from the upper Midwest and Northeast regions of the country had the highest average clozapine prescriptions per 10,000 Medicaid enrollees (ND: 190.0, SD: 176.6, CT: 166.2). States from the Southeast and Southwest had much lower average rates (NV: 17.9, KY: 19.3, MS: 19.7). There was an over ten-fold difference in clozapine prescriptions between states from 2015-2019 (2015 = 19.9-fold, 2016=11.4 fold, 2017=11.6 fold, 2018=13.3 fold, and 2019=13.0 fold). There was a moderate correlation of (r(48) = 0.49, p < .05) between prescriptions per 10,000 enrollees and the Medicaid spending per enrollee in each state in 2019. There was a small, but significant, correlation between prescriptions per enrollee and percent white (r(48) = 0.30, p < .05).

ConclusionClozapine is an important pharmacotherapy for refractory schizophrenia. Overall, clozapine use tends to be highest among the upper Midwest and Northeast states. Further research is ongoing to better understand the origins of the thirteen-fold regional disparities in clozapine use in 2019 and the state level variation in Medicaid spending.


title: Significant impacts of the COVID-19 pandemic on race/ethnic differences in USA mortality

abstract:
The COVID-19 pandemic triggered declines in life expectancy at birth around the world. The United States of America (USA) was hit particularly hard among high income countries. Early data from the USA showed that these losses varied greatly by race/ethnicity in 2020, with Hispanic and Black Americans suffering much larger losses in life expectancy compared to white people. We add to this research by examining trends in lifespan inequality, average years of life lost, and the contribution of specific causes of death and ages to race/ethnic life expectancy disparities in the USA from 2010 to 2020. We find that life expectancy in 2020 fell more for Hispanic and Black males (4.5 years and 3.6 years, respectively) compared to white males (1.5 years). These drops nearly eliminated the previous life expectancy advantage for the Hispanic compared to white population, while dramatically increasing the already large gap in life expectancy between Black and white people. While the drops in life expectancy for the Hispanic population were largely attributable to official COVID-19 deaths, Black Americans additionally saw increases in cardiovascular disease and "deaths of despair" over this period. In 2020, lifespan inequality increased slightly for Hispanic and white populations, but decreased for Black people, reflecting the younger age pattern of COVID-19 deaths for Hispanic people. Overall, the mortality burden of the COVID-19 pandemic hit race/ethnic minorities particularly hard in the USA, underscoring the importance of the social determinants of health during a public health crisis.

Significance statementPublic interest in social and health inequalities is increasing. We examine the impact of COVID-19 on mortality in the USA across racial/ethnic groups and present four key findings. First, all groups suffered sizable life-expectancy losses and increases in years of life lost. Mortality from cardiovascular diseases, "deaths of despair", and COVID-19 explained most of these losses. Second, working-age mortality accounted for substantial life-expectancy losses, especially among Hispanic males. Third, lifespan inequality increased for Hispanic and white people, but decreased slightly for Black people. Fourth, the pandemic shifted racial/ethnic mortality differentials in favor of white people: narrowing the Hispanic advantage and widening the Black disadvantage. Our results provide a comprehensive assessment of mortality trends to inform policies targeting inequalities.


title: Self-supervised neural network improves tri-exponential intravoxel incoherent motion model fitting in non-alcoholic fatty liver disease.

abstract: Neural network generated intravoxel incoherent motion (IVIM) parameter maps are visually more detailed, less noisy and have a higher test-retest repeatability than conventional least-squares (LSQ) generated images. Recent literature suggests that tri-exponential models may fit liver IVIM data more accurately than conventional bi-exponential models, warranting investigation into the use of a neural network (NN) to estimate tri-exponential IVIM parameters. Here, we developed a tri-exponential IVIM unsupervised physics-informed deep neural network (IVIM3-NET), assessed its performance in non-alcoholic fatty liver disease (NAFLD) and compared outcomes with bi-exponential LSQ and NN fits and tri-exponential LSQ fits. Scanning was performed using a 3.0T free-breathing multi-slice diffusion-weighted single-shot echo-planar imaging sequence with 18 b-values. Images were analysed for visual quality, comparing the bi- and tri-exponential IVIM models for LSQ fits and NN fits using parameter-map signal-to-noise ratios (SNR) and adjusted R2. IVIM parameters were compared to histological fibrosis, disease activity and steatosis grades. Parameter map quality improved with bi- and tri-exponential NN approaches, with average parameter-map SNR increasing from 3.38 to 5.59 and 2.45 to 4.01 for bi- and tri-exponential LSQ and NN models respectively. In 33 out of 36 patients, the tri-exponential model exhibited higher adjusted R2 values than the bi-exponential model. Correlating IVIM data to liver histology showed that the bi- and tri-exponential NN outperformed both LSQ models for the majority of IVIM parameters (10 out of 15 significant correlations). Overall, our results support the use of a tri-exponential IVIM model in NAFLD. We show that the IVIM3-NET can be used to improve image quality compared to a tri-exponential LSQ fit and provides promising correlations with histopathology.

category: radiology and imaging


title: Performance in Fundamentals of Laparoscopic Surgery (FLS): Does it Reflect Global Rating Scales in Objective Structured Assessment of Technical Skills (OSATS) in Porcine Laparoscopic Surgery?

abstract:
BackgroundTo correlate the utility of Fundamentals of Laparoscopic Surgery (FLS) manual skills program with the Objective Structured Assessment of Technical Skills (OSATS) global rating scale in evaluating operative performance.

Materials and MethodsThe Asian Urological Surgery Training and Educational Group (AUSTEG) Laparoscopic Upper Tract Surgery Course (LUTSC) implemented and validated the FLS program for its usage in laparoscopic surgical training. Delegates basic laparoscopic skills were assessed using three different training models (Peg Transfer, Precision Cutting and Intra-corporeal Suturing). They also performed live porcine laparoscopic surgery at the same workshop. Live surgery skills were assessed by blinded faculty using the OSATS rating scale.

ResultsFrom 2016 to 2019, a total of 81 certified urologists participated in the course, with a median of 5 years experience post residency. Although differences in task timings did not reach statistical significance, those with more surgical experience were visibly faster at completing the peg transfer and intra-corporeal suturing FLS tasks. However, they took longer to complete the precision cutting task than participants with less experience. Overall OSATS scores correlated weakly with all three FLS tasks (Peg Transfer Time: R = -0.331, R2 = 0.110; Precision Cutting Time: R = - 0.240, R2 = 0.058; Suturing with Intra-corporeal Knot Time: R = -0.451, R2 = 0.203).

ConclusionFLS task parameters did not correlate strongly with OSATS globing rating scale performance. Although the FLS task models demonstrated strong validity, it is important to assimilate the inconsistencies when benchmarking technical proficiency against real-life operative competence, as evaluated by FLS and OSATS respectively.

category: medical education


title: Formative usability assessment of a new connector design for peritoneal dialysis

abstract:
BackgroundThis paper presents a first, formative study to explore the usability of a new peritoneal dialysis connector design intended for use by patients. The study was conducted with a user population of both naive users and experienced peritoneal dialysis patients across a range of ages. The goals of the study were to evaluate the usability of the key user interfaces of this connector design by test participants representative of new and experienced peritoneal dialysis patients, as well as to evaluate the use of the connector as it interacts with other components of the peritoneal dialysis system including peritoneal dialysis fluid bags and tubing. Further objectives were to capture any usability issues and obtain participants feedback on the design.

MethodsA total of 7 patient and non-patient participants received brief training and performed simulated connection and disconnection of peritoneal catheter extension sets for therapy with the new design.

ResultsAll 7 participants completed the simulated connection and disconnection tasks successfully, with only one use error (0.22%), 18 close calls (4.0%), 6 use difficulties (1.3%) observed from the total of 449 use steps performed by all participants. Other findings include usability improvement with repeated use, participants feedback and suggestions for the  protective enclosure, a novel feature of the touchless connector design.

ConclusionThe studied connector design showed minimal use errors or difficulties and based on participant feedback, the usability can be significantly improved with minimal modifications in future prototypes.

category: nephrology


title: Diagnostic Accuracy of Simple Postoperative AKI Risk (SPARK) Classification and General Surgery AKI (GS AKI) Index in Predicting Postoperative Acute Kidney Injury among Patients Undergoing Non-Cardiac Surgery at a Tertiary Hospital in the Philippines

abstract:
BackgroundPostoperative AKI is a significant postoperative complication. Clinical risk prediction models are lacking for patients undergoing non-cardiac surgery. SPARK Classification and GS AKI Index are tools that have shown fair discriminative ability to predict post-operative AKI in non-cardiac surgery and have external validation in their original cohorts. There is no study that compares the diagnostic accuracy of both tools.

ObjectivesThis study aims to compare the diagnostic accuracy of SPARK Classification vs GS-AKI Risk Index in predicting post-operative AKI among patients who will undergo non-cardiac surgery at a tertiary hospital in the Philippines.

MethodsThis is a cross-sectional study, including adult patients who underwent non-cardiac surgeries from January 2019 to July 2021. The individual risk of post-operative AKI for both models were determined. Descriptive data was described using t-test and logistic regression. Measures of accuracy were described using sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio, and discriminative ability using concordance (c) statistic.

ResultsOf the 340 patients in this study, 77 (22.65%) developed post-operative AKI and 24 (7.06%) developed critical AKI. Based on demographic data, older age, pre-existing renal disease, longer duration of surgery, anemia, hypoalbuminemia, and hyponatremia were associated with higher incidence of post-operative AKI. SPARK had a sensitivity ranging from 17-43% and specificity ranging from 58-93% for Class B to C. GS AKI had a sensitivity ranging from 10-26% and specificity ranging from 61-97% for Class I to V. SPARK had a discriminative power (c statistic) ranging from 0.46 to 0.61 while GS AKI had a discriminative power ranging from 0.41 to 0.54.

ConclusionBased on this study, there is an association between higher risk classification in both SPARK and GS AKI and postoperative AKI. However, both clinical prediction models demonstrate poor discriminative power to predict post-operative AKI.


title: Neuromodulation through Brain Stimulation-assisted Cognitive Training in Patients with Post-Chemotherapy Cognitive Impairment (Neuromod-PCCI): Study Protocol of a Randomized Controlled Trial

abstract:
IntroductionBreast cancer is the most common form of cancer in women. A considerable number of women with breast cancer who have been treated with chemotherapy, subsequently develop neurological symptoms such as concentration and memory difficulties (also known as  chemobrain). Currently, there are no validated therapeutic approaches available to treat these symptoms. Cognitive training holds the potential to counteract cognitive impairment. Combining cognitive training with concurrent transcranial direct current stimulation (tDCS) could enhance and maintain the effects of this training, potentially providing a new approach to treat post-chemotherapy cognitive impairment (PCCI). With this study, we aim to investigate the effects of multi-session tDCS over the left dorsolateral prefrontal cortex in combination with cognitive training on cognition and quality of life in women with PCCI.

Methods and analysisThe Neuromod-PCCI trial is a monocentric, randomized, double-blind, placebo-controlled study. Fifty-two women with PCCI after breast cancer therapy will receive a 3-week tDCS-assisted cognitive training with anodal tDCS over the left dorsolateral prefrontal cortex (target intervention), compared to cognitive training plus sham tDCS (control intervention). Cognitive training will consist of a letter updating task. Primary outcome will be the performance in an untrained task (n-back task) after training. In addition, feasibility, safety and tolerability, as well as quality of life and performance in additional untrained tasks will be investigated. A follow-up visit will be performed one month after intervention to assess possible long-term effects. In an exploratory approach, structural and functional magnetic resonance imaging (MRI) will be acquired before the intervention and at post-intervention to identify possible neural predictors for successful intervention.

Ethics and disseminationEthical approval was granted by the ethics committee of the University Medicine Greifswald (BB236/20). Results will be available through publications in peer-reviewed journals and presentations at national and international conferences.

Trial registrationThis trial was prospectively registered at ClinicalTrials.gov (Identifier: NCT04817566, registered March 26, 2021).

Strength and limitations of this study- This is the first randomized controlled trial to investigate the feasibility and effects of combined cognitive training and tDCS on cognitive outcomes and quality of life in patients with post-chemotherapy cognitive impairment
- Results will help the development of treatment options for breast cancer patients with post-chemotherapy cognitive impairment
- Results may not be generalizable to male cancer patients
- Monocentric trial design may increase risk of bias


title: Retinal aging transcriptome and cellular landscape in association with the progression of age-related macular degeneration

abstract: Age is the main risk factor for age-related macular degeneration (AMD), a leading cause of blindness in the elderly, with limited therapeutic options. Here we systematically analyzed the transcriptomic characteristics and cellular landscape of the aging retina from controls and patients with AMD. We identify the aging genes in the retina that are associated with innate immune response and inflammation. Deconvolution analysis reveals that the estimated proportion of M2 and M0 macrophages is increased and decreased, respectively with both age and AMD severity. Moreover, we find that Muller glia are increased with age but not with disease severity. Several genes associated with both age and disease severity in AMD, particularly C1s and MR1, are strong positively correlated with the proportions of Muller glia. Our studies expand the genetic and cellular landscape of AMD and provide avenues for further studies on the relationship between age and AMD.

category: genetic and genomic medicine


title: WikiProject Clinical Trials for Wikidata

abstract:
WikiProject Clinical Trials is a Wikidata community project to integrate clinical trials metadata with the Wikipedia ecosystem. Using Wikidata methods for data modeling, import, querying, curating, and profiling, the project brought ClinicalTrials.gov records into Wikidata and enriched them. The motivation for the project was gaining the benefits of hosting in Wikidata, which include distribution to new audiences and staging the content for the Wikimedia editor community to develop it further. Project pages present options for engaging with the content in the Wikidata environment. Example applications include generation of web-based profiles of clinical trials by medical condition, research intervention, research site, principal investigator, and funder.

The projects curation workflows including entity disambiguation and language translation could be expanded when there is a need to make subsets of clinical trial information more accessible to a given community. This projects methods could be adapted for other clinical trial registries, or as a model for using Wikidata to enrich other metadata collections.

category: health informatics


title: Frequent Cocaine Use is Associated with Larger HIV Latent Reservoir Size

abstract:
BackgroundWith the success of combination antiretroviral therapy, HIV is now treated as a chronic disease, including among drug users. Cocaine--one of the most frequently abused illicit drugs among persons living with HIV (PLWH)-- slows the decline of viral production after ART, and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality. We examined the impact of cocaine use on the CD4+ T-cell HIV Latent Reservoir (HLR) in virally suppressed PLWH.

MethodsCD4+ T-cell genomic DNA was isolated from peripheral blood mononuclear cells collected from 434 women of diverse ancestry (i.e., 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (i.e., 160 cocaine users, 59 prior users, 215 non-users). Participants had to have an undetectable HIV RNA viral load measured by commercial assay for at least 6 months. The Intact Proviral HIV DNA Assay (IPDA) provided estimates of intact provirus per 106 CD4+ T-cells.

ResultsThe HLR size differed by cocaine use (i.e., median [interquartile range]: 72 [14, 193] for never users, for prior users 165 [63, 387], 184 [28, 502] for current users), which was statistically significantly larger in both prior (p=0.023) and current (p=0.001) cocaine users compared with never users.

ConclusionOur study is the first to provide evidence that cocaine use may contribute to a larger replication competent HLR in CD4* T-cells among virologically suppressed women living with HIV. Our findings are important, because women are under-represented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH.

category: hiv aids


title: The mobilome associated with Gram-negative bloodstream infections: A large-scale observational hybrid sequencing based study

abstract: Plasmids carry genes conferring antimicrobial resistance (AMR), and other clinically important traits; their ability to move within and between species may provide the machinery for rapid dissemination of such genes. Existing studies using complete plasmid assemblies, which are essential for reliable inference, have been small and/or limited to those carrying particularly antimicrobial resistance genes (ARGs). In this study, we sequenced 1,880 complete plasmids from 738 isolates from bloodstream infections (BSI) in 2009 (194 isolates) and 2018 (368 isolates) in Oxfordshire, UK, plus a stratified selection from intervening years (176 isolates). We demonstrate that plasmids are largely, but not entirely, constrained to host species, although there is substantial overlap between species of plasmid gene-repertoire. Most ARGs are carried by a relatively small number of plasmid groups with biological features that are predictable. Plasmids carrying ARGs (including those encoding carbapenemases) share a putative  backbone of core genes with those carrying no such genes. These findings suggest that future surveillance should, in addition to tracking plasmids currently associated with clinically important genes, focus on identifying and monitoring the dissemination of high-risk plasmid groups with the potential to rapidly acquire and disseminate these genes.


title: A mixed cross-sectional and case-control study approach to investigate the risk-factors of Noma/Cancrum oris in Ethiopia

abstract:
IntroductionNoma is a polymicrobial gangrenous facial disease affecting people living in the most impoverished areas of low- and middle-income countries. If left untreated, the disease is fatal or else severely disfigure people with the condition. The compromised immune system, poor oral hygiene, measle infection, diarrheal disease, inaccessibility to health education and proper medical care, and lack of a balanced diet and good sanitary facilities are found to be some of the predisposing factors for the development and progression of the disease. Furthermore, debilitating diseases like malaria and measles were considered as significant precursors to Noma.

Materials and MethodA mix of cross-sectional and case-control study approaches was conducted to assess the risk factors of Noma in Ethiopia. The raw data of the cases were obtained from Yekatik 12 Hospital, Facing Africa, and the Harar project Ethiopia. Three controls were selected per single case. The Odd ratio (ORs) and Chi-square test were calculated to rule out the statistical significance of the association observed between the factors and the disease.

ResultsA total of 64 cases were selected for the case-control study. Considering the 1:3 case to control ratio, 192 matching controls were identified. Malaria, helminths, measle, diarrheal diseases, and living with domestic animals were found to be risk factors for Noma with a respective p-value < 0.01. Contrarily, the analysis has identified vaccination (p < 0.01) as a protective factor.

DiscussionNoma/face of poverty is mostly preventable by providing proper nutrition, sanitary and water facilities, awareness about the disease, oral health education, and vaccinations. Poverty-related diseases such as malaria, helminths infection, measle, diarrheal diseases, and unfavorable living conditions were identified to be the risk factor for Noma. As such the disease is truly preventable. Prevention of the disease can be achieved through promoting overall awareness of the disease, poverty reduction, improved nutrition, and promotion of exclusive breastfeeding in the first 3-6 months of life. Furthermore, optimum prenatal care, timely immunizations against common childhood diseases, initiating vaccination, and improving the social living conditions are the other preventive mechanisms. Moreover, long-lasting economic development should be considered to effectively and sustainably prevent the disease.

category: epidemiology


title: The trustworthiness and impact of trial preprints for COVID-19 decision-making: A methodological study

abstract:
PurposeTo assess the trustworthiness and impact of preprint trial reports during the COVID-19 pandemic.

Data sourcesWHO COVID-19 database and the L-OVE COVID-19 platform by the Epistemonikos Foundation (up to August 3rd, 2021)

DesignWe compare the characteristics of COVID-19 trials with and without preprints, estimate time to publication of COVID-19 preprint reports, describe discrepancies in key methods and results between preprint and published trial reports, report the number of retracted preprints and publications, and assess whether including versus excluding preprint reports affects meta-analytic estimates and the certainty of evidence. For the effects of eight therapies on mortality and mechanical ventilation, we performed meta-analyses including preprints and excluding preprints at 1 month, 3 months, and 6 months after the first trial addressing the therapy became available either as a preprint or publication (120 meta-analyses in total).

ResultsWe included 356 trials, 101 of which are only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. Half of all preprints remain unpublished at six months and a third at one year. There were few important differences in key methods and results between trial preprints and their subsequent published reports. We identified four retracted trials, three of which were published in peer-reviewed journals. With two exceptions (2/60; 3.3%), point estimates were consistent between meta-analyses including versus excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. There were nine comparisons (9/60; 15%) for which the rating of the certainty of evidence differed when preprints were included versus excluded, for four of these comparisons the certainty of evidence including preprints was higher and for five of these comparisons the certainty of evidence including preprints was lower.

LimitationsThe generalizability of our results is limited to COVID-19. Preprints that are subsequently published in journals may be the most rigorous and may not represent all trial preprints.

ConclusionWe found no compelling evidence that preprints provide less trustworthy results than published papers. We show that preprints remain the only source of findings of many trials for several months, a length of time that is unacceptable in a health emergency. We show that including preprints may affect the results of meta-analyses and the certainty of evidence. We encourage evidence users to consider data from preprints in contexts in which decisions are being made rapidly and evidence is being produced faster than can be peer-reviewed.

O_TEXTBOXSummary Box 1O_ST_ABSWhat is already known on this topicC_ST_ABSO_LIClinicians and decision-makers need rapidly available and credible data addressing the comparative effectiveness of treatments and prophylaxis for COVID-19.
C_LIO_LIInvestigators have adopted preprint servers, which allow the rapid dissemination of research findings before publication in peer-reviewed journals.
C_LI

What this study addsO_LIWe found no compelling evidence that preprints provide less trustworthy results than published papers.
C_LIO_LIWe show that including preprints may affect the results of meta-analyses and the certainty of evidence and we encourage evidence users to consider data from preprints in contexts in which decisions are being made rapidly and evidence is being produced faster than can be peer-reviewed.
C_LI

C_TEXTBOX


title: Haemolysis detection in microRNA-seq from clinical plasma samples

abstract: The abundance of cell-free microRNA (miRNA) has been measured in many body fluids, including blood plasma, which has been proposed as a source with novel, minimally invasive biomarker potential for several diseases. Despite improvements in quantification methods for plasma miRNAs, there is no consensus on optimal reference miRNAs or to what extent haemolysis may affect plasma miRNA content. Here we propose a new method for the detection of haemolysis in miRNA high-throughput sequencing (HTS) data from libraries prepared using human plasma. To establish a miRNA haemolysis signature in plasma we first identified differentially expressed miRNAs between samples with known haemolysis status and selected miRNA with statistically significant higher abundance in our haemolysed group. Given there may be both technical and biological reasons for differential abundance of signature miRNA, and to ensure the method developed here was relevant outside of our specific context, that is women of reproductive age, we tested for significant differences between pregnant and non-pregnant groups. Here we report a novel 20 miRNA signature (miR-106b-3p, miR-140-3p, miR-142-5p, miR-532-5p, miR-17-5p, miR-19b-3p, miR-30c-5p, miR-324-5p, miR-192-5p, miR-660-5p, miR-186-5p, miR-425-5p, miR-25-3p, miR-363-3p, miR-183-5p, miR-451a, miR-182-5p, miR-191-5p, miR-194-5p, miR-20b-5p) that can be used to identify the presence of haemolysis, in silico, in high throughput miRNA sequencing data. Given the potential for haemolysis contamination, we recommend that assay for haemolysis detection become standard pre-analytical practice and provide here a simple method for haemolysis detection.


title: Using Geographically Weighted Linear Regression for County-Level Breast Cancer Modeling in the United States

abstract: Due to the continued disparities in breast cancer, improved models are being needed to inform policy related to existing social disparities related to cancer. First ordinal least squares regression was used to determine the relationship of sociodemographic measures (i.e. poverty rate and social inequity) on breast cancer incidence in the United States. Gini coefficient was used as a measure of income inequality. Next, Geographically Weighted Regression (GWR), a local spatial model, was used to explore the impact location has on the relationship between sociodemographic measures and breast cancer. Mappings of the results are presented, which can assist policymakers to address inequities and social determinants when funding cancer interventions. The GWR model is then compared to linear regression models that do not take into consideration location, highlighting the benefits of spatial models in cancer policy research. More studies applying spatial regression techniques are needed in order to accurately inform policy.


title: Identification of novel microcephaly-linked protein ABBA that mediates cortical progenitor cell division and corticogenesis through NEDD9-RhoA

abstract: The cerebral cortex is responsible for higher cognitive functions. Its correct development depends on coordinated asymmetric division cycles by polarized radial glial progenitor cells. Mitotic defects in neuronal stem cells are linked to the aetiology of microcephaly, but the underlying mechanisms remain incompletely understood. Here we describe a novel role of the membrane deforming cytoskeletal regulator protein Abba (MTSS1L/MTSS2) in cortical development. Loss of Abba in the developing brain resulted in radial glia proliferation arrest, disorganized radial fibers and abnormal migration of neuronal progenitors. During cell division, Abba localized to the cleavage furrow where it recruited the scaffolding protein Nedd9 and positively regulated RhoA activity. Importantly, we identified a human variant Abba (R671W) in a patient with microcephaly and intellectual disability. Ectopic expression of this mutant protein in mice phenocopied Abba knockdown. Taken together, these data provide novel mechanistic insight into human microcephaly and cortical development by identifying ABBA as a novel regulator of faithful mitotic progression of neuronal progenitor cells.


title: Biochemical, Biophysical, and Immunological Characterization of Respiratory Secretions in Severe SARS-CoV-2 (COVID-19) Infections

abstract: Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19 disease, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e. resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We find the percent solids and protein content are greatly elevated in COVID-19 compared to heathy control samples and closely resemble levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) are major components of respiratory secretions in COVID-19 and are likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibit heterogeneous rheological behaviors with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observe increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor-stimulated gene-6 (TSG6) staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicate that increases in HA and DNA in COVID-19 respiratory secretion samples correlate with enhanced inflammatory burden and suggest that DNA and HA may be viable therapeutic targets in COVID-19 infection.


title: Identification and Genomic Assessment of Daptomycin-, Linezolid-, Vancomycin-resistant Enterococcus faecium During Protracted Infection

abstract: Linezolid and daptomycin resistance among Enterococccus faecium (Efm) isolates, while rare, is a major challenge for clinicians who are often limited to broad-spectrum or combination antibiotic therapies for management. Combination therapy with a beta-lactam has been reported, but limited clinical evidence exists to support its use. We describe the clinical management of a prolonged Efm intraabdominal (IA) infection and subsequent bacteremia, along with observed multidrug resistance development and use of serial whole genome sequencing to better understand resistance mechanisms. Combination antimicrobial therapy with daptomycin (DAP) and ceftaroline (CPT) was used to treat the patients catheter-associated daptomycin-, linezolid-, vancomycin-resistant Efm (DLVRE) bloodstream infection. In vitro antimicrobial testing of this DLVRE revealed only minor synergy between daptomycin and ceftaroline; However, the patients bacteremia cleared following initiation of combination therapy in conjunction with catheter removal. Sequencing of the patients DLVRE revealed multiple genomic mutations which explain both linezolid and daptomycin resistance and the presence of a plasmid containing known resistance determinants for vancomycin. Daptomycin resistance was attributed to the presence of chromosomal mutations in liaS (Thr120Ala), liaR (Trp73Cys), and cls (Asp13Ile), while linezolid resistance was attributed to the presence of the G2576T variant allele in some of 23S rRNA gene copies. Sequential whole genome sequencing of two additional bacterial isolates from the same patient revealed protracted colonization with a single DLVRE clone and suggested the development of bacterial subpopulations. Pairing clinical isolate susceptibilities with whole genome sequencing should be encouraged in clinical practice to better inform antimicrobial management in cases of multidrug resistance.


title: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is mediated by a stereotyped clonotypic antibody

abstract:
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare thromboembolic complication of adenoviral-vectored SARS-CoV2 vaccines, mediated by antibodies directed against platelet factor 4 (PF4). Given their causal role in VITT, identification of the molecular composition of anti-PF4 antibodies is crucial for developing better diagnostics and treatments. Here, we utilised a novel proteomic workflow to analyse the immunoglobulin variable (IgV) region composition of anti-PF4 antibodies at the level of the secreted proteome. Serum anti-PF4 IgG antibodies from five patients with VITT triggered by ChAdOx1 nCoV-19 vaccination were affinity purified by PF4-coupled magnetic beads and sequenced by mass spectrometry. We revealed a single IgG heavy (H)-chain species paired with a single lambda light (L)-chain species in all five unrelated patients. Remarkably, all L-chains were encoded by the identical IGLV3-21*02 gene subfamily with identical L-chain third complementarity determining region (LCDR3) lengths. Moreover, striking stereotypic features were also identified in heavy-chains anti-PF4 antibodies characterised by identical HCDR3 length and homologous sequences. In summary, we unravelled the molecular signature of highly stereotyped clonotypic anti-PF4 antibodies, indicating shared pathways of antibody production in VITT patients. These discoveries are critical to understand the molecular basis of this serious condition and develop novel therapies aimed at removing pathogenic clones.

KEY POINTSO_LIAnti-PF4 antibodies in VITT comprise highly stereotyped clonotype
C_LIO_LIA single IGLV3-21*02 encoded light chain is found in unrelated patients
C_LI

category: allergy and immunology


title: Glasses and risk of COVID-19 transmission - analysis of the Virus Watch Community Cohort study.

abstract:
BackgroundRespiratory viruses, including SARS-CoV-2, can infect the eyes or pass into the nose via the nasolacrimal duct. The importance of transmission via the eyes is unknown but might plausibly be reduced in those who wear glasses. Previous studies have mainly focussed on protective eyewear in healthcare settings.

MethodsParticipants from the Virus Watch prospective community cohort study in England and Wales responded to a questionnaire on the use of glasses and contact lenses. This included frequency of use, purpose, and likelihood of wearing a mask with glasses. Infection was confirmed through data linkage with Second Generation Surveillance System (Pillar 1 and Pillar 2), weekly questionnaires to self-report positive polymerase chain reaction or lateral flow results, and, for a subgroup, monthly capillary blood testing for antibodies (nucleocapsid and spike). A multivariable logistic regression model, controlling for age, sex, income and occupation, was used to identify odds of infection depending on the frequency and purpose of using glasses or contact lenses.

Findings19,166 Virus Watch participants responded to the questionnaire, with 13,681 (71.3%, CI 70.7-72.0) reporting they wore glasses. A multivariable logistic regression model showed a 15% lower odds of infection for those who reported using glasses always for general use (OR 0.85, 95% 0.77-0.95, p = 0.002) compared to those who never wore glasses. The protective effect was reduced in those who said that wearing glasses interfered with mask wearing. No protective effect was seen for contact lens wearers.

InterpretationPeople who wear glasses have a moderate reduction in risk of COVID-19 infection highlighting the importance of the eye as a route of infection. Eye protection may make a valuable contribution to the reduction of transmission in community and healthcare settings.

FundingThe research costs for the study have been supported by the MRC Grant Ref: MC_PC 19070 awarded to UCL on 30 March 2020 and MRC Grant Ref: MR/V028375/1 awarded on 17 August 2020. The study also received $15,000 of Facebook advertising credit to support a pilot social media recruitment campaign on 18th August 2020. The study also received funding from the UK Government Department of Health and Social Cares Vaccine Evaluation Programme to provide monthly Thriva antibody tests to adult participants. This study was supported by the Wellcome Trust through a Wellcome Clinical Research Career Development Fellowship to RA [206602]. Funding from the HSE Protect study, GOSH Childrens Charity and the Great Ormond Street Hospital BRC supported the involvement of CO in the project.

Research in contextO_ST_ABSEvidence before the studyC_ST_ABSDespite the risk of SARS-CoV-2 transmission via the eyes, very few countries have advocated eye protection to reduce transmission amongst the public and, except when providing close care for those known or suspected to be infected, is variable and based on case-by-case assessment of exposure risk. The mechanism, but not the extent, of the transmission route through the eyes is well described in the literature, with several studies reporting detection of SARS-CoV-2 RNA in the tear film, conjunctiva and conjunctival sac. There have been a small number of hospital based observational studies suggesting that eye protection may help prevent COVID-19 infection. A literature search was carried out on 23rd February 2022 across Medline and Embase using the search terms  eyewear,  glasses,  SARS-CoV-2,  COVID-19,  SARS,  transmission and  infectivity, providing 105 manuscripts. Of these, only eight investigated the risk of infection associated with eye protection, all in hospital settings or followed a cohort of healthcare workers. Among the studies was a systematic review that identified 5 observational studies from 898 articles that were screened. The cohort study with the largest sample size, 345 healthcare professionals, demonstrated a relative risk of 10.25 (95% CI 1.28-82.39; P = 0.009) for infection when not using eye protection. No studies of the potential protective effect of glasses wearing, for visual correction, in community settings were identified.

Added value of this studyThe Virus Watch study is a prospective community household study across England and Wales. 19,166 participants responded to the monthly questionnaire on glasses and contact lens use, assessing reported frequency, the purpose of use and how likely they were to wear a mask with glasses. Infections were identified in data linked to the Second Generation Surveillance System (Pillar 1 and Pillar 2 testing), weekly surveys seeking self-reports of polymerase chain reaction or lateral flow device results and, in a subset of 11,701, self-collected capillary blood testing for antibodies (nucleocapsid and spike - nucleocapsid antibodies were taken as evidence of prior infection as these are unaffected by vaccination). Our multivariable logistic regression model, controlling for age, sex, household income and occupation, demonstrated 15% lower odds of infection for those who reported always using glasses for general use compared to those who never wear glasses. The protective effect was not observed in those who strongly agreed with the statement,  I am less likely to wear a face covering when I have my glasses on because my glasses steam up. Counterfactual analysis of contact lenses did not suggest a protective effect regardless of frequency of use.

Implications of all the available evidenceThe findings of this study demonstrate a moderate reduction in risk of SARS-CoV-2 infection in those who always wear glasses compared to never. Unlike other studies, our results are representative of a community setting, adjust for potential confounders and provide a counterfactual analysis with contact lenses. This extends the current evidence to community settings and validates proposed biological mechanisms of eye protection reducing the risk of SARS-CoV-2 transmission.


title: The new normal? Dynamics and scale of the SARS-CoV-2 variant Omicron epidemic in England

abstract: The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants which have led to substantial changes in the epidemiology of the virus. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant was first detected in late November 2021 and exhibited a high degree of immune evasion, leading to increased infection rates in many countries. However, estimates of the magnitude of the Omicron wave have relied mainly on routine testing data, which are prone to several biases. Here we infer the dynamics of the Omicron wave in England using PCR testing and genomic sequencing obtained by the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys testing random samples of the population of England. We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections in England during February-March 2022 as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct genomic variants, intermittent epidemics of similar magnitude as the Omicron wave may become the  new normal.


title: Effect of xenon and argon inhalation on erythropoiesis and steroidogenesis: a systematic review

abstract:
BackgroundXenon and argon inhalation were included in the WADA Prohibited List in 2014 due to the reported positive effects on erythropoiesis. There has also been suggestions that steroidogenesis stimulation occurs as a result of the use of these substances. Currently, Xenon is on the WADA Prohibited List notable affecting erythropoiesis as a Hypoxia-inducible factor (HIF) activating agent. Thus, the systematic review of studies supporting these notions is of great interest.

MethodsA thorough search for articles on the effects of Xenon and argon inhalation on erythropoiesis and steroidogenesis, as well as their negative effects on human health and methods of their detection in body fluids was conducted. Pubmed and Google Scholar databases were researched, as well as the special research section of the WADA website. The search was conducted in accordance with PRISMA guidelines. All articles in English published between 2000 and 2021 were analyzed, as well as reference studies meeting the search criteria.

ResultsOnly two publications in healthy human subjects evaluating the effects of Xenon inhalation on erythropoiesis were found with no conclusive evidence of a positive effect on erythropoiesis. Both articles were published after 2014 when the gases were included on the WADA Prohibited List. Three more studies were conducted in animal models and one further study was conducted with human patients who had undergone Xenon anesthesia. There were no studies on the effect of argon inhalation on erythropoiesis. No studies were found on the effect of Xenon or argon inhalation on steroidogenesis in healthy subjects. No studies related to the effects of Xenon or argon inhalation on erythropoiesis and steroidogenesis were found on the WADA website.

ConclusionThere is still inconclusive evidence to support the administration of Xenon and argon inhalations on erythropoiesis and steroidogenesis and their positive effects on health. Further research is needed to establish the effects of these gases. Additionally, improved communication between the anti-doping authorities and all key stakeholders is required to support the inclusion of various substances on the Prohibited List.

category: sports medicine


title: A non-muscle myosin heavy chain 9 genetic variant is associated with graft failure following kidney transplantation.

abstract:
BackgroundDespite current matching efforts to identify optimal donor-recipient pairs in kidney transplantation, alloimmunity remains a major proponent of late transplant failure. While kidney allocation based on human leukocyte antigen (HLA) matching has markedly prolonged short-term graft survival, new data suggests that additional genetic parameters in donor-recipient matching could help improve the long-term outcomes. Here, we studied the impact of a recently discovered non-muscle myosin heavy chain 9 gene (MYH9) polymorphism on kidney allograft failure.

MethodsWe conducted a prospective observational cohort study, analyzing the DNA of 1,271 kidney donor-recipient transplant pairs from a single academic hospital for the MYH9 rs11089788 C>A polymorphism. The association of the MYH9 genotype with the risk of graft failure (primary outcome), biopsy-proven acute rejection (BPAR), and delayed graft function (DGF) (secondary outcomes) were determined.

ResultsThe MYH9 polymorphism in the donor was not associated with 15-year death-censored kidney graft survival, whereas a trend was seen for the association between the MYH9 polymorphism in the recipient and graft failure (recessive model, P=0.056). Having the AA-genotype of the MYH9 polymorphism in recipients was associated with a higher risk of DGF (P=0.031) and BPAR (P=0.021), although the significance was lost after adjustment for potential confounders (P=0.15 and P=0.10, respectively). The combined presence of the MYH9 polymorphism in donor-recipient pairs was significantly associated with long-term kidney allograft survival (P=0.036), in which recipients with an AA-genotype receiving a graft with an AA-genotype had the worst outcome. After adjustment for covariates, this combined genotype remained significantly associated with 15-year death-censored kidney graft survival (HR 1.68, 95%-CI: 1.05 - 2.70, P=0.031).

ConclusionsOur results reveal that recipients with an AA-genotype MYH9 polymorphism receiving a donor kidney with an AA-genotype, have a significantly elevated risk of graft failure after kidney transplantation.

Key pointsO_LIIn recipients, the MYH9 SNP was associated with delayed graft function and biopsy-proven acute rejection after kidney transplantation, although the significance was lost in multivariable analysis.
C_LIO_LIPresence of the MYH9 variant in both the donor and recipient significantly associated with long-term kidney allograft survival in multivariable analysis.
C_LIO_LIOur present findings suggests that matching donor-recipient transplant pairs based on the MYH9 polymorphism may attenuate the risk of graft loss.
C_LI

category: transplantation


title: Estimating the impact of the wMel release program on dengue and chikungunya incidence in Rio de Janeiro, Brazil

abstract:
BackgroundIntrogression of the insect bacterium Wolbachia into Aedes aegypti mosquito populations been shown in randomised and non-randomised trials to reduce the incidence of dengue in treated communities, however evidence for the real-world effectiveness of large-scale Wolbachia mosquito deployments for arboviral disease control in endemic settings is still limited and no effectiveness studies have been conducted for chikungunya virus. A large Wolbachia (wMel strain) program was implemented in 2017 in Rio de Janeiro, Brazil. Here we assess the impact of the release program on dengue and chikungunya incidence.

Methods and findingsThe program released 67 million wMel infected mosquitoes across 28,489 release locations over a 86.8km2 area in Rio de Janeiro between August 2017 and the end of 2019. Following releases, mosquitoes were trapped and the presence of wMel determined. To assess the impact of the release program on dengue and chikungunya incidence, we used spatiotemporally explicit models applied to geocoded dengue (N=194,330) and chikungunya cases (N=58,364) from 2010 (2016 for chikungunya) to 2019 from across the city. On average, 32% of mosquitoes collected from the release zones between 1 and 29 months after releases were positive for wMel. Reduced wMel introgression occurred in locations and seasonal periods when dengue and chikungunya cases were historically high. Despite incomplete introgression, we found that the releases were associated with a 38% (95%CI: 32-44%) reduction in dengue incidence and a 10% (95%CI: 4-16%) reduction in chikungunya incidence.

ConclusionsStable establishment of wMel in this diverse, urban setting appears more complicated than has been observed elsewhere. However, even intermediate levels of wMel appear to reduce the incidence of two different arboviruses.


title: Cerebrovascular risk factors impact brain phenotypes and cognitive function in healthy population

abstract: Cognitive decline is a major characteristic of ageing. Studies show that cardiovascular risk factors (CVR) are associated with cognitive declines and brain phenotypes, but the causality between CVR and cognitive function needs further understanding. In this study, we seek to investigate the causalities between CVR, brain phenotypes and cognitive function. We first generate a general factor (gCVR) representing common CVR and a score representing the polygenic risk (PRS). We then identify phenotypes of brain and cognitive functions associated with gCVR and PRS. Moreover, we conduct causal mediation analysis to evaluate the indirect effect of PRS through CVR, which infers the causality of gCVR on brain phenotypes and cognition. Further, we test the mediation effect of gCVR on the total effect of brain phenotypes on cognitive function. Finally, the causality between CVR and brain phenotypes is cross validated using Mendelian randomization (MR) with genetic instruments. The results show that CVR mediates the effect of PRS on brain phenotypes and cognitive function, and CVR also mediates the effect of brain phenotypes on cognitive changes. Additionally, we validate that the variation in a few brain phenotypes., e.g., volume of grey matter, are caused by CVR.


title: Deep learning applied to 4-electrode EEG resting-state data detects depression in an untrained external population

abstract: In this study we trained and tested several deep learning algorithms to classify depressive individuals and controls based on their electroencephalography data. Traditionally, classification methods based on electroencephalography resting-state are based primarily on linear features or a combination of linear and non-linear features. Based on different theoretical grounds, some authors claim that the more electrodes, the more accurate the classifiers, while others consider that working on a selection of electrodes is a better approach{square}. In this study, a data-driven approach was initially applied on a selection of electrodes to classify 25 depressive and 24 control participants. Using a classifier with just four electrodes, based on non-linear features with high temporo-spatial complexity, proved accurate enough to classify depressive and control participants. After the classifier was internally trained and tested, it was applied to electroencephalography resting-state data of control and depressive individuals available from a public database, obtaining a classifier accuracy of 93% in the depressive and 100% in the control group. This validates the generalizability of the classifier to untrained data from different teams, populations and settings. We conclude that time-window span analysis is a promising approach to understand the neural dynamics of depression and to develop an independent biomarker.


title: Framework for prioritizing variants of unknown significance from clinical genetic testing in kidney disease: utility of multidisciplinary approach to gather evidence of pathogenicity for Hepatocyte Nuclear Factor-1 (HNF1B) p.Arg303His

abstract: Monogenic causes in over 300 kidney-associated genes account for roughly 12% of end stage kidney disease (ESKD) cases. Advances in next generation sequencing, and large customized panels enable the diagnosis of monogenic kidney disease noninvasively at relatively low cost, allowing for more precise management for patients and their families. A major challenge is interpreting rare variants, many of which are classified as variants of unknown significance (VUS). We present a framework in which we thoroughly evaluated and provided evidence of pathogenicity for HNF1B-p.Arg303His, a VUS returned from clinical genetic testing for a kidney transplant candidate. This blueprint, designed by a multi-disciplinary team of clinicians, molecular biologists, and diagnostic geneticists, includes using a health system-based cohort with genetic and clinical information to perform deep phenotyping of VUS carriers, examination of existing genetic databases, as well as functional testing. With our approach, we demonstrate evidence for pathogenicity for HNF1B-p.Arg303His by showing similar burden of kidney manifestations in this variant to known HNF1B pathogenic variants, and greater burden compared to non-carriers. Determination of a molecular diagnosis for the example family allows for proper surveillance and management of HNF1B-related manifestations such as kidney disease, diabetes, and hypomagnesemia with important implications for safe living-related kidney donation. The candidate gene-variant pair also allows for clinical biomarker testing for aberrations of linked pathways. This working model may be applicable other diseases of genetic etiology.


title: AI-Driven Longitudinal Characterization of Neonatal Health and Morbidity

abstract: While prematurity is the single largest cause of death in children under 5 years of age, the current definition of prematurity, based on gestational age, lacks the precision needed for guiding care decisions. Here we propose a longitudinal risk assessment for adverse neonatal outcomes in newborns based on a multi-task deep learning model that uses electronic health records (EHRs) to predict a wide range of outcomes over a period starting shortly after the time of conception and ending months after birth. By linking the EHRs of the Lucile Packard Childrens Hospital and the Stanford Healthcare Adult Hospital, we developed a cohort of 22,104 mother-newborn dyads delivered between 2014 and 2018. This enabled a unique linkage between long-term maternal information and newborn outcomes. Maternal and newborn EHRs were extracted and used to train a multi-input multi-task deep learning model, featuring a long short-term memory neural network, to predict 24 different neonatal outcomes. An additional set of 10,250 mother-newborn dyads delivered at the same Stanford Hospitals from 2019 to September 2020 was used to independently validate the model, followed by a separate analysis of 12,256 mothers-newborn dyads at the University of California, San Francisco. Moreover, comprehensive association analysis identified multiple known and new associations between various maternal and neonatal features and specific neonatal outcomes. To date, this is the largest study utilizing linked EHRs from mother-newborn dyads and would serve as an important resource for the investigation and prediction of neonatal outcomes. An interactive website is available for independent investigators to leverage this unique dataset: https://maternal-child-health-associations.shinyapps.io/shiny_app/.

category: pediatrics


title: Real-World Evidence of the Neutralizing Monoclonal Antibody Sotrovimab for Preventing Hospitalization and Mortality in COVID-19 Outpatients

abstract:
BackgroundIt is not known whether sotrovimab, a neutralizing monoclonal antibody (mAb) treatment authorized for early symptomatic COVID-19 patients, is effective against the SARS-CoV-2 Delta variant to prevent progression to severe disease and mortality.

MethodsObservational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from October 1st 2021 - December 11th 2021, using electronic health records from a statewide health system plus state-level vaccine and mortality data. We used propensity matching to select 3 patients not receiving mAbs for each patient who received outpatient sotrovimab treatment. The primary outcome was 28-day hospitalization; secondary outcomes included mortality and severity of hospitalization.

ResultsOf 10,036 patients with SARS-CoV-2 infection, 522 receiving sotrovimab were matched to 1,563 not receiving mAbs. Compared to mAb-untreated patients, sotrovimab treatment was associated with a 63% decrease in the odds of all-cause hospitalization (raw rate 2.1% versus 5.7%; adjusted OR 0.37, 95% CI 0.19-0.66) and an 89% decrease in the odds of all-cause 28-day mortality (raw rate 0% versus 1.0%; adjusted OR 0.11, 95% CI 0.0-0.79), and may reduce respiratory disease severity among those hospitalized.

ConclusionReal-world evidence demonstrated sotrovimab effectiveness in reducing hospitalization and all-cause 28-day mortality among COVID-19 outpatients during the Delta variant phase.


title: Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial

abstract:
BackgroundA profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19 to prevent respiratory decline or death. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess the safety and efficacy of dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, in those hospitalized with COVID-19.

MethodsWe conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days, with collection of clinical outcomes, adverse events and immunologic biomarkers at multiple time points throughout the study period. The primary endpoint was the proportion of patients alive and free of invasive mechanical ventilation at 28 days analyzed in logistic regression.

ResultsForty eligible subjects were enrolled from June 23, 2021 through November 11, 2021. There was no difference in adverse events nor in proportion of patients alive and free of mechanical ventilation at day 28 between study treatment groups. However, for the secondary endpoint of mortality at day 60, subjects randomized to dupilumab had a higher survival rate: 89.5% of subjects in the dupilumab group were alive compared to 76.2% in the placebo group (adjusted HR 0.05, 95% CI: 0.0-0.72, p=0.03). There was a trend toward reduction in ICU admission in the dupilumab group compared to the placebo group (33.3% vs 66.7%; adjusted HR 0.44, 95% CI: 0.09-2.09, p=0.30). Lastly, we saw downstream evidence of IL-4 and IL-13 signaling blockade through analysis of immune biomarkers at multiple study time points.

ConclusionsDupilumab was well tolerated and improved 60-day survival in patients hospitalized with moderate to severe COVID-19. Blockade of type 2 immunity offers promise as a novel treatment for COVID-19.


title: SARS-CoV-2 hyperimmune globulin for severely immunocompromised patients with COVID-19: a randomised, controlled, double-blind, phase 3 trial

abstract:
BackgroundSeverely immunocompromised patients are at risk for severe COVID-19. Benefit from convalescent plasma in these patients is suggested but data from randomised trials are lacking. The aim of this study is to determine efficacy of SARS-CoV-2 hyperimmune globulin ("COVIG") in treatment of severely immunocompromised, hospitalised COVID-19 patients.

MethodsIn this randomised, controlled, double-blind, multicentre, phase 3 trial, severely immunocompromised patients who were hospitalised with symptomatic COVID-19 were randomly assigned (1:1) to receive 15 grams of COVIG or 15 grams of intravenous immunoglobulin without SARS-CoV-2 antibodies (IVIG, control). Patients included were solid organ transplant patients with three drugs from different immunosuppressive classes or patient with disease or treatment severely affecting B-cell function. Patients that required mechanical ventilation or high flow nasal oxygen were excluded. All investigators, research staff, and participants were masked to group allocation. The primary endpoint was occurrence of severe COVID-19 evaluated up until day 28 after treatment, defined as the need for mechanical ventilation, high-flow nasal oxygen, readmission for COVID-19 after hospital discharge or lack of clinical improvement on day seven or later. This trial is registered with Netherlands Trial Register (NL9436).

FindingsFrom April, 2021, to July, 2021, 18 participants were enrolled at three sites in the Netherlands; 18 patients were analysed. Recruitment was halted prematurely when casirivimab/imdevimab became the recommended therapy in the Dutch COVID-19 treatment guideline for seronegative, hospitalised COVID-19 patients. Median age was 58 years and all but two were negative for SARS-CoV-2 spike IgG at baseline. Severe COVID-19 was observed in two out of ten (20%) patients treated with COVIG compared to seven of eight (88%) in the IVIG control group (p = 0{middle dot}015, Fishers exact test).

InterpretationCOVIG reduced the incidence of severe COVID-19 in severely immunocompromised patients, hospitalised with COVID-19. COVIG may be a valuable treatment in this patient group and can be used when no monoclonal antibody therapies are available.

FundingThe Netherlands Organisation for Health Research and Development, Sanquin Blood Supply Foundation.


title: A comparative analysis of serial measurements of Soluble Urokinase-type Plasminogen Activator Receptor (suPAR) and C-reactive protein in patients with moderate COVID-19: a single center study from India

abstract:
Soluble urokinase plasminogen-activator receptor (suPAR) is a secreted protein associated with inflammation and proven its usefulness in triage/risk stratifications. This prospective study aimed to evaluate the utility of suPAR in comparison to C-reactive protein (CRP) in hospitalized moderate COVID-19 patients.

This is a prospective comparative study during second pandemic wave. Serum suPAR level and CRP were measured serially in 31 confirmed COVID-19 hospitalized patients (20 males, 11 females) on day-1 (24-hours of admission), day-3 and day-5 using suPARnostic AUTO flex ELISA and Nephelometry (ThermoFischer) respectively. Schapiro Wilk test verified the data distribution; Wilcoxon signed rank test compared CRP and suPAR between deceased/alive subject and identified link between co-morbidity and COVID-19 severity.

In our study, the mean age was 61.8 ranging from 28-82 with 9.7% (n=3/31) mortality rate. Deceased patients showed significant higher suPAR levels correlating with increasing severity from day 1 to 5 (p<0.016-0.006) than CRP (p=0.717). Patients with pre-existing co-morbidities showed significantly elevated suPAR levels on days 1-5, especially those with hypertension (HTN;p<0.03) and chronic kidney disease (CKD;p<0.001).

In conclusion, levels of suPAR were higher in deceased patients with severe symptoms of COVID-19 during hospitalization and in patients with pre-existing co-morbid conditions, HTN and CKD. This preliminary study provides evidence suggesting that circulating suPAR can be a potential biomarker to assess the severity of COVID 19 compared to CRP.


title: Accurate diagnosis of atopic dermatitis by applying random forest and neural networks with transcriptomic data

abstract: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. But the great heterogeneity of AD makes it difficult to design an accurate diagnostic pipeline based on traditional diagnostic methods. In other words, the AD diagnosis has suffered from an inaccurate bottleneck. Thus, it is necessary to develop a novel and accurate diagnostic model to supplement existing methods. The recent development of advanced gene sequencing technologies enables potential in accurate AD diagnosis. Inspired by this, we developed an accurate AD diagnosis based on transcriptomic data in skin tissue. Using these data of 149 subjects, including AD patients and healthy controls, from Gene Expression Omnibus (GEO) database, we screened differentially expressed genes (DEGs) of AD and identified six critical genes (PPP4R1, SERPINB4, S100A7, S100A9, BTC, and GALNT6) by random forest classifier. In a follow-up study of these genes, we constructed a neural network model (average AUC=0.943) to automatically distinguish subjects with AD from healthy controls. Among these critical genes, we found that PPP4R1 and GALNT6 had never been reported to be associated with AD. Although further replications in other cohorts are needed, our findings suggest that these genes may be developed into useful biomarkers of AD diagnosis and may provide invaluable clues or perspectives for further researches on the pathogenesis of AD.

category: dermatology


title: A prospective cohort study of presenteeism and increased risk of unemployment among Japanese workers

abstract:
ObjectiveWe examined the association between presenteeism and risk of job resignations and unemployment among Japanese workers during the COVID-19 pandemic.

MethodsA prospective study of 27,036 Internet monitors was conducted, starting in December 2020, with 18,560 (68.7%) participating in the follow-up by December 2021. The Work Functioning Impairment Scale (WFun) was used to measure the degree of work function impairment.

ResultsThe group with the highest WFun scores had higher odds ratios (ORs) for both retirement and unemployment for health reasons than the group with the lowest WFun scores. ORs were 2.97 (95%CI: 2.46-3.59, p<0. 001) and 1.80 (95%CI: 1.64-1.98, p<0.001), respectively.

ConclusionsWorkers with work functioning impairment were at increased risk of resignation or unemployment. Management strategies for workers with work functioning impairment are needed to reduce their disadvantages in employment.


title: Why is leptospirosis hard to avoid for the impoverished? Deconstructing leptospirosis transmission risk and the drivers of knowledge, attitudes, and practices in a disadvantaged community in Salvador, Brazil

abstract: Several studies have identified socioeconomic and environmental risk factors for infectious disease, but the relationship between these and knowledge, attitudes, and practices (KAP), and more importantly their web of effects on individual infection risk, have not previously been evaluated. We conducted a cross-sectional KAP survey in an urban disadvantaged community in Salvador, Brazil, leveraging on simultaneously collected fine-scale environmental and epidemiological data on leptospirosis transmission. Residents knowledge influenced their attitudes which influenced their practices. However, different KAP variables were driven by different socioeconomic and environmental factors; and while improved KAP variables reduced risk, there were additional effects of socioeconomic and environmental factors on risk. For example, males and those of lower socioeconomic status were at greater risk, but once we controlled for KAP, male gender and lower socioeconomic status themselves were not direct drivers of seropositivity. Employment was linked to better knowledge and a less contaminated environment, and hence lower risk, but being employed was independently associated with a higher, not lower risk of leptospirosis transmission, suggesting travel to work as a high risk activity. Our results show how such complex webs of influence can be disentangled. They indicate that public health messaging and interventions should take into account this complexity and prioritize factors that limit exposure and support appropriate prevention practices.


title: SEN support from the start of school and its impact on unplanned hospital utilisation in children with cleft lip and palate: a demonstration target trial emulation protocol using ECHILD

abstract:
Special Educational Needs (SEN) provision for school children provides extra support and reasonable adjustments for children and young people with additional educational, behavioural or health needs to ensure equal education opportunities; for example those born with a healthcare need such as cleft lip and palate may be provided SEN to aid with challenges in communications. However, there is limited knowledge of whether SEN provisions impact academic or health outcomes in such a population and conducting a randomised controlled trial to establish this evidence is not plausible. In lieu of randomised controlled trials, target trial emulation methods can be used in attempt to answer causal questions using observational data whilst reducing confounding and other biases likely to arise with such data. The Education and Child Health Insights from Linked Data (ECHILD) dataset could be used as part of trial emulation methods to understand the impact of SEN provisions on academic and healthcare outcomes. ECHILD is the first dataset to hold longitudinal school, health and social care data on all pupils in England, obtained by linking the National Pupil Database (NPD) with Hospital Episode Statistics (HES). In this protocol, we describe how the ECHILD dataset could be used to explore and conduct a target trial emulation to evaluate whether children who were born with cleft lip and palate would have different unplanned hospital utilisation if they received or did not receive SEN provisions by Year 1 (specifically by January in their second year of school) when they are aged 5 or 6.

MethodsFocussing on the population of children who are identified as having been born with cleft lip and palate, an intervention of varying levels of SEN provision (including no SEN provision) by January of the second year of school, and an outcome of unplanned hospital utilisation, we apply a trial emulation design to reduce confounding when using observational data to investigate the causal impact of SEN on unplanned hospital admissions. Our target population is children born 2001-2014 who had a recording of cleft lip and palate in HES and who started their second year of primary school (Year 1) in a state school between 2006 and 2019; children with a first recording of cleft lip and palate after Year 1 were excluded (these were pupils who likely immigrated to England after birth). We intend to use a time window of SEN provision assignment between the start of school (reception) and by the January school census in Year 1. Using target trial emulation, we aim to estimate the average treatment effect of SEN provision on the number of unplanned hospital admissions (including admissions to accident and emergency) between the January school census in Year 1 and Year 6 (the end of primary school, when children are 10-11 years old).

Ethics and disseminationPermissions to use linked, de-identified data from Hospital Episode Statistics and the National Public Database were granted by DfE (DR200604.02B) and NHS Digital (DARS-NIC-381972). Ethical approval for the ECHILD project was granted by the National Research Ethics Service (17/LO/1494), NHS Health Research Authority Research Ethics Committee (20/EE/0180) and UCL Great Ormond Street Institute of Child Healths Joint Research and Development Office (20PE06). Stakeholders (academics, clinicians, educators and child/young people advocacy groups) will consistently be consulted to refine populations, interventions and outcomes of studies that use the ECHILD dataset to conduct target trial emulation. Scientific, lay and policy briefings will be produced to inform public health policy through partners in the Department of Education and the Department of Health and Social Care.


title: Clinicians perspective on use of immune checkpoint inhibitors and related biomarkers for solid tumors

abstract:
BackgroundImmune checkpoint inhibitors (ICIs) are a valuable treatment option for patients with malignant tumors, but only selected patients respond to ICIs. Available biomarkers are of limited use in guiding ICI therapy.

ObjectiveTo examine clinicians perspective on the use of ICIs and biomarkers for treatment of malignant tumors and to identify unmet needs related to their use.

MethodsWe conducted in-depth telephone interviews of eight oncologists, and 100 oncologists completed online surveys.

ResultsOncologists have a positive attitude toward use of ICIs, and 98% of them prescribe them in all approved indications. Clinicians report that only about half of the patients with solid tumors responded to treatment, overestimated the response rate to ICIs across most types of tumors they treat compared with data in the literature. They ranked the lack of reliability of biomarkers to guide treatment (rating of 4.4 out of 7) as the top challenge with use of ICIs, followed by lack of overall efficacy and toxicity or occurrence of immune-related adverse events. The biomarkers most often used by survey participants were: a comprehensive panel including driver mutations and tumor mutational burden(69% of respondents), programmed cell death ligand-1 (PD-L1) expression (62%), and microsatellite instability (MSI) (56%). Oncologists indicated that they ordered biomarkers for each type of cancer according to their perceived usefulness of each biomarker in predicting the outcomes for ICI therapy, being more likely to use those perceived as useful or very useful.

ConclusionClinicians indicate that more reliable therapy-response prediction biomarkers would have a great impact on treatment decisions for patients with solid tumors, reducing unnecessary treatments, side effects, and health care expenditures.

category: pharmacology and therapeutics


title: Health conditions associated with sexual assault in a large hospital population

abstract:
ObjectiveTo develop a clinical informatics approach to identify patients with a history of sexual assault and to characterize the clinical risk factors and comorbidities of this population in a sex-stratified manner.

MethodsWe developed and applied a keyword-based approach to clinical notes to identify patients with a history of sexual assault in the Vanderbilt University Medical Center (VUMC) electronic health record from 1989 to 2021. Using a phenome-wide association study (PheWAS), we then examined diagnoses that co-occurred with evidence of sexual assault. We also examined whether sex assigned at birth modified any of these associations.

ResultsOur keyword-based algorithm achieved a positive predictive value of 90.4%, as confirmed by manual patient chart review. Out of 1,703 diagnoses tested across all subgroup analyses, we identified a total of 465 associated with sexual assault, many of which have been previously observed in the literature. Interaction analysis revealed 55 sex-differential phenotypic associations.

ConclusionsIn a large hospital setting, disclosures of sexual assault were associated with increased rates of hundreds of health conditions.

category: public and global health


title: Effectiveness of a nation-wide COVID-19 vaccination program in Mexico

abstract:
BACKGROUNDVaccination has been effective in ameliorating the impact of COVID-19. However, estimation of vaccine effectiveness (VE) is still unavailable for some widely used vaccines and underrepresented groups. Here, we report on the effectiveness of a nation-wide COVID-19 vaccination program in Mexico.

METHODSWe used a test-negative design within a national COVID-19 surveillance system to assess VE of the BNT162b2, mRNA-12732, Gam-COVID-Vac, Ad5-nCoV, Ad26.COV2.S, ChAdOx1 and CoronaVac vaccines, against SARS-CoV-2 infection, COVID-19 related hospitalization and death for adults [≥]18 years in Mexico. VE was estimated using Cox proportional hazard models considering time-varying vaccination status in partial and fully vaccinated individuals compared to unvaccinated adults, adjusted by age, sex, comorbidities and municipality. We also estimated VE for adults [≥]60 years, for cases with diabetes and comparing periods with predominance of variants B.1.1.519 and B.1.617.2.

RESULTSWe assessed 793,487 vaccinated compared to 4,792,338 unvaccinated adults between December 24th, 2020, and September 27th, 2021. VE against SARS-CoV-2 infection was highest for fully vaccinated individuals with mRNA-12732 (91.5%, 95%CI 90.3-92.4) and Ad26.COV2.S (82.2%, 95%CI 81.4-82.9), whereas for COVID-19 related hospitalization were BNT162b2 (84.3%, 95%CI 83.6-84.9) and Gam-COVID-Vac (81.4% 95%CI 79.5-83.1) and for mortality BNT162b2 (89.8%, 95%CI 89.2-90.2) and mRNA-12732 (93.5%, 95%CI 86.0-97.0). VE for all evaluated vaccines was reduced for adults [≥]60 years, people with diabetes, and in periods of Delta variant predominance.

CONCLUSIONSAll evaluated vaccines were effective against SARS-CoV-2 infection and COVID-19 related hospitalization and death. Mass vaccination campaigns with multiple vaccine products are feasible and effective to maximize vaccination coverage.


title: Linking private health sector to public COVID-19 response in Kisumu, Kenya: Lessons Learnt

abstract:
BackgroundCOVID-19 is overwhelming health systems universally. Increased capacity to combat the epidemic is important, while continuing regular healthcare services. This paper describes an innovative Public Private Partnership (PPP) against COVID-19 that from the onset of the epidemic was established in Kisumu County, Western Kenya.

MethodsAn explanatory research design was used. Qualitative in-depth interviews (n=49) were conducted with purposively selected participants including patients, health workers, and policy makers. Thematic analysis was undertaken on interview transcripts and triangulation was performed.

ResultsThe PPP hinged through the provision of central diagnostic COVID-19 services through a parastatal institute (KEMRI). Complementary tasks were divided between Kisumu Department of Health and public and private healthcare providers, supported by an NGO. Facilitators to this PPP included implementation of MoH Guidelines, digitalization of data, strengthening of counseling services and free access to COVID-19 testing services in private facilities. Barriers included, data accessibility, sub optimal financial management.

ConclusionCoordinated PPP can rapidly enhance capacity and quality of COVID-19 epidemic management in African settings. Our PPP model appears scalable, as proven by current developments. Lessons learnt from this initial PPP in Kisumu County will be beneficial to expanding epidemic preparedness to other Counties in Kenya and beyond.