title: If we cannot eliminate them, should we tame them? Mathematics underpinning the dose effect of virus infection and its application on covid-19 virulence evolution

abstract:
There is a dose effect in the infection process, that is, different initial virus invasion loads will lead to nonlinear changes in infection probability. Experiments already proved that there was a sigmoid functional relationship between virus infection probability and inoculum dose. By means of mathematical simulation of stochastic process, we theoretically demonstrate that there is a sigmoid function relationship between them. At the same time, our model found three factors that influence the severity of infection symptoms, those are virus toxicity, virus invasion dose and host immunity respectively. Therefore, the mortality rate cannot directly reflect the change of virus toxicity, but is the result of the comprehensive action of these three factors. Protective measures such as masks can effectively reduce the severity of infection while reducing the probability of infection. Based on the sigmoid function relationship between virus infection probability and initial virus invasion dose, we deduce that for highly infectious viruses, such as SARS-COV-2, the evolution of its toxicity is closely related to the host population density, and its toxicity will first increase and then decrease with the increase of host population density. That is to say, on the basis of extremely low host population density, increasing population density is beneficial to the development of virus towards strong toxicity. However, this trend is not sustainable, and there is a turning point of population density. Beyond this turning point, increasing population density will be beneficial to the development of virus towards weak toxicity. This theory can well explain the differences of mortality in Covid-19 in different countries. Countries with high population density and extremely low population density often correspond to lower mortality, while countries with population density in the range of 20-100/km2 often have higher mortality. At the same time, we propose that social distance and masks can effectively accelerate the evolution of virus towards low toxicity, so we should not give up simple and effective protection measures while emphasizing vaccination.

HighlightsThrough mathematical simulation of random process, we prove the sigmoid function relationship between virus infection probability and initial virus invasion dose theoretically.

Our model found three factors that influence the severity of infection symptoms: virus toxicity, virus invasion dose and host immunity. This can help explain why the average infection age was declining as the epidemic went through.

With the increase of host population density, virus toxicity will increase at first and then decrease, which will explain the difference of mortality in different population density areas.

From the mathematical level, social distance, masks and other protective measures were proved to be positive in promoting the virus evolving into the less toxicity one. Vaccination could also promote virus virulence attenuation.


title: Simulating the impact of non-pharmaceutical interventions limiting transmission in COVID-19 epidemics using a membrane computing model

abstract: Epidemics caused by microbial organisms are part of the natural phenomena of increasing biological complexity. The heterogeneity and constant variability of hosts, in terms of age, immunological status, family structure, lifestyle, work activities, social and leisure habits, daily division of time, and other demographic characteristics make it extremely difficult to predict the evolution of epidemics. Such prediction is, however, critical for implementing intervention measures in due time and with appropriate intensity. General conclusions should be precluded, given that local parameters dominate the flow of local epidemics. Membrane computing models allows us to reproduce the objects (viruses, hosts) and their interactions (stochastic but also with defined probabilities) with an unprecedented level of detail. Our LOIMOS model helps reproduce the demographics and social aspects of a hypothetical town of 10,320 inhabitants in an average European country where COVID-19 is imported from the outside. The above-mentioned characteristics of hosts and their lifestyle are minutely considered. The dynamics of the epidemics are reproduced and include the effects on viral transmission of innate and acquired immunity at various ages. The model predicts the consequences of delaying the adoption of non-pharmaceutical interventions (between 15 and 45 days after the first reported cases) and the effect of those interventions on infection and mortality rates (reducing transmission by 20%, 50%, and 80%) in immunological response groups. The lockdown for the elderly population as a single intervention appears to be effective. This modelling exercise exemplifies the application of membrane computing for designing appropriate interventions in epidemic situations.

category: epidemiology


title: Relating SARS-CoV-2 shedding rate in wastewater to daily positive tests data: A consistent model based approach

abstract:
During the COVID-19 pandemic, wastewater-based epidemiology (WBE) has been engaged to complement medical surveillance and in some cases to also act as an early diagnosis indicator of viral spreading in the community. Most efforts worldwide by the scientific community and commercial companies focus on the formulation of protocols for SARS CoV-2 analysis in wastewater and approaches addressing the quantitative relationship between WBE and medical surveillance are lacking. In the present study, a mathematical model is developed which uses as input the number of daily positive medical tests together with the highly non-linear shedding rate curve of individuals to estimate the evolution of virus shedding rate in wastewater along calendar days. A comprehensive parametric study by the model using as input actual medical surveillance and WBE data for the city of Thessaloniki ([~]700,000 inhabitants, North Greece) during the outbreak of November 2020 reveals the conditions under which WBE can be used as an early warning tool for predicting pandemic outbreaks. It is shown that early warning capacity is different along the days of an outbreak and depends strongly on the number of days apart between the day of maximum shedding rate of infected individuals in their disease cycle and the day of their medical testing. The present data indicate for Thessaloniki an average early warning capacity of around 2 days. Moreover, the data imply that there exists a proportion between unreported cases (asymptomatic persons with mild symptoms that do not seek medical advice) and reported cases. The proportion increases with the number of reported cases. The early detection capacity of WBE improves substantially in the presence of an increasing number of unreported cases. For Thessaloniki at the peak of the pandemic in mid-November 2020, the number of unreported cases reached a maximum around 4 times the number of reported cases.

HIGHLIGHTSO_LIModel estimates viral load evolution in wastewater from infected people dynamics
C_LIO_LIIdentifying actual conditions for which WBE can be used as an early warning tool
C_LIO_LIEarly warning capacity increases with an increasing number of unreported cases
C_LIO_LIIn Thessaloniki Nov20 outbreak, the early warning capacity of WBE was about 2 days
C_LIO_LIIn Thessaloniki Nov20 outbreak, unreported cases were up to 4 times reported cases
C_LI


title: Demographic and Mental Health Assessments in the Adolescent Brain and Cognitive Development Study: Updates and Longitudinal Trajectories

abstract: The Adolescent Brain Cognitive Development (ABCD) Study of 11,880 youth incorporates a comprehensive range of measures assessing predictors and outcomes related to mental health across childhood and adolescence in participating youth, as well as information about family mental health history. We have previously described the logic and content of the mental health assessment battery at Baseline and Year 1. Here, we describe changes to that battery and issues and clarifications that have emerged, as well as additions to the mental health battery at the 2-, 3-, 4-, and 5-year follow-ups. We capitalize on the recent release of longitudinal data for caregiver and youth report of mental health data to evaluate trajectories of dimensions of psychopathology as a function of demographic factors. For both caregiver and self-reported mental health symptoms, males showed age-related decreases in internalizing and externalizing symptoms, while females showed an increase in internalizing symptoms with age. Multiple indicators of socioeconomic status (caregiver education, family income, financial adversity, neighborhood poverty) accounted for unique variance in both caregiver and youth-reported externalizing and internalizing symptoms. These data highlight the importance of examining developmental trajectories of mental health as a function of key factors such as sex and socioeconomic environment.

category: psychiatry and clinical psychology


title: Implementation, adoption and perceptions of telemental health during the COVID-19 pandemic: a systematic review

abstract:
BackgroundEarly in 2020, mental health services had to rapidly shift from face-to-face models of care to delivering the majority of treatments remotely (by video or phone call or occasionally messaging) due to the COVID-19 pandemic. This resulted in several challenges for staff and patients, but also in benefits such as convenience or increased access for people with impaired mobility or in rural areas. There is a need to understand the extent and impacts of telemental health implementation, and barriers and facilitators to its effective and acceptable use. This is relevant both to future emergency adoption of telemental health, and to debates on its future use in routine mental health care.

ObjectiveTo investigate the adoption and impacts of telemental health approaches during the COVID-19 Pandemic, and facilitators and barriers to optimal implementation.

MethodsFour databases (PubMed, PsycINFO, CINAHL and Web of Science) were searched for primary research relating to remote working, mental health care, and the COVID-19 pandemic. Preprint servers were also searched. Results of studies were synthesised using framework synthesis.

ResultsA total of 77 papers met our inclusion criteria. In most studies, the majority of contacts could be transferred to a remote form during the pandemic, and good acceptability to service users and clinicians tended to be reported, at least where the alternative to remote contacts was interrupting care. However, a range of impediments to dealing optimal care by this means were also identified.

ConclusionsImplementation of telemental health allowed some continuing support to the majority of service users during the COVID-19 pandemic and has value in an emergency situation. However, not all service users can be reached by this means, and better evidence is now needed on long-term impacts on therapeutic relationships and quality of care, and on impacts on groups at risk of digital exclusion and how to mitigate these.


title: Tau pathology mediates the effects of amyloid on neocortical tau propagation and neurodegeneration among individuals without dementia

abstract: Amyloid-{beta}(A{beta}) pathology is associated with greater tau pathology and facilitates tau propagation from the medial temporal lobe (MTL) to the neocortex, where tau is closely associated with local neurodegeneration. The degree of the involvement of A{beta} versus existing tau pathology in tau propagation and neurodegeneration has not been fully elucidated in human studies. Careful quantification of these effects can inform the development and timing of therapeutic interventions. We conducted causal mediation analyses to investigate these questions in two longitudinal studies of individuals without dementia. As proxies of neurodegeneration, we investigated cerebral blood flow (CBF), glucose metabolism, and regional volume. We first confirmed that A{beta} moderates the association between tau in the entorhinal cortex and in the inferior temporal gyrus, a neocortical region exhibiting early tau pathology (amyloid group x entorhinal tau interaction term {beta} = 0.486, SE = 0.126, p < 0.001 in the Baltimore Longitudinal Study of Aging [BLSA]; {beta} = 0.658, SE = 0.137, p < 0.001 in the Alzheimers Disease Neuroimaging Initiative [ADNI]). In causal mediation analyses accounting for this facilitating effect of amyloid, amyloid positivity had a statistically significant direct effect on inferior temporal tau as well as an indirect effect via entorhinal tau (average direct effect [ADE]= 0.46, p < 0.001 and average causal mediation effect [ACME]= 0.46, p = 0.0012 in BLSA; ADE= 0.47, p < 0.001 and ACME= 0.254, p = 0.021 in ADNI). Entorhinal tau mediated up to 50% of the total effect of amyloid on inferior temporal tau. Higher inferior temporal tau was associated with lower colocalized CBF, glucose metabolism, and regional volume, whereas amyloid had only an indirect effect on these measures via tau, implying tau as the primary driver of neurodegeneration (amyloid-CBF indirect effect ACME = -0.29, p = 0.014 in BLSA; amyloid-volume indirect effect ACME = -0.23, p < 0.001 in ADNI). Our findings suggest targeting amyloid or MTL tau might slow down neocortical spread of tau and subsequent neurodegeneration, but a combination therapy may yield better outcomes.

category: neurology


title: Tau pathology mediates the effects of amyloid on neocortical tau propagation and neurodegeneration among non-demented individuals


title: Noradrenergic deficits contribute to apathy in Parkinson's disease through the precision of expected outcomes

abstract: AO_SCPLOWBSTRACTC_SCPLOWApathy is a debilitating feature of many diseases, including Parkinsons disease. We tested the hypothesis that degeneration of the locus coeruleus-noradrenaline system contributes to apathy by modulating the relative weighting of prior beliefs about action outcomes. Participants with mild-to-moderate idiopathic Parkinsons disease (N=17) completed a double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinsons disease, subject to stratification according to locus coeruleus integrity.


title: Sulfation of O-glycans on mucin-type proteins from serous ovarian epithelial tumors

abstract: Despite that sulfated O-linked glycans are abundant on ovarian cancer (OC) glycoproteins, their regulation during cancer development and involvement in cancer pathogenesis remain unexplored. We characterized O-glycans carrying sulfation on galactose residues and compared their expression to defined sulfotransferases regulated during OC development. Desialylated sulfated oligosaccharides were released from acidic glycoproteins in the cyst fluid from one patient with a benign serous cyst and one patient with serous OC. Oligosaccharides characterized by LC-MSn were identified as core 1 and core 2 O-glycans up to the size of decamers, and with 1-4 sulfates linked to GlcNAc residues and to C-3 and/or C-6 of Gal. To study the specificity of the potential ovarian sulfotransferases involved, Gal3ST2 (Gal-3S)-, Gal3ST4 (Gal-3S)-, and CHST1 (Gal-6S)-encoding expression plasmids were transfected individually into CHO cells also expressing the P-selectin glycoprotein ligand-1/mouse immunoglobulin G2b (PSGL-1/mIg G2b) fusion protein and the human core 2 transferase (GCNT1). Characterization of the PSGL-1/mIg G2b O-glycans showed that Gal3ST2 preferentially sulfated Gal on the C-6 branch of core 2 structures and Gal3ST4 preferred Gal on the C-3 branch independently if core-1 or-2. CHST1 sulfated Gal residues on both the C-3 (core 1/2) and C-6 branches of core 2 structures. Using serous ovarian tissue micro array, Gal3ST2 was found to be decreased in tissue classified as malignant compared to tissues classified as benign or borderline, with the lowest expression in poorly differentiated malignant tissue. Neither Gal3ST4 nor CHST1 were differentially expressed in benign, borderline or malignant tissue, and there was no correlation between expression level and differentiation stage. The data displays a complex sulfation pattern of O-glycans on OC glycoproteins and that aggressiveness of the cancer is associated with a decreased expression of the Gal3ST2 transferase.

category: oncology


title: Gender Affirming Hormone Therapy induces specific DNA methylation changes in blood

abstract: DNA methylation is an epigenetic mark that is influenced by underlying genetic profile, environment, and aging. It also plays a key role in female-specific X-chromosome silencing in mammals. In addition to X-linked DNA methylation, sex-specific methylation patterns are widespread across autosomal chromosomes and can be present from birth or arise over time. In individuals where gender identity and sex assigned at birth are markedly and consistently incongruent, as in the case of transgender people, feminization or masculinization may be sought through gender affirming hormone therapy (GAHT). In this study we profiled genome-wide DNA methylation in blood of transgender women and transgender men, before and during GAHT (6 months and 12 months into hormone treatment). We identified several thousand differentially methylated CpG sites (DMPs) in both people undergoing feminizing and masculinizing hormone therapy, the vast majority of which were progressive changes over time. Sex-specific DNA methylation patterns established in early development are largely refractory to change in association with GAHT. The small number of sex-DMPs that were affected by GAHT were those that become sex-specific during the lifetime, known as sex-and-age DMPs.

category: genetic and genomic medicine


title: Incorporating family disease history and controlling case-control imbalance for population based genetic association studies

abstract: In the genome-wide association analysis of population-based biobanks, most diseases have low prevalence, which results in low detection power. One approach to tackle the problem is using family disease history, yet existing methods are unable to address type I error inflation induced by increased correlation of phenotypes among closely related samples, as well as unbalanced phenotypic distribution. We propose a new method for genetic association test with family disease history, TAPE (mixed-model-based Test with Adjusted Phenotype and Empirical saddlepoint approximation), which controls for increased phenotype correlation by adopting a two-variance-component mixed model, accounts for case-control imbalance by using empirical saddlepoint approximation, and is flexible to incorporate any existing adjusted phenotypes such as phenotypes from the LT-FH method. We show through simulation studies and analysis of UK-Biobank data of white British samples and the Korean Genome and Epidemiology Study (KoGES) of Korean samples that the proposed method is robust and yields better calibration compared to existing methods while gaining power for detection of variant-phenotype associations.


title: COVID-19 and regional differences in the timeliness of hip-fracture surgery: an interrupted time-series analysis

abstract:
BackgroundIt is of great importance to examine the impact of the healthcare reorganization adopted to confront the COVID-19 pandemic on the quality of care provided by healthcare systems to non-COVID-19 patients. The aim of this study is to assess the impact of the COVID-19 national lockdown (March 9, 2020) on the quality of care provided to patients with hip fracture (HF) in Piedmont and Emilia-Romagna, 2 large regions of northern Italy severely hit by the pandemic.

MethodsWe calculated the percentage of HF patients undergoing surgery within 2 days of hospital admission. An interrupted time-series analysis was performed on weekly data from December 11, 2019 to June 9, 2020 ({approx}6 months), interrupting the series in the 2nd week of March. The same data observed the year before were included as a control time series with no "intervention" (lockdown) in the middle of the observation period.

ResultsBefore the lockdown, 2-day surgery was 69.9% in Piedmont and 79.2% in Emilia-Romagna; after the lockdown, these proportions were equal to 69.8% (-0.1%) and 69.3% (- 9.9%), respectively. While Piedmont did not experience any drop in the amount of surgery, Emilia-Romagna exhibited a significantly decline at a weekly rate of -1.29% (95% CI = -1.71 to -0.88).

Divergent trend patterns in the 2 study regions reflect local differences in pandemic timing as well as in healthcare services capacity, management, and emergency preparedness.

category: health policy


title: Mathematical modelling of SARS-CoV-2 variant outbreaks reveals their probability of extinction

abstract: When a virus spreads, it may mutate into, e.g., vaccine resistant or fast spreading lineages, as was the case for the Danish Cluster-5 mink variant (belonging to the B.1.1.298 lineage), the British B.1.1.7 lineage, and the South African B.1.351 lineage of the SARS-CoV-2 virus. A way to handle such spreads is through a containment strategy, where the population in the affected area is isolated until the spread has been stopped. Under such circumstances, it is important to monitor whether the mutated virus is extinct via massive testing for the virus sub-type. If successful, the strategy will lead to lower and lower numbers of the sub-type, and it will eventually die out. An important question is, for how long time one should wait to be sure the sub-type is extinct? We use a hidden Markov model for infection spread and an approximation of a two stage sampling scheme to infer the probability of extinction. The potential of the method is illustrated via a simulation study. Finally, the model is used to assess the Danish containment strategy when SARS-CoV-2 spread from mink to man during the summer of 2020, including the Cluster-5 sub-type. In order to avoid further spread and mink being a large animal virus reservoir, this situation led to the isolation of seven municipalities in the Northern part of the country, the culling of the entire Danish 17 million large mink population, and a bill to interim ban Danish mink production until the end of 2021.

category: infectious diseases


title: Generation of false positive SARS-CoV-2 antigen results with testing conditions outside manufacturer recommendations: A scientific approach to pandemic misinformation

abstract:
ObjectivesAntigen-based rapid diagnostics tests (Ag-RDTs) are useful tools for SARS-CoV-2 detection. However, misleading demonstrations of the Abbott Panbio COVID-19 Ag-RDT on social media claimed that SARS-CoV-2 antigen could be detected in municipal water and food products. To offer a scientific rebuttal to pandemic misinformation and disinformation, this study explored the impact of using the Panbio SARS-CoV-2 assay with conditions falling outside of manufacturer recommendations.

MethodsUsing Panbio, various water and food products, laboratory buffers, and SARS-CoV-2-negative clinical specimens were tested, with and without manufacturer buffer. Additional experiments were conducted to assess the role of each Panbio buffer component (tricine, NaCl, pH, and tween-20), as well as the impact of temperatures (4{degrees}C, 20{degrees}C, and 45{degrees}C) and humidity (90%) on assay performance.

ResultsDirect sample testing (without the kit buffer), resulted in false positive signals resembling those obtained with SARS-CoV-2-positive controls tested under proper conditions. The likely explanation of these artifacts is non-specific interactions between the SARS-CoV-2-specific conjugated and capture antibodies, as proteinase K treatment abrogated this phenomenon, and thermal shift assays showed pH-induced conformational changes under conditions promoting artifact formation. Omitting, altering, and reverse engineering the kit buffer all supported the importance of maintaining buffering capacity, ionic strength, and pH for accurate kit function. Interestingly, the Panbio assay could tolerate some extremes of temperature and humidity outside of manufacturer claims.

ConclusionsOur data support strict adherence to manufacturer instructions to avoid false positive SARS-CoV-2 Ag-RDT reactions, otherwise resulting in anxiety, overuse of public health resources, and dissemination of misinformation.


title: Heterologous prime-boost vaccination with ChAdOx1 nCoV-19 and BNT162b2 mRNA

abstract: Administration of a first dose of the COVID-19 vaccine ChAdOx1 nCoV-19 (Vaxzevria(R), AstraZeneca) is associated with a certain risk for vaccine-induced immune thrombotic thrombocytopenia. Therefore, several countries have recommended replacing the second dose of ChAdOx1 nCoV-19 with an mRNA-based vaccine as a precautionary measure, although data on safety and efficacy of such heterologous prime-boost regimen are sparse. Therefore, vaccinees, who had received a heterologous vaccination using ChAdOx1 nCoV-19 as prime and BNT162b2 (Comirnaty(R), BioNTech-Pfizer) mRNA as boost vaccination were offered SARS-CoV-2 antibody testing to quantify their vaccine-induced neutralizing antibody response5. The results were compared to cohorts of healthcare workers or volunteers, who received homologous BNT162b2 or homologous ChAdOx1 nCoV-19 vaccination regimens, respectively. A striking increase of vaccine-induced SARS-CoV-2 neutralizing antibody activity was observed in 229 vaccinees that received a BNT162b2 boost 9 to 12 weeks after ChAdOx1 nCoV-19 prime. In our cohort comprising over 480 individuals, the heterologous vaccination scheme induced significantly higher neutralizing antibody titers than homologous ChAdOx1 nCoV-19 and even than homologous BNT162b2 vaccination. This proves that a single dose of a COVID-19 mRNA vaccine after ChAdOx1 nCoV-19 prime vaccination is sufficient to achieve high neutralizing antibody levels predicting immune protection from SARS-CoV-2 infection, and may even increase vaccine efficacy offering an alternative in a setting of vaccine shortage.


title: Estimation of Oral Disease Burden from Claims and Self-Reported Data.

abstract:
ObjectiveTo examine the use of Medicaid, commercial claims, and self-reported survey data to estimate the prevalence of oral disease burden.

MethodsWe analyzed 2018 Medicaid claims from IBM Watson Medicaid Marketscan database, commercial claims from the IBM Dental Database, and Medical Expenditure Panel Survey (MEPS) data. The estimate of oral disease burden was based on standard metrics using periodontal and caries-related treatment procedure codes. Examples are restorations: D2000-D2999, root Canals: D3230 - D3334, periodontics: D4000 - D4999, prosthodontics: D5000 - D6999 and extractions: D7000 - D7251. A direct comparison between the data sets was also done. Enrollees from the different databases were broken down by gender, race/ethnicity, and into age groups.

ResultsMedicaid and commercial enrollees were 11.6 million and 10.5 million. The weighted proportion from MEPS for Medicaid and commercial plans ranged from 80-208 million people. Prevalence of caries-related treatments was estimated for IBM Watson and MEPS for total enrollees for Medicaid (13% vs. 12%); and commercial claims (25% vs. 17%), respectively. Prevalence of periodontal related treatments was estimated for IBM Watson and MEPS total enrollees for Medicaid (0.7% vs. 0.5%) and commercial claims (7% vs. 1.6%), respectively. Prevalence of dental diseases was higher in patients with at least one visit for Medicaid, commercial plans, and MEPS. Prevalence based on specific procedures were higher in commercial plans than in Medicaid.

ConclusionsClaims data has the potential to serve as a proxy measure for the estimate of dental disease burden in a population. In addition, in rare events, claims data provides a better estimate of disease burden because it is based on a larger dataset.

category: dentistry and oral medicine


title: Prevalence of Long COVID symptoms in Bangladesh: A Prospective Inception Cohort Study of COVID-19 survivors.

abstract:
ObjectiveThe objective of this study was to identify the prevalence of  Long COVID symptoms (LCS) in a large cohort of survivors and identify any potential associated risk factors.

DesignA prospective survey was undertaken of an inception cohort of confirmed COVID-19 survivors (Aged 18 to 87 years).

Participants and Setting14392 participants were recruited from 24 testing facilities across Bangladesh between June, and November 2020. All participants had a previously confirmed positive COVID-19 diagnosis, and reported persistent symptoms and difficulties in performing daily activities.

Main Outcome MeasuresParticipants who consented, were contacted by face-to-face interview, and were interviewed regarding LCS, and restriction of activities of daily living using Post COVID-19 functional scale. Cardio-respiratory parameters were also measured.

ResultsAmong 2198 participants, the prevalence of LCS at 12 weeks was 16.1%. Overall, eight LCS were identified and in descending order of prominence are: fatigue, pain, dyspnea, cough, anosmia, appetite loss, headache, and chest pain. COVID survivors experienced between 1 to 5 LCS with an overall duration period of 21.8 {+/-} 5.2 weeks. SEM predicted the length of LCS to be related to younger age, female gender, rural residence, prior functional limitation and smoking.

ConclusionIn this cohort of survivors, at 31 weeks post diagnosis, the prevalence of LCS was 16.1%. The risk factors identified for presence and longer length of LCS warrant further research and consideration to support public health initiatives.


title: Indirect impact on number of admitted children with COVID-19 in the first three months of emergency use of two vaccines, in Rio de Janeiro, Brazil

abstract:
IntroductionSince January 19, 2021, two vaccines against SARS-COV-2 are available in Brazil for emergency use for selected groups, not including children.

AimTo describe indirect impact on the number of hospitalized children with COVID-19 in the first three months after beginning of emergency use of two vaccines.

MethodsA retrospective study was conducted in children (0-18 years), admitted in two pediatric hospitals of Rio de Janeiro city, between January and April 2021 with confirmed COVID-19 by reverse transcription polymerase chain reaction or serological tests. Number of cases, clinical signs, symptoms and outcomes were compared with the first wave of disease (April-June 2020). A p value of less than .05 were considered was significant.

ResultsThe number of total admitted patients (with all diseases) were 1097 in 2020 period, being 46 (4.2%) of them with confirmed COVID-19, and 2187 in the 2021 period, with 47 (2.1%) cases (p=0.006). Predominant respiratory symptoms were present in 29/46 (63%) as the main presentation in 2020 patients and 37/47 (78.7%) in 2021 children (p=0.09). The main symptoms were fever, cough and dyspnoea in both periods. The median of lenght of stay after diagnosis were 4 days in 2020 and 2021 (p=0.9). Just one patient died in 2021.

ConclusionThere was reduction of relative percentage of admitted confirmed pediatric cases in the the first three months of emergency use of two vaccines against SARS-COV-2, but its uncertain to atribute this finding to vaccination due to high circulation of the virus in the city.

category: pediatrics


title: Varenicline Versus Cytisine for Smoking Cessation in a Primary Care Setting: A Randomized Controlled Trial

abstract:
Our study aims to implement a smoking cessation program using pharmacotherapy in a real-life setting -- primary care practices in Croatia and Slovenia -- and to investigate whether cytisine is at least as feasible and effective as Varenicline in helping smokers to quit in a randomized non-inferiority trial. The use of these medications as an intervention tool for smoking cessation in Croatia and Slovenia is not previously explored and the level of awareness and interest in pharmacotherapy among smokers is unknown.

BackgroundTobacco addiction is a chronic disorder that accounts for more than 8 million premature deaths each year worldwide1. While more than 7 million deaths are the result of direct tobacco use, around 1.2 million are the result of non-smokers being exposed to second-hand smoke.2 Smokers suffer from poorer health and are at greater risk of cancer, cardiovascular and respiratory diseases. As a result, half of them die prematurely, on average 14 years earlier.3 Among the World Health Organization (WHO) regions, Europe, with 28% of the total population smoking, has the highest prevalence of tobacco smoking in adults and increasing rates among adolescent and female populations.4 The European Union and Central Europe in particular has one of the highest proportions of deaths attributable to tobacco use, causing more than 700.000 deaths annually in the European Union.5 WHO has estimated that tobacco use is currently responsible for 16% of all deaths in adults over 30 years of age in this region.6

Croatia and Slovenia, countries in Central Europe, have a high prevalence of smoking due in part to 1) cultural habits and a tradition of smoking tobacco; 2) problems with financing health care insurance systems; and 3) the strong influence of the tobacco industries on government and national policies. During the past two decades, Croatian and Slovenian tobacco control policies followed the strategies set forth by WHO. However, the impact on the prevalence of smoking differed in each country. Croatia and Slovenia, two European neighboring countries with similar levels of economic development, education and culture have a very high but different smoking prevalence: in Croatia, 39.4% of males and 33.5% of females smoke7; in Slovenia, 27.5% of males and 21.1% of females.8 Comprehensive tobacco control programs in Slovenia have resulted in significant declines in cigarettes sales and the prevalence of smoking among adults and youth as tobacco control programs have become a national health policy priority.

AimOur study aims to implement a smoking cessation program using pharmacotherapy in a real life setting -- primary care practices in Croatia and Slovenia -- and to investigate whether cytisine is at least as feasible and effective as Varenicline in helping smokers to quit in a randomized non-inferiority trial.

HypothesisCytisine is at least as feasible and effective as Varenicline in helping smokers to quit in a randomized non-inferiority trial.

ImplicationsThe use of these medications as an intervention tool for smoking cessation in Croatia and Slovenia is not previously explored and the level of awareness and interest in pharmacotherapy among smokers is unknown.

Varenicline (trade name: Chantix and Champix) is a prescription medication used to treat nicotine addiction. It reduces craving for smoking cigarettes and other tobacco products. It is a high-affinity partial agonist for the 4{beta}2 nicotinic acetylcholine receptor subtype (nACh) that leads to the release of dopamine in the nucleus acumbens when activated. It has the capacity to reduce the feelings of desire and unpleasant effectsc of the withdrawal caused by smoking cessation9.

Cytisine is a generic agent manufactured by Sopharma (trade name Tabex) and by Aflofarm Farmacia Polska (trade name Desmoxan). Cytisine acts by reducing the rewarding effect of nicotine and attenuating nicotine withdrawal symptoms. Its a plant-based alkaloid found in members of the Leguminosae family (e.g., Cytisus laburnum). Cytisine is a partial agonist of nicotinic acetylcholine receptors (nAChRs), binding with high affinity to the 4{beta}2 subtype, which is central to the effect of nicotine on the reward pathway10.

Several studies have shown that pharmacotherapy using Varenicline or cytisine is effective for smoking cessation. 11,12,13 The current evidence shows that Varenicline is the most effective pharmacotherapy for smoking cessation. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation. It is estimated that Varenicline successfully helps one of every 11 people who smoke remain abstinent from tobacco at six months14. A meta-analysis found that less than 20% of people treated with varenicline remain abstinent from smoking at one year.15,16 Four systematic reviews report cytisine to be superior to placebo for short-term and long-term abstinence. The results of the CASCAID trial showed that cytisine was superior to NRT for smoking cessation and, specifically, that cytisine was 1.43 times more likely than nicotine patches with gum or lozenges to help participants stop smoking and remain non-smokers for six months.11 However, head to head comparisons in real-life settings are lacking and needed17, including a cost-effectiveness analysis taking into the account the fact that cytisine is a low-cost therapy compared with Varenicline and other smoking cessation medications (cytisine at $19.61 for 25 days of treatment; varenicline at $416 for 12 weeks and $832 for 24 weeks). If shown to be non-inferior, therapy with cytisine would be known to result in a lower cost for a similar efficacy.

Primary care practices are an ideal real-life setting for the implementation and evaluation of pharmacotherapy for smoking cessation, as they are exactly the setting where participants would normally receive treatment from their medical care providers, thus addressing possible concerns about generalizations which may limit a study conducted in a context importantly different from that where the investigated treatments would be used.18

category: pharmacology and therapeutics


title: Measuring Physical Intimate Partner Violence to Monitor Sustainable Development Goal 5: A Global Psychometric Assessment

abstract:
BackgroundOne third of women experience IPV and potential sequelae. Sustainable Development Goal (SDG) 5.2--to eliminate all violence against women, including IPV-- compels national governments to monitor such violence. We conducted the first global measurement-invariance assessment of standardized physical IPV items.

MethodsThirty-six Demographic and Health Surveys (DHS) from 36 Lower-/Middle-Income Countries (LMICs) administering the same 18 IPV items during 2012-2018 were included. We performed exploratory and confirmatory factor analyses (EFA/CFA) with seven physical IPV items, which are the most behaviorally specific and reliable. Datasets meeting EFA/CFA model fit criteria (loadings>.35, RMSEA<.08, CFI/TLI>.95) were included in multiple-group CFA to test strict measurement invariance, and in alignment optimization (AO) to test approximate measurement invariance. We compared national rankings based on AO-derived scores and lifetime physical IPV prevalences, and correlated AO-dervied scores with physical, sexual, and psychological IPV prevalences.

ResultsEstimated lifetime physical IPV varied widely (5.6%-50.5%). All loadings and fit statistics met thresholds in country-specific EFA/CFAs. A unidimensional, seven-item physical IPV construct lacked scalar invariance in multiple-group CFA but achieved approximate measurement invariance in AO analysis, as 12.3% (<25%) of model parameters were non-invariant. National rankings of AO-derived scores and estimated physical IPV prevalences were similarly distributed, but national estimates often were not significantly different, so grouped score ranges or prevalence ranges are advised. Three items (slap, twist, choke) warrant cognitive testing to improve their psychometric performance. Correlations of AO-derived scores with IPV prevalences ranged from .48 to .66.

ConclusionsSeven DHS physical-IPV items were approximately invariant across 36 LMICs spanning five regions and are reasonable for cross-national, grouped comparison of physical IPV. Measurement-invariance testing over time will inform their utility to monitor SDG5.2.1; cross-national and cross-time measurement-invariance testing of other IPV item sets is warranted.

category: public and global health


title: The Ultra Fit Community Mask - Toward Maximal Respiratory Protection via Personalized Face Fit

abstract:
Effective masking policies to prevent the spread of airborne infections depend on public access to masks with high filtration efficacy. However, poor face-fit is almost universally present in pleated multilayer disposable face masks, severely limiting both individual and community respiratory protection. We developed a set of simple mask modifications to mass-manufactured disposable masks, the most common type of mask used by the public, that dramatically improves both their personalized fit and performance in a low-cost and scalable manner. These modifications comprise a user-moldable full mask periphery wire, integrated earloop tension adjusters, and an inner flange to trap respiratory droplets. We demonstrate that these simple design changes improves quantitative fit factor by 320%, triples the level of protection against aerosolized droplets, and approaches the model efficacy of N95 respirators in preventing the community spread of COVID-19, for an estimated additional cost of less than 5 cents per mask with automated production.

TeaserA personalizable, low-cost mask improves facial fit, reduces user exposure, and decreases spread of contagious aerosols.

category: occupational and environmental health


title: Surgical Treatments for Lumbar Spine Diseases: A Systematic Review and Meta-Analysis

abstract:
PurposeSurgical treatment is mandatory in some patients with lumbar spine diseases. To obtain spine fusion, many operative techniques were developed with different fusion rates and clinical results. This study aimed to collect randomized controlled trial (RCT) data to compare fusion rate, clinical outcomes, complications among Transforaminal Lumbar Interbody Fusion (TLIF), and other techniques for lumbar spine diseases.

MethodsA systematic literature search of PubMed, Embase, Scopus, Web of Science, and CENTRAL databases was searched for studies up to 13 February 2020. The meta-analysis was done using a random-effects model. Pooled risk ratio (RR) or mean difference (MD) with a 95% confidence interval of fusion rate, clinical outcomes, and complication in TLIF and other techniques for lumbar diseases.

ResultsThe literature search identified 3,682 potential studies, 15 RCTs (915 patients) were met our inclusion criteria and were included in the meta-analysis. Compared to other techniques, TLIF had slightly lower fusion rate (RR=0.84 [95% CI 0.72, 0.97], p=0.02, I2=0.0%) at 1-year follow-up while there was no difference on fusion rate at 2-year follow up (RR=1.06 [95% CI 0.96, 1.18], p=0.27, I2=69.0%). The estimated risk ratio of total adverse events (RR=0.90 [95% CI 0.59, 1.38], p=0.63, I2=0.0%) and revision rate (RR=0.78 [95%CI 0.34, 1.79], p=0.56, I2=39.0%) showed no difference. TLIF had approximately half an hour more operative time than other techniques (MD=31.88 [95% CI 5.33, 58.44], p=0.02, I2=92.0%). There was no significant difference between TLIF and other techniques in terms of the blood loss, and clinical outcomes.

ConclusionsBesides fusion rate at 1-year follow-up and operative time, our study demonstrated similar outcomes of TLIF with other techniques for lumbar diseases in regard to fusion rate, clinical outcomes, and complications.

category: orthopedics


title: Epidemiological dynamics of SARS-CoV-2 VOC Gamma in Rio de Janeiro, Brazil

abstract: The emergence and widespread circulation of SARS-CoV-2 variants of concern (VOC) or interest (VOI) imposes an enhanced threat to global public health. In Brazil, one of the countries most severely impacted throughout the pandemic, a complex dynamics involving variants co-circulation and turnover events has been recorded with the emergence and spread of VOC Gamma in Manaus in late 2020. In this context, we present a genomic epidemiology investigation based on samples collected between December 2020 and May 2021 in the second major Brazilian metropolis, Rio de Janeiro. By sequencing 244 novel genomes through all epidemiological weeks in this period, we were able to document the introduction and rapid dissemination of VOC Gamma in the city, driving the rise of the third local epidemic wave. Molecular clock analysis indicates this variant has circulated locally since the first weeks of 2021 and only seven weeks were necessary for it to achieve a frequency above 70%, consistent with rates of growth observed in Manaus and other states. Moreover, a Bayesian phylogeographic reconstruction indicates VOC Gamma spread throughout Brazil between December 2020 and January 2021, and that it was introduced in Rio de Janeiro through at least 13 events coming from nearly all regions of the country. Comparative analysis of RT-qPCR cycle threshold (Ct) values provides further evidence that VOC Gamma induces higher viral loads (N1 target; mean reduction of Ct: 2.7, 95% CI = {+/-}0.7). This analysis corroborates the previously proposed mechanistic basis for this variant enhanced transmissibility and distinguished epidemiological behavior. Our results document the evolution of VOC Gamma and provide independent assessment of scenarios previously studied in Manaus, therefore contributing to the better understanding of the epidemiological dynamics currently being surveyed in other Brazilian regions.


title: Colorectal Cancer Disparities: A Systematic Review and Meta-Analysis

abstract:
ImportanceDespite increases in screening among vulnerable populations, colorectal cancer disparities persist.

ObjectiveTo direct future efforts towards high impact opportunities in addressing these disparities, we performed a systematic review and meta-analysis of the colorectal cancer disparities literature with a focus on the utilization of Surgery, the primary treatment for colorectal cancer.

Data SourcesTwo electronic databases (PubMed and SCOPUS) were searched for prospective and retrospective studies reporting on colorectal cancer disparities between 2011 and March 29, 2021.

Study SelectionStudies for the systematic review were selected if: (1) reported on disparities within colorectal, colon, or rectal cancer (2) articles were published in the English language (3) articles used only United States-sourced data.

Studies for the meta-analysis were selected if: (1) reported on at least one of three utilization of surgery outcomes: receipt of colorectal, colon, or rectal surgery, refusal of surgery, or receipt of laparoscopic versus open surgery (2) Outcomes were reported as Odds ratio according to multivariate analysis.

Data Extraction and SynthesisQuality appraisal and data extraction were performed independently by 2 reviewers using the Newcastle-Ottawa Scale for quality assessment. For the meta-analysis, pooled multivariate odds ratios for the three outcomes regarding utilization of surgery were separately calculated according to fixed or random-effects models. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines.

Main Outcomes and MeasuresSystematic Review: The volume of publications attributed to the following sectors of the colorectal cancer care continuum: (1) Prevention, Screening, or Diagnosis (2) Treatment (3) Survivorship (4) End-of-life Care. Meta-analysis: Receipt of Colorectal, Colon, or Rectal Surgery and Black Race, Refusal of Surgery and Black Race, or Receipt of Laparoscopic versus Open Surgery and Black Race.

ResultsThe systematic review included 1,199 relevant publications. Among them, 60% were focused on Prevention, Screening, or Diagnosis, followed by Survivorship (20%), Treatment (15%), and End-of-Life Care (1%). Within the studies reporting on treatment disparities, 46% were focused on Race/Ethnicity, followed by Socioeconomic Status (28%), Age (17%), Gender (6%), Disabilities/Comorbidities (3%), and LGBTQI+ (0%). A total of 16 studies, including 1,110,674 patients, were applied to three separate meta-analyses regarding utilization of Surgery. Patients of black race were less likely to receive colorectal, or colon, or rectal surgery (OR 0.75, 95% CI 0.67-0.83), less likely to receive laparoscopic versus open colorectal cancer surgery (OR 0.91, 95% CI 0.88-0.94), and twice as likely to refuse colon surgery (OR 2.41, 95% CI 1.91-3.06).

Conclusions and RelevanceThe majority of research, to date, related to colorectal cancer disparities is focused on prevention, screening, or diagnosis and a minimal amount is dedicated to treatment. Additionally, all of the limited publications related to colorectal cancer surgery, as a treatment modality, are observational in nature. The application of this knowledge of past efforts and current continuing adverse outcomes is required in order to shift the focus of the research community towards treatment. In particular, research addressing surgical disparities is necessary, as surgery remains the primary treatment for colorectal cancer.

category: surgery


title: Colorectal Cancer Disparities Across the Continuum of Cancer Care with a Focus on Surgery and Black Patients: A Systematic Review and Meta-Analysis


title: Colorectal Cancer Disparities Across the Continuum of Cancer Care: A Systematic Review and Meta-Analysis


title: Serum asymmetric dimethyl arginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

abstract:
ObjectiveTo investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS.

MethodsSerum ADMA levels of patients with sporadic ALS (n = 68) and disease control patients (n = 54) were measured using liquid chromatography-tandem mass spectrometry. Serum samples were obtained at the time of patient registration for diagnosis. Correlations of ADMA level and other markers (nitric oxide [NO] and neurofilament light chain [NFL] levels) were analyzed. Changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) score from the onset of disease (ALSFRS-R preslope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan-Meier analysis.

ResultsThe concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001), and was independently associated with the ALSFRS-R preslope (r = 0.505. p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF NfL level (r = 0.456, p = 0.0002) but not with NO level (r = 0.194, p = 0.219).

ConclusionADMA level is an independent biomarker of ALS disease progression and prognosis, and reflects the degree of motor neuron degeneration. The increased ADMA level in ALS patients was not associated with the inhibition of NO production.


title: Mpilo Outcomes for Stroke Study (MOSS): Does taking antihypertensives prior to stroke affect mortality during acute stroke admissions?

abstract:
ObjectiveTo assess if taking outpatient antihypertensives prior to stroke onset influences acute stroke inpatient mortality.

DesignRetrospective chart review of 417 adults admitted for acute stroke from January 2013 to December 2014.

SettingSingle tertiary hospital in Zimbabwe.

ParticipantsOf the 417 adult patients admitted with stroke, 40 were excluded (2 rheumatic heart disease, 10 transient ischemic attacks, and 28 incomplete documentation).

MethodsStudy registry was obtained from acute stroke billing codes in the hospital database and SPSS 23 was used for analysis.

Primary and secondary outcomes and measuresInpatient mortality was the primary outcome and determination of reported outpatient antihypertensive regimens was the secondary outcome.

ResultsAmong the 377 patients in the final analysis the mean age was 65.8 {+/-} 15.7 years, 64.5% were female, 68.9% had known hypertension, and 51.2% were taking outpatient antihypertensives. Overall inpatient mortality was 134 (35.5%, 95 CI: 30.6 -39.6). Mortality was similar among patients taking and not taking outpatient antihypertensives, 39.2% and 31.5% respectively (X2 test, p=0.4; 95 CI 31.3-40.3). Four most common antihypertensive regimens were: calcium channel blocker/thiazides dual therapy, thiazide monotherapy, calcium channel blocker monotherapy, and calcium channel blocker/ angiotensin converting enzyme inhibitor or angiotensin receptor blocker dual therapy.

Conclusions and RelevanceOnly half of the patients admitted for stroke were taking antihypertensives prior to stroke onset. There was no statistical significance in inpatient mortality associated with taking antihypertensives prior to developing stroke, suggesting either the limited impact of outpatient antihypertensives on in-hospital mortality or low outpatient antihypertensive adherence.

Strengths and Limitations of the StudyO_LIWe studied a large group of patients at a major safety net center in a region of Zimbabwe that is chronically under-represented in stroke studies
C_LIO_LIThe degree of outpatient hypertension control among patients on antihypertensives could not be determined due to lack of access to outpatient records
C_LIO_LIPoor medical knowledge, altered mental status from stroke, and the absence of an integrated outpatient pharmacy database limited accurate medication reconciliations
C_LIO_LILack of neuroimaging data limited the ability to discern between ischemic versus hemorrhagic strokes and rule out structural stroke mimics such as intracranial tumors
C_LIO_LIInconsistent and incomplete documentation practices such as omission of vital sign documentation on admission limited data collection
C_LI

Funding StatementThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Competing InterestsNone of the authors have any competing interests to declare.

Statement of Ethics ApprovalThis research was approved by the ethics body of Mpilo Central Hospital on 21 June 2016 as part of the mandate to assess The Burden of Hypertension and its Co-morbidities in Patients Admitted at Mpilo Central Hospital.


title: A Cross Sectional Study To Assess The Attitude Regarding Online Lecture Among Nursing College Students After Impact of Covid-19 At Selected College of Nursing, Nadiad.

abstract:
BackgroundIn December 2019, a pathogenic human corona virus SARS- CoV-2, corona virus disease 2019 (COVID-19), was recognized and has caused serious illness and numerous deaths. The epidemics of COVID-19 have been recorded over 200 countries, territories, and areas with 2 878 196 confirmed cased and 198 668 death cases.

AimsThe current study is to assess the attitude of nursing college students regarding online classes.

Objective1. To determine the perceptions of students towards e-learning during the lock down. 2. To assess nursing students attitude towards the online lectures

MethodologyO_ST_ABSSetting and DesignC_ST_ABSDescriptive cross sectional survey research design was used and not probability sampling methods was used to drawn samples through online Google form. The sample collected from nursing college students and study setting was Dinsha Patel College of nursing, Nadiad, Gujarat. There were total 20 attitude question with five point rating scale were used. Total sample were 136 nursing college students. Data has been collected online through Google form.

Statistical Analysis usedDescriptive statistics applied where, data was analyzed by using SPSS software, and Frequency, percentage, tables etc were used to represent the statistical data.

ResultsOut of 136, 64(47.05%) were belong age 17-18 years, 115(84.56%) were female, 68(50%) were GNM students, 51(37.50%) B.Sc. nursing Students, 83(61.02%) were third year, 75(55.24%) were live urban, 61(44.86%) were rural area, 56(41.17%) were travel 21-30km, 40(29.41%) more than 30km, 65(47.79%) have above 15000 monthly family income 132(97.05%) were used mobile for online lecture 79(58.08%) were have average network.

Attitude regarding Online Classes where 7 (5.14%) had Inadequate Attitude 86(63.25%) had Moderate Attitude, 43(31.61%) Had adequate Attitude.

ConclusionsRegarding the online lecture 63.25% nursing college students has moderate attitude and 31.61% had adequate attitude it means now days students are line online classes than physical mode due to various reasons such as, time consuming, reduce traveling, risk of accidents and corona, more time can spend with family etc

category: nursing


title: ANTI - SARS-CoV-2 ANTIBODY SCREENING IN HEALTH CARE WORKERS AND ITS CORRELATION WITH CLINICAL PRESENTATION

abstract:
BackgroundAntibody titration and the life span of the antibody against SARS-CoV-2 have been found to be determined by the clinical presentation as well. The extent of exposure of health care workers and the general public to SARS-CoV-2 needs to be assessed to monitor the COVID-19 pandemic. Thus, this study is an attempt in assessing the anti-SARs-COV-2 antibody in health care workers.

MethodsThis laboratory-based cross-sectional study was performed in Manmohan Memorial Medical College and Teaching Hospital, Kathmandu from November 2020 to January 2021. A total of 185 HCWs were screened for anti-SARS-CoV-2 antibody in the blood serum specimens. A structured questionnaire was administered to collect information from HCWs. Anti-SARS- CoV-2 antibody screening was performed using a lateral flow immunoassay. Data were analyzed according to standard statistical methods using SPSS version 20.

ResultsA total of 185 HCWs were participated in the study, among which 41 (22.2%) of them tested positive for anti-SARS-CoV-2 antibody. Among the 41 individuals who tested positive, 37 of them tested positive for IgG only and 4 of them tested positive for both IgM and IgG antibodies. Presence of history of SARS-CoV-2 infection (p<0.001), presence of flu-like symptoms within the last 6 months (p<0.001), and presence of positive contact history (p=0.002) were statistically significant with antibody screening among HCWs.

ConclusionThe burden of SARS-CoV-2 infection among healthcare workers seems to be high and HCWs are at risk of acquiring infection in the workplace. Anti-SARS-CoV-2 antibody screening among health care workers is highly recommended in multiple healthcare settings that can help in monitoring transmission dynamics and evaluation of infection control policies.


title: Multi-site clinical validation of Isothermal Amplification based SARS-COV-2 detection assays using different sampling strategies

abstract:
BackgroundIsothermal amplification-based tests were developed as rapid, low-cost, and simple alternatives to real-time reverse transcriptase-polymerase chain reaction (RT-PCR) tests for SARS-COV-2 detection.

MethodsClinical performance of two isothermal amplification-based tests (Atila Biosystems iAMP COVID-19 detection test and OptiGene COVID-19 Direct Plus RT-LAMP test) was compared to clinical RT-PCR assays using different sampling strategies. A total of 1378 participants were tested across four study sites.

ResultsCompared to standard of care RT-PCR testing, the overall sensitivity and specificity of the Atila iAMP test for detection of SARS-CoV-2 were 76.2% and 94.9%, respectively, and increased to 88.8% and 89.5%, respectively, after exclusion of an outlier study site. Sensitivity varied based on the anatomic collected site. Sensitivity for nasopharyngeal was 65.4% (range across study sites:52.8%-79.8%), mid-turbinate 88.2%, saliva 55.1% (range across study sites:42.9%-77.8%) and anterior nares 66.7% (range across study sites:63.6%-76.5%). The specificity for these anatomic collection sites ranged from 96.7% to 100%. Sensitivity improved in symptomatic patients (overall 82.7%) and those with a higher viral load (overall 92.4% for ct[≤]25). Sensitivity and specificity of the OptiGene Direct Plus RT-LAMP test, conducted at a single study-site, were 25.5% and 100%, respectively.

ConclusionsThe Atila iAMP COVID test with mid-turbinate sampling is a rapid, low-cost assay for detecting SARS-COV-2, especially in symptomatic patients and those with a high viral load, and could be used to reduce the risk of SARS-COV-2 transmission in clinical settings. Variation of performance between study sites highlights the need for site-specific clinical validation of these assays before clinical adoption.


title: The toll of COVID-19 on African children: A descriptive analysis on the COVID-19-related morbidity and mortality among the pediatric population in Sub-Saharan Africa

abstract:
IntroductionSince the beginning of the COVID-19 pandemic, very little data on the epidemiological characteristics among the pediatric population in Africa has been published. This paper examines the age and sex distribution of the morbidity and mortality rate in children with COVID-19 and compares it to the adult population within 15 Sub-Saharan African countries.

MethodsA merge line listing dataset using a reverse engineering model shared by countries within the Regional Office for Africa was analyzed. Patients diagnosed within 1 March 2020 and 1 September 2020 with confirmed positive RT-PCR test for SARS-CoV-2 were analyzed. Childrens data were stratified into three age groups: 0-4 years, 5-11 years, and 12-17 years, while adults were combined. The cumulative incidence of cases including its medians and 95% confidence intervals were calculated.

Results9% of the total confirmed cases and 2.4% of the reported deaths were pediatric cases. The 12-17 age group in all 15 countries showed the highest cumulative incidence proportion in children. COVID-19 cases in males and females under the age of 18 were evenly distributed. Among adults, a higher case incidence per 100,000 people was observed compared to children.

ConclusionThe cases and deaths within the childrens population was smaller than the adult population. These differences can reflect biases in COVID-19 testing protocols and reporting implemented by countries, highlighting the need for more extensive investigation and focus on the effects of COVID-19 in children.


title: A nationwide study of Chlamydia trachomatis infections in Denmark during the COVID-19 pandemic

abstract:
ObjectivesCOVID-19 policies have been employed in Denmark since March 2020. We examined whether COVID-19 restrictions had an impact on Chlamydia trachomatis infections compared with 2018 and 2019.

MethodsThis retrospective nation-wide Danish observational study was performed using monthly incidences of laboratory confirmed chlamydia cases and number of tests, obtained from nation-wide surveillance data. Additionally, Oxford COVID-19 Government Response Tracker data, and Google COVID-19 Community Mobility Reports were used to contextualise the behavioural adaptions seen as a result of COVID-19 policies. Testing rates were compared using Poisson regression and test positivity rates were compared using logistic regression.

ResultsThe crude incidence rate (IR) of laboratory confirmed chlamydia infections was reduced to 66.5 per 105 during the first (March-April 2020) lockdown period as compared to 88.3 per 105 in March-April 2018-2019, but the testing rate was also reduced (Rate ratio 0.72 95% CI 0.71 - 0.73), whereas the odds ratio for a positive test between the two periods was 0.98 (95% CI 0.96 - 1.00). The period of eased COVID 19 restrictions (May - December 2020) and the second lockdown period (December 2020 - March 2021) were characterised by marginally increased crude IRs, while the number of tests performed, and test positivity rates returned very close to the levels seen in 2018-2019. These results were independent of sex, age group, and geographical location.

ConclusionThe first Danish COVID-19 lockdown resulted in a reduction in the number of chlamydia tests performed and a consequent reduction in the number of laboratory-identified cases. This period was followed by a return of testing and test positivity close to the level seen in 2018 - 2019. Altogether the Danish COVID-19 restrictions have had negligible effects on laboratory confirmed C. trachomatis transmission.


title: Randomized, double blind, placebo controlled, clinical trial to study co-administration of Ashwagandha on safety, immunogenicity, and protection with COVID-19 vaccine: A Study Protocol

abstract:
IntroductionThe government of India has rolled out COVID-19 vaccine program for individuals who are 18 years of age and above and priority is being given to the elderly, and individuals with morbidity. Oxford-AstraZeneca COVID-19 vaccine (COVISHIELD) is most widely used in India. A large number of Indian people have been consuming various traditional medicines in the hope of better protection against COVID-19 infection. Several studies have reported immunological benefits of Ashwagandha and its potential as vaccine adjuvant. We plan to study co-administration of Ashwagandha with COVISHIELD vaccine on safety, immunogenicity and protection.

Methods and analysisWe designed a prospective, randomized, double blind, parallel group, placebo controlled, two arm, exploratory study on healthy volunteers receiving the COVISHIELD vaccine. In addition to the two dose schedule of COVISHIELD vaccine as per national guidelines, participants will be administered 8gm Ashwagandha or placebo tablets respectively per day. Primary outcome measure is immunogenicity as measured by SARS-CoV-2 spike (S1) and RBD-specific IgG antibody titres. Secondary outcome measures are safety, protective immune response and quality of life measures. Adverse event following immunization will be monitored at each time throughout the study. Participants will be tracked on a daily basis with a user friendly mobile phone application. Following power calculation 600 participants will be recruited per arm to demonstrate superiority by a margin of 7% with 80% power. Study duration is 28 weeks with interim analysis at the end of 12 weeks.

Ethics and disseminationEthical approval was obtained through the Central and institutional Ethics Committees. Participant recruitment is expected to commence by August 2021. Results will be presented in conferences and published in preprint followed by peer-reviewed medical journals.

Registration detailsClinical Trial Registry - India (CTRI) Registration Number: CTRI/2021/06/034496. Date of Registration June 30, 2021.

Strengths and limitations of this studyO_LINovel study to demonstrate effect of coadministration of immune adjuvant and COVID-19 vaccine on safety and immunogenicity.
C_LIO_LIRandomised placebo controlled 28 weeks study with 80 percent power to demonstrate role of putative natural immunomodulator to augment the protection and reduce breakthrough infections
C_LIO_LIState of art immune assays to measure specific antibodies to SARS-CoV-2 to demonstrate both persistent and late upsurge in immune response
C_LIO_LIDaily tracking of participants using a study specific designed mobile app
C_LIO_LIAn interim analysis is planned to provide information on early immune response after first dose of vaccine
C_LIO_LIParticipants may be reluctant to donate blood repeatedly for immune assays; compliance with the test drug may be a challenge; asymptomatic infections may be missed; the study is not measuring cellular immune response.
C_LI


title: Comorbidity accounts for severe COVID-19 risk, but how do we measure it? Retrospective assessment of the performance of three measures of comorbidity using 4,607 hospitalizations

abstract:
BackgroundComorbidity burden has been identified as a relevant predictor of critical illness in patients hospitalized with coronavirus disease 2019 (COVID-19). However, comorbidity burden is often represented by a simple count of few conditions that may not fully capture patients complexity.

PurposeTo evaluate the performance of a comprehensive index of the comorbidity burden (Queralt DxS), which includes all chronic conditions present on admission, as an adjustment variable in models for predicting critical illness in hospitalized COVID-19 patients and compare it with two broadly used measures of comorbidity.

Patients and methodsWe analyzed data from all COVID-19 hospitalizations reported in eight public hospitals of Catalonia (North-East Spain) between June 15 and December 8 2020. The primary outcome was a composite of critical illness that included the need for invasive mechanical ventilation, transfer to ICU, or in-hospital death. Predictors included age, sex, and comorbidities present on admission measured using three indices: the Charlson index, the Elixhauser index, and the Queralt DxS index for comorbidities on admission. The performance of different fitted models was compared using various indicators, including the area under the receiving operating characteristics curve (AUC).

ResultsOur analysis included 4,607 hospitalized COVID-19 patients. Of them, 1,315 experienced critical illness. Comorbidities significantly contributed to predicting the outcome in all summary indices used. The AUC for prediction of critical illness was 0.641 (95% CI 0.624-0.660) for the Charlson index, 0.665 (0.645-0.681) for the Elixhauser index, and 0.787 (0.773-0.801) for Queralt DxS. Other metrics of model performance also showed Queralt DxS being consistently superior to the other indices.

ConclusionIn our analysis, the ability of comorbidity indices to predict hospital outcomes in hospitalized COVID-19 patients increased with their exhaustivity. The comprehensive Queralt DxS index may improve the accuracy of predictive models for resource allocation and clinical decision-making in the hospital setting.

category: health systems and quality improvement


title: Application of nasal spray containing dimethyl sulfoxide (DSMO) and ethanol during the COVID-19 pandemic may protect healthcare workers: A randomized controlled trials

abstract:
BackgroundCoronavirus pandemic has affected a large population worldwide. Currently, the standard care for individuals who are exposed is supportive care, symptomatic management, and isolation. The aim of our study was to evaluate effects of combined use of ethanol and DMSO as a nasal spray in preventing COVID-19.

MethodsWe conducted a randomized controlled trial on volunteer healthcare workers of medical centers that were at the forefront of the fight against COVID-19 in Shahroud, Iran. Two hundred and thirty-two participants were randomly assigned to intervention and control groups to receive DMSO/ethanol or routine care, respectively. The subjects were followed for 4 weeks to determine the incidence of COVID-19 infection in each group based on the RT-qPCR test. Finally, absolute risk difference and relative risk were calculated to evaluate the effect of DMSO in prevent COVID-19.

ResultsThe results showed that the incidence of COVID-19 in the control group and intervention group were 0.07 and 0.008, respectively. The relative risk (RR) was 0.12 (0.9-0.02) according to the incidence rate in the two groups.

Conclusioncombined application of DMSO and ethanol in healthcare providers can considerably prevent COVID-19.


title: Application of nasal spray containing dimethyl sulfoxide (DMSO) and ethanol during the COVID-19 pandemic may protect healthcare workers: A randomized controlled trials


title: Pre-exposure prophylaxis adherence with real-time adherence feedback and partner HIV self-testing: A pilot trial among postpartum women

abstract:
BackgroundPre-exposure prophylaxis (PrEP) is safe and effective in postpartum women. HIV self-testing (HIVST) for partners combined with biofeedback counselling through real-time adherence measures may improve daily PrEP use among postpartum women.

MethodsBetween August 2020 and April 2021 we conducted a pilot study in one primary care clinic in Cape Town, South Africa. We randomized postpartum women who initiated PrEP in pregnancy 1:1 to the intervention group (HIVST + biofeedback counselling following urine tenofovir test) or to standard of care (facility-based HIV tests and routine counselling without biofeedback). The outcomes of interest were PrEP adherence in the past 48-72hours via urine tenofovir tests and partner HIV testing, measured 1-month after randomisation. Secondary outcomes included proportion of partners who tested for HIV and discrepancy between self-reported PrEP adherence and urine tenofovir result.

FindingsWe enrolled 106 women (median age=26 years; median months postpartum=2). Almost half of women reported having sex since giving birth (48%); 76% of those reported condomless sex at last sex. At enrolment most women (72%) reported missing <2 doses in the past 7-days; 36% of women had tenofovir present in her urine (no significant differences by arm). One month after enrolment, 62% (n=33) of women in the intervention arm had tenofovir present in their urine compared to 34% (n=18) in the standard of care arm (RR=1.83; 95% CI=1.19, 2.82). Two-thirds of women in the intervention arm reported that her partner tested for HIV (66%; n=35); compared to 17% (n=9) in the standard of care arm (RR=3.89; 95% CI=2.08, 7.27). The proportion of women with a discrepant adherence result (self-reported good recent adherence with no tenofovir in urine test) was significantly lower in the intervention group (n=8; 17%) compared to the standard of care group (n=24; 46%) (RR=0.33; 95% CI=0.17, 0.67). No social or clinical adverse events were reported in the intervention arm.

InterpretationIn this pilot study, HIVST for partners and biofeedback counseling increased levels of recent PrEP adherence, pointing to the importance of these interventions to support PrEP use in this population.

FundingOur study is funded by Fogarty International Center (K01TW011187) with additional support from NIMH (R01MH116771). Trial registration: Clinicaltrials.gov (NCT04897737). Funders had no role in data collection or analysis.


title: Lockdowns exert selection pressure on overdispersion of SARS-CoV-2 variants

abstract:
The SARS-CoV-2 ancestral strain has caused pronounced super-spreading events, reflecting a disease characterized by overdispersion, where about 10% of infected people causes 80% of infections. New variants of the disease have different person-to-person variations in viral load, suggesting for example that the Alpha (B.1.1.7) variant is more infectious but relatively less prone to superspreading. Meanwhile, mitigation of the pandemic has focused on limiting social contacts (lockdowns, regulations on gatherings) and decreasing transmission risk through mask wearing and social distancing. Using a mathematical model, we show that the competitive advantage of disease variants may heavily depend on the restrictions imposed. In particular, we find that lockdowns exert an evolutionary pressure which favours variants with lower levels of overdispersion. We find that overdispersion is an evolutionarily unstable trait, with a tendency for more homogeneously spreading variants to eventually dominate.

SignificanceOne of the most important and complex properties of viral pathogens is their ability to mutate. The SARS-CoV-2 pandemic has been characterized by overdispersion - a propensity for superspreading, which means that around 10% of those who become infected cause 80% of infections. However, evidence is mounting that this is not a stable property of the virus and that the Alpha variant spreads more homogeneously. We use a mathematical model to show that lockdowns exert a selection pressure, driving the pathogen towards more homogeneous transmission. In general, we highlight the importance of understanding how non-pharmaceutical interventions exert evolutionary pressure on pathogens. Our results imply that overdispersion should be taken into account when assessing the transmissibility of emerging variants.


title: Children's emotional wellbeing during spring 2020 COVID-19 restrictions: a qualitative study with parents of young children in England

abstract:
BackgroundDuring COVID-19 restrictions in England in spring 2020, early years settings for young children were closed to all but a small percentage of families, social contact was limited and play areas in parks were closed. Concerns were raised about the impact of these restrictions on young childrens emotional wellbeing. The aim of this study was to explore parents perceptions of young childrens emotional wellbeing during these COVID-19 restrictions.

MethodsWe interviewed 20 parents of children 3-4 years due to begin school in England in September 2020. Interviews were conducted via telephone (n=18) and video call (n=2), audio-recorded and transcribed verbatim. Interviews focused on childcare arrangements, childrens behaviour and transition to school. A sample of transcripts were coded line-by-line to create a coding framework, which was subsequently applied to the remaining transcripts. Coded data were then analysed using a nurture lens to develop themes and further understanding.

ResultsParticipants were predominantly mothers (n=16), White British (n=10), and educated to degree level (n=13), with half the sample living in the highest deprivation quintile in England (n=10). Five were single parents. Three themes developed from nurturing concepts were identified: creating age-appropriate explanations; understanding childrens behaviour; concerns about school transition. Parents recognised their childrens emotional wellbeing was impacted but attempted to support their young children whilst looking ahead to their transition to primary school.

ConclusionsThis study is one of the first to examine in-depth the impact of COVID-19 restrictions on young childrens emotional wellbeing. The longer-term impacts are not yet understood. Although young children may be unable to understand in detail what the virus is, they undoubtedly experience the disruption it brings to their lives. The wellbeing of families and children needs to be nurtured as they recover from the effects of the pandemic to allow them to thrive.

Key messagesCOVID-19 restrictions are predicted to have a negative impact on young children.

We interviewed parents of children in England due to begin primary school to understand their experiences of COVID-19 restrictions.

Nurture concepts helped us understand the challenges families faced.

Key themes identified were: creating age-appropriate explanations; understanding childrens behaviour; and concerns about school transition.

We suggest a nurturing approach to recovery to best support children and their families.


title: Vaccination willingness for COVID-19 among health care workers in Switzerland

abstract:
Aims of the studyVaccination is regarded as the most promising response to the COVID-19 pandemic. We assessed opinions towards COVID-19 vaccination, willingness to be vaccinated, and reasons for vaccination hesitancy among health care workers (HCWs).

MethodsWe conducted a cross-sectional, web-based survey among 3,793 HCWs in December 2020 in the Canton of Solothurn, Switzerland, before the start of the national COVID-19 vaccination campaign.

ResultsMedian age was 43 years (interquartile range [IQR] 31-53), 2,841 were female (74.9%). 1,511 HCWs (39.8%) reported willingness to accept vaccination, while 1,114 (29.4%) were unsure, and 1,168 (30.8%) would decline vaccination. Among medical doctors, 76.1% were willing, while only 27.8% of nurses expressed willingness. Among 1,168 HCWs who would decline vaccination, 1,073 (91.9%) expressed concerns about vaccine safety and side effects. The willingness of HCWs to be vaccinated was associated with older age (adjusted odds ratio [aOR] 1.97, 95%Cl 1.71-2.27) and having been vaccinated for influenza this year (aOR 2.70, 95%Cl 2.20-3.31). HCWs who reported a lack of confidence in government were less likely to be willing to be vaccinated (aOR 0.58, 95%Cl 0.40-0.84), and women were less willing to be vaccinated than men (OR 0.33 (0.28-0.38).

ConclusionLess than half of HCWs reported willingness to be vaccinated before the campaign start, but proportions varied greatly depending on the profession and workplace. Strategies with clear and objective messages that particularly address the concerns of HCWs are needed if their willingness to be vaccinated is to be increased.


title: Depression predicts chronic pain interference in racially-diverse, low-income patients

abstract:
BackgroundChronic pain is one of the most common reasons adults seek medical care in the US, with estimates of prevalence ranging from 11% to 40%. Mindfulness meditation has been associated with significant improvements in pain, depression, physical and mental health, sleep, and overall quality of life. Group medical visits are increasingly common and are effective at treating myriad illnesses including chronic pain. Integrative Medical Group Visits (IMGV) combine mindfulness techniques, evidence based integrative medicine, and medical group visits and can be used as adjuncts to medications, particularly in diverse underserved populations with limited access to non-pharmacological therapies.

Objective and DesignThe objective of the present study was to use a blended analytical approach of machine learning and regression analyses to evaluate the potential relationship between depression and chronic pain in data from a randomized clinical trial of IMGV in socially diverse, low income patients suffering from chronic pain and depression.

MethodsThis approach used machine learning to assess the predictive relationship between depression and pain and identify and select key mediators, which were then assessed with regression analyses. It was hypothesized that depression would predict the pain outcomes of average pain, pain severity, and pain interference.

ResultsOur analyses identified and characterized a predictive relationship between depression and chronic pain interference. This prediction was mediated by high perceived stress, low pain self-efficacy, and poor sleep quality, potential targets for attenuating the adverse effects of depression on functional outcomes.

ConclusionsIn the context of the associated clinical trial and similar interventions, these insights may inform future treatment optimization, targeting, and application efforts in racially diverse, low income populations, demographics often neglected in studies of chronic pain.

category: pain medicine


title: Aetiology of Lobar Pneumonia Determined by Multiplex Molecular Analyses of Lung and Pleural Aspirate Specimens in The Gambia

abstract:
BackgroundPneumonia aetiology generally relies on insensitive blood cultures or an assumption that organisms in the pharynx are causal. We determined the causes of lobar pneumonia in rural Gambia using lung aspiration.

MethodsPneumonia surveillance was undertaken among all ages. Blood culture and chest radiographs were performed routinely while lung or pleural aspirates were collected from selected patients. 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in August 2009 and replaced by PCV13 from May 2011. We used conventional microbiology, and from April 8, 2011 to July 17, 2012, utilized a multiplex PCR assay on lung aspirates. We calculated proportions with pathogens, associations between co-infecting pathogens, and PCV effectiveness.

Results2,550 patients were admitted with clinical pneumonia; 741 with lobar pneumonia or pleural effusion. We performed multiplex PCR on 156 lung and 4 pleural aspirates. Pathogens were detected in 116 specimens, Streptococcus pneumoniae (n=68), Staphylococcus aureus (n=26), and Haemophilus influenzae type b (n=11). Bacteria (n=97) were more common than viruses (n=49). Common viruses were bocavirus (n=11) and influenza (n=11). Co-infections were frequent (n=55). M. catarrhalis was detected in eight patients and in every case there was co-infection with S. pneumoniae. The odds ratio of vaccine-type pneumococcal pneumonia in patients with two or three compared to zero doses of PCV was 0.17 (95% CI 0.06, 0.51).

ConclusionsLobar pneumonia in rural Gambia was caused primarily by bacteria, particularly S. pneumoniae and S. aureus. Co-infection was common and M. catarrhalis always co-infected with S. pneumoniae. PCV was highly efficacious against vaccine-type pneumococcal pneumonia.

Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSUsing specimens directly from the infected lung, what is the aetiology of lobar pneumonia in rural West Africa?

What is the bottom line?Using specimens directly from the infected lung, Streptococcus pneumoniae and Staphylococcus aureus were the predominant causes of lobar pneumonia in rural West Africa and pneumococcal conjugate vaccine effectively prevented pneumococcal pneumonia.

Why read on?Learn about the certain aetiology of lobar pneumonia in 160 Gambian patients with specimens directly from the lung.


title: Neurological, neuropsychiatric and psychiatric symptoms during COVID-19 infection and after recovery: a systematic review of observational studies

abstract:
BackgroundThe SARS-CoV-2 virus causes a wide spectrum of disease severity. Initial manifestations include fever, dry cough, and constitutional symptoms, which may progress to respiratory disease. There may also be neurological and psychiatric manifestations, involving both the central and peripheral nervous system.

MethodsWe performed a literature search of the databases PubMed, EMBASE, The Cochrane Library and Web of Science for observational studies reporting neurological, psychiatric, and neuropsychiatric effects of COVID-19. This was followed by a narrative synthesis to summarise the data and discuss neuropsychiatric associations, symptom severity, management, and recovery.

FindingsThe most frequently reported neurological symptoms were ageusia, hyposmia/anosmia, dizziness, headache, and loss of consciousness. Statistically significant relationships were noted between Asian ethnicity and peripheral neuropathy (p=0.0001) and neuro-syndromic symptoms (p=0.001). ITU admission was found to have a statistically significant relationship with male sex (p=0.024). Depression and anxiety were also identified both during and after infection. The most frequent treatments used were intravenous immunoglobulins, followed by antibiotics, antivirals, and hydroxychloroquine; with mean treatment duration of 6 days.

InterpretationVarious neuropsychiatric symptoms have been associated with COVID-19 infection. More studies are required to further our knowledge in the management of neurological and psychiatric symptoms during and after COVID-19 infection


title: Evaluation of gait cycle time variability in patients with knee osteoarthritis using a triaxial accelerometer

abstract: Knee osteoarthritis can alter gait variability. However, few studies have compared the temporal factors of the gait cycle between patients with knee osteoarthritis and healthy subjects. Furthermore, no studies have investigated the relationship between gait variability and potential contributing factors (knee joint functions such as muscle strength) in knee osteoarthritis. The first objective of this study was to compare gait cycle variability between female patients with knee osteoarthritis and healthy elderly women to determine gait characteristics in patients with knee osteoarthritis. The second objective was to examine whether gait cycle variability in knee osteoarthritis is associated with potential contributing factors. Twenty-four female patients diagnosed with knee osteoarthritis and 12 healthy elderly women participated. Gait cycle variability (coefficient of variation of gait cycle time), knee extension range of motion, knee extension strength, 5-meter walk test, Timed Up & Go Test, and Western Ontario and McMaster Universities Osteoarthritis Index were measured. All assessment results were compared between the knee osteoarthritis and healthy groups. Gait cycle variability was significantly higher in the knee osteoarthritis group (3.2%{+/-}1.5%) compared to the healthy group (2.1%{+/-}0.7%). A significant positive correlation was found between the gait cycle variability and 5-meter walk test (r=0.46) and Western Ontario and McMaster Universities Osteoarthritis Index (r=0.43). The gait of patients with knee osteoarthritis may be more unstable than that of healthy individuals. In addition, unstable gait may be associated with gait speed and quality of life. Therefore, we believe that rehabilitation to improve unstable gait can enhance the quality of life of patients with knee osteoarthritis.

category: rehabilitation medicine and physical therapy


title: Nonresponse adjustment using clinical and perioperative patient characteristics is critical for understanding post-discharge opioid consumption

abstract:
BackgroundPost-discharge opioid consumption is an important source of data in guiding appropriate opioid prescribing guidelines, but its collection is tedious and requires significant resources. Furthermore, the reliability of post-discharge opioid consumption surveys is unclear. Our group developed an automated short messaging service (SMS)-to-web survey for collecting this data from patients. In this study, we assessed its effectiveness in estimating opioid consumption by performing causal adjustment and comparison to a phone-based survey as reference.

MethodsPatients who underwent surgical procedures at our institution from 2019-2020 were sent an SMS message with a link to a secure web survey to quantify opioids consumed after discharge. Several patient factors extracted from the EHR were tested for association with survey response. Following targeted learning (TL) nonresponse adjustment using these EHR-based factors, opioid consumption survey results were compared to a prior telephone-based survey at our institution as a reference.

Results6,553 patients were included. Opioid consumption was measured in 2,883 (44%), including 1,342 (20.5%) through survey response. Characteristics associated with inability to measure opioid consumption included age, length of stay, race, tobacco use, and missing preoperative assessment. Among the top 10 procedures by volume, EHR-based TL nonresponse bias adjustment corrected the median opioid consumption reported by an average of 57%, and corrected the 75th percentile of reported consumption by an average of 11%. This brought median estimates for 6/10 procedures closer to telephone survey-based consumption estimates, and 75th percentile estimates for 3/10 procedures closer to telephone survey-based consumption estimates.

ConclusionWe found that applying electronic health record (EHR)-based machine learning nonresponse bias adjustment is essential for debiased opioid consumption estimates from patient surveys. After adjustment, post-discharge surveys can generate reliable opioid consumption estimates. Clinical factors from the EHR combined with TL adjustment appropriately capture differences between responders and nonresponders and should be used prior to generalizing or applying opioid consumption estimates to patient care.


title: Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics

abstract:
BackgroundInherited genetic variants play an important role in cancer susceptibility. Recent studies show that rare, deleterious variants (RDVs) in a few genes are critical determinants of heritable cancer risk. Better understanding of germline RDVs will contribute to improved precision prevention, screening and treatment.

MethodsWe have performed the largest to date jointly processed germline pan-cancer case-control association study from whole-exome sequencing (WES) data of 20,789 participants, split into discovery and validation cohorts. We focused on high-penetrance RDVs based on ClinVar database. To increase the statistical power, we pursued a collapsing approach and compared the cumulative RDV burden at gene and gene-set levels using penalized logistic regression. Next, we investigated how the accumulation of RDVs in an individual (RDV load) is associated with cancer risk. Finally, we studied how personal RDV load in specific gene-sets affected i) age of diagnosis; ii) tumor immune microenvironment; and iii) tumor mutational burden using Mann-Whitney U test and Kruskal-Wallis test.

ResultsOur results confirm known associations between cancer risk and germline RDVs in BRCA1/2 genes, and show associations with risk for RDVs in Fanconi Anemia (FA), DNA damage repair (DDR), cancer predisposition (CPD) and somatic cancer driver gene-sets in two independent cohorts. Furthermore, increased personal germline RDV load in these gene-sets increased cancer risk, and once cancer developed, tumor characteristics. Notably, we show that the personal RDV load of an individual in FA, DDR or CPD genes is a potential marker for younger age of onset, M1 macrophage fraction in tumor microenvironment, and, in specific cancers, increased tumor mutation burden.

ConclusionsOur findings will help better stratification of individuals at high cancer risk, as well as the characterization of the influence of their personal germline RDV load on age of diagnosis, tumor microenvironment and mutational burden. These high-risk individuals may benefit from increased surveillance, earlier screening and prevention efforts, and treatments that exploit their tumor characteristics, improving prognosis.


title: Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets

abstract:
BackgroundStudies of cognitive impairment (CI) in Amish communities have identified sibships containing multiple CI and cognitively unimpaired (CU; unaffected after age 75) individuals. We hypothesize that these CU individuals may carry protective alleles delaying age at onset (AAO) of CI, preserving cognition in older age despite increased genetic risk. As well, the genetic and cultural isolation in the Amish since the early 1800s may have reduced the complexity of the genetic architecture of CI, increasing the power to detect protective alleles in this population. With this in mind we conducted a genome-wide study (GWAS) to identify loci associated with AAO of CI in a sample of Amish adults over age 75.

Methods1,522 individuals aged 43-99 (mean age 73.1, 42% men) screened at least once for CI using the Modified Mini-Mental State exam (3MS) were genotyped using Illumina chipsets. Genotypes were imputed for 7,815,951 single nucleotide variants (SNV) with minor allele frequency (MAF) > 1%. The outcome studied was age, defined as 1) age at the first 3MS result indicating impairment (AAO; 3MS <87; 362 CI individuals) or 2) age at last normal exam (3MS >=87, 1,160 CU individuals). Cox mixed-effects models examined association between age and each SNV, adjusting for sex and familial relationships. To replicate genome-wide significant findings, SNVs in a 1 Megabase region centered on the peak SNV were examined for association with age using these same methods in the NIA-LOAD family study dataset (1,785 AD cases, 1,565 unaffected controls, mean age 73.5.

ResultsThree SNV were significantly associated (p<5 x 10-8) with AAO in the Amish, on chromosomes 6 (rs14538074; HR=3.35), 9 (rs534551495; HR=2.82), and 17 (rs146729640; Hazard Ratio (HR)=6.38). Each region found the common allele associated with later AAO. Replication analysis detected association at rs146729640, with nominal statistical significance (HR=1.49, p=0.02).

ConclusionsThe replicated genome-wide significant association with AAO on chromosome 17 suggest this may be novel locus associated with delayed onset of AD. The associated SNP is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for AD.


title: Evaluating Adoption, Impact, and Factors Driving Adoption for TREWS, a Machine Learning-Based Sepsis Alerting System

abstract: Machine learning-based clinical decision support tools for sepsis create opportunities to identify at-risk patients and initiate treatments earlier, critical to improving sepsis outcomes. Increasing use of such systems necessitates quantifying and understanding provider adoption. Using real-time provider interactions with a sepsis early detection tool (Targeted Real-time Early Warning System) deployed at five hospitals over a two-year period (469,419 screened encounters, 9,805 (2.1%) retrospectively-identified sepsis cases), we found high sensitivity (82% of sepsis cases identified), high adoption rates (89% of alerts evaluated by a physician or advanced practice provider and 38% of evaluated alerts confirmed) and an association between use of the tool and earlier treatment of sepsis patients (1.85 (95% CI:1.66-2.00) hour reduction in median time to first antibiotics order). Further, we found that provider-related factors were strongly associated with adoption. Beyond improving system performance, efforts to improve adoption should focus on provider knowledge, experience, and perceptions of the system.

category: health informatics


title: Time Windows Voting Classifier for COVID-19 Mortality Prediction

abstract:
BackgroundThe ability to predict COVID-19 patients level of severity (death or survival) enables clinicians to prioritise treatment. Recently, using three blood biomarkers, an interpretable machine learning model was developed to predict the mortality of COVID-19 patients. The method was reported to be suffering from performance stability because the identified biomarkers are not consistent predictors over an extended duration.

MethodsTo sustain performance, the proposed method partitioned data into three different time windows. For each window, an end-classifier, a mid-classifier and a front-classifier were designed respectively using the XGboost single tree approach. These time window classifiers were integrated into a majority vote classifier and tested with an isolated test data set.

ResultsThe voting classifier strengthens the overall performance of 90% cumulative accuracy from a 14 days window to a 21 days prediction window.

ConclusionsAn additional 7 days of prediction window can have a considerable impact on a patients chance of survival. This study validated the feasibility of the time window voting classifier and further support the selection of biomarkers features set for the early prognosis of patients with a higher risk of mortality.