title: Effectiveness of Financial Incentives for a Pedometer-Based Walking Promotion Program

abstract: Physical inactivity contributes significantly to poor health and the onset of disease. Physical inactivity is also associated with severe economic burdens. Japans Ministry of Health, Labor and Welfare (MHLW) cites the provision of various health promotion incentives aimed at health-indifferent groups, which are made up of individuals less interested in health promotion. This study investigated the relationship between medical costs and a pedometer-based walking program providing monetary incentives based on daily step counts. The study sample included 16,816 citizens aged 40-75 years who lived in Takaishi City and were enrolled in the NIH from October 2016 to March 2018. The results of the ordinal logistic regression analysis showed that participation in a walking promotion program with an HPFI was correlated with a reduction in healthcare costs over 1 year in a sample of Takaishi City residents. In fact, there was a difference of 67,077 yen in the average medical cost per person per year between the walking and control groups. With 1,923 walking group participants, the total medical cost reduction was predicted to be at least 12,898,904 yen. In this study, we evaluated the effectiveness of a walking promotion program with incentives. With program context differing widely from region to region and country to country, future investigations are needed to inform the selection of appropriate incentive schemes for programs offered in other regions and countries.

category: health economics


title: Validating saliva as a biological sample for cost-effective, rapid and routine screening for SARS-CoV-2

abstract:
PurposeCompared to nasopharyngeal/oropharyngeal swabs, non-invasive saliva samples have enormous potential for scalability and routine population screening of SARS-CoV-2. In this study, we are investigating the efficacy of saliva samples relative to nasopharyngeal/oropharyngeal swabs for use as a direct source for the RT-PCR based SARS-CoV-2 detection.

MethodsPaired nasopharyngeal/oropharyngeal swabs and saliva samples were collected from suspected positive SARS-CoV-2 patients and tested using RT-PCR. Generalised linear models were used to investigate factors that explain result agreement. Further, we used simulations to evaluate the effectiveness of saliva-based screening in restricting the spread of infection in a large campus such as an educational institution.

ResultsWe observed 75.4% overall result agreement. Prospective positive samples stored for three or more days showed a drastic reduction in the probability of result agreement. We observed 83% result agreement and 74.5% test sensitivity in samples processed and tested within two days of collection. Our simulations suggest that a test with 75% sensitivity, but high daily capacity can be very effective in limiting the size of infection clusters in a workspace. Guided by these results, we successfully implemented a saliva-based screening in the Bangalore Life Sciences Cluster (BLiSC) campus.

ConclusionThese results suggest that saliva may be a viable sample source for SARS-CoV-2 surveillance if samples are processed immediately. We strongly recommend the implementation of saliva-based screening strategies for large workplaces and in schools, as well as for population-level screening and routine surveillance as we learn to live with the SARS-CoV-2 virus.

category: infectious diseases


title: Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity

abstract:
BackgroundPeople with diabetes are more likely to develop tuberculosis (TB) and to have poor TB treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and reduced interferon responses at TB diagnosis. It is unknown whether this persists through treatment, potentially underlying adverse outcomes.

MethodsPulmonary TB patients were recruited in South Africa, Indonesia and Romania, and classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or uncomplicated TB, based on glycated haemoglobin (HbA1c) concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood samples collected at diagnosis and at regular intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification.

ResultsGene expression was modulated by TB treatment in all groups but to different extents, such that differences remained in people with TB-DM relative to TB-only throughout, including genes involved in innate responses, anti-microbial immunity and the inflammasome. People with prediabetes or with TB-related hyperglycaemia had gene expression more similar to people with TB-DM than TB-only throughout treatment. The overall pattern of change was similar across clinical groups irrespective of glycaemic index, permitting models predictive of TB treatment to be developed.

ConclusionsThe exacerbated transcriptome changes seen in TB-DM take longer to resolve during TB treatment, indicating that prolonged treatment or host-directed therapy may be needed to improve TB treatment outcomes. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes to be useful across populations.

Key PointsHost blood transcriptomes are altered in tuberculosis, and further altered with diabetes co-morbidity. We have shown that there is similar resolution of transcriptomes through treatment, but with differing magnitude and kinetics in TB patients with or without diabetes.


title: Effectiveness of Covid-19 Vaccines against the SARS-COV-2-Delta (B.1.617.2) in China-A Real World Study

abstract:
AbstractsO_ST_ABSBackgroundC_ST_ABSSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta (B.1.617.2) variant is highly transmissible and has contributed to a surge in cases globally. This study aimed to explore the potential of vaccines against SARS-CoV-2 delta (B.1.617.2) variant in China.

MethodsIn this real-world study, all data were extracted from Xian Chest Hospital. Confirmed cases infected with Delta VOC with exact date of positive viral testing were included for analysis. Patients meeting the study criteria were divided into unvaccinated and partially vaccinated (one dose), full vaccinated (two doses), and booster vaccination of COVID-19.

ResultsA total of 455 cases were enrolled in this study. Proportion of severe and critical cases in full vaccinated cases (1.82%) and cases with booster vaccination (1.35%) of COVID-19 were much lower than that of unvaccinated and partially vaccinated cases (8.16%). In addition, cases with booster vaccination (12.78 days) and full vaccinated cases (12.59 days) showed shorter duration of viral shedding than that in unvaccinated and partially vaccinated cases (13.87 days).

ConclusionThis is the first real world study indicating that Covid-19 vaccines showed much powerful effectiveness against the SARS-COV-2-Delta (B.1.617.2) in China, including lowing the proportion of severe illness and shorting the virus shedding time.


title: Historical contingency, rather than higher transmissibility, behind the long-term success of a Mycobacterium tuberculosis outbreak strain

abstract: Infectious disease outbreaks are a major public health problem. Tracking their spread and understanding the main factors associated with it are key to assist in disease control. Whole genome sequencing (WGS) of pathogens has been demonstrated to be the best tool to investigate outbreaks, since it helps to answer central questions about their origin and dynamics, and also factors associated with strain success and outbreak evolution. Identification of highly transmissible strains in Mycobacterium tuberculosis is a main area of research. Long-lived outbreak strains have been proposed as candidates with high intrinsic transmissibility. However, limited resolution of available typing methods have prevented testing this hypothesis. Here we study an outbreak strain that started to circulate in Gran Canaria (GC, Canary Islands) in 1993 and has caused around 20% of TB cases since then. By using WGS, and phylodynamics analysis we could trace the origin of the strain to 700 years ago in China and infer its introduction in Gran Canaria in the early 90s. Once established, we document the topology of the outbreak within the Canary Islands. Importantly, we were able to trace the spread of the outbreak beyond the studied area by searching for related sequences within the whole sequence repository, revealing a high success of GC strain in the Canarian archipelago but a limited expansion into the continent. The phylodynamics analyses suggest that determinants associated with the host, instead of higher transmissibility or virulence of the bacteria, are responsible for this long-lived outbreak. We show that historical contingency in the form of a founder effect rather than intrinsic transmissibility explains better the success of the GC strain and probably others of the same nature. Like the GC outbreak strain, many other similar strains in the literature had their origin in the late 20 th century suggesting that past epidemics driven by extrinsic factors like HIV are still contributing to the present TB epidemic in local settings.


title: Acoustic Epidemiology in Pulmonary Tuberculosis & Covid19 leveraging Explainable AI/ML

abstract: Involuntary cough is a prominent symptom for many a Lung Ailments ranging from Infectious to non-Infectious diseases. Early research around human cough established that the spectral signatures do not vary between Involuntary and Voluntary coughs. The study aimed at evaluating voluntary human cough sounds recorded under a stringent clinical protocol. Indias ambitious goal to eliminate and eradicate TB by 2025 shall be facilitated by Machine Learning tools that address subjectivity in that the healthcare worker can now take the solution as a screening modality to the last mile as a part of outreach programs without having to rely on infrastructure & connectivity. In this paper we present the findings of Clinical Trials for Pulmonary TB registered at CTRI/2019/02/017672 conducted independently and included Covid19 during the pandemic as a part of Bi-Directional screening modality. The reference standards used were CBNAAT (Cartridge based nucleic acid amplification test) & CXR (Chest X-Ray) for TB while for Covid19; RT-PCR was used as the reference standard. As a non-invasive and contactless screening modality, a sophisticated third party Microphone Array was used to record the cough under a stringent infection control protocol. Sensitivity achieved across the sites for TB ranged between 80% - 83% and Specificity was to the tune of 92% while using CBNAAT as a reference standard. CXR when used as a reference standard for TB achieved a sensitivity and specificity of 59% and 60% respectively. Covid19 achieved a sensitivity & specificity of 92% and 96% while using RT-PCR as the reference standard. The study was primarily focused on the Frequency domain that paved way for feature extraction and explainable Machine Learning Models operating upon lossless WAV files hypothesizing acoustic theory and demographic inputs. The solution titled "TimBre" can now be added to the healthcare workers arsenal in situations where a RT-PCR or CXR is not available and seamlessly conduct bi-directional screening with a single recording of cough and also offer insights into Non-Communicable diseases as a part of differential diagnosis.


title: Influenza Outbreak Prevention and Management in U.S. Carceral Settings: A Scoping Review

abstract:
BackgroundDetention settings preparedness against respiratory virus outbreaks is essential, with implications for preventing illness and deaths from future pandemics. We sought to identify influenza outbreak prevention and management evidence in U.S. detention settings.

MethodsWe conducted a scoping review, first searching PubMed, OVID, Google Scholar, Medline databases and the reference lists of identified manuscripts published on outbreak prevention and management of influenza in detention settings in English. Search terms included prison, jail, vaccine, influenza, outbreak, management, prevention, carceral.

ResultsTwenty-five studies met the search criteria, ultimately narrowed down to seven studies. Four studies focused on prevention and three on management. The studies on prevention identified restructuring housing, vaccinations, and widespread screening to prevent outbreaks and highlighted the importance of collaboration between prison staff and public health departments. The management studies emphasized hygiene, isolation of sick individuals, and vaccination of unexposed patients. Staff expressed the concern that the public may view prisoners as low priority based on prior experiences with influenza vaccine shortages, with a spillover effect in obtaining vaccines and medications for staff. No studies mentioned decarceration as a prevention and mitigation measure.

ConclusionThere is limited data on influenza outbreak prevention and management in detention settings. The approaches described are partially in line with public health recommendations but fall short due to lack of, and delays in resource allocation. There is an urgent need for researchers and public health officials to examine and report influenza outbreak prevention and mitigation strategies in detention settings to develop scalable interventions and a national standard for all detention settings.


title: Spatio-temporal epidemiology of SARS-CoV-2 virus lineages in Teesside, UK, in 2020: effects of social deprivation, weather and lockdown on lineage dynamics

abstract:
SARS-CoV-2 emerged in the UK in January 2020 and the Government introduced national  lockdowns and regional  tiers to control virus transmission. As the outbreak continued, new variants were detected. We analysed spatio-temporal dynamics of positive tests for COVID-19 on Teesside, UK throughout 2020, in relation to: socio-economic deprivation, weather, and Government interventions. We used a combination of disease mapping and mixed-effect modelling to investigate the dynamics of positive tests from two sampling strategies and the spread of particular variants of the virus as they emerged on Teesside. SARS-CoV-2 spread was related to the extent of social deprivation, lockdown interventions and weather. SARS-CoV-2 spread faster in some lineages than others, with positive tests related to levels of socio-economic deprivation. The interventions appeared to have different effects in the two waves of disease, and were associated with reduced numbers of records in the first wave, but having no effect during the second.

ARTICLE SUMMARY LINERegional spread of SARS-CoV-2 is dependent on weather, socio-economic and mandatory lockdowns, but the effectiveness of the latter varies with virus lineage.

category: epidemiology


title: Circulating polyunsaturated fatty acids and COVID-19: a prospective cohort study and Mendelian randomization analysis

abstract:
BackgroundHigher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 ones, have been linked to a better prognosis in patients of coronavirus disease 2019 (COVID-19). However, the effects and causality of pre-infection PUFA levels remain unclear.

ObjectiveTo investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity.

DesignWe first performed a prospective cohort study in UK Biobank, with 20,626 controls who were tested negative and 4,101 COVID-19 patients, including 970 hospitalized ones. Plasma PUFAs at baseline were measured by nuclear magnetic resonance, including total PUFAs, omega-3 PUFAs, omega-6 PUFAs, docosahexaenoic acid (DHA), linoleic acid (LA), and the omega-6/omega-3 ratio. Moreover, bidirectional two-sample Mendelian randomization (MR) analyses were performed to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity using summary statistics from existing genome-wide association studies.

ResultsIn the observational association analysis, total PUFAs, omega-3 PUFAs, omega-6 PUFAs, DHA, and LA were associated with a lower risk of severe COVID-19. Omega-3 PUFAs and DHA were also associated with a lower risk of testing positive for COVID-19. The omega-6/omega-3 ratio was positively associated with risks of both susceptibility and severity. The forward MR analysis indicated that arachidonic acid (AA) and docosapentaenoic acid (DPA-n3) might be causally associated with a lower risk of severe COVID-19, with OR (95% CI) per one SD increase in the plasma level as 0.96 (0.94, 0.99) and 0.89 (0.81, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs.

ConclusionsOur observational analysis supported that higher circulating PUFAs, either omega-3 or omega-6, are protective against severe COVID-19, while omega-3 PUFAs, especially DHA, were also associated with reducing COVID-19 susceptibility. Our MR analysis further supported causal associations of AA and DPA-n3 with a lower risk of severe COVID-19.


title: Gastric dysfunction in patients with chronic nausea and vomiting syndromes defined by a novel non-invasive gastric mapping device

abstract:
ImportanceChronic nausea and vomiting syndromes (NVS) are prevalent and debilitating disorders. Putative mechanisms include gastric neuromuscular disease and dysregulation of brain-gut interaction, but clinical tests for objectively defining gastric motor function are lacking.

ObjectiveA novel medical device enabling non-invasive body surface gastric mapping (BSGM) was developed and applied to evaluate NVS pathophysiology.

DesignA case-control study where BSGM was performed in NVS patients and matched controls using Gastric Alimetry (Alimetry, New Zealand), comprising a conformable high-resolution array (8x8 electrodes; 20 mm inter-electrode spacing), wearable Reader, and validated symptom logging App. Continuous measurement encompassed a fasting baseline (30 min), 482 kCal meal (10 min), and 4-hr post-prandial recording.

SettingMulticenter study in Auckland, New Zealand and Calgary, Canada.

Participants43 NVS patients (gastroparesis and Rome IV chronic NVS) and 43 matched controls.

Main outcomes and measuresSymptom severity and quality of life were measured using Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), Gastroparesis Cardinal Symptom Index (GCSI), and Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QOL) instruments. Health psychology metrics included the State Trait Anxiety Inventory Short Form (STAI-SF) and Patient Health Questionnaire-2 (PHQ-2) questionnaires. Spectral analyses including frequency, amplitude, and fed-fasting power ratio. Spatial biomarker analyses included spatial frequency stability and average spatial covariance.

ResultsMeal responses were impaired in NVS, with reduced amplitudes compared to controls (median 23.3 vs 38.0 {micro}V, p<0.001), impaired fed-fasting power-ratios (1.1 vs 1.6, p=0.02), and disorganized slow-waves (spatial frequency stability 13.6 vs 49.5; p<0.001). However, two distinct NVS subgroups were evident with indistinguishable symptoms (all p>0.05). A majority (62%) had normal BSGM studies (all biomarkers non-significant vs controls) with increased psychological comorbidities (43.5% vs 7.7%; p=0.03) and anxiety scores (median 16.5 vs 13.0; p=0.035). A smaller subgroup (31%) had markedly abnormal BSGM, with test biomarkers correlating with symptoms (nausea, pain, excessive fullness, early satiety, bloating; all r>0.35, p<0.05).

Conclusions and RelevanceNVS patients share overlapping symptoms, but comprise distinct underlying phenotypes as revealed by a novel BSGM device. These phenotypes correlate with symptoms, which should inform clinical management and allocations into therapeutic trials.

Key PointsO_ST_ABSQuestionC_ST_ABSHow does body surface gastric mapping, a novel non-invasive medical device for evaluating gastric motility, aid assessment of patients with chronic nausea and vomiting.

FindingsTwo subgroups were revealed in chronic nausea and vomiting syndromes, which could not be differentiated by symptoms alone. Where body surface gastric mapping was normal, symptoms correlated with psychological comorbidities, and where body surface gastric mapping was abnormal, symptoms correlated with gastric electrophysiology metrics.

MeaningDistinct phenotypes revealed by body surface gastric mapping correlate with symptoms, which should inform targeted clinical management and allocations into therapeutic trials.

category: gastroenterology


title: Results from EDIFICE : A French pilot study on COVID-19 and the gut microbiome in a hospital environment

abstract:
BACKGROUND & AIMSEarly reports suggest that both fecal shedding and dysbiosis of the gut microbiome are associated to disease severity in COVID-19 patients. We investigated the gut microbiome as well as the prevalence of SARS-CoV-2 in stool samples from two French populations: exposed healthcare workers and elderly hospitalized COVID-19 patients. The predictive power of bacterial loss of diversity and detection of SARS-CoV-2 in stool was assessed at 4 weeks against clinical outcomes in the patient group.

METHODS79 healthcare workers in contact with COVID-19 patients and 64 elderly patients hospitalised in a COVID-19 unit in France were included in the EDIFICE trial from April 2020 until May 2021. Stool samples were collected at inclusion. Loss of bacterial diversity was diagnosed based on 16S rRNA gene sequencing. Stool positivity to SARS-CoV-2 was determined by RT-PCR. Clinical outcomes were recorded at a 4 weeks follow up visit. In particular, these include whether the patient had been put under oxygen during the 4 weeks follow up, whether he had been discharged with or without aggravation from initial symptoms or whether the patient had died. The primary end point was to validate the hypothesis that hospitalized COVID-19 patients had more often lost their bacterial diversity than highly exposed active healthcare workers.

RESULTSElderly hospitalised patients with COVID-19 had more frequently lost their bacterial diversity when compared to exposed healthcare workers (p-value = 0.005), their severe dysbiosis was characterized by enrichment of the family Erysipelotrichaceae and depletion of beneficial bacteria at the genus level such as butyrate producers (Butyrivibrio, Roseburia, Faecalibacterium) and Bifidobacterium. The virus was detected in 61% of hospitalized patients and in only one healthcare workers (2%) who had previously been diagnosed with COVID-19 (p-value<0.001). No significant difference in the gut microbiome composition at the genus level of patients that tested positive in stool versus patients that tested negative was observed. Neither bacterial loss of diversity nor positivity to SARS-CoV-2 were associated to clinical outcome at 4 weeks.

CONCLUSIONSWe report findings of the first French trial investigating the clinical interest of stool based diagnosis of SARS-CoV-2 and loss of bacterial diversity in a population of elderly hospitalised COVID-19 patients and highly exposed healthcare workers. Our findings of reduced bacterial diversity and a strong gut dysbiosis in elderly hospitalized COVID-19 patients are highly consistent with previous reports mostly from Chinese populations. A major limitation is that observed differences in the gut microbiome between the two studied groups cannot be attributed to COVID-19 per se given the large number of confounding factors. SARS-CoV-2 was detected in the stool of the majority of hospitalized patients even several weeks after initial diagnosis by nasopharyngeal swabs. This high prevalence warrants further investigation by the scientific community into mechanism.


title: SARS-CoV-2 infects, replicates, elevates angiotensin II and activates immune cells in human testes

abstract: Although much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and the potential consequences for reproductive health. We investigated testicular alterations in deceased COVID-19-patients, the precise location of the virus, its replicative activity, and the molecules involved in the pathogenesis. We found that SARS-CoV-2 testicular tropism is higher than previously thought and that reliable viral detection in the testis requires sensitive nanosensoring or RT-qPCR using a specific methodology. Macrophages and spermatogonial cells are the main SARS-CoV-2 lodging sites and where new virions form inside the Endoplasmic Reticulum Golgi Intermediate Complex. Moreover, we showed infiltrative infected monocytes migrating into the testicular parenchyma. SARS-CoV-2 maintains its replicative and infective abilities long after the patients infection, suggesting that the testes may serve as a viral sanctuary. Further, infected testes show thickening of the tunica propria, germ cell apoptosis, Sertoli cell barrier loss, evident hemorrhage, angiogenesis, Leydig cell inhibition, inflammation, and fibrosis. Finally, our findings indicate that high angiotensin II levels and activation of mast cells and macrophages may be critical for testicular pathogenesis. Importantly, our data suggest that patients who become critically ill exhibit severe damages and may harbor the active virus in testes.

category: sexual and reproductive health


title: Preclinical Efficacy in Investigator's Brochures: Stakeholders' views on measures to improve Completeness and Robustness

abstract:
Research ethics committees (RECs) and regulatory agencies assess whether the benefits of a proposed early-stage clinical trial outweigh the risks based on preclinical studies reported in investigators brochures (IBs). Recent studies have indicated that preclinical evidence presented in IBs is reported in a way that does not enable proper risk-benefit assessment. We interviewed different stakeholders (regulators, REC members, industry representatives, preclinical and clinical researchers, ethicists, and metaresearchers) about their views on measures to increase the completeness and robustness of preclinical evidence reporting in IBs.

This study was preregistered (https://osf.io/nvzwy/). We used purposive sampling and invited stakeholders to participate in an online semistructured interview between March and June 2021. The themes were derived using inductive content analysis. We used a strengths, weaknesses, opportunities, and threats (SWOT) matrix to categorize our findings.

Twenty-seven international stakeholders participated. The interviewees pointed to several strengths and opportunities to improve completeness and robustness, mainly more transparent and systematic justifications of the inclusion of studies. However, weaknesses and threats were mentioned that could undermine efforts to enable more thorough assessment: The interviewees stressed that current review practices are sufficient to ensure the safe conduct of first-in-human trials. They feared that changes to the IB structure or review process could overburden stakeholders and slow drug development.

In principle, having more robust decision-making processes in place aligns with the interests of all stakeholders and with many current initiatives to increase the translatability of preclinical research and limit uninformative or ill-justified trials early in the development process. Further research should investigate measures that could be implemented to benefit all stakeholders.

category: medical ethics


title: Feasibility, usability and acceptability of a novel digital hybrid-system for reporting of routine health information in Southern Tanzania A mixed-methods study

abstract:
BackgroundHealth information systems are important for health planning and monitoring of progress. Still, data from health facilities are often of limited quality in Low-and-Middle-Income Countries. Quality deficits are partially rooted in the fact that paper-based documentation is still the norm at facility level, leading to mistakes in summarizing and manual copying. Digitalization of data at facility level would allow automatization of these procedural steps. Here we aimed to evaluate the feasibility, usability and acceptability of a scanning innovation called Smart Paper Technology for digital data processing.

MethodsWe used a mixed-methods design to understand users engagement with Smart Paper Technology and to identify potential positive and negative effects of this innovation in three health facilities in Southern Tanzania. Eight focus group discussions and 11 in-depth interviews with users were conducted. We quantified time used by health care providers for documentation and patient care using time-motion methods. Thematic analysis was used to analyze qualitative data. Descriptive statistics and multivariable linear models were generated to compare the difference before and after introduction and adjust for confounders.

ResultsHealth care providers and health care managers appreciated the forms simple design features and perceived Smart Paper Technology as time-saving and easy to use. The time-motion study with 273.3 and 224.0 hours of observations before and after introduction of Smart Paper Technology, respectively, confirmed that working time spent on documentation did not increase (27.0% at baseline and 26.4% post-introduction; adjusted p=0.763). Time spent on patient care was not negatively impacted (26.9% at baseline and 37.1% at post-intervention; adjusted p=0.001). Health care providers described positive effects on their accountability for data and service provision relating to the fact that individually signed forms were filled.

DiscussionHealth care providers perceived Smart Paper Technology as feasible, easy to integrate and acceptable in their setting, particularly as it did not add time to documentation.

category: health informatics


title: Development of Prognostic Models for Survival and Care Status in Sporadic Creutzfeldt-Jakob disease

abstract: Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. 537 patients were visited by mobile teams of doctors and nurses from the NHS National Prion Clinic within 5 days of notification of a suspected diagnosis of sCJD, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. 280 (52.1%) patients were female and the median age was 67.2 (IQR 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; MRC (Medical Research Council) Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical sCJD phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for MM compared to MV polymorphism; 95% CI 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sCJD patients using clinical, imaging and genetic data routinely available in a tertiary national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care.

category: neurology


title: COVID-19 excess death rate in Eastern European countries associated with weaker regulation implementation and lower vaccination coverage

abstract:
AimThe objective of this analysis was to assess the association of excess COVID-19 mortality with regulation enforcement and vaccination rate in selected countries.

MethodsThis analysis included 50 countries pertinent to the WHO European Region, in addition to USA and Canada. Excess mortality and vaccination data were retrieved from "Our World In Data" database, while regulation implementation was measured from a well-respected, standardized measure. Outpatient visits were also included in the analysis. Multiple linear regression was used to assess the independent association between excess mortality and each covariate.

ResultsExcess mortality increased by 4.1/100 000 for every percent decrease in vaccination rate and with 6/100 000 for every decreased unit in the regulatory implementation score a country achieved in the Rule of Law Index.

ConclusionDegree of regulation enforcement, likely including public health measure enforcement, may be an important factor in controlling COVID-19s deleterious health impacts.

category: health policy


title: Latent classes of mens intimate partner violence perpetration and attitudes towards gender norms: a UN multi-country, cross-sectional study in Asia and the Pacific

abstract:
ObjectiveTo examine distinct patterns of IPV perpetration and examined gender equitable attitudes as a predictor of these patterns among men from six countries in Asia and the Pacific.

Design2011-12 UN Multi-country Study on Men and Violence cross-sectional study.

SettingHouseholds in Bangladesh, Cambodia, China, Indonesia, Sri Lanka and Papua New Guinea.

Participants10,178 men aged 18-49 years residing in Bangladesh, Cambodia, China, Indonesia, Sri Lanka and Papua New Guinea.

Primary outcomes measureOur primary outcome was distinct patterns of IPV perpetration which were derived from multilevel latent class analyses.

ResultsThe odds of being assigned to the Low All Forms of IPV Perpetration class than the High All Forms of IPV Perpetration class was lower for men in the middle tertile group than men in the high tertile group for gender equitable attitudes. The odds of being assigned to the High Emotional IPV Perpetration class than the High All Forms of IPV Perpetration class was greater for men in the low tertile group than men in the high tertile group for gender equitable attitudes. The odds of being assigned to the High Physical/Emotional/Economic IPV Perpetration class than the High All Forms of IPV Perpetration class was lower for men in the low tertile group than men in the high tertile group for gender equitable attitudes.

ConclusionsGender transformative interventions that use an adaptive, personalized approach to mens typology of IPV perpetration may be beneficial to reduce violence against for women in the Asia-Pacific region.

Strengths and limitations of the studyO_LIThis is one of the first studies to examined distinct patterns of intimate partner violence (IPV) perpetration among men in low- and middle-income countries, include the Asia-Pacific region.
C_LIO_LIThis study used a large sample of 10,178 men aged 18-49 years in the Asia-Pacific region.
C_LIO_LIThe measures of IPV perpetration were well-defined but the data was self-reported data, and IPV perpetration may be under-reported, if perceived as a private matter.
C_LIO_LIThe current analysis is a cross-sectional study and thus unable to make inferences regarding causality.
C_LI

category: public and global health


title: Clinical outcomes in hospitalized vaccine-breakthrough COVID-19 cases compared with contemporary unvaccinated hospitalized adults

abstract:
SummaryThe inactivated SARS-CoV-2 vaccine (CoronaVac(R)) has been the principal vaccine used in Chiles pre-booster immunization campaign. We compared major outcomes in 260 hospitalized vaccinated vs 507 unvaccinated adults with COVID-19 (mid-2021). The vaccinated group was much older, required less critical care, had lower hospital mortality (adjusted by age), and had shorter hospitalization than the unvaccinated. Benefits were most pronounced in those older than 59 years

ObjectiveTo compare major outcomes in fully vaccinated and unvaccinated adult persons hospitalized for COVID-19 in a general private hospital in Santiago, Chile during mid2021.


title: Antibody response after a single dose of BBV152 vaccine negatively correlates with pre-existing antibodies and induces a significant but low levels of neutralizing antibodies to Omicron variant

abstract: Most adults in India have received at least one dose of COVID-19 vaccine and also been infected naturally during the pandemic. As immunization of individuals continues under this situation where the virus has attained endemicity, we assessed whether this hybrid immunity is further boosted by a single dose of BBV152, an inactivated SARS-CoV-2 vaccine, and, if these antibodies can neutralize SARS-CoV-2 delta and omicron variants. We found that natural infection during the second wave in 2021 led to generation of neutralizing antibodies against other lineages of SARS-CoV-2 including the omicron variant, albeit at a significantly lower level for the latter. A single dose of BBV152 boosted antibody titers against the delta and the omicron variants but the antibody levels remained low for the omicron variant. Boosting of antibodies showed negative correlation with baseline neutralizing antibody titers suggesting anergy of the immune system in individuals with high levels of antibodies.


title: Time to reinfection and vaccine breakthrough SARS-CoV-2 infections: a retrospective cohort study

abstract:
BackgroundIt is important to understand how BNT162b2, mRNA-1273, and JNJ-78436735 COVID-19 vaccines, as well as prior infection, protect against breakthrough cases and reinfections. Real world evidence on acquired immunity from vaccines, and from SARS-CoV-2 infection, can help public health decision-makers understand disease dynamics and viral escape to inform resource allocation for curbing the spread of pandemic.

MethodsThis retrospective cohort study presents demographic information, survival functions, and probability distributions for 2,627,914 patients who received recommended doses of COVID-19 vaccines, and 63,691 patients who had a prior COVID-19 infection. In addition, patients receiving different vaccines were matched by age, sex, ethnic group, state of residency, and the quarter of the year in 2021 the COVID-19 vaccine was completed, to support survival analysis on pairwise matched cohorts.

FindingsEach of the three vaccines and infection-induced immunity all showed a high probability of survival against breakthrough or reinfection cases (mRNA-1273: 0.997, BNT162b2: 0.997, JNJ-78436735: 0.992, previous infection: 0.965 at 180 days). The incidence rate of reinfection among those unvaccinated and previously infected was higher than that of breakthrough among the vaccinated population (reinfection: 0.9%; breakthrough:0.4%). In addition, 280 vaccinated patients died (0.01% all-cause mortality) within 21 days of the last vaccine dose, and 5898 (3.1 %) died within 21 days of a positive COVID-19 test.

ConclusionsDespite a gradual decline in vaccine-induced and infection-induced immunity, both acquired immunities were highly effective in preventing breakthrough and reinfection. In addition, for unvaccinated patients with COVID-19, those who did not die within 90 days of their initial infection (9565 deaths, 5.0% all-cause mortality rate), had a comparable asymptotic pattern of breakthrough infection as those who acquired immunity from a vaccine. Overall, the risks associated with COVID-19 infection are far greater than the marginal advantages of immunity acquired by prior infection.


title: Bias amplification of unobserved confounding in pharmacoepidemiological studies using indication-based sampling: there is no free lunch in restricting the sample to those with a particular drug-indication

abstract:
Estimating causal effects in observational pharmacoepidemiology is a challenging task, as it is often plagued by confounding by indication. Restricting the sample to those with an indication for drug use is a commonly performed procedure; indication-based sampling ensures that the exposed and unexposed are exchangeable on the indication - limiting the potential for confounding by indication. However, indication-based sampling has received little scrutiny, despite the hazards of exposure-related covariate control.

Using causal diagrams, simulations, and empirical examples, we demonstrate that indication-based sampling in the presence of unobserved confounding can give rise to bias amplification, a self-inflicted phe-nomenon where one inflates pre-existing bias through inappropriate covariate control. Additionally, we show that indication-based sampling generally leads to a greater net bias than alternative approaches, such as regression adjustment. Finally, we expand on how bias amplification should be reasoned about when distinct clinically relevant effects on the outcome among those with an indication (effect-heterogeneity) exist.

We conclude that studies using indication-based sampling should have robust justification - and that it should by no means be considered a "free lunch" to adopt such approaches. As such, we suggest that future observational studies stay wary of bias amplification when considering drug indications.


title: Duration of protection of BNT162b2 and mRNA-1273 COVID-19 vaccines against symptomatic SARS-CoV-2 Omicron infection in Qatar

abstract:
BACKGROUNDQatar has been experiencing a large SARS-CoV-2 Omicron (B.1.1.529) wave that started on December 19, 2021. We assessed duration of protection of BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines after second dose and after third/booster dose against symptomatic Omicron infection and against COVID-19 hospitalization and death, between December 23, 2021 and February 2, 2022.

METHODSVaccine effectiveness was estimated using the test-negative, case-control study design, applying the same methodology used earlier to assess waning of BNT162b2 and mRNA-1273 effectiveness in the same population during earlier infection waves.

RESULTSBNT162b2 effectiveness against symptomatic Omicron infection was highest at 61.9% (95% CI: 49.9-71.1%) in the first month after the second dose, but then gradually declined and was at 10% or less starting from the 5th month after the second dose. After the booster, effectiveness rapidly rebounded to peak at about 55% between 2-5 weeks after the booster, but then started to decline again thereafter. Effectiveness against severe, critical, or fatal COVID-19 was maintained at >70% after the second dose and at >90% after the booster with no evidence for declining effectiveness over time. mRNA-1273 effectiveness against symptomatic Omicron infection was highest at 44.8% (95% CI: 16.0-63.8%) in the first three months after the second dose, before gradually declining to negligible levels thereafter. After the booster, effectiveness rapidly rebounded to peak at about 55% between 2-5 weeks after the booster, but then declined again thereafter. Effectiveness against severe, critical, or fatal COVID-19 was high at >60% after the second dose and at >80% after the booster, but the confidence intervals were wide owing to the small number of cases.

CONCLUSIONSBNT162b2 and mRNA-1273 vaccines show a similar level and pattern of protection against symptomatic Omicron infection. Protection against Omicron is lower than that against Alpha, Beta, and Delta variants, and wanes more rapidly than against earlier variants after the second and booster doses. Meanwhile, protection against hospitalization and death appears robust and durable after both the second and booster doses.


title: Inequalities in mental and social wellbeing during the COVID-19 pandemic: prospective longitudinal observational study of five UK cohorts

abstract:
BackgroundResearch suggests that there have been inequalities in the impact of the COVID-19 pandemic and related non-pharmaceutical interventions on population mental health. We explored these inequalities during the first year of the pandemic using nationally representative cohorts from the UK.

MethodsWe analysed data from 26,772 participants from five longitudinal cohorts representing generations born between 1946 and 2000, collected in May 2020, September-October 2020, and February-March 2021 across all five cohorts. We used a multilevel growth curve modelling approach to explore sociodemographic and socioeconomic differences in levels of anxiety and depressive symptomatology, loneliness, and life satisfaction over time.

ResultsYounger generations had worse levels of mental and social wellbeing throughout the first year of the pandemic. Whereas these generational inequalities narrowed between the first and last observation periods for life satisfaction (-0.33 [95% CI: -0.51, -0.15]), they became larger for anxiety (0.22 [0.10, 0.33]). Pre-existing generational inequalities in depression and loneliness did not change, but initial depression levels of the youngest cohort were worse than expected if the generational inequalities had not accelerated. Women and those experiencing financial difficulties had worse initial mental and social wellbeing levels than men and those financially living comfortably, respectively, and these gaps did not substantially differ between the first and last observation periods. Inequalities by additional factors are reported.

ConclusionsBy March 2021, mental and social wellbeing inequalities persisted in the UK adult population. Pre-existing generational inequalities may have been exacerbated with the pandemic onset. Policies aimed at protecting vulnerable groups are needed.


title: Trends in Racial and Ethnic Disparities in Barriers to Timely Medical Care Among US Adults, 1999 to 2018

abstract:
BackgroundRacial and ethnic disparities in delayed medical care due to reasons not related to cost of care remain understudied. We aimed to describe recent 20-year trends in such disparities.

MethodsThe study used data from the National Health Interview Survey from 1999-2018 and included individuals [≥]18 years of age. Respondents were categorized by their sex, income, and self-reported race and ethnicity. The main outcomes were trends in disparities in any of 5 specific barriers to timely medical care: inability to get through by phone, no appointment available soon enough, long waiting times, inconvenient doctors office/clinic hours, or lack of transportation.

ResultsThe study included 590,603 adults (mean age 46.0 [SE, 0.07] years; 51.9% female). Of these, 4.7% were Asian, 11.8% Black, 13.8% Latino/Hispanic, and 69.7% White. In 1999, the proportion reporting any of the barriers to timely medical care was 7.3% among Asian, 6.9% among Black, 7.9% among Latino/Hispanic, and 7.0% among White individuals (P >0.05 for each difference with White individuals). From 1999 to 2018, this proportion increased across all 4 race/ethnicity groups (P<0.001 for each), slightly increasing the disparities between groups. In 2018, compared with White individuals, the proportion reporting any barrier was 2.1 and 3.1 percentage points higher among Black and Latino/Hispanic individuals (P=0.03 and P=0.001, respectively). The racial/ethnic disparities increased mostly among males and were attenuated when stratified by income level.

ConclusionsFrom 1999 to 2018, barriers to timely medical care increased for all populations with increasing disparities between racial/ethnic groups.


title: Factors associated with higher levels of grief and support needs among people bereaved during the pandemic: Results from a national online survey

abstract:
BackgroundThe COVID-19 pandemic has affected millions of peoples experiences of bereavement. We aimed to identify risk factors for grief and support needs.

MethodsOnline survey of people bereaved in the UK (deaths 16 March 2020-2 January 2021), recruited via media, social media, national associations/organisations. Grief was assessed using the Adult Attitude to Grief (AAG) scale, which calculates an overall index of vulnerability (IOV) (range 0-36). Practical and emotional support needs were assessed in 13 domains.

Results711 participants, mean age 49.5 (SD 12.9, range 18-90). 628 (88.6%) were female. Mean age of the deceased 72.2 (SD 16.1). 311 (43.8%) deaths were from confirmed/suspected COVID-19. Mean IOV was 20.41 (95% CI = 20.06 to 20.77). 28.2% exhibited severe vulnerability (IOV [≥] 24). In six support domains relating to psycho-emotional support, 50% to 60% of respondents reported high/fairly high levels of need. Grief and support needs increased strongly for close relationships with the deceased (versus more distant) and with reported social isolation and loneliness (P < 0.001), whereas they reduced with age of the deceased above 40 to 50. Other risk factors were place of death and reduced support from health professionals after death (P < 0.05).

ConclusionsHigh overall levels of vulnerability in grief and support needs were observed. Relationship with the deceased, age of the deceased, and social isolation and loneliness are potential indicators of those at risk of even higher vulnerability in grief and support needs. Healthcare professional support after death is associated with more positive bereavement outcomes.


title: TOWARDS A SINGLE PARAMETER FOR THE ASSESSMENT OF EEG OSCILLATIONS

abstract: The single macroscopic flow on the boundary of a closed curve equals the sum of the countless microscopic flows in the enclosed area. According to the dictates of the Greens theorem, the counterclockwise movements on the border of a two-dimensional shape must equal all the counterclockwise movements taking place inside the shape. This mathematical approach might be useful to analyse neuroscientific data sets for its potential capability to describe the whole cortical activity in terms of electric flows occurring in peripheral brain areas. Once mapped raw EEG data to coloured ovals in which different colours stand for different amplitudes, the theorem suggests that the sum of the electric amplitudes measured inside every oval equals the amplitudes measured just on the ovals edge. This means that the collection of the vector fields detected from the scalp can be described by a novel, single parameter summarizing the counterclockwise electric flow detected in the outer electrodes. To evaluate the predictive power of this parameter, in a pilot study we investigated EEG traces from ten young females performing Ravens intelligence tests of various complexity, from easy tasks (n=5) to increasingly complex tasks (n=5). Despite the seemingly unpredictable behavior of EEG electric amplitudes, the novel parameter proved to be a valuable tool to to discriminate between the two groups and detect hidden, statistically significant differences. We conclude that the application of this promising parameter could be expanded to assess also data sets extracted from neurotechniques other than EEG.


title: Social cognition deficits and its biometric signatures in the behavioral variant of Alzheimer's disease

abstract: The behavioral variant of Alzheimers disease (bvAD) is characterized by early and predominant behavioral changes, resembling the clinical profile of the behavioral variant of frontotemporal dementia (bvFTD). Social cognition deficits form hallmark features in bvFTD and altered biometric responses to socioemotional cues have been observed in bvFTD. However, little is known about social cognition and its biometric signature in bvAD. In this explorative study, we investigated all levels of social cognition (i.e., level-1: perception, level-2: interpretation and level-3: reasoning), using the Ekman 60 faces test (level-1), Interpersonal Reactivity Index (IRI) and empathy eliciting videos (level-2), the Social Norms Questionnaire (SNQ) and moral dilemmas (level-3), while measuring eyemovements and galvanic skin response (GSR). We compared 12 patients with bvAD with patients with bvFTD (n=14), typical AD (tAD, n=13) and controls (n=15), using ANCOVAs and post hoc testing, adjusting for age and sex. Regarding perception, bvAD (40.1{+/-}8.6) showed lower scores on the Ekman test compared to controls (50.1{+/-}4.6, p<0.001), and tAD (46.2{+/-}5.3, p=0.05) and higher scores compared to bvFTD (32.4{+/-}7.3, p=0.002). Eyetracking during the Ekman test revealed that groups did not differ in dwell time on the eyes (all p>0.05), but bvAD (18.7{+/-}9.5%) and bvFTD (19.4{+/-}14.3%) spent significantly less dwell time on the mouth when viewing the faces than controls (30.4{+/-}10.6%, p<0.05) and tAD (32.7{+/-}12.1%, p<0.01). Regarding empathy, bvAD (11.3{+/-}4.6) exhibited lower scores on the IRI Perspective Taking subscale compared with controls (15{+/-}3.4, p=0.02) and similar scores to bvFTD (8.7{+/-}5.6, p=0.19) and tAD (13.0{+/-}3.2, p=0.43). The GSR to empathy eliciting videos did not differ between groups (all p>0.05). Regarding knowledge of social norms, bvAD (16.0{+/-}1.6) and bvFTD (15.2{+/-}2.2) showed lower scores on the SNQ than tAD (17.8{+/-}2.1, both p<0.05) and controls (18.1{+/-}1.3, both p<0.01). Regarding moral reasoning, no differences among the groups were observed in responses to moral dilemmas (all p>0.05), while only bvFTD (0.9{+/-}1.1) showed a lower GSR during the personal condition compared with controls (3.2{+/-}3.3 peaks per minute, p=0.02). In conclusion, bvAD showed a similar though milder social cognition profile and a similar eyetracking signature compared with bvFTD and greater social cognition impairments and divergent eyemovement patterns compared with tAD. Our results suggest that bvAD and bvFTD show reduced attention to salient features during facial expression perception, potentially contributing to their emotion recognition deficits. These social cognition and biometric measures provide important insights into the basis of behavioral changes in bvAD, and might be valuable for its clinical diagnosis.


title: Impaired reaching adaptation links to vestibular symptoms

abstract:
About 30% of adults suffer from some mild to severe vestibular dysfunction. Vestibular disorders can be expressed as acute vestibular syndrome (AVS), episodic vestibular syndrome. Only half of the sufferers can compensate for their dysfunction after three months after the onset, while the other half of them become chronic, the mechanisms behind this compensation remain unclear. Several behavioural studies have explored the role of the vestibulo-ocular reflex and saccades in the process, linking to the interaction between the superior colliculus and the cerebellum. Yet, despite cerebellar involvement in vestibular function and oculomotor adaptation, thus far, no studies have focused on the specific role of the cerebellum in the compensation process in vestibular dysfunction.

In this study, we test the hypothesis that undiagnosed cerebellar dysfunction might hinder chronic vestibulopathy sufferers from compensating and recovering. We recruited 19 patients who had suffered from an acute peripheral vestibular syndrome (10 clinically recovered and 9 with chronic symptoms) and ten individuals with no history of vestibular alterations (controls). We assessed their implicit motor learning capacity with a visuomotor rotation task and measured by the angular aiming error, which showed an impaired implicit motor adaptation in chronic patients (7.04 {+/-} 1.6{o}) compared to recovered (11.06 {+/-} 1.94{o}, p = 0.007) and control groups (10.89 {+/-} 7.96{o}, p = 0.03). These findings indicate the involvement of the cerebellum in vestibular compensation and suggest that implicit motor adaptation of reaching movements could be potentially used as an early prognostic tool in unilateral peripheral vestibular dysfunction (UPVD) patients.


title: Identifying variation in GP referral rates: an observational study of outpatient headache referrals.

abstract:
ObjectiveThis study provides a framework methodology for identifying GP surgeries with unexpected rates of referral to specialist services, using headache referrals to outpatient neurology as an example.

DesignThis is a retrospective observational study using routinely collected and open-source data.

Setting and participantsData was collected from a single consultant outpatient neurology clinic and 202 GP surgeries across seven CCGs in the Northwest of England.

Primary OutcomeThe number of headache referrals from each GP surgery during the study period of 3 [1/4] years was used as the primary outcome in a generalised linear model. The standardised residuals from this model were then used to identify GP surgeries that were likely to have referred unexpected patient numbers for headaches to an outpatient neurology clinic during the study period.

ResultsIn the model using data from the CCG in which the outpatient neurology clinic is located we identified one GP surgery referring more headache patients than expected. The model showed that the clearest predictor of headache referrals was the number of referrals for other types of neurological disorders. In the model using data from all seven CCGs we identified four GP surgeries with unexpected numbers of referrals. This model showed that there were two predictors of headache referral, namely other neurology referrals and the distance from the clinic.

ConclusionWe have developed a flexible methodology for identifying GP surgeries with unexpected numbers of referrals to specialist services. This methodology was demonstrated using headache referrals but could be adapted to any type of referral or geographical area.

STRENGTHS AND LIMITATIONS OF THIS STUDYO_LIIdentifying GP surgeries with unexpected levels of referral allows further investigation and potential support to be targeted where it is most likely to be effective.
C_LIO_LIWe used standard Generalised Linear Models (GLMs) which are flexible and can be adapted to investigate any type of referral, not just headache referrals to outpatient neurology.
C_LIO_LISpecialist knowledge of the potential drivers of referral is required in order to include the most influential variables in the GLMs.
C_LIO_LIThe current lack of systematic coding of outpatient neurology diagnoses means we are currently unable to extend this study to a larger geographical area or to include other clinics.
C_LI


title: Deuterium metabolic imaging and hyperpolarized 13C-MRI of the normal human brain at clinical field strength reveals differential cerebral metabolism

abstract: Deuterium metabolic imaging (DMI) and hyperpolarized 13C-pyruvate MRI (13C-HPMRI) are two emerging methods for non-invasive and non-ionizing imaging of tissue metabolism. Imaging cerebral metabolism has potential applications for cancer, neurodegeneration, multiple sclerosis, traumatic brain injury, stroke, and inborn errors of metabolism. Here we directly compare these two non-invasive methods at 3 T for the first time in humans, and how they simultaneously probe both glycolytic and oxidative metabolism. DMI was undertaken 1-2 hours after oral administration of [6,6-2H2]glucose, and 13C-MRI was performed immediately following intravenous injection of hyperpolarized [1-13C]pyruvate in ten and nine normal volunteers within each arm. DMI provided maps of deuterium-labelled water, glucose, lactate, and glutamate/glutamine. 13C-HPMRI generated maps of hyperpolarized carbon-13 labelled pyruvate, lactate, and bicarbonate. There was clear spectral separation in the spectroscopic imaging data with both DMI and 13C-HPMRI at 3 T. The ratio of 13C-lactate/13C-bicarbonate (mean = 3.7 {+/-} 1.2) acquired with 13C-HPMRI was higher than the equivalent 2H-lactate/2H-Glx ratio (mean = 0.18 {+/-} 0.09) acquired with DMI. These differences can be explained by the route of administering each probe, the timing of imaging after ingestion or injection, as well as the biological differences in cerebral uptake and cellular physiology between the two molecules. The results demonstrate these two metabolic imaging methods provide different yet complementary readouts of oxidative and glycolytic metabolism within a clinically feasible timescale. Furthermore, as DMI was undertaken at a clinical field strength within a ten-minute scan time, it demonstrates its potential as a routine clinical tool in the future.

category: oncology


title: Can you hear me now? Clinical applications of audio recordings

abstract: Audio and speech have several implicit characteristics that have the potential for the identification and quantification of clinical disorders. This PRISMA-guided review is designed to provide an overview of the landscape of automated clinical audio processing to build data-driven predictive models and infer phenotypes of a variety of neuropsychiatric, cardiac, respiratory and other disorders. We detail the important components of this processing workflow, specifically data acquisition and processing, algorithms used and their customization for clinical applications, commonly used tools and software, and benchmarking and evaluation methodologies. Finally, we discuss important open challenges for the field, and potential strategies for addressing them.


title: Multicenter Validation of a Machine Learning Algorithm for Diagnosing Pediatric Patients with Multisystem Inflammatory Syndrome and Kawasaki Disease

abstract:
BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a novel disease identified during the COVID-19 pandemic characterized by systemic inflammation following SARS-CoV-2 infection. Delays in diagnosing MIS-C may lead to more severe disease with cardiac dysfunction or death. Most pediatric patients recover fully with anti-inflammatory treatments, but early detection of MIS-C remains a challenge given its clinical similarities to Kawasaki disease (KD) and other acute childhood illnesses.

MethodsWe developed KIDMATCH (KawasakI Disease vs Multisystem InflAmmaTory syndrome in CHildren), a deep learning algorithm for screening patients for MIS-C, KD, or other febrile illness, using age, the five classical clinical KD signs, and 17 laboratory measurements prospectively collected within 24 hours of admission to the emergency department from 1448 patients diagnosed with KD or other febrile illness between January 1, 2009 and December 31, 2019 at Rady Childrens Hospital. For MIS-C patients, the same data was collected from 131 patients between May 14, 2020 to June 18, 2021 at Rady Childrens Hospital, Connecticut Childrens Hospital, and Childrens Hospital Los Angeles. We trained a two-stage model consisting of feedforward neural networks to distinguish between MIS-C and non MIS-C patients and then KD and other febrile illness. After internally validating the algorithm using 10-fold cross validation, we incorporated a conformal prediction framework to tag patients with erroneous data or distribution shifts, enhancing the model generalizability and confidence by flagging unfamiliar cases as indeterminate instead of making spurious predictions. We externally validated KIDMATCH on 175 MIS-C patients from 16 hospitals across the United States.

FindingsKIDMATCH achieved a high median area under the curve in the 10-fold cross validation of 0.988 [IQR: 0.98-0.993] in the first stage and 0.96 [IQR: 0.956-0.972] in the second stage using thresholds set at 95% sensitivity to detect positive MIS-C and KD cases respectively during training. External validation of KIDMATCH on MIS-C patients correctly classified 76/83 (2 rejected) patients from the CHARMS consortium, 47/50 (1 rejected) patients from Boston Childrens Hospital, and 36/42 (2 rejected) patients from Childrens National Hospital.

InterpretationKIDMATCH has the potential to aid frontline clinicians with distinguishing between MIS-C, KD, and similar febrile illnesses in a timely manner to allow prompt treatment and prevent severe complications.

FundingEunice Kennedy Shriver National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, Patient-Centered Outcomes Research Institute, National Library of Medicine


title: A 'step too far' or 'perfect sense'? A qualitative study of British adults' views on mandating COVID-19 vaccination and vaccine passports

abstract:
BackgroundDebate is ongoing about mandating COVID-19 vaccination to maximise uptake. Policymakers must consider whether to mandate, for how long, and in which contexts, taking into account not only legal and ethical questions but also public opinion. Implementing mandates among populations who oppose them could be counterproductive.

MethodsQualitative telephone interviews (Feb-May 2021) with British adults explored views on vaccine passports and mandatory vaccination. Participants (n=50) were purposively selected from respondents to a probability-based national survey of attitudes to COVID-19 vaccination, to include those expressing vaccine-hesitancy. Data were analysed thematically.

FindingsSix themes were identified in participants narratives concerning mandates: (i) mandates are a necessary and proportionate response for some occupations to protect the vulnerable and facilitate the resumption of free movement; (ii) mandates undermine autonomy and choice; (iii) mandates represent an over-reach of state power; (iv) mandates could potentially create  vaccine apartheid; (v) the importance of context and framing; and (vi) mandates present considerable feasibility challenges. Those refusing vaccination tended to argue strongly against mandates. However, those in favour of vaccination also expressed concerns about freedom of choice, state coercion and social divisiveness.

DiscussionTo our knowledge, this is the first in-depth UK study of public views on COVID-19 vaccine mandates. It does not assess support for different mandates but explores emotions, principles and reasoning underpinning views. Our data suggest that debate around mandates can arouse strong concerns and could entrench scepticism. Policymakers should proceed with caution. While surveys can provide snapshots of opinion on mandates, views are complex and further consultation is needed regarding specific scenarios.


title: Chronic Disease and Workforce Participation Among Medicaid Enrollees Over 50: The Potential Impact of Medicaid Work Requirements Post-COVID-19

abstract:
As the COVID-19 pandemic wanes, states may reintroduce Medicaid work requirements to reduce enrollment. Using the Health and Retirement Study, we evaluated chronic disease burden among beneficiaries aged >50 (n=1460) who might be impacted by work requirements (i.e. working <20 hours per week). Seven of eight chronic conditions evaluated were associated with reduced workforce participation, including history of stroke (OR: 7.35; 95% CI: 2.98-18.14) and lung disease (OR: 4.39; 95% CI: 2.97-7.47). Those with more severe disease were also more likely to work fewer hours. Medicaid work requirements would likely have great impact on older beneficiaries with significant disease burden.

Key PointsO_LIChronic disease linked to reduced work among older Medicaid beneficiaries.
C_LIO_LIWork requirements would greatly impact those aged >50 with chronic conditions.
C_LIO_LICoverage loss would have negative implications for long-term disease management.
C_LI


title: Anti-spike antibody trajectories in individuals previously immunised with BNT162b2 or ChAdOx1 following a BNT162b2 booster dose

abstract: The two most commonly-used SARS-CoV-2 vaccines in the UK, BNT162b2 (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca), employ different immunogenic mechanisms. Compared to BNT162b2, two-dose immunisation with ChAdOx1 induces substantially lower peak anti-spike antibody (anti-S) levels and is associated with a higher risk of breakthrough infections. To provide preliminary indication of how a third booster BNT162b2 dose impacts anti-S levels, we performed a cross-sectional analysis using capillary blood samples from vaccinated adults (aged [≥]18 years) participating in Virus Watch, a prospective community cohort study in England and Wales. Blood samples were analysed using Roche Elecsys Anti-SARS-CoV-2 S immunoassay. We analysed anti-S levels by week since the third dose for vaccines administered on or after September 1, 2021 and stratified the results by second dose vaccine type (ChAdOx1 or BNT162b2), age, sex and clinical vulnerability. Anti-S levels peaked at two weeks post-booster for BNT162b2 (22,185 U/mL; 95%CI: 21,406-22,990) and ChAdOx1 second dose recipients (19,203 U/mL; 95%CI: 18,094-20,377). These were higher than the corresponding peak antibody levels post-second dose for BNT162b2 (12,386 U/mL; 95%CI: 9,801-15,653, week 2) and ChAdOx1 (1,192 U/mL; 95%CI: 818-1735, week 3). No differences emerged by second dose vaccine type, age, sex or clinical vulnerability. Anti-S levels declined post-booster for BNT162b2 (half-life=44 days) and ChAdOx1 second dose recipients (half-life=40 days). These rates of decline were steeper than those post-second dose for BNT162b2 (half-life=54 days) and ChAdOx1 (half-life=80 days). Our findings suggest that peak anti-S levels are higher post-booster than post-second dose, but that levels are projected to be similar after six months for BNT162b2 recipients. Higher peak anti-S levels post-booster may partially explain the increased effectiveness of booster vaccination compared to two-dose vaccination against symptomatic infection with the Omicron variant. Faster waning trajectories post third-dose may have implications for the timing of future booster campaigns or four-dose vaccination regimens for the clinically vulnerable.


title: Safety and efficacy of two immunization schedules with an inactivated SARS-CoV-2 vaccine in adults. A randomized non-inferiority clinical trial.

abstract:
BackgroundSeveral vaccines have been developed to control the COVID-19 pandemic. CoronaVac(R) (Sinovac Life Sciences), an inactivated SARS-CoV-2 vaccine, has demonstrated safety and immunogenicity in previous studies, preventing severe COVID-19 cases. We further investigated the safety and efficacy of two immunization schedules of CoronaVac(R) in a non-inferiority trial in healthy adults.

MethodsThis is a multi-center and randomized clinical trial. Healthy adults were enrolled at eight centers in Chile. Participants were randomly assigned to two vaccination schedules, receiving two doses with either 14 (0-14) or 28 (0-28) days between each. 2302 participants were vaccinated. The primary safety and efficacy endpoints were solicited adverse events (AE) within 7 days after each dose and compared the number of cases of SARS-CoV-2 infection 14 days after the second dose between schedules, respectively.

FindingsThe most frequent local AE was pain at the injection site, which was less frequent in participants aged [≥]60 years. Other local AEs were reported in less than 5% of participants. The most frequent systemic AEs were headache, fatigue, and myalgia. The remaining AEs were minor allergic reactions and fever. Most AEs were mild and transient. There were no significant differences for local and systemic AE between schedules. No anaphylactic reactions or vaccine-related severe AEs were observed. 58 COVID-19 cases were confirmed, and all but two of them were mild. No differences were observed in protection between schedules.

InterpretationCoronaVac(R) is safe, especially in [≥]60 years-old participants. Both schedules protected against COVID-19 hospitalizations.

FundingMINSAL, Chile, CPC & IMII, Chile.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCoronaVac(R) (an inactivated SARS-CoV-2 vaccine) was approved on June 1st, 2021, by the WHO for its use in humans. Sinovac Life Sciences generated this vaccine in China and conducted phase 1/2 trials. Good safety, efficacy, and immunogenicity profiles were reported. The results from this study led to the use of CoronaVac(R) in other countries, such as Brazil, Turkey, and Chile, with phase 3 trials being held on them.

Added-value of this studyThis work compares the safety and efficacy of two immunization schedules with CoronaVac(R), with each dose administrated two or four weeks after the first dose on healthy Chilean adults. To date, no studies showing the safety and efficacy of these two immunization schedules with CoronaVac(R) in healthy adults in a population other than the Chinese have been published. We show that CoronaVac(R) is safe and prevents hospitalization due to COVID-19 in both immunization schedules. No differences were found in the incidence of adverse events between both schedules, and no related severe adverse events were reported. These results give further insight into the immune response induced by CoronaVac(R) and are relevant when deciding on the immunization schedule chosen for vaccination.

Implications of all the available evidenceThe data reported here show that using either immunization schedule with two doses of CoronaVac(R) protects against SARS-CoV-2. The data also indicate that CoronaVac(R) does not induce severe adverse events in either immunization schedule, and the adverse events registered are mild and transient, confirming the safety of this vaccine.


title: Genetic immune response and antibody repertoire of heterologous ChAdOx1-BNT162b2 vaccination in a Korean cohort

abstract: Heterologous ChAdOx1-BNT162b2 vaccination induces a stronger immune response than two doses of BNT162b2 or ChAdOx1. Yet, the molecular transcriptome, the germline allelic variants of immunoglobulin loci and anti-Omicron antibody levels induced by the heterologous vaccination have not been formally investigated. Moreover, there is a paucity of COVID vaccine studies including diverse genetic populations. Here, we show a robust molecular immune transcriptome and antibody repertoire in 51 office workers from the Republic of Korea after a heterologous ChAdOx1-BNT162b2 vaccination or a homologous ChAdOx1-ChAdOx1 vaccination. Anti-spike-specific IgG antibody levels in the heterologous group increased from 14,000 U/ml to 142,000 AU/ml within eight days after the BNT162b2 vaccination. In contrast, antibody levels in the homologous group increased two-fold after the second ChAdOx1 dose. Antibody titers against the Omicron spike protein as compared to the ancestral strain were reduced to a lesser extent in the heterologous group. RNA-seq conducted on immune cells demonstrated a stronger activation of interferon-induced genetic programs in the heterologous cohort. An increase of specific IGHV clonal transcripts encoding neutralizing antibodies was preferentially detected in the heterologous cohort. Enrichment of B cell and CD4+ T cell responses were observed following both heterologous and homologous vaccination using scRNA-seq, but clonally expanded memory B cells were relatively stronger in the ChAdOx1-BNT162b2 cohort. In summary, a heterologous vaccination with ChAdOx1 followed by BNT162b2 provides an innate and adaptive immune response exceeding that seen in homologous ChAdOx1 vaccinations but equivalent to that seen in homologous BNT162b2 vaccination.


title: Five years follow-up of patients with non-melanoma skin cancer treated with HeberFERON

abstract:
IntroductionNon-melanoma skin cancer is the most common tumor. The combination of IFN-alpha 2b and IFN-gamma has been used as a new therapeutic opportunity to treat basal cell carcinomas and cutaneous squamous cell carcinomas. The aim of this report is to record prospectively the recurrence and new lesions rates in patients participating in phase II clinical trials.

MethodsPhase II clinical trials (double-blind randomized one center study, InCarbacel-III, in patients with basal cell carcinoma; and open, non-randomized multicenter study, CECIN, in patients with cutaneous squamous cell carcinomas), with the use of the combination of IFN-alpha 2b and IFN-gamma were conducted to evaluate the efficacy, safety and the 5-year duration of clinical responses. Both studies were approved by institutional ethic committees and all the patients given their written informed consent. The investigational treatment was administered, peri- or intralesionally, three times per week, during 3 weeks. Clinical (RECIST 1.0) responses were evaluated three months after the end of treatment.

ResultsThe combination of IFNs in InCarbacel-III study showed the best clinical response (complete response of 64.3%, overall response of 85.7%) with the highest doses (10.5 MIU); without patients recurrence at 5 years follow-up (3.5 MUI and 10.5 MUI groups). The frequency of new lesions decreased in the treated patients 8 times. In the CECIN study 14 patients achieved complete response and 4 partial responses (overall response rate 67%). Up to the 5-year follow-up none of the patients with complete response had recurrence or new lesion. In both studies the cosmetic results were excellent and the reported adverse events were mostly of mild intensity.

ConclusionsThe use of the combination of IFN-alpha 2b and IFN-gamma showed efficacy in basal cell carcinoma and cutaneous squamous cell carcinoma promoting a long term response for at least 5 years and decreasing the rate of new lesions, safely and with excellent cosmetic effects.

category: dermatology


title: Post-marketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12-39 years in Italy: a multi-database, self-controlled case series study

abstract:
ObjectivesTo investigate the association between SARS-CoV-2 mRNA vaccines, BNT162b2 and mRNA-1273, and myocarditis/pericarditis.

DesignSelf-Controlled Case Series study (SCCS) using national data on COVID-19 vaccination and emergency care/hospital admissions.

SettingItalian Regions (Lombardia, Friuli Venezia Giulia, Veneto, Lazio).

Participants2,861,809 individuals, aged 12-39 years, vaccinated with the first doses of mRNA vaccines (2,405,759 BNT162b2 and 456,050 mRNA-1273) between 27 December 2020 and 30 September 2021.

Main outcome measuresFirst diagnosis of myocarditis/pericarditis within the study period. The incidence of events in the exposure risk periods (0-21 days from the vaccination day, subdivided in three equal intervals) for first and second dose was compared with baseline period. The SCCS model was fitted using conditional Poisson regression to estimate Relative Incidences (RI) and Excess of Cases (EC) per 100,000 vaccinated by dose, age, gender and brand.

ResultsDuring the study period, 441 participants aged 12-39 years developed myocarditis/pericarditis (346 BNT162b2 and 95 mRNA-1273). During the 21-day risk interval there were 114 cases of myocarditis/pericarditis (74 BNT162b2 and 40 mRNA-1273) corresponding to a RI of 1.27 (0.87-1.85) and 2.16 (1.50-3.10) after first and second dose, respectively.

An increased risk of myocarditis/pericarditis at [0-7) days was observed after first [RI=6.55; 95% Confidence Interval (2.73-15.72); EC per 100,000 vaccinated=2.0 (1.5-2.3)] and second dose [RI=7.59 (3.26-17.65); EC=5.5 (4.4-5.9)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.39 (2.02-5.68); EC=0.8 (0.6-1.0)]. In males, an increased risk at [0-7) days was observed after first [RI=12.28, 4.09-36.83; EC=3.8 (3.1-4.0)] and second dose [RI=11.91 (3.88-36.53); EC=8.8 (7.2-9.4)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.45 (1.78-6.68); EC=1.0 (0.6-1.2)]. In females, an increased risk at [0-7) days was observed after second dose of BNT162b2 [RI=3.38 (1.47-7.74); EC=0.7 (0.3-0.9)]. At [0-7) days an increased risk following second dose of BNT162b2 was observed in the 12-17 years old [RI=5.74, (1.52-21.72); EC=1.7 (0.7-1.9)] and in 18-29 years old [RI=4.02 (1.81-8.91); EC=1.1 (0.6-1.3)]. At [0-7) days an increased risk after first [RI=7.58 (2.62-21.94); EC=3.5 (2.4-3.8)] and second [RI=9.58 (3.32-27.58); EC=8.3 (6.7-9.2)] dose of mRNA-1273 was found in 18-29 years old and after first dose in 30-39 years old [RI=6.57 (1.32-32.63); EC=1.0 (0.3-1.1)].

ConclusionsThis population-based study indicates that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years, whereas no association was observed in older subjects. The risk increased after the second dose and in the youngest for both vaccines, remained moderate following vaccination with BNT162b2, while was higher in males following vaccination with mRNA-1273. The public health implication of these findings should be weighed in the light of the overall efficacy and safety profile of both vaccines.


title: Role of Covid vaccine in determining ICU admission and death due to Covid -19 in Tamil Nadu

abstract: COVID-19 pandemic threatened the world in terms of its rapid spread, strain on health infrastructure and many people lost their lives due to COVID. Mass Vaccination of public against Covid-19 were done with the notion that it protects against the severe form of the disease and death due to Covid-19. Covid vaccination was rolled out in Tamil Nadu from 16th January 2021 in a phased manner. This study was done using secondary data to assess the role of COVID vaccination in preventing ICU admission and death due to Covid-19 in Tamil Nadu for the period of August - December 2021. Unvaccinated individuals contributed to a higher proportion of hospitalization (60.9%) and ICU admission (65.5%) among Covid-19 infected during this period. Similarly, among patients who died due to Covid-19, 75.5% were unvaccinated. Odds of ICU admission and death among unvaccinated was 2.01 and 3.19 - times higher compared to fully vaccinated individuals infected with Covid-19. Unvaccinated Covid-19 patients had 2.73- and 1.46- times increased odds of dying and ICU admission respectively, compared to partially vaccinated. Population Attributable Risk showed that receiving at least one dose of vaccine could have reduced the mortality among Covid patients by 54% and ICU admission by 23.3%. This article emphasizes the need for vaccination against Covid-19 to reduce ICU admission and death among those infected with Covid-19.


title: History of SARS-CoV-2 infection, anti-spike IgG antibody kinetics and neutralization capacities following the second and third dose of BNT162b2 vaccine in nursing home residents

abstract:
ImportanceDuration of post-vaccination protection against COVID-19 in individuals is a critical issue, especially in nursing home (NH) residents, i.e. one of the most vulnerable populations.

ObjectiveTo estimate the duration of the IgG(S) response to the mRNA BNT162b2 vaccine in NH residents with (COV-Yes) or without (COV-No) history of natural infection with SARS-CoV-2.

Design, setting and participantsIgG(S) quantification was carried out at 3 different time periods following administration of the Pfizer BioNtech vaccine: three then seven months after the 2nd dose and one month after the 3rd dose. 574 COV-Yes and COV-No NH residents were included in 2 cohorts: Main (n=115, mean age 84 years) or Confirmatory (n=459, mean age 88 years).

ExposureAll subjects received the BNT162b2 vaccine.

Main outcomes and measurementsIgG(S) antibodies and seroneutralization capacity.

ResultsNeutralization capacity was strongly correlated with IgG(S) levels (R2:76%) without any difference between COV-Yes and COV-No groups for the same levels of IgG(S). COV-Yes, compared to the COV-No subjects showed 5-fold and 15-fold higher IgG(S) titers 3 and 7 months after the 2nd dose, but less than 2-fold higher IgG(S) after the 3rd dose, due to a more pronounced effect of the 3rd dose in the COV-No group. These results were similar in both cohorts. After the 2nd dose, duration of assumed robust protection (IgG(S) >264 BAU/ml) was 2-fold higher in the COV-Yes vs. COV-No group: 12.60 (10.69-14.44) vs 5.76 (3.91-8.64) months, and this advantage was mainly due to the higher IgG(S) titers after the 2nd dose and secondary to a slower decay over time. After the 3rd dose, duration (months) of robust protection was estimated at 11.87 (9.88-14.87) (COV-Yes) and 8.95 (6.85-11.04) (COV-No).

Conclusions and relevanceIn old subjects living in NH, history of SARS-CoV-2 infection provides a clear advantage in the magnitude and duration of high IgG(S) titers following the 2nd dose. Importantly, the 3rd dose induces a much more pronounced IgG(S) response than the 2nd dose in COV-No subjects, the effect of which should be able to ensure in these subjects a prolonged protection against severe forms of COVID-19.

category: geriatric medicine


title: Heterologous SARS-CoV-2 IgA neutralising antibody responses in convalescent plasma

abstract: Following infection with SARS-CoV-2, virus-specific antibodies are generated which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS-CoV-2 has been extensively reported. In comparison, other antibody isotypes including IgA have been poorly characterized. Here we characterized plasma IgA from 41 early convalescent COVID-19 subjects for neutralisation and Fc effector functions. We find that convalescent plasma IgA from >60% of the cohort have the capacity to inhibit the interaction between wild-type RBD and ACE2. Furthermore, a third of the cohort induced stronger IgA-mediated inhibition of RBD binding to ACE2 than IgG, when tested at equivalent concentrations. Plasma IgA and IgG from the cohort, broadly recognize similar RBD epitopes and showed similar ability to inhibit ACE2 from binding 22 of 23 different prevalent RBD proteins with single amino acid mutations. Plasma IgA was largely incapable of mediating antibody-dependent phagocytosis in comparison to plasma IgG. Overall, convalescent plasma IgA contributes to neutralisation towards wild-type RBD and various RBD single mutants in most subjects, although this response is heterogeneous and less potent than IgG.


title: Individual and community-level determinants of intention to use contraceptive among married women in Ethiopia: A multi-level analysis of National Survey

abstract:
BackgroundContraceptives are the most effective strategies to prevent unwanted pregnancies and their consequences. Realizing intention to use contraceptives is a crucial stage to draft and implement a successful family planning program.

ObjectiveThis study aimed to identify individual and community level of factors affecting womens intention to use contraceptives in Ethiopia.

MethodThis study was based on a large national survey, Ethiopian Demographic and Health Survey. A total weighted sample of 6,555 married/in union reproductive-age women were included. Because of the hierarchical nature of the DHS data, a multilevel logistic regression model was used to study individual and community-level factors that may influence intention to contraceptive use. A 95% confidence interval and a p value of less than 0.05 were used to declare statistical significance.

ResultThe overall intention to use contraceptives was 48.63% (95% CI 47.42, 49.84). Participants age range of 25-34 years (AOR = 0.42, 95 CI% (0.22, 0.79)) and 35-49 years (AOR = 0.12, 95% CI: (0.05, 0.28)), husband with primary education (AOR = 1.60, 95% CI: (1.02, 2.50)), heard of contraceptives from their community (AOR = 1.91. 95% CI: (1.29, 2.83)), ever used contraceptives (AOR = 4.48, 95% CI: (2.91, 6.88)) and having six or more children (AOR = 0.46, 95% CI: (0.23, 0.9)) were individual factors significantly associated with interceptive intention. From community level factors, high community family planning utilization rate (AOR = 2.29, 95% CI: (1.36,3.86)) was associated with intention to use contraceptive.

ConclusionMore than half of married women were not intended to use contraceptives. Intention to use contraceptive was affected by individual and community level attributes. Thus, public health interventions particularly that could increase information dissemination regarding contraceptives among the communities and enhance community level contraceptive utilization rate are required at the national level to improve contraceptive utilization.


title: SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS

abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease. Recently, several gain-of-function mutations in SPTLC1 were associated with juvenile ALS. SPTLC1 encodes for a subunit of the serine-palmitoyltransferase (SPT) - the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL).

Here we identified a novel SPTLC1p.L38R mutation in a young Chinese girl with a signature of juvenile ALS. The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs. A blood lipid analysis showed overall increased SL levels and particularly a pronounced increase in dihydro-SL species. Increased SL de novo synthesis was confirmed in an SPTLC1 deficient HEK cell model that expressed the mutant form. An experimental therapy based on extracts of the fungus C. cicadae resulted in a significant lowering of plasma sphingolipids. A subsequent metabolomics analysis identified Myriocin, a potent SPT inhibitor as an active component of the extract. The inhibitory effect of the C. cicadae extract on SL de novo synthesis was confirmed in a HepG2 cell model. These results suggest that a pharmacological inhibition of SPT could be a therapeutic option for this form of ALS.


title: Risk Factors for Early PICC Removal: A Retrospective Study of Adult Inpatients at an Academic Medical Center

abstract:
BackgroundUse of PICCs has been rising since 2001. They are used when long-term intravenous access is needed and for blood draws in patients with difficult venous access.

ObjectiveTo determine which risk factors contribute to inappropriate PICC line insertion defined as removal of a PICC within five days of insertion for reasons other than a PICC complication.

DesignRetrospective, observational study.

SettingTertiary-care, Level 1 trauma center.

PatientsAdult patients with a PICC removed 1/1/2017 to 5/4/2020.

MeasurementsFrequency of PICC removal within five days of insertion and associated risk factors for early removal.

ResultsBetween 1/1/17 and 5/4/2020, 995 of 5348 PICCs inserted by the IV nursing team were removed within five days (19%). In 2017, 5 of 429 PICCs developed a central line-associated infection (1.2%) and 29 of 429 PICCs developed symptomatic venous thromboembolism (6.7%). Patients with PICCs whose primary service was a medical subspecialty were independently at higher risk of early removal (OR 1.44, 95% CI 1.14, 1.83); weekday insertion was independently associated with a lower likelihood of early removal compared to weekend insertion (OR 0.60; 95% CI 0.49, 0.75).

LimitationPICC removal after discharge was not assessed and paper records were likely incomplete and biased.

ConclusionNearly one in five PICCs were removed within five days. Patients whose primary team was a medical subspecialty were at independently higher risk of early removal.

category: health systems and quality improvement


title: Clinical and Economic Impact of COVID-19 on Plantation Workers: Preliminary Results from the Guatemala Agricultural Workers and Respiratory Illness Impact (AGRI) Study

abstract: We evaluated the clinical and socioeconomic burdens of respiratory disease in a cohort of Guatemalan banana plantation workers. All eligible workers were offered enrollment from June 15-December 30, 2020, and annually, then followed for influenza-like illnesses (ILI) through: 1) self-reporting to study nurses, 2) sentinel surveillance at health posts, and 3) absenteeism. Workers with ILI submitted nasopharyngeal swabs for influenza, RSV, and SARS-CoV-2 testing, then completed surveys at days 0, 7, and 28. Through October 10, 2021, 1,833 workers developed 169 ILIs (12.0/100 person-years) and 43 (25.4%) of these ILIs were laboratory-confirmed SARS-CoV-2 (3.1/100 person-years). Workers with SARS-CoV-2-positive ILI reported more anosmia (p<0.01), dysgeusia (p<0.01), difficulty concentrating (p=0.01), and irritability (p=0.01), and greater clinical and well-being severity scores (Flu-iiQ) than test-negative ILIs; they also had greater absenteeism (p<0.01) and lost income (median US$127.1, p<0.01). These results support the prioritization of Guatemalan farm workers for COVID-19 vaccination.


title: Antibody and memory B-cell immunity in a heterogeneously SARS-CoV-2 infected and vaccinated population

abstract: Global population immunity to SARS-CoV-2 is accumulating through heterogenous combinations of infection and vaccination. Vaccine distribution in low- and middle-income countries has been variable and reliant on diverse vaccine platforms. We studied B-cell immunity in Mexico, a middle-income country where five different vaccines have been deployed to populations with high SARS-CoV-2 incidence. Levels of antibodies that bound a stabilized prefusion spike trimer, neutralizing antibody titers and memory B-cell expansion correlated with each other across vaccine platforms. Nevertheless, the vaccines elicited variable levels of B-cell immunity, and the majority of recipients had undetectable neutralizing activity against the recently emergent omicron variant. SARS-CoV-2 infection, experienced prior to or after vaccination potentiated B-cell immune responses and enabled the generation of neutralizing activity against omicron and SARS-CoV for all vaccines in nearly all individuals. These findings suggest that broad population immunity to SARS-CoV-2 will eventually be achieved, but by heterogenous paths


title: Antimicrobial susceptibility and risk factors for resistance among Escherichia coli isolated from canine specimens submitted to a diagnostic laboratory in Indiana, 2010-2019

abstract: Escherichia coli (E. coli) is the most common Gram-negative pathogen isolated in human infections. Antimicrobial resistant (AMR) E. coli originating from dogs may directly or indirectly cause disease in humans. The objective of this study was to calculate the proportion of antimicrobial susceptible E. coli isolated from canine specimens submitted to the Indiana Animal Disease Diagnostic Laboratory and to identify temporal patterns of susceptibility among these isolates. Susceptibility data of 2,738 E. coli isolates from dogs from 2010 through 2019 were used in this study. Proportions of isolates susceptible to the various antimicrobials were calculated using SAS statistical software and the Cochran-Armitage trend test was used to investigate the temporal trends in susceptibility. A multivariable binary logistic regression model was built to investigate the association between host factors and AMR. Overall, 553/2,738 (20.2%) of the isolates were susceptible to 17 of the 27 antimicrobials examined. Of the 2,638 isolates examined for amikacin susceptibility, 2,706 (97.5%) were susceptible, 2,657/2,673 (99.4%) isolates were susceptible to imipenem, and 2,099/2,670 (78.6%) were susceptible to marbofloxacin. A significant decreasing trend in susceptibility was observed for amoxicillin-clavulanic acid (P<0.0001), ampicillin (P<0.0001), Cefazolin (P<0.0001), ceftazidime (P=0.0067), chloramphenicol (P<0.0001), and orbifloxacin (P=0.008). The overall percentage of AMR isolates (isolates not susceptible to at least one antimicrobial) was 61.7% (1,690/2,738) and 29.3 % (801/2,738) of isolates were multidrug resistant. Multivariable regression analyses showed significant associations between AMR and age (P=0.0091), breed (P=0.0008), and sample isolation site/source (P<0.0001). The decreasing trend in the proportion of isolates susceptible to several beta-lactam antimicrobials suggests that resistance of Escherichia coli in dogs to these antimicrobials could be increasing in Indiana. The decreasing trend in susceptibility to these drugs could be due to selection pressure from antimicrobial use.


title: Rapid, High-Throughput, Cost Effective Whole Genome Sequencing of SARS-CoV-2 Using a Condensed One Hour Library Preparation of the Illumina DNA Prep Kit

abstract: The ongoing COVID-19 pandemic necessitates cost-effective, high-throughput, and timely genomic sequencing of SARS-CoV-2 viruses for outbreak investigations, identifying variants of concern (VoC), characterizing vaccine breakthrough infections, and public health surveillance. Additionally, the enormous demand of genomic sequencing on supply chains and the resulting shortages of laboratory supplies necessitate the use of low-reagent and low-consumable methods. Here, we report an optimized library preparation method where the same protocol can be used in a STAT scenario, from sample to sequencer in as little as eight hours, and a high-throughput scenario, where one technologist can perform 576 library preparations over the course of one 8-hour shift. This new method uses Freed et al.s 1200 bp primer sets (Biol Methods Protoc 5:bpaa014, 2020, https://doi.org/10.1093/biomethods/bpaa014) and a modified and truncated Illumina DNA Prep workflow (Illumina, CA, USA). Compared to the original, application of this new method in hundreds of clinical specimens demonstrated equivalent results to the full-length DNA Prep workflow at 45% the cost, 15% of consumables required (such as pipet tips), 25% of manual hands-on time, and 15% of on-instrument time if performing on a liquid handler, with no compromise in sequence quality. Results suggest that this new method is a rapid, simple, cost-effective, and high-quality SARS-CoV-2 whole genome sequencing protocol.

category: pathology