title: Characteristics of Patients Referred to a Cardiovascular Disease Clinic for Post-Acute Sequelae of SARS-CoV-2 Infection

abstract: There is limited literature on the cardiovascular manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC). We aimed to describe the characteristics, diagnostic evaluations, and cardiac diagnoses in patients referred to a cardiovascular disease clinic designed for patients with PASC from May 2020 to September 2021. Of 126 patients, average age was 46 years (range 19-81 years), 43 (34%) were male. Patients presented on average five months after COVID-19 diagnosis. 30 (24%) patients were hospitalized for acute COVID-19. Severity of acute COVID-19 was mild in 37%, moderate in 41%, severe in 11%, and critical in 9%. Patients were also followed for PASC by pulmonology (53%), neurology (33%), otolaryngology (11%), and rheumatology (7%). Forty-three patients (34%) did not have significant comorbidities. The most common symptoms were dyspnea (52%), chest pain/pressure (48%), palpitations (44%), and fatigue (42%), commonly associated with exertion or exercise intolerance. The following cardiovascular diagnoses were identified: nonischemic cardiomyopathy (5%); new ischemia (3%); coronary vasospasm (2%); new atrial fibrillation (2%), new supraventricular tachycardia (2%); myocardial involvement (15%) by cardiac MRI, characterized by late gadolinium enhancement (LGE; 60%) or inflammation (48%). The remaining 97 patients (77%) exhibited common symptoms of fatigue, dyspnea on exertion, tachycardia, or chest pain, which we termed "cardiovascular PASC syndrome." Three of these people met criteria for postural orthostatic tachycardia syndrome. Lower severity of acute COVID-19 was a significant predictor of cardiovascular PASC syndrome. In this cohort of patients referred to cardiology for PASC, 23% had a new diagnosis, but most displayed a pattern of symptoms associated with exercise intolerance.

category: cardiovascular medicine


title: Assessment of validity and reliability of the Tuberculosis Related Stigma Scale in Colombian patients

abstract:
ObjectiveTo know the dimensionality and internal consistency of the Tuberculosis-Related Stigma Scale in patients living with tuberculosis in Santa Marta, Colombia. Method: One hundred and twenty-two patients between the ages of 18 and 75 participated (M=40.3, SD=14.9), 63.9% were men, 44.3% were single, 69.7% had low income, 80.3% had pulmonary tuberculosis, and 13.1% had co-infection with HIV. The Tuberculosis-Related Stigma Scale was applied; it is composed of two subscales: perceived and internalized stigma. The internal structure was explored by confirmatory factor analysis (EFA). Internal consistency was measured with Cronbachs alpha and McDonalds omega. Besides, the differential functioning of the scales according to gender was explored with Kendalls tau-b coefficient.

ResultsCFA did not show excellent goodness-of-fit indicators for the perceived stigma scale (Satorra-Bentlers chi-square of 184.48, degree of freedom of 44, p=0.001, RMSEA of 0.16, 95%CI 0.14 - 0.19, CFI of 0.77, TLI of 0.72, and SRMR of 0.08) and internalized (Satorra-Bentlers chi-square of 189.14, degree of freedom of 54, p=0.001; RMSEA of 0.14, 95%CI 0.12 - 0.17, CFI of 0.82, TLI of 0.78, and SRMR of 0.07). The alpha and omega coefficients were 0.89 and 0.91 for both scales, respectively. Non-gender differential functioning was observed; Kendalls tau-b were between 0.00 and 0.15.

ConclusionsThe Tuberculosis-Related Stigma Scale has an excellent internal consistency but poor goodness-of-fit indicators of unidimensionality. Evaluating the scales psychometric performance is recommenced in future research.

category: public and global health


title: Risk assessment of banknotes as a fomite of SARS-CoV-2 in cash payment transactions

abstract:
BackgroundThe COVID 19 pandemic has triggered concerns and assumptions globally about transmission of the SARS-CoV-2 virus via cash transactions.

ObjectivesAssess the risk of contracting COVID-19 through exposure to SARS-CoV-2 via cash acting as a fomite in payment transactions.

MethodsA quantitative microbial risk assessment was conducted for a worst-case scenario assuming an infectious person at the onset of symptoms, when virion concentrations in coughed droplets are at their highest. This person then contaminates a banknote by coughing on it and immediately hands it over to another person, who might then be infected by transferring the virions with a finger from the contaminated banknote to a facial mucous membrane. The scenario considered transfer efficiency of virions on the banknote to fingertips when droplets were still wet and after having dried up and subsequently being touched by finger printing or rubbing the object.

ResultsAccounting for the likelihood of the worst-case scenario to occur by considering 1) a local prevalence of 100 COVID-19 cases/100,000 persons, 2) a maximum of about 1/5th of infected persons transmit high virus loads and 3) the numbers of cash transactions/person/day, the risk of contracting COVID-19 via person-to-person cash transactions was estimated to be much lower than once per 39,000 days (107 years) for a single person. In the general populace, there will be a maximum of 2.6 expected cases/100,000 persons/day. The risk for a cashier at an average point of sale was estimated to be much less than once per 430 working days (21 months).

DiscussionThe worst-case scenario is a rare event, therefore, for a single person, the risk of contracting COVID-19 via person-to-person cash transactions is very low. At a point of sale, the risk to the cashier proportionally increases but it is still low.


title: Worldwide routine immunisation coverage regressed during the first year of the COVID-19 pandemic

abstract: We modelled historical, country-specific routine immunisation trends using publicly available vaccination coverage data for diphtheria, tetanus and pertussis-containing vaccine first-dose (DTP1) and third-dose (DTP3) from 2000 to 2019. We evaluate changes in coverage in 2020 by comparing model predictions to WUENIC-reported coverage. We report a 2.9% (95%CI: [2.2%; 3.6%]) global decline in DTP3 coverage, and important increases in missed immunisations in some countries with middle-income countries, and the Americas, being most affected.


title: Post-traumatic Stress Risk among COVID-19 Survivors in Colombia

abstract: The studys objective was to establish the prevalence and variables associated with post-traumatic stress disorder risk (PTSD-R) in a sample of COVID-19 survivors in Santa Marta, Colombia. A cross-sectional study was designed with a non-probabilistic sample of adult COVID-19 survivors. Participants were demographically characterized and completed scales for depression risk, insomnia risk, and PTSD-R. Three hundred and thirty COVID-19 survivors between 18 and 89 years participated; 61.52% were women. The frequency of depression risk was 49.70%; insomnia risk, 60.61%; and PTSD-R, 13.33%. Depression risk (OR = 41.43, 95% CI 5.54 - 311.63), insomnia risk (OR = 5.25, 95% CI 1.77 - 18.71), low income (OR = 3.46, 95% CI 1.38 - 8.67) and being married or free union (OR = 2.65, 95% CI 1.13 - 6.22) were associated with PTSD-R. In conclusion, two out of every fifteen COVID-19 survivors are in PTSD-R. Depression and insomnia risk are strongly associated with PTSD-R in COVID-19 survivors.


title: Healthcare worker risk of COVID-19: A 20-month analysis of protective measures from vaccination and beyond

abstract:
BackgroundAs the COVID-19 pandemic continues and new variants such as Omicron emerge, we aimed to re-evaluate vaccine effectiveness as well as impacts of rigorously implemented infection control, public health and occupational health measures in protecting healthcare workers (HCWs).

MethodsFollowing a cohort of 21,242 HCWs in Vancouver, British Columbia, Canada, for 20 months since the pandemic started, we used Cox regression and test-negative-design to examine differences in SARS-COV-2 infection rates compared to community counterparts, and within the HCW workforce, assessing the role of occupation, testing accessibility, vaccination rates, and vaccine effectiveness over time.

ResultsNurses, allied health professionals and medical staff in this jurisdiction had a significantly lower rate of infection compared to their age-group community counterparts, at 47.4, 41.8, and 55.3% reduction respectively; controlling for vaccine-attributable reductions, the protective impact was still substantial, at 33.4, 28.0, and 36.5% respectively. Licensed practical nurses and care aides had the highest risk of infection among HCWs, more than double that of medical staff. However, even considering differences in vaccination rates, no increase in SARS-CoV-2 infection was found compared to community rates, with combined protective measures beyond vaccination associated with a 17.7% reduced SARS-COV-2 rate in the VCH workforce overall. There was also no evidence of waning immunity within at least 200 days after second dose.

ConclusionRigorously implemented occupational health, public health and infection control measures results in a well-protected healthcare workforce with infection rates at or below rates in community counterparts. Greater accessibility of vaccination worldwide is essential; however, as implementing measures to protect this workforce globally also requires considerable health system strengthening in many jurisdictions, we caution against overly focusing on vaccination to the exclusion of other crucial elements for wider protection of HCWs, especially in facing ongoing mutations which may escape current vaccines.

Health and care workers are the foundation of health systems and the driving force to achieving universal health coverage and global health security. ...However, too many of them have become infected, ill or died as a result of COVID-19.... These deaths are a tragic loss. They are also an irreplaceable gap in the worlds pandemic response...the world cannot be complacent.

World Health Organization Steering Committee for the International Year of Health and Care Workers in 2021 (1)


title: Non-muscle Invasive Bladder Cancer Molecular Subtypes Predict Differential Response to Intravesical Bacillus Calmette-Guerin

abstract:
The recommended treatment for patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guerin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. In case of progression to advanced disease, patients must undergo a radical cystectomy with significant morbidity and have a poor clinical outcome. Identifying tumors least likely to respond to BCG can translate into alternative treatments, such as early radical cystectomy or novel targeted or immunotherapies. Here we present molecular profiling of 132 BCG-naive, HR-NMIBC patients, and 44 post-BCG recurrences (34 matched), which uncovered three distinct BCG Response Subtypes (BRS1-3). Patients with BRS3 tumors have reduced recurrence and progression-free survival compared to BRS1-2. BRS3 tumors expressed high EMT-basal markers and had an immunosuppresive profile, which was confirmed with spatial proteomics. Tumors which recurred post-BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive HR-NMIBC patients and the molecular subtypes outperformed guideline recommended risk stratification based on clinicopathological variables. For clinical application, we validated that a commercially approved assay was able to accurately predict BRS3 tumors (AUROC 0.86). Our findings provide a potential clinical tool for improved identification of HR-NMIBC patients at the highest risk of progression, which can be used to select patients for early radical cystectomy or novel subtype-directed therapies.

One Sentence SummaryMolecular subtypes are predictive of response to intravesical Bacillus Calmette-Guerin immunotherapy in non-muscle invasive bladder cancer.

category: urology


title: In vivo NMDA receptor function in people with NMDA receptor antibody encephalitis

abstract:
In N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis, NMDAR-autoantibodies are hypothesised to cause prominent neuropsychiatric symptoms by internalizing NMDARs. However, supporting evidence comes chiefly from in vitro and rodent data with scant direct evidence from affected humans. Here, we used in vivo positron emission tomography (PET) with [18F]GE-179 to show a mean 30% reduction of the density of open, activated NMDARs in grey matter of persistently NMDAR-autoantibody seropositive patients following NMDAR-antibody encephalitis compared to healthy controls. The reduction was most prominent in the anterior temporal and superior parietal cortices. These patients had normal structural MRIs and mild residual symptoms. In contrast, one symptom-free patient who recovered from NMDAR-antibody encephalitis and was not NMDAR-autoantibody seropositive had normal density of active NMDARs. These findings reveal a functional deficit of open, activated NMDARs in humans with NMDAR-autoantibodies. Moreover, we observed a functional NMDAR deficit for up to 8 months following the disease peak, despite only mild residual symptoms, highlighting the considerable compensatory capacity of the human brain.

One Sentence SummaryReductions of activated NMDA receptors detected in vivo in female patients following NMDA-receptor-antibody encephalitis.

category: neurology


title: Serum uric acid and total bilirubin as putative biomarkers of resistance in Prodromal Parkinson's disease: Longitudinal data from the PPMI study.

abstract:
BackgroundThe role of blood uric acid and more recently bilirubin as biomarkers in symptomatic motor PD has been increasingly established in the literature.

ObjectiveOur present study assessed the role of serum uric acid and total bilirubin as putative biomarkers in a prodromal PD cohort followed longitudinally.

MethodsLongitudinal 5-year serum uric acid and total bilirubin measurement data of 65 Prodromal PD patients (including REM Sleep Behavior disorder (RBD), N=39 and Hyposmia, N=26) with an abnormal DATSCAN imaging were downloaded from the Parkinsons Progression Markers Initiative (PPMI) database. This cohort was compared with 423 de novo sporadic PD patients and 196 healthy controls enrolled in the same study.

ResultsAfter adjusting for age, sex and Body Mass Index (BMI), baseline and 5-year longitudinal serum uric acid levels were higher in the Prodromal cohort and RBD subgroup as compared to the motor PD cohort. This was also true for longitudinal measurements in the Hyposmic subgroup. In contrast, baseline and longitudinal serum total bilirubin did not differ between each prodromal group and the PD cohort.

ConclusionsOur results are indicative of a role of serum uric acid (but probably not of total bilirubin) as a marker of neuroprotection, in a certain subgroup of premotor patients exhibiting exclusively non motor features (hyposmia or RBD). It is possible that an inherent antioxidant resistance of a subset of RBD or hyposmia patients with high serum uric acid level delayed or precluded the emergence of a motor PD phenotype as opposed to the PD cohort.


title: Asymptomatic carriers of the p.A53T SNCA mutation: data from the PPMI study

abstract:
IntroductionThere has been great interest in the prodromal phase of Parkinsons disease (PD), especially in subjects who are asymptomatic carriers of genetic mutations leading to PD because of the high risk to convert to PD. The objective of the present study was to assess non motor characteristics of asymptomatic p.A53T mutation carriers (A53T-AC) compared with healthy controls (HC).

MethodsWe compared 12 A53T-AC with 36 matched HC enrolled into in the Parkinsons Progression Markers Initiative (PPMI) study. Baseline data extracted from the PPMI database, contained demographics and non-motor symptoms (e.g. the Montreal Cognitive Assessment (MOCA) for cognition, the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction, MDS-UPDRS I etc.)

ResultsThe mean UPSIT score was lower in A53T-AC vs HC (p =0.000). MoCA test showed a trend towards lower scores in A53T AC. We found a significant positive correlation between UPSIT score and MOCA in A53T-AC (rs = 0,68, p=0,021) but not in HC. Total scores for MDS-UPDRS I did not differ between the groups but the subscore of anxiety was more prevalent in A53T-AC.

ConclusionThe more affected olfaction in A53T-AC may indicate that olfactory function is affected quite early in A53T carriers. The strong positive correlation between UPSIT and MOCA in the A53T-AC group may indicate that cognitive dysfunction and olfactory impairment progress alongside, prior to nigrostriatal degeneration. Anxiety was also more prevalent in A53T-AC and may represent an additional prodromal feature in this group of subjects.


title: Detailed patient-individual reporting of lymph node involvement in oropharyngeal squamous cell carcinoma with an online interface

abstract:
Purpose/ObjectiveWhereas the prevalence of lymph node level (LNL) involvement in head & neck squamous cell carcinomas (HNSCC) has been reported, the details of lymphatic progression patterns are insufficiently quantified. In this study, we investigate how the risk of metastases in each LNL depends on the involvement of upstream LNLs, T-category, HPV status and other risk factors.

Materials/MethodsWe retrospectively analyzed patients with newly diagnosed oropharyngeal HNSCC treated at a single institution, resulting in a dataset of 287 patients. For all patients, involvement of LNLs I-VII was recorded individually based on available diagnostic modalities (PET, MR, CT, FNA) together with clinicpathological factors. To analyze the dataset, a web-based graphical user interface (GUI) was developed, which allows querying the number of patients with a certain combination of co-involved LNLs and tumor characteristics.

ResultsThe full dataset and GUI is part of the publication. Selected findings are: Ipsilateral level IV was involved in 27% of patients with level II and III involvement, but only in 2% of patients with level II but not III involvement. Prevalence of involvement of ipsilateral levels II, III, IV, V was 79%, 34%, 7%, 3% for early T-category patients (T1/T2) and 85%, 50%, 17%, 9% for late T-category (T3/T4), quantifying increasing involvement with T-category. Contralateral levels II, III, IV were involved in 41%, 19%, 4% and 12%, 3%, 2% for tumors for tumors with and without midline extension, respectively. T-stage dependence of LNL involvement was more pronounced in HPV negative than positive tumors, but overall involvement was similar. Ipsilateral level VII was involved in 14% and 6% of patients with primary tumors in the tonsil and the base of tongue, respectively.

ConclusionsDetailed quantification of LNL involvement in HNSCC depending on involvement of upstream LNLs and clinicopathological factors may allow for further personalization of CTV-N definition in the future.

category: oncology


title: Facial basal cell carcinoma: a clinicopathological analysis of incomplete excision

abstract: Basal cell carcinoma (BCC) is the most common malignancy in humans. Incomplete excision following conventional surgical excision requires careful consideration given the potential for disease recurrence. We performed a retrospective study analyzing facial BCC treated by conventional surgical excision to investigate factors influencing the likelihood of tumour clearance. In total, 456 cases of facial BCC were reviewed to collect a dataset of 50 tumours with involved margins and these compared to 50 completely excised tumours from the same cohort. Statistical comparison between incomplete and complete excision cases was performed using several metrics including tumour location, histology, grade, surgeon experience and method of wound reconstruction. Interestingly, our results demonstrated that only tumour location and histological type had a statistically significant impact on the completeness of resection. Infiltrative, morphoeic and mixed tumours had a higher chance of incomplete excision, as did tumours located on the inner canthus and ala nasi. In addition, the overall incomplete excision rate was 10.96% in line with previous studies. Our results help inform surgical practice and support consideration of extending the recommended macroscopic surgical margin for higher risk tumours. More research is needed to further categorize facial BCC to optimize surgical management.

category: otolaryngology


title: Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis

abstract: Trans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-analysis and identified 124 loci (P < 5 x 10-8), of which 34 were novel. Candidate genes at the novel loci suggested essential roles of the immune system (e.g., TNIP2 and TNFRSF11A) and joint tissues (e.g., WISP1) in RA etiology. Trans-ancestry fine mapping identified putatively causal variants with biological insights (e.g., LEF1). Moreover, PRS based on trans-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between European and East Asian populations. Our study provides multiple insights into the etiology of RA and improves genetic predictability of RA.

category: genetic and genomic medicine


title: Fusion of Imaging and Non-Imaging Data for Disease Trajectory Prediction for COVID-19 Patients

abstract:
ABSTRCATO_ST_ABSPurposeC_ST_ABSThis study investigates whether graph-based fusion of imaging data with non-imaging EHR data can improve the prediction of disease trajectory for COVID-19 patients, beyond the prediction performance of only imaging or non-imaging EHR data.

Materials and MethodsWe present a novel graph-based framework for fine-grained clinical outcome prediction (discharge, ICU admission, or death) that fuses imaging and non-imaging information using a similarity-based graph structure. Node features are represented by image embedding and edges are encoded with clinical or demographic similarity.

ResultsOur experiments on data collected from Emory Healthcare network indicate that our fusion modeling scheme performs consistently better than predictive models using only imaging or non-imaging features, with f1-scores of 0.73, 0.77, and 0.66 for discharge from hospital, mortality, and ICU admission, respectively. External validation was performed on data collected from Mayo Clinic. Our scheme highlights known biases in the model prediction such as bias against patients with alcohol abuse history and bias based on insurance status.

ConclusionThe study signifies the importance of fusion of multiple data modalities for accurate prediction of clinical trajectory. Proposed graph structure can model relationships between patients based on non-imaging EHR data and graph convolutional networks can fuse this relationship information with imaging data to effectively predict future disease trajectory more effectively than models employing only imaging or non-imaging data. Forecasting clinical events can enable intelligent resource allocation in hospitals. Our graph-based fusion modeling frameworks can be easily extended to other prediction tasks to efficiently combine imaging data with non-imaging clinical data.

category: health informatics


title: Deep Learning for Alzheimer's Disease Drug Repurposing using Knowledge Graph and Multi-level Evidence

abstract: Developing drugs for treating Alzheimers disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies. To address the challenge in AD drug development, we developed a multi-task machine learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi-level evidence on drug efficacy, to identify repurposable drugs and their combination candidates. We developed and computationally validated a heterogeneous graph representation model with transfer learning from universal biomedical databases and with joint optimization with AD risk genes. Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population-based treatment effect, and Phase II/III clinical trials. We experimentally validated the top-ranked candidates in neuronal cells, identifying drug combinations with efficacy in reducing oxidative stress and safety in maintaining neuronal viability and morphology. Our neuronal response experiments confirmed several biologically efficacious drug combinations (e.g., Galantamine + Mifepristone). This pipeline showed that harmonizing heterogeneous and complementary data/knowledge, including human interactome, transcriptome patterns, experimental efficacy, and real-world patient data shed light on the drug development of complex diseases.


title: Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1

abstract: Broadly neutralizing antibodies (bNAbs) are promising targets for vaccination and therapy against HIV. Passive infusions of bNAbs have shown promise in clinical trials as a potential alternative for anti-retroviral therapy. A key challenge for the potential clinical application of bnAbs is the suppression of viral escape, which is more effectively achieved with a combination of bNAbs. However, identifying an optimal bNAb cocktail is combinatorially complex. Here, we propose a computational approach to predict the efficacy of a bNAb therapy trial based on the population genetics of HIV escape, which we parametrize using high-throughput HIV sequence data from a cohort of untreated bNAb-naive patients. By quantifying the mutational target size and the fitness cost of HIV-1 escape from bNAbs, we reliably predict the distribution of rebound times in three clinical trials. Importantly, we show that early rebounds are dominated by the pre-treatment standing variation of HIV-1 populations, rather than spontaneous mutations during treatment. Lastly, we show that a cocktail of three bNAbs is necessary to suppress the chances of viral escape below 1%, and we predict the optimal composition of such a bNAb cocktail. Our results offer a rational design for bNAb therapy against HIV-1, and more generally show how genetic data could be used to predict treatment outcomes and design new approaches to pathogenic control.

category: hiv aids


title: A randomized clinical trial to stimulate the cholinergic anti-inflammatory pathway in patients with moderate COVID-19-pneumonia using a slow-paced breathing technique

abstract:
ImportanceVagus nerve stimulation via slow-paced breathing could serve as an adjuvant therapeutic approach to reduce excessive inflammation in coronavirus disease 2019 (COVID-19) pneumonia.

ObjectiveDoes a slow-paced breathing technique increasing vagal activity reduce Interleukin-6 (IL-6) in patients hospitalized with moderate COVID-19 pneumonia compared to standard care?

DesignSingle-center randomized controlled clinical trial with enrolment from February 23rd 2021 through June 17th 2021 and follow-up until July 22nd 2021.

SettingWard for infectious diseases and temporary COVID-19 ward, Ulm University Hospital, Germany

ParticipantsConsecutive sample of patients hospitalized with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (primary diagnosis). Of 131 patients screened, 48 patients were randomized and 46 patients analyzed (N=23 per group).

InterventionsSlow-paced 20-minute breathing exercise three times a day with six breaths per minute (inhalation-to-exhalation ratio 4:6).

Main outcomes and measuresDifferences between intervention and control group in IL-6 calculated using multilevel mixed-effect linear regression models with random slope including the covariates relevant comorbidities, COVID-19 medication, and age.

ResultsMean age 57 years{+/-}13 years, N= 28 (60%) male, N=30 (65%) with relevant comorbidities.

The model including group by time interaction revealed a significantly lower trajectory of IL-6 in the intervention group compared to the control group (effect size Cohens f2=0.11, LR-test p=.040) in the intention-to-treat sample, confirmed by treatment-per-protocol analysis (f2=0.15, LR-test p=.022). Exploratory analysis using the median split of practice time to predict IL-6 of the next morning indicated a dose-response relationship with beneficial effects of practice time above 45 minutes a day.

Three patients in each group were admitted to ICU, one died. Oxygen saturation increased during slow-paced breathing (from 95.1%{+/-}2.1% to 95.4%{+/-}1.6%, p=0.006).

Conclusion and relevancePatients practicing slow-paced breathing had significantly lower IL-6 values than controls with a small to medium effect size and without relevant side effects. Further trials should evaluate clinical outcomes as well as an earlier start of the intervention, i.e., at symptom onset. This would offer an access to a therapy option not only for high-income, but also for low- and middle-income countries.

Trial registrationGerman register of clinical trials (ID: DRKS00023971) https://www.drks.de, Universal Trial Number (UTN) U1111-1263-8658;

category: infectious diseases


title: A multiplex protein panel assay determines disease severity and is prognostic about outcome in COVID-19 patients

abstract: Global healthcare systems continue to be challenged by the COVID-19 pandemic, and there is a need for clinical assays that can both help to optimize resource allocation and accelerate the development and evaluation of new therapies. Here, we present a multiplex proteomic panel assay for the assessment of disease severity and outcome prediction in COVID-19. The assay quantifies 50 peptides derived from 30 COVID-19 severity markers in a single measurement using analytical flow rate liquid chromatography and multiple reaction monitoring (LC-MRM), on equipment that is broadly available in routine and regulated analytical laboratories. We demonstrate accurate classification of COVID-19 severity in patients from two cohorts. Furthermore, the assay outperforms established risk assessments such as SOFA and APACHE II in predicting survival in a longitudinal COVID-19 cohort. The prognostic value implies its use for support of clinical decisions in settings with overstrained healthcare resources e.g. to optimally allocate resources to severely ill individuals with high chance of survival. It can furthermore be helpful for monitoring of novel therapies in clinical trials.


title: Time trends in social contacts of individuals according to comorbidity and vaccination status, before and during the COVID-19 pandemic: repeated cross-sectional population-based surveys

abstract:
BackgroundAs we are confronted with more transmissible/severe variants with immune escape and the waning of vaccine efficacy, it is particularly relevant to understand how the social contacts of individuals at greater risk of COVID-19 complications evolved over time. We described time trends in social contacts of individuals according to comorbidity and vaccination status before and during the first three waves of the COVID-19 pandemic in Quebec, Canada.

MethodsWe used data from CONNECT, a repeated cross-sectional population-based survey of social contacts conducted before (2018/2019) and during the pandemic (April 2020 to July 2021). We recruited non-institutionalized adults from Quebec, Canada, by random digit dialling. We used a self-administered web-based questionnaire to measure the number of social contacts of participants (two-way conversation at a distance [≤]2 meters or a physical contact, irrespective of masking). We compared the mean number of contacts/day according to the comorbidity status of participants (pre-existing medical conditions with symptoms/medication in the past 12 months) and 1-dose vaccination status during the third wave. All analyses were performed using weighted generalized linear models with a Poisson distribution and robust variance.

ResultsA total of 1441 and 5185 participants with and without comorbidities, respectively, were included in the analyses. Contacts significantly decreased from a mean of 6.1 (95%CI 4.9-7.3) before the pandemic to 3.2 (95%CI 2.5-3.9) during the first wave among individuals with comorbidities, and from 8.1 (95%CI 7.3-9.0) to 2.7 (95%CI 2.2-3.2) among individuals without comorbidities. Individuals with comorbidities maintained fewer contacts than those without comorbidities in the second wave, with a significant difference before the Christmas 2020/2021 holidays (2.9 (95%CI 2.5-3.2) v 3.9 (95%CI 3.5-4.3); P<0.001). During the third wave, contacts were similar for individuals with (4.1, 95%CI 3.4- 4.7) and without comorbidities (4.5, 95%CI 4.1-4.9; P=0.27). This could be partly explained by individuals with comorbidities vaccinated with their first dose who increased their contacts to the level of those without comorbidities.

ConclusionsIt will be important to closely monitor COVID-19-related outcomes and social contacts by comorbidity and vaccination status to inform targeted or population-based interventions (e.g., booster doses of the vaccine).


title: Prevalence of SARS-CoV-2 infection among COVID-19 RT-PCR laboratory workers in Bangladesh

abstract:
BackgroundHealth care workers (HCWs) at the frontline are confronting a substantial risk of infection during the coronavirus disease 2019 (COVID-19) pandemic. This emerging virus created specific hazards to researchers and laboratory staff in a clinical setting, underlined by rapid and extensive worldwide transmission. This study aimed to investigate the prevalence of SARS-CoV-2 infection among COVID-19 RT-PCR laboratory health workers in Bangladesh.

Materials & MethodsThis retrospective study was conducted between October 2 to December 2, 2020. A total of 508 participants, including doctors, scientific officers, medical technologists, and cleaners working in several COVID-19 RT-PCR laboratories, were included in this study. Data were collected from each participant using a semi-structured questionnaire prepared in the format of an anonymous Google form. All participants provided informed consent. The Ethical clearance was obtained from the Institutional Ethics Review Committee of Shaheed Suhrawardy Medical College, Dhaka, Bangladesh. All statistical analyses were performed using SPSS (Statistical Package for the Social Sciences) version 25.0 software (SPSS, Inc).

ResultsOut of the 508 participants, 295 tested positive for SARS CoV-2 RT-PCR. Among the positive cases, 202 were men, 93 were women, with the median age of 30 years. The most positive cases were medical technologists (53.22%) followed by doctors (28.8%). Out of the 271 symptomatic positive cases, the most typical symptoms were fever (78.5%), fatigue (70%), loss of smell and taste (65%), cough (64%), and others. Hypertension, obesity, and diabetes were found in 8.8%, 8.8%, and 7.1% positive cases. A + blood group was present in 37% of the positive cases, followed by the B+ blood group (27%) and O+ blood group (25%). Inadequate supply of personal protection equipment (PPE), absence of negative pressure ventilation, laboratory contamination, and no training on molecular test methods were found in 13.8%, 67.8%, 44.7%, and 40.6% of positive cases, respectively.

ConclusionEvaluating the infection status of laboratory health workers is crucial for drawing attention from the public, providing practical suggestions for government agencies, and increasing protective measures for laboratory health workers.


title: Metagenomic and single-cell RNA-seq survey of the H. pylori-infected stomach in asymptomatic individuals

abstract:
ObjectiveHelicobacter pylori colonization of the gastric niche can persist for years in asymptomatic individuals. Although latent H. pylori infection can progress to cancer, a detailed survey of the microbiome and immune composition in the chronically infected stomach is still lacking.

DesignWe collected human gastric tissues and performed metagenomic sequencing, single-cell RNA sequencing (scRNA-seq), flow cytometry and fluorescent microscopy to deeply characterize the host-microbiota environment in H. pylori-infected (HPI) stomachs.

ResultsHPI asymptomatic individuals showed dramatic changes in the composition of gastric microbiome and immune cells compared to non-infected individuals. With metagenomic data, we also demonstrated antibiotic resistant genes, enzymes and pathway alterations related to metabolism and immune response. scRNA-seq and flow cytometry data revealed that in contrast to murine stomachs, ILC2 are virtually absent in the human gastric mucosa, whereas ILC3 are the dominant population in asymptomatic HPI individuals. Specifically, NKp44+ ILC3s were highly increased in the gastric mucosa of asymptomatic HPI individuals, and their proportions correlated with the abundance of selected microbial taxa found to be enriched in the infected mucosa. In addition, CD11c+ myeloid cells, activated CD4 T cells and B cells were expanded in HPI individuals. In HPI individuals, B cells acquired an activated phenotype and progressed into a highly proliferating germinal center stage and plasmablast maturation, which correlated with the presence of tertiary lymphoid structures within the gastric lamina propria.

ConclusionOur study provides a comprehensive atlas of the gastric mucosa-associated microbiome and immune cell landscape when comparing asymptomatic HPI and uninfected individuals.

SIGNIFICANCE OF THE STUDYWhat is already known on this subject? O_LIPrevious studies on the gastric microbiome were performed via 16S rRNA gene sequencing.
C_LIO_LIAcute Helicobacter spp. infection in murine models and symptomatic H. pylori-driven pathology in humans result in remodeling of the stomach immune cell compartment.
C_LIO_LIILC2 is the dominant ILC population in the murine stomach.
C_LI

What are the new findings? O_LIWe described the effect of chronic asymptomatic H. pylori infection on the gastric microbiome via whole-genome sequencing.
C_LIO_LISingle cell census of the gastric mucosa reveals ILC3 to be the dominant ILC population in the human stomach, whereas ILC2 were virtually absent.
C_LIO_LIscRNA-seq reveals the gastric immune cell programs in asymptomatic H. pylori-infected individuals, which is characterized by the formation of tertiary lymphoid structures.
C_LI

How might it impact on clinical practice in the foreseeable future? O_LIWhole genome sequencing of uninfected and H. pylori-infected gastric mucosa bolsters collective knowledge of stomach physiology with respect to the gastric microbiome and microbiota function.
C_LIO_LIWe present a comprehensive immune cellular landscape of the human stomach, which will be a valuable resource to interrogate pathology of gastric diseases.
C_LI


title: Estimation of heterogeneous instantaneous reproduction numbers with application to characterize SARS-CoV-2 transmission in Massachusetts counties

abstract:
The reproductive number is an important metric that has been widely used to quantify the infectiousness of communicable diseases. The time-varying instantaneous reproductive number is useful for monitoring the real time dynamics of a disease to inform policy making for disease control. Local estimation of this metric, for instance at a county or city level, allows for more targeted interventions to curb transmission. However, simultaneous estimation of local reproductive numbers must account for potential sources of heterogeneity in these time-varying quantities - a key element of which is human mobility. We develop a statistical method that incorporates human mobility between multiple regions for estimating region-specific instantaneous reproductive numbers. The model also can account for exogenous cases imported from outside of the regions of interest. We propose two approaches to estimate the reproductive numbers, with mobility data used to adjust incidence in the first approach and to inform a formal priori distribution in the second (Bayesian) approach. Through a simulation study, we show that region-specific reproductive numbers can be well estimated if human mobility is reasonably well approximated by available data. We use this approach to estimate the instantaneous reproductive numbers of COVID-19 for 14 counties in Massachusetts using CDC case report data and the human mobility data collected by SafeGraph. We found that, accounting for mobility, our method produces estimates of reproductive numbers that are distinct across counties. In contrast, independent estimation of county-level reproductive numbers tends to produce similar values, as trends in county case-counts for the state are fairly concordant. These approaches can also be used to estimate any heterogeneity in transmission, for instance, age-dependent instantaneous reproductive number estimates. As people are more mobile and interact frequently in ways that permit transmission, it is important to account for this in the estimation of the reproductive number.

Author summaryTo control the spreading of an infectious disease, it is very important to understand the real-time infectiousness of the pathogen that causes the disease. An existing metric called instantaneous reproductive number is often used to quantify the average number of secondary cases generated by individuals who are infectious at a certain time point, assuming no changes to current conditions. In practice, we might be interested in using the metric to describe the infectiousness in multiple regions. However, this is challenging when there are visitors traveling between these regions, since this could lead to a misclassification of where an individual is actually infected and create biased estimates for the instantaneous reproductive numbers. We developed a method that takes account of human mobility to estimate the instantaneous reproductive numbers for multiple regions simultaneously, which could reveal the heterogeneity of the metric. This method aims to provide helpful information on region-specific infectiousness for disease control measures that focus on the region with higher pathogen infectiousness. This approach is also applicable for estimating the reproductive number in the presence of other sources of heterogeneity, including by age.


title: Comparative magnitude and persistence of SARS-CoV-2 vaccination responses on a population level in Germany

abstract:
BackgroundWhile SARS-CoV-2 vaccinations were successful in decreasing COVID-19 caseloads, recent increases in SARS-CoV-2 infections have led to questions about duration and quality of the subsequent immune response. While numerous studies have been published on immune responses triggered by vaccination, these often focused on the initial peak response generated in specific population subgroups (e.g. healthcare workers or immunocompromised individuals) and have often only examined the effects of one or two different immunisation schemes.

Methods and FindingsWe analysed serum samples from participants of a large German seroprevalence study (MuSPAD) who had received all available vaccines and dose schedules (mRNA-1273, BNT162b2, AZD1222, Ad26.CoV2S.2 or a combination of AZD1222 plus either mRNA-1273 or BNT162b2). Antibody titers against various SARS-CoV-2 antigens and ACE2 binding inhibition against SARS-CoV-2 wild-type and the Alpha, Beta, Gamma and Delta variants of concern were analysed using a previously published multiplex immunoassay MULTICOV-AB and an ACE2-RBD competition assay. Among the different vaccines and their dosing regimens, homologous mRNA-based or heterologous prime-boost vaccination produced significantly higher antibody responses than vector-based homologous vaccination. Ad26.CoV2S.2 performance was significantly reduced, even compared to AZD1222, with 91.67% of samples being considered non-responsive forACE2 binding inhibition. mRNA-based vaccination induced a higher ratio of RBD- and S1-targeting antibodies than vector-based vaccination, which resulted in an increased proportion of S2-targeting antibodies. Previously infected individuals had a robust immune response once vaccinated, regardless of which vaccine they received. When examining antibody kinetics post-vaccination after homologous immunisation regimens, both titers and ACE2 binding inhibition peaked approximately 28 days post-vaccination and then decreased as time increased.

ConclusionsAs one of the first and largest population-based studies to examine vaccine responses for all currently available immunisation schemes in Germany, we found that homologous mRNA or heterologous vaccination elicited the highest immune responses. The high percentage of non-responders for Ad26.CoV2.S requires further investigation and suggests that a booster dose with an mRNA-based vaccine may be necessary. The high responses seen in recovered and vaccinated individuals could aid future dose allocation, should shortages arise for certain manufacturers. Given the role of RBD- and S1-specific antibodies in neutralising SARS-CoV-2, their relative over-representation after mRNA vaccination may explain why mRNA vaccines have an increased efficacy compared to vector-based formulations. Further investigation on these differences will be of particular interest for vaccine development and efficacy, especially for the next-generation of vector-based vaccines.


title: Respiratory Syncytial Virus (RSV) RNA in wastewater settled solids reflects RSV clinical positivity rates

abstract:
Wastewater based epidemiology (WBE) uses concentrations of infectious agent targets in wastewater to infer infection trends in the contributing community. To date, WBE has been used to gain insight into infection trends of gastrointestinal diseases, but its application to respiratory diseases has been limited to COVID-19. Here we report Respiratory Syncytial Virus (RSV) genomic RNA can be detected in wastewater settled solids at two publicly owned treatment works (POTWs). We further show that its concentration in settled solids is strongly associated with clinical positivity rates for RSV at sentinel laboratories across the state in 2021, a year with anomalous seasonal trends in RSV disease. Given that RSV infections have similar clinical presentations to COVID-19, can be life threatening for some, and immunoprophylaxis distribution for vulnerable people is based on outbreak identification, WBE represents an important tool to augment current RSV surveillance and public health response efforts.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=60 SRC="FIGDIR/small/21267014v1_ufig1.gif" ALT="Figure 1">
View larger version (13K):
org.highwire.dtl.DTLVardef@18e66a3org.highwire.dtl.DTLVardef@1f48857org.highwire.dtl.DTLVardef@123485borg.highwire.dtl.DTLVardef@1636fc5_HPS_FORMAT_FIGEXP  M_FIG C_FIG SynopsisRespiratory Syncytial Virus RNA concentrations in settled solids from wastewater treatment plants are associated with state-wide RSV clinical positivity rates.


title: Cellular and humoral responses to SARS-CoV-2 vaccination in immunosuppressed patients

abstract:
ObjectiveSARS-CoV-2 vaccinations have demonstrated vaccine immunogenicity in healthy volunteers, however, efficacy in immunosuppressed patients is less well characterised. Subsequently, there is an urgent need to address the impact of immunosuppression on vaccine immunogenicity.

MethodsSerological, T-cell ELISpot, cytokines and immunophenotyping investigations were used to assess vaccine responses (either BNT162b2 mRNA or ChAdOx1 nCoV-19) in double-vaccinated patients receiving immunosuppression for renal transplants or haematological malignancies (n=13). Immunological responses in immunosuppressed patients (VACC-IS) were compared to immunocompetent vaccinated (VACC-IC, n=12), unvaccinated (UNVACC, n=11) and infection-naive unvaccinated (HC, n=3) cohorts. All participants, except HC, had prior COVID-19 infection.

ResultsT-cell responses were identical between VACC-IS and VACC-IC (92%) to spike-peptide (S) stimulation. UNVACC had the highest T-cell non-responders (n=3), whereas VACC-IC and VACC-IS both had one T-cell non-responder. No significant differences in humoral responses were observed between VACC-IC and VACC-IS, with 92% (12/13) of VACC-IS patients demonstrating seropositivity. One VACC-IS failed to seroconvert, however had detectable T-cell responses. All VACC-IC participants were seropositive for anti-spike antibodies. Furthermore, both VACC-IS and VACC-IC participants elicited strong Th1 cytokine response with immunodominance towards S-peptide. Differences in T-cell immunophenotyping were seen between VACC-IS and VACC-IC, with lower CD8+ activation and T-effector memory phenotype observed in VACC-IS.

ConclusionSARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppressive therapy, with responses comparable to vaccinated immunocompetent participants. Lower humoral responses were seen in patients treated with B-cell depleting therapeutics, but with preserved T-cell responses. We suggest further work to correlate both protective immunity and longevity of these responses in both healthy and immunosuppressed patients.

category: allergy and immunology


title: A six-month periodic fasting reduces microalbuminuria and improves metabolic control in patients with type 2 diabetes and diabetic nephropathy: a randomized controlled study

abstract:
AimNovel dietary interventions focused on fasting, have gained scientific and public attention. Periodic fasting has emerged as a dietary modification promoting beneficial effects on metabolic syndrome. This study aimed to assess whether periodic fasting reduces albuminuria in patients with type 2 diabetes and diabetic nephropathy and determine whether a reduction in albuminuria relates to activation of nephropathy-driven pathways.

MethodsForty patients with type 2 diabetes (HbA1c 7.8{+/-}0.2% [62.1{+/-}2.3 mmol/mol]) and increased albumin-to-creatinine ratio (ACR) were randomized to fasting-mimicking diet (FMD) (n=21) or Mediterranean diet (n=19) for six months with three-month follow-up. Primary endpoint was the difference of the change in ACR from baseline to after six months between study groups. Subgroup analysis for patients with micro-versus macroalbuminuria at baseline was performed. Secondary endpoints comprised HOMA-IR, circulating markers of dicarbonyl detoxification (MG-H1, glyoxalase-1 and hydroxyacetone), lipid oxidation (acylcarnitines), DNA-damage/repair, (yH2Ax) and senescence (suPAR). Comparison was done by ANCOVA adjusted for age, sex, weight loss and baseline values of the respective outcome.

ResultsDifference of change in ACR between FMD and control group after six months was 110.3mg/g (95% CI 99.2, 121.5mg/g; P=0.45) in all patients, -30.3mg/g (95% CI -35.7, -24.9mg/g; P[≤]0.05] in patients with microalbuminuria, and 434.0mg/g (95% CI 404.7, 463.4mg/g; P=0.23) in those with macroalbuminuria at baseline. FMD led to change in HOMA-IR of -3,8 (95% CI -5,6, -2.0; P[≤]0.05) and in suPAR of - 156.6pg/ml (95% CI -172.9, -140.4pg/ml; P[≤]0.05) after six months, while no change was observed in markers of dicarbonyl detoxification or DNA-damage/repair. Change in AC profile was related to patient responsiveness to ACR improvement. At follow-up only HOMA-IR reduction (-1.9 [95% CI -3.7, -0.1], P[≤]0.05) was sustained.

ConclusionsWhen accompanied by intensive diabetes care, FMD improves microalbuminuria, HOMA-IR and suPAR levels. Lack of changes in markers of dicarbonyl detoxification and DNA-damage/repair might explain the relapse of albuminuria at follow-up.

Trial registrationGerman Clinical Trials Register (Deutsches Register Klinischer Studien DRKS), DRKS-ID: DRKS00014287

category: endocrinology


title: Prevalence, Comorbidity, and Sociodemographic Correlates of Psychiatric Disorders in the All Of Us Biobank

abstract:
ImportanceAll of Us is a landmark initiative for population-scale research into the etiology of psychiatric disorders and disparities across various sociodemographic categories.

ObjectiveTo estimate the prevalence, comorbidity, and demographic covariates of psychiatric and substance use disorders in the All of Us biobank.

Design, Setting, and ParticipantsWe estimated prevalence, overlap, and demographic correlates for psychiatric disorders derived from electronic health records in the All of Us biobank (release 5; N = 331,380)

ExposuresSocial and demographic covariates.

Main Outcome and MeasuresPsychiatric disorders derived from ICD10CM codes and grouped into phecodes across six broad domains: mood disorders, anxiety disorders, substance use disorders, stress-related disorders, schizophrenia, and personality disorders.

ResultsThe prevalence of various disorders ranges from approximately 15% to less than 1%, with mood and anxiety disorders being the most common, followed by substance use disorders, stress-related disorders, schizophrenia, and personality disorders. There is substantial overlap among disorders, with a large portion of those with a disorder (~57%) having two or more registered diagnoses and tetrachoric correlations ranging from 0.43 - 0.74. The prevalence of disorders across demographic categories demonstrates that non-Hispanic whites, those of low socioeconomic status, women and those assigned female at birth, and sexual minorities are at greatest risk for most disorders.

Conclusions and RelevanceAlthough the rates of disorders in All of Us are lower than rates for disorders in the general population, there is considerable variation, comorbidity, and differences across social groups. Large-scale resources like All of Us will prove to be invaluable for understanding the causes and consequences of psychiatric conditions. As we move towards an era of precision medicine, we must work to ensure it is delivered in an equitable manner.

category: epidemiology


title: Helicobacter pylori infection reduces likelihood of death from advanced cancer: A longitudinal analysis from the Japanese DAIKO prospective cohort study

abstract:
BackgroundParadoxically, patients with advanced stomach cancer who are Helicobacter pylori-positive (HP+) have a higher survival rate than those who are HP-. This finding suggests that HP infection has beneficial effects for cancer treatment. Present study examines whether HP+ individuals have a lower likelihood of death from cancer than those who are HP-.

Methods and findingsProspective cohort data (n = 4,982 subjects enrolled in the DAIKO study between 2008-2010) was used to assess whether anti-HP antibody status as a surrogate for past-present HP infection was associated with cancer incidence. The median age in the primary registry was 53 years-old (range 34-69 years-old). Over the 8-year observation period there were 234 (4.7%) cancer cases in the cohort and 88 (1.8%) all-cause deaths. Urine anti-HP antibody data was available for all but one participant (n = 4,981; 99.97%). The number of HP+ and HP- individuals was 1,826 (37%) and 3,156 (63%), respectively. Anti-HP antibody distribution per birth year revealed that earlier birth year was associated with higher HP+ rates. To remove confounding factors associated with birth year, a birth year-matched cohort (n = 3,376) was generated for subsequent analyses. All-cancer incidence was significantly higher in HP+ individuals than those who were HP- (p=0.00328), whereas there was no significant difference in the cancer death rate between HP+ and HP- individuals (p=0.888). Strikingly, we found that HP+ individuals who developed cancer had a better survival rate than would be expected based on cancer incidence. These results suggest that cancer patients who are HP+ may have a higher likelihood of survival than those who are HP-. Cox regression analysis for prognostic factors revealed that the hazards ratio of HP+ was 1.59-fold (95%CI 1.17-2.26) higher than HP- in all-cancer incidence.

ConclusionsPotential systemic effects of HP+ status may contribute to reduced likelihood of death for patients with cancer.

Data Availability StatementThe data cannot be shared publicly as data sharing is not permitted according to Japanese Government data protection policies. Requests for data analysis may be accepted anonymously and conditionally upon IRB approval from Iwate Medical University and Nagoya University Graduate School of Medicine.

FundingThis study is supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer (No. 17015018); Grants-in-Aid for Innovative Areas (No. 221S0001); and the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant (No. 19K09130 and No. 16H06277 [CoBiA]) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interestsThe authors declare that no competing interests exist.

Author summaryO_ST_ABSWhy was this study done?C_ST_ABS> Although HP infection is a major cause of gastric diseases including cancer, how HP infection affects prolonged survival of advanced gastric cancer patients is unknown.

> Reports of studies carried out in different countries and regions revealed that advanced gastric cancer patients who are HP+ exhibited prolonged post-treatment survival, even though the genetic background of patients, HP strains, and cancer treatment procedures differed.

> Since most advanced gastric cancer patients underwent gastrectomy, the favorable prognosis of HP+ patients after multidisciplinary treatment may be due to putative systematic mechanisms associated with HP infection.

> If putative systemic mechanisms associated with HP infection reduce the likelihood of death due to cancer, the cancer survival rate in the HP+ population should be lower than that for the HP- population.

What did the researchers do and find?> Using data from the DAIKO prospective cohort study in Nagoya, Japan, we analyzed the association between anti-HP antibody status, cumulative cancer incidence and all-cause and cancer-specific deaths.

> The HP+ rate increased as birth year decreased. Thus, matching based on birth year between 1935 and 1975 was performed to correct for confounding factors associated with birth year.

> Despite a significantly higher all-cancer incidence for HP+ individuals compared to those who were HP-, no difference in the all-cause and cancer death rate was observed between HP+ and HP- individuals.

What do these findings mean?> HP+ individuals are less susceptible to death relative to their incidence of cancer.

> Patients with advanced stage cancer who are HP+ may have a better treatment response/tolerance than those who are HP-.

> Additional longitudinal analyses are warranted to evaluate the effect of HP+ status on prolonged survival of patients with advanced-stage cancer.


title: Impact of individual-level characteristics and transmission mitigation behaviors on SARS-CoV-2 infection and seroprevalence in a large Northern California Bay Area cohort

abstract: Comprehensive data on transmission mitigation behaviors and both SARS-CoV-2 infection and serostatus are needed from large, community-based cohorts to identify COVID-19 risk factors and the impact of public health measures. From July 2020-March 2021, approximately 5,500 adults from the East Bay Area, California were followed over three data collection rounds to investigate the association between geographic and demographic characteristics and transmission mitigation behavior with SARS-CoV-2 prevalence. We estimated the populated-adjusted prevalence of antibodies from SARS-CoV-2 infection and COVID-19 vaccination, and self-reported COVID-19 test positivity. Population-adjusted SARS-CoV-2 seroprevalence was low, increasing from 1.03% (95% CI: 0.50-1.96) in Round 1 (July-September 2020), to 1.37% (95% CI: 0.75-2.39) in Round 2 (October-December 2020), to 2.18% (95% CI: 1.48-3.17) in Round 3 (February-March 2021). Population-adjusted seroprevalence of COVID-19 vaccination was 21.64% (95% CI: 19.20-24.34) in Round 3, with Whites having 4.35% (95% CI: 0.35-8.32) higher COVID-19 vaccine seroprevalence than non-Whites. No evidence for an association between transmission mitigation behavior and seroprevalence was observed. Despite >99% of participants reporting wearing masks, non-Whites, lower-income, and lower-educated individuals had the highest SARS-CoV-2 seroprevalence and lowest vaccination seroprevalence. Results demonstrate that more effective policies are needed to address these disparities and inequities.


title: Health inequities in SARS-CoV-2 infection, seroprevalence, and COVID-19 vaccination: Results from the East Bay COVID-19 study


title: The rise and spread of the SARS-CoV-2 AY.122 lineage in Russia

abstract:
BackgroundDelta has outcompeted most preexisting variants of SARS-CoV-2, becoming the globally predominant lineage by mid-2021. Its subsequent evolution has led to emergence of multiple sublineages, many of which are well-mixed between countries.

AimHere, we aim to study the emergence and spread of the Delta lineage in Russia.

MethodsWe use a phylogeographic approach to infer imports of Delta sublineages into Russia, and phylodynamic models to assess the rate of their spread.

ResultsWe show that nearly the entire Delta epidemic in Russia has probably descended from a single import event despite genetic evidence of multiple Delta imports. Indeed, over 90% of Delta samples in Russia are characterized by the nsp2:K81N+ORF7a:P45L pair of mutations which is rare outside Russia, putting them in the AY.122 sublineage. The AY.122 lineage was frequent in Russia among Delta samples from the start, and has not increased in frequency in other countries where it has been observed, suggesting that its high prevalence in Russia has probably resulted from a random founder effect.

ConclusionThe apartness of the genetic composition of the Delta epidemic in Russia makes Russia somewhat unusual, although not exceptional, among other countries.


title: Epidemiology of myocarditis and pericarditis following mRNA vaccines in Ontario, Canada: by vaccine product, schedule and interval

abstract:
ImportanceIncreased rates of myocarditis/pericarditis following COVID-19 mRNA vaccines have been observed. However, little data are available related to product-specific differences, which have important programmatic impacts.

ObjectiveThe objective of this study was to estimate reporting rates of myocarditis/pericarditis following COVID-19 mRNA vaccine by product, age, sex, and dose number, as well inter-dose interval.

DesignWe conducted a population-based cohort study using passive vaccine safety surveillance data. All individuals in Ontario, Canada who received at least one dose of COVID-19 mRNA vaccine between December 14, 2020 and September 4, 2021 were included.

SettingThis study was conducted in Ontario, Canada (population: 14.7 million) using the provincial COVID-19 vaccine registry and provincial adverse events following immunization database.

ParticipantsWe included all individuals with a reported episode of myocarditis/pericarditis following COVID-19 vaccine in the study period. We obtained information on all doses administered in the province to calculate reporting rates.

ExposureReceipt of COVID-19 mRNA vaccine (mRNA-1273 [Moderna Spikevax] or BNT162b2 [Pfizer-BioNTech Comirnaty]).

Main Outcome(s) and Measure(s)Reported rate of myocarditis/pericarditis meeting level 1-3 of the Brighton Collaboration case definitions.

ResultsThere were 19,740,741 doses of mRNA vaccines administered and 297 reports of myocarditis/pericarditis meeting our inclusion criteria. Among these, 69.7% occurred following the second dose of COVID-19 mRNA vaccine and 76.8% occurred in males. The median age of individuals with a reported event was 24 years. The highest reporting rate of myocarditis/pericarditis was observed in males aged 18-24 years following mRNA-1273 as the second dose; the rate in this age group was 5.1 (95% CI 1.9-15.5) times higher than the rate following BNT162b2 as the second dose. Overall reporting rates were higher when the inter-dose interval was shorter (i.e., [≤]30 days) for both vaccine products. Among individuals who received mRNA-1273 for the second dose, rates were higher for those who had a heterologous as opposed to homologous vaccine schedule.

Conclusions and RelevanceOur results suggest that vaccine product, inter-dose interval and vaccine schedule combinations may play a role in the risk of myocarditis/pericarditis, in addition to age and sex. Certain programmatic strategies could reduce the risk of myocarditis/pericarditis following mRNA vaccines.


title: Persistent Symptoms Among Frontline Health Workers Post-acute COVID-19 Infection

abstract:
BackgroundGrowing evidence shows that a significant number of patients with COVID-19 experience prolonged/persistent symptoms, also known as Long COVID. Reports of Long COVID are rising but little is known about prevalence in non-hospitalized patients.

ObjectiveWe sought to identify the persistent symptoms of COVID-19 in frontline workers at Right to Care (RTC) South Africa who have past the acute phase of illness with a view to establishing rehabilitation programs for its employees and the community at large.

MethodsThis was a cross-sectional survey. We analysed data from 207 eligible COVID-19 positive RTC frontline workers who participated in a post-COVID online self-administered survey. The survey was active for two months. Frequencies and median were calculated for categorical and continuous variables, respectively.

ResultsThe survey response rate was 30% (62 out of 207); of the 62 respondents with a median age of 33.5 years (IQR= 30-44 years), 47 (76%) were females. The majority (n=55; 88.7%) self-isolated and 7 (11.3%) were admitted to hospital at time of diagnosis. The most common comorbid condition reported was hypertension particularly among workers aged 45-55 years. Headache, body ache, fatigue, loss of smell, dry cough, fever, and loss of appetite were the most common reported symptoms at time of diagnosis. Persistent symptoms were characterized by fatigue, anxiety, difficulty sleeping, chest pain, muscle pain and brain fog, being the six most reported.

ConclusionThe impact of persistent/Long COVID-19 on the health of frontline workers could have direct impact in health service delivery. Given the rise in cases of COVID-19 in South Africa and the world at large, the prevalence of Long COVID is likely to be substantial and therefore need for rehabilitation programs targeted at each of the persistent (Long) COVID symptoms is critical.


title: New Interval-Specific Phylodynamic Models Improve Inference of the Geographic History of Disease Outbreaks

abstract: Phylodynamic methods reveal the spatial and temporal dynamics of viral geographic spread, and have featured prominently in studies of the COVID-19 pandemic. Virtually all previous studies are based on phylodynamic models that assume--despite direct and compelling evidence to the contrary--that rates of viral geographic dispersal are constant through time. Here, we: (1) extend phylodynamic models to allow both the average and relative rates of viral dispersal to vary independently between pre-specified time intervals; (2) implement methods to infer the number and timing of viral dispersal events between areas; and (3) develop statistics to assess the absolute fit of phylodynamic models to empirical datasets. We first validate our new methods using analyses of simulated data, and then apply them to a SARS-CoV-2 dataset from the early phase of the COVID-19 pandemic. We show that: (1) under simulation, failure to accommodate interval-specific variation in the study data will severely bias parameter estimates; (2) in practice, our interval-specific phylodynamic models can significantly improve the relative and absolute fit to empirical data; and (3) the increased realism of our interval-specific phylodynamic models provides qualitatively different inferences regarding key aspects of the COVID-19 pandemic--revealing significant temporal variation in global viral dispersal rates, viral dispersal routes, and number of viral dispersal events between areas--and alters interpretations regarding the efficacy of intervention measures to mitigate the pandemic.


title: Estimating area-level variation in SARS-CoV-2 infection fatality ratios

abstract:
BackgroundDuring a pandemic, estimates of geographic variability in disease burden are important but limited by the availability and quality of data.

MethodsWe propose a framework for estimating geographic variability in testing effort, total number of infections, and infection fatality ratio (IFR). Because symptomatic people are more likely to seek testing, we use a noncentral hypergeometric model that accounts for differential probability of positive tests. We apply this framework to the United States (U.S.) COVID-19 pandemic to estimate county-level SARS-CoV-2 IFRs from March 1, 2020 to October 31, 2020. Using data on population size, number of observed cases, number of reported deaths in each U.S. county and state, and number of tests in each U.S. state, we develop a series of estimators to identify the number of SARS-CoV-2 infections and IFRs at the county level. We then perform a simulation and compare the estimated values to simulated values to demonstrate the validity of our approach.

FindingsApplying the county-level estimators to the real, unsimulated COVID-19 data spanning March 1, 2020 to October 31, 2020 from across the U.S., we found that IFRs varied from 0 to 0.0273, with an interquartile range of 0.0022 and a median of 0.0018. The estimators for IFRs, number of infections, and number of tests showed high accuracy and precision; for instance, when applied to simulated validation data sets, across counties, Pearson correlation coefficients between estimator means and true values were 0.88, 0.95, and 0.74, respectively.

InterpretationWe propose an estimation framework that can be used to identify area-level variation in IFRs and performs well to estimate county-level IFRs in the U.S. COVID-19 pandemic.


title: Protection and waning of natural and hybrid COVID-19 immunity

abstract:
BACKGROUNDInfection with SARS-CoV-2 provides substantial natural immunity against reinfection. Recent studies have shown strong waning of the immunity provided by the BNT162b2 vaccine. The time course of natural and hybrid immunity is unknown.

METHODSData on confirmed SARS-CoV-2 infections were extracted from the Israeli Ministry of Health database for the period August to September 2021 regarding all persons previously infected or vaccinated. We compared infection rates as a function of time since the last immunity-conferring event using Poisson regression, adjusting for possible confounding factors.

RESULTSConfirmed infection rates increased according to time elapsed since the last immunity-conferring event in all cohorts. For unvaccinated previously infected individuals they increased from 10.5 per 100,000 risk-days for those previously infected 4-6 months ago to 30.2 for those previously infected over a year ago. For individuals receiving a single dose following prior infection they increased from 3.7 per 100,000 person days among those vaccinated in the past two months to 11.6 for those vaccinated over 6 months ago. For vaccinated previously uninfected individuals the rate per 100,000 person days increased from 21.1 for persons vaccinated within the first two months to 88.9 for those vaccinated more than 6 months ago.

CONCLUSIONSProtection from reinfection decreases with time since previous infection, but is, nevertheless, higher than that conferred by vaccination with two doses at a similar time since the last immunity-conferring event. A single vaccine dose after infection helps to restore protection.


title: Urine as a non-invasive alternative to blood for germline and somatic mutation detection in hepatocellular carcinoma

abstract:
Cell-free DNA (cfDNA) from blood has become a promising analyte for cancer genetic liquid biopsy. Urinary cfDNA has been shown to contain mutations associated with non-genitourologic cancers including hepatocellular carcinoma (HCC). In this study, we evaluate urine as a noninvasive alternative to blood-based liquid biopsy in both germline and circulating tumor DNA (ctDNA) genotyping in HCC. Using quantitative PCR (qPCR), whole-genome sequencing (WGS), and targeted NGS, DNA isolated from blood or urine of patients with HCC was analyzed for overall genome coverage, HCC hotspot coverage, and germline or somatic mutation concordance. Targeted NGS of plasma and urine cfDNA was also performed for detection of somatic variants. We found urine cfDNA, similar to plasma cfDNA, showed a major mononucleosomal species of 150-180 bp in both healthy individuals and patients with HCC. By WGS, overall genome coverage breadth was similar between urine and plasma cfDNA, with higher fraction of covered cancer-associated mutation hotspots in urine cfDNA. qPCR analyses of HCC-associated mutations (TP53, CTNNB1, and TERT) in 101 patients with HCC revealed 78% overall concordance between plasma and urine. Targeted NGS of HCC-associated gene regions in additional 15 HCC patients showed a 97% overall position-level concordance between plasma and urine cfDNA. Collectively, urine DNA can potentially be used as a completely noninvasive liquid biopsy for HCC.

Significance StatementHepatocellular carcinoma (HCC) is the most common liver cancer worldwide and the fastest growing gastrointestinal cancer in the U.S. Cell-free DNA (cfDNA) which originates from various cells undergoing apoptosis or necrosis including tumor cells, is present in all body fluids levels including urine. Urinary cfDNA isolated from patients with HCC showed a similar fragment size distribution, overall genome coverage, and comparable sensitivity for detecting HCC-associated variants compared to plasma cfDNA. Urine was also determined to be a reliable source of germline genotype information, similar to peripheral blood mononuclear cells in blood-based liquid biopsies. Urine cfDNA can be used as a completely non-invasive liquid biopsy in HCC.

category: gastroenterology


title: The relationship between visually evoked effects and concussion in youth

abstract: Increased sensitivity to light is common following concussion. Viewing a flickering light can also produce uncomfortable somatic sensations like nausea or headache. Here we examined effects evoked by viewing a patterned, flickering screen in a cohort of 81 uninjured youth athletes and 84 youth with concussion. We used exploratory factor analysis and identified two primary dimensions of variation: the presence or absence of visually evoked effects, and variation in the tendency to manifest effects that localized to the eyes (e.g., eye watering), versus more generalized neurologic symptoms (e.g., headache). Based on these two primary dimensions, we grouped participants into three categories of evoked symptomatology: no effects, eye-predominant effects, and brain-predominant effects. A similar proportion of participants reported eye-predominant effects in the uninjured (33.3%) and concussion (32.1%) groups. By contrast, participants who experienced brain-predominant effects were almost entirely from the concussion group (1.2% of uninjured, 35.7% of concussed). The presence of brain-predominant effects was associated with a higher concussion symptom burden and reduced performance on visio-vestibular tasks. Our findings indicate that the experience of negative constitutional, somatic sensations in response to a dynamic visual stimulus is a salient marker of concussion and is indicative of more severe concussion symptomatology. We speculate that differences in visually evoked effects reflect varying levels of activation of the trigeminal nociceptive system.

category: pediatrics


title: Long-term ozone exposure and associated cause-specific mortality risks with adjusted metrics by cohort studies: A systematic review and meta-analysis

abstract:
BACKGROUNDLong-term ozone (O3) exposure could lead to a series of non-communicable diseases and increase the mortality risks. However, cohort-based studies were still rather rare, and inconsistent exposure metrics might impair the credibility of epidemiological evidence synthetisation. To provide more accurate meta-estimation, this review updated the systematic review with inclusion of recent studies and summarised the quantitative associations between O3 exposure and cause-specific mortality risks based on unified exposure metrics.

METHODSResearch articles reporting relative risks between incremental long-term O3 exposure and causes of mortality covering all-cause, cardiovascular diseases, respiratory diseases, chronic obstructive pulmonary disease, pneumonia, ischaemic heart diseases, ischaemic stroke, congestive heart failure, cerebrovascular diseases, and lung cancer, estimated from cohort studies were identified through systematic searches in MEDLINE, Embase and Web of Science. Cross-metric conversion factors were estimated linearly by decadal of observations during 1990-2019. The Hunter-Schmidt random effect estimator was applied to pool the relative risks.

RESULTSA total of 25 studies involving 226,453,067 participants (14 unique cohorts covering 99,855,611 participants) were included in the systematic review. After linearly adjusting the inconsistent O3 exposure metrics into congruity, the pooled relative risks (RR) associated with every 10 nmol mol-1 (ppbV) incremental O3 exposure, by mean of warm-season daily maximum 8-hour average metric, was: 1.014 with 95% confidence interval (CI) ranging 1.009-1.019 for all-cause mortality; 1.025 (95% CI: 1.010-1.040) for respiratory mortality; 1.056 (95% CI: 1.029-1.084) for COPD mortality; 1.019 (95% CI: 1.004-1.035) for cardiovascular mortality; and 1.096 (95% CI: 1.065-1.129) for congestive heart failure mortality. Insignificant mortality risk associations were found for ischaemic heart disease, cerebrovascular diseases and lung cancer.

DISCUSSIONThis review covered up-to-date studies, expanded the O3-exposure associated mortality causes into wider range of categories, and firstly highlighted the issue of inconsistency in O3 exposure metrics. Non-intercept linear regression-based cross-metric RR conversion was another innovation, but limitation lay in the observation reliance, indicating further calibration with more credible observations available. Large uncertainties in the multi-study pooled RRs would inspire more future studies to corroborate or contradict the results from this review.

CONCLUSIONAdjustment for exposure metrics laid more solid foundation for multi-study meta-analysis, and wider coverage of surface O3 observations are anticipated to strengthen the cross-metric conversion in the future. Ever-growing numbers of epidemiological studies supported unneglectable cardiopulmonary hazards and all-cause mortality risks from long-term O3 exposure. However, evidences on long-term O3 exposure associated health effects were still scarce, and hence more relevant studies are encouraged to cover more population with regional diversity.

REGISTRATIONThe review was registered in PROSPERO (CRD42021270637).

FUNDINGThis study is mainly funded by UK Natural Environment Research Council, UK National Centre for Atmospheric Science, Australian Research Council and Australian National Health and Medical Research Council.

HighlightsO_LIUpdated evidence for O3-mortality associations from 25 cohorts has been provided.
C_LIO_LIAdjusting various O3 exposure metrics can provide more accurate risk estimations.
C_LIO_LILong-term O3-exposure was associated with increased mortality from all-causes, respiratory disease, COPD, cardiovascular disease and congestive heart failure.
C_LI


title: Long-term ozone exposure associated cause-specific mortality risks with adjusted metrics by cohort studies: A systematic review and meta-analysis


title: Heterogeneity in statin responses explained by variation in the human gut microbiome

abstract: Statins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with several side effects for a subset of patients, including disrupted metabolic control and increased risk of type II diabetes. We investigated the potential role of the gut microbiome in modifying patient response to statin therapy. In a cohort of >1840 individuals, we find that the hydrolyzed substrate for 3-hydroxy-3-methylglutarate-CoA (HMG-CoA) reductase, HMG, may serve as a reliable marker for statin on-target effects. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and metabolic health parameters among statin users and non-users, we find that heterogeneity in statin response is associated with variation in the gut microbiome. A Bacteroides rich, -diversity depleted, microbiome composition corresponds to the strongest statin on-target response, but also greatest disruption to glucose homeostasis, indicating lower treatment doses and/or complementary therapies may be beneficial in those individuals. Our findings suggest a potential path towards personalizing statin treatment through gut microbiome monitoring.


title: Liver Volumetry from Magnetic Resonance Images with Convolutional Neural Networks

abstract:
Measurements of liver volume from MR images can be valuable for both clinical and research applications. Automated methods using convolutional neural networks have been used successfully for this using a variety of different MR image types as input. In this work, we sought to determine which types of magnetic resonance images give the best performance when used to train convolutional neural networks for liver segmentation and volumetry.

Abdominal MRI scans were performed at 3 Tesla on 42 adolescents with obesity. Scans included Dixon imaging (giving water, fat, and T2* images) and low-resolution T2-weighted anatomical scans. Multiple convolutional neural network models using a 3D U-Net architecture were trained with different input images. Whole-liver manual segmentations were used for reference. Segmentation performance was measured using the Dice similarity coefficient (DSC) and 95% Hausdorff distance. Liver volume accuracy was evaluated using bias, precision, and normalized root mean square error (NRMSE).

The models trained using both water and fat images performed best, giving DSC = 0.94 and NRMSE = 4.2%. Models trained without the water image as input all performed worse, including in participants with elevated liver fat. Models using the T2-weighted anatomical images underperformed the Dixon-based models, but provided acceptable performance (DSC [≥] 0.92, NMRSE [≤] 6.6%) for use in longitudinal pediatric obesity interventions. The model using Dixon water and fat images as input gave the best performance, with results comparable to inter-reader variability and state-of-the-art methods.

category: radiology and imaging


title: Smartphone Movement Sensors for Remote Monitoring of Respiratory Rate: Observational Study

abstract:
BackgroundMobile health offers potential benefits to patients and healthcare systems alike. Existing remote technologies to measure respiratory rate (RR) have limitations, such as cost, accessibility and reliability. Using smartphone sensors to measure RR may offer a potential solution.

ObjectiveThe aim of this study was to conduct a comprehensive assessment of a novel mHealth smartphone application designed to measure RR using movement sensors.

MethodsIn Study 1, 15 participants simultaneously measured their RR with the app, and an FDA cleared reference device. A novel reference method to allow the app to be evaluated  in the wild was also developed. In Study 2, 165 participants measured their RR using the app, and these measures were compared to the novel reference. Usability of the app was also assessed in both studies.

ResultsThe app, when compared to the FDA-cleared and novel references, respectively, showed a mean absolute error (MAE) of 1.65 (SD=1.49) and 1.14 (1.44), relative MAE of 12.2 (9.23) and 9.5 (18.70) and bias of 0.81 (limits of agreement (LoA) =-3.27-4.89) and 0.08 (-3.68-3.51). Pearson correlation coefficients were 0.700 and 0.885. 93% of participants successfully operated the app on their first use.

ConclusionsThe accuracy and usability of the app demonstrated here show promise for the use of mHealth solutions employing smartphone sensors to remotely monitor RR. Further research should validate the benefits that this technology may offer patients and healthcare systems.

category: respiratory medicine


title: A systematic review of anaesthetic agents used in Drug Induced Sedation Endoscopy (DISE) and a description of a new DISE technique.

abstract:
ObjectivesDrug induced sleep endoscopy (DISE) is a standardly used investigation for surgical planning in obstructive sleep apnoea management once conservative treatments have proven inadequate. There are a variety of anaesthetic agents used to obtain sedation necessary for DISE. These agents may have different effect on the upper airway and other parameters important in the diagnosis of the site of collapse during sleep. We aimed to review the commonly agents and evaluate the significance of their impact on the the diagnosis.

MethodsA search was conducted through PubMed looking for studies on commonly used anaesthetic agents and their effect on the upper airway and cardiopulmonary parameters. Results: Of the 109 studies yielded by the search, 19 were deemed relevant to the review and met all inclusion criteria. The agents reviewed were: propofol, dexmedetomidine, remifentanil, isoflurane, sevoflurane, midazolam and topical lidocaine. A meta-analysis was not conducted due to the limited number of relevant studies and the heterogeneity of outcomes measured. All agents examined gave some element of airway collapse and impact on cardiopulmonary measures. Most of these effects were shown to be dose-dependent. Of the agents considered dexmedetomidine and propofol gave the most consistently reliable and physiologically safe representations of upper airway collapse seen in OSA patients.

ConclusionThere is limited information and no industry standard for the sedative regimen used for DISE. Of the agents reviewed those that caused least cardiopulmonary instability, respiratory depression and exaggerated upper airway collapse were deemed the most appropriate for DISE. The agent that best meet these criteria is dexmedetomidine followed by propofol.


title: Using an electronic frailty index to predict adverse outcomes in geriatric COVID-19 patients: data from the Stockholm GeroCovid study

abstract:
BackgroundThe Clinical Frailty Scale (CFS) is a strong predictor for worse outcomes in geriatric COVID-19 patients, but it is less clear whether an electronic frailty index (eFI) constructed from routinely collected electronic health records (EHRs) provides similar predictive value. This study aimed to investigate the predictive ability of an eFI in comparison to other frailty and comorbidity measures, using mortality, readmission, and the length of stay as outcomes in geriatric COVID-19 patients.

MethodsWe conducted a retrospective cohort study using EHRs from nine geriatric clinics in Stockholm, Sweden, comprising 3,405 COVID-19 patients (mean age 81.9 years) between 1/3/2020 and 31/10/2021. Frailty was assessed using a 48-item eFI developed for Swedish geriatric patients, the CFS, and Hospital Frailty Risk Score (HFRS). Comorbidity was measured using the Charlson Comorbidity Index (CCI). We analyzed in-hospital mortality and 30-day readmission using logistic regression and area under receiver operating characteristic curve (AUC). 30-day and 6-month mortality were modelled by Cox regression, and the length of stay by linear regression.

ResultsControlling for age and sex, a 10% increase in the eFI was associated with higher risks of in-hospital mortality (odds ratio [OR]=2.84; 95% confidence interval=2.31-3.51), 30-day mortality (hazard ratio [HR]=2.30; 1.99-2.65), 6-month mortality (HR=2.33; 2.07-2.62), 30-day readmission (OR=1.34; 1.06-1.68), and longer length of stay ({beta}=2.28; 1.90-2.66).

The CFS, HFRS and CCI similarly predicted these outcomes, but the eFI had the best predictive accuracy for in-hospital mortality (AUC=0.775).

ConclusionsAn eFI based on routinely collected EHRs can be applied in identifying high-risk geriatric COVID-19 patients.

category: geriatric medicine


title: My family sold a cow to pay for my Traditional doctor and now there's no money to travel to the HIV clinic: barriers to antiretroviral adherence among rural-Indigenous peoples living with HIV in the Comarca Ngabe-Bugle, Panama

abstract:
IntroductionThe Comarca Ngabe-Bugle (CNB) is an administratively autonomous Indigenous region in Western Panama that is home to over 200,000 individuals of Ngabe and Bugle ethnicities. The CNB is the most impoverished region in Panama and is relatively isolated from outside influences, with limited roads, electricity, and internet connection. Around 1.5% of all rapid HIV tests are positive, compared to a national prevalence of 0.9%; in CNB, diagnosis tends to be late where 56.3% of individuals had an initial CD4 count of <350 cells/mm3. In this region, antiretroviral treatment (ART) dropout is five times higher than the national average; there is high early mortality due to opportunistic infections. This study aims to describe some of the barriers associated with ART adherence and retention in HIV care among PLHIV the CNB. A better understanding of factors that obstruct adherence could lead to more effective HIV care and prevention in CNB.

MethodsWe conducted 21 semi-structured interviews with PLHIV who reside across all three regions of the CNB and who have attended an ART clinic at least once. The interviews took place between November 2018 and December 2019.

DiscussionPsychological health and social support and discrimination acted as both individual-level facilitators and barriers to adherence and retention. Notably, structural barriers included difficult access to ART care due to travel costs, ART shortages, and uncooperative Western/Traditional medical systems. Recommended interventions used in other Low- and Middle-Income settings include increasing peer and family-level support and community knowledge and understanding of HIV infection. Additionally, we suggest structural interventions, including decreasing cost and distance of travel to the ART clinic through decentralization of services and multi-month dispensing, decreasing food scarcity, and increasing collaboration between Western and Traditional providers.


title: Bacille Calmette-Guerin vaccine reprograms human neonatal lipid metabolism in vitro and in vivo

abstract:
Vaccines have generally been developed with limited insight into their molecular impact. While systems vaccinology, including metabolomics, enables new characterization of vaccine mechanisms of action, these tools have yet to be applied to infants at high risk of infection and receive the most vaccines. Bacille Calmette-Guerin (BCG) protects infants against disseminated tuberculosis (TB) and TB-unrelated infections via incompletely understood mechanisms. We employed mass spectrometry-based metabolomics of blood plasma to profile BCG-induced infant responses in Guinea Bissau in vivo and the U.S. in vitro. BCG selectively altered plasma lipid pathways, including lysophospholipids. BCG-induced lysophosphatidylcholines (LPCs) correlated with both TLR agonist- and purified protein derivative (PPD, mycobacterial antigen)-induced blood cytokine production in vitro, raising the possibility that LPCs contribute to BCG immunogenicity. Analysis of an independent newborn cohort from The Gambia demonstrated shared vaccine-induced metabolites such as phospholipids and sphingolipids. BCG-induced changes to the plasma lipidome and LPCs may contribute to its immunogenicity and inform the discovery and development of early life vaccines.

HighlightsO_LINeonatal BCG immunization generates distinct metabolic shifts in vivo and in vitro across multiple independent cohorts.
C_LIO_LIBCG induces prominent changes in concentrations of plasma lysophospholipids (LPLs)
C_LIO_LIBCG induced changes in plasma lysophosphatidylcholines (LPCs) correlate with BCG effects on TLR agonist- and mycobacterial antigen-induced cytokine responses.
C_LIO_LICharacterization of vaccine-induced changes in metabolism may define predictive signatures of vaccine responses and inform early life vaccine development.
C_LI

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/21267251v1_ufig1.gif" ALT="Figure 1">
View larger version (31K):
org.highwire.dtl.DTLVardef@16e922eorg.highwire.dtl.DTLVardef@3f170dorg.highwire.dtl.DTLVardef@26c26org.highwire.dtl.DTLVardef@10a3d0d_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOGraphical abstract:C_FLOATNO BCG vaccination perturbs metabolic pathways in vivo and in vitro.

Vaccines have traditionally been developed empirically, with limited insight into their impact on molecular pathways. Metabolomics provides a new approach to characterizing vaccine mechanisms but has not yet been applied to human newborns, who are at the highest risk of infection and receive the most vaccines. Bacille Calmette-Guerin (BCG) prevents disseminated mycobacterial disease in children and can induce broad protection to reduce mortality due to non-TB infections. Underlying mechanisms are incompletely characterized. Employing mass spectrometry-based metabolomics, we demonstrate that early BCG administration alters the human neonatal plasma metabolome, especially lipid metabolic pathways such as lysophosphatidylcholines (LPCs), both in vivo and in vitro. Plasma LPCs correlated with both innate TLR-mediated and PPD antigen-induced cytokine responses suggesting that BCG-induced lipids might contribute to the immunogenicity of this vaccine. Vaccine-induced metabolic changes may provide fresh insights into vaccine immunogenicity and inform the discovery and development of early life vaccines.

C_FIG


title: Treatment-seeking for children with suspected severe malaria attending community health workers and primary health centres in Adamawa State, Nigeria

abstract:
BackgroundThe Community Access to Rectal Artesunate for Malaria project investigated the feasibility of introducing pre-referral rectal artesunate into existing community-based health services. In that study, the case fatality rate of children visiting primary health centres (PHCs) was 19% compared to 6% in children first visiting community health workers, locally called Community Oriented Resource Persons (CORPs). As case management practices did not fully explain this finding, this publication investigates other reasons underlying the observed difference in case fatality.

MethodsThe observational study enrolled 589 children under the age of five years with fever and danger signs indicative of severe malaria attending CORPs and PHCs in Adamawa State, Nigeria, between June 2018 and July 2020. After 28 days, follow-up visits were conducted with caregivers to understand background characteristics, severity of symptoms, home treatment administration, and treatment seeking practices during the childs illness. These factors were compared between children visiting CORPs versus those visiting PHCs as their first health provider.

ResultsChildren visiting PHCs were more likely to display danger signs indicative of central nervous system involvement (90% vs. 74%, p < 0.01) and have four or more danger signs (50% vs. 39%, p = 0.02). The delay between illness onset and visiting the community-based provider did not differ between children attending a CORP and children attending a PHC. PHC attendances more often lived in urban areas (16% vs 4%, p=0.01) and travelled farther to their first health provider, which was usually a community-based provider. Although practicing home treatment was common, especially among children attending PHCs (42% vs 33%, p=0.04), almost none of the children were given an antimalarial. PHCs were visited for their professionalism and experience while CORPs were visited for their low cost and because caregivers personally knew and trusted the provider.

ConclusionsOur comparison of children with suspected severe malaria seeking care from two kinds of community-based health care providers in Nigeria suggest that illness severity may be the primary driver behind the observed difference in case fatality rate.

category: public and global health