title: Integrated genomic and histopathological analysis of low grade serous ovarian carcinoma identifies clinically distinct disease subtypes

abstract:
BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a distinct, under-investigated and relatively chemotherapy-resistant ovarian cancer type. Understanding the molecular landscape is crucial to maximise the impact of molecularly-targeted therapy.

MethodsWhole exome sequencing and copy number data were integrated with histopathological patterns, ER/PR expression, and detailed clinical annotation, including survival, in a carefully curated LGSOC cohort.

Results63 tumours were analysed in the largest comprehensive genomic LGSOC study to date. Three genomic subgroups were identified: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated mutation (27%, 14 MAPK-associated genes) and MAPK wild-type (MAPKwt: 21%). MAPKwt patients were younger at diagnosis (median 47 versus 62 years in the cMAPKm subgroup) and demonstrated shorter survival [multivariable HR (mHR) 4.17]. The inferior survival in the MAPKwt subgroup was due to shorter post-relapse survival (mHR 5.22) rather than shorter time to first progression (mHR 1.15). Patients in the MAPK-associated mutation subgroup had similar survival to cMAPKm cases. The cMAPKm subgroup more frequently demonstrated macropapillary invasion. Desmoplasia and micropapillary invasion were independently associated with poor survival. NOTCH pathway activation occurred independently of MAPK subgroup.

ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical, molecular and histopathological features. True MAPKwt cases represent around a fifth of patients: they are younger but have poorer survival. New therapeutic strategies with activity in this subgroup are urgently required. NOTCH inhibitors represent a therapeutic strategy worthy of exploration.


title: Comparative complete scheme and booster effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infections with SARS-CoV-2 Omicron (BA.1) and Delta (B.1.617.2) variants

abstract:
IntroductionInformation on vaccine effectiveness and viral loads in a context of novel variants of concern (VOC) emergence is of key importance to inform public health policies. This study aimed to estimate a measure of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.617.2 and sub-lineages) VOC according to vaccination exposure (primary or booster) and time since primary vaccination and to compare cycle threshold (Ct) values between Omicron and Delta VOC infections according to the vaccination status as an indirect measure of viral load.

MethodsWe developed a case-case study using data on RT-PCR SARS-CoV-2 positive cases notified in Portugal during weeks 49-51 2021. The odds of vaccination in Omicron cases were compared to Delta using logistic regression adjusted for age group, sex, region and week of diagnosis and laboratory of origin. RT-PCR Ct values were compared by vaccination status and variant using linear regression model.

ResultsHigher odds of vaccination were observed in cases infected by Omicron (BA.1) VOC compared to Delta (B.1.617.2) VOC cases for both complete primary vaccination (OR=2.1; CI 95% :1.8 to 2.4) and booster dose (OR= 5.2; CI 95%: 3.1 to 8.8), indicating vaccine effectiveness reduction against Omicron. No differences in distribution of Ct-values between these two VOC were observed for any vaccination exposure categories.

ConclusionConsistent lower VE was observed against Omicron infection. Complete primary vaccination may not be protective against SARS-CoV-2 infection in regions where Omicron variant is dominant, but a massive rollout of booster vaccination campaign can contribute to reduce SARS-CoV-2 incidence in the population.

category: infectious diseases


title: Real-life performance of a COVID-19 rapid antigen detection test targeting the SARS-CoV-2 nucleoprotein for diagnosis of COVID-19 due to the Omicron variant

abstract:
ObjectivesIt has been suggested that rapid antigen detection assays (RADT) may perform suboptimally in terms of sensitivity for the diagnosis of SARS-CoV-2 Omicron variant infection. To address this issue, we conducted a prospective study in primary health centers to evaluate the clinical performance of the Panbio COVID-19 Ag Rapid Test Device in nasopharyngeal specimens (NP) carried out at the point of care.

MethodsWe recruited 244 patients (median age, 40 years; range 2-96; 141 female) with clinical suspicion of COVID-19 (232 adults and 12 children). 228/244 patients had been fully vaccinated (two doses) with licensed COVID-19 vaccines prior to recruitment. Most patients (222/244) were SARS-CoV-2 naive prior to enrollment. Patients were tested by RT-PCR and RADT within 5 days since symptoms onset.

Results126 patients (51.6%) tested positive by both RT-PCR and RADT, 90 patients (36.8%) returned negative results by both assays and 28 patients (11.4%) yielded discordant results (RT-PCR+/RADT-). No patients tested RT-PCR-/RADT+. Overall specificity and sensitivity of RADT was 100% (95% CI, 95.9-100%) and 81.8% (95% CI, 75-87.1%) respectively. The sensitivity of the assay increased from 79.6% (95% CI, 66.4-88.5) when considering specimens collected at days 0-1 after symptoms onset, to 86.4% (95% CI, 66.7-95.3) when grouping the specimens obtained on days 4-5.

ConclusionThe Panbio COVID-19 Ag Rapid Test Device perform well ([≥]80% sensitivity) as a point-of-care test for early diagnosis of COVID-19 due to the Omicron variant in primary healthcare centers.


title: Association study of HLA with the kinetics of SARS-CoV-2 spike specific IgG antibody responses to BNT162b2 mRNA vaccine

abstract: BNT162b2, an mRNA-based SARS-CoV-2 vaccine (Pfizer-BioNTech), is one of the most effective COVID-19 vaccines and has been approved by more than 130 countries worldwide. However, several studies have reported that the COVID-19 vaccine shows high interpersonal variability in terms of humoral and cellular responses, such as those with respect to SARS-CoV-2 spike protein immunoglobulin (Ig)G, IgA, IgM, neutralizing antibodies, and CD4+ & CD8+ T cells. The objective of this study is to investigate the kinetic changes in anti-SARS-CoV-2 spike IgG (IgG-S) profiles and adverse reactions and their associations with HLA profiles among 100 hospital workers from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. DQA1*03:03:01 (P = 0.017; Odd ratio (OR) 2.80, 95%Confidence interval (CI) 1.05-7.25) was significantly associated with higher IgG-S production after two doses of BNT162b2 while DQB1*06:01:01:01 (P = 0.028, OR 0.27, 95%CI 0.05-0.94) was significantly associated with IgG-S declines after two doses of BNT162b2. No HLA alleles were significantly associated with either local symptoms or fever. However, C*12:02:02 (P = 0.058; OR 0.42, 95%CI 0.15-1.16), B*52:01:01 (P = 0.031; OR 0.38, 95%CI 0.14-1.03), DQA1*03:02:01 (P = 0.028; OR 0.39, 95%CI 0.15-1.00) and DPB1*02:01:02 (P = 0.024; OR 0.45, 95%CI 0.21-0.97) appeared significantly associated with protection against systemic symptoms after two doses of BNT162b2 vaccination. Further studies with larger sample sizes are clearly warranted to determine HLA allele associations with the production and long-term sustainability of IgG-S after COVID-19 vaccination.


title: Exposing and Overcoming Limitations of Clinical Laboratory Tests in COVID-19 by Adding Immunological Parameters

abstract:
BackgroundAlmost two years since the onset of the COVID-19 pandemic no predictive algorithm has been generally adopted, nor new tests identified to improve the prediction and management of SARS-CoV-2 infection.

MethodsRetrospective observational analysis of the predictive performance of clinical parameters and laboratory tests in hospitalised patients with COVID-19. Outcomes were 28-day survival and maximal severity in a cohort of 1,579 patients and two validation cohorts of 598 and 434 patients. A pilot study conducted in a patient subgroup measured 17 cytokines and 27 lymphocyte phenotypes to explore additional predictive laboratory tests.

Findings1) Despite a strong association of 22 clinical and laboratory variables with the outcomes, their joint prediction power was limited due to redundancy. 2) Eight variables: age, comorbidity index, oxygen saturation to fraction of inspired oxygen ratio, neutrophil-lymphocyte ratio, C-reactive protein, aspartate aminotransferase/alanine aminotransferase ratio, fibrinogen, and glomerular filtration rate captured most of the statistical predictive power. 3) The interpretation of clinical and laboratory variables was improved by grouping them in categories. 4) Age and organ damage-related tests were the best predictors of survival, and inflammatory-related tests were the best predictors of severity. 5) The pilot study identified several immunological tests (including chemokine ligand 10, chemokine ligand 2, and interleukin 1 receptor antagonist), that performed better than currently used tests.

ConclusionsCurrently used tests for clinical management of COVID-19 patients are of limited predictive value due to redundancy, as all measure aspects of two major processes: inflammation, and organ damage. There are no independent predictors based on the quality of the nascent adaptive immune response. Understanding the limitations of current tests would improve their interpretation and simplify clinical management protocols. A systematic search for better biomarkers is urgent and feasible.

This study was funded by Instituto de Salud Carlos III, Madrid, Spain, grants COV20/00416, Cov20/00654 and COV20/00388 to R.P-B, ATS and JBM respectively and co-financed by the European Regional Development Fund (ERDF). DA-S is recipient of a doctoral fellowship from the Vall dHebron Research Institute, Barcelona, Spain. ASM was supported by a postdoctoral grant "Juan Rodes" (JR18/00022) from Instituto de Salud Carlos III through the Ministry of Economy and Competitiveness, Spain


title: Exposing Limitations of Clinical Laboratory Tests in COVID-19 and the Promise of Immunological Biomarkers


title: Neutralization profile of Omicron variant convalescent individuals

abstract:
Recently, the Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been described as immune escape variant.

Here, we analyzed samples from BA.1 (Omicron) convalescent patients with different constellations of prior SARS-CoV-2 immunity regarding vaccination and previous infection with a non-Omicron variant and determined titers of neutralizing antibodies against different SARS-CoV-2 variants (D614G, Alpha, Beta, Delta, Gamma, Omicron).

We found high neutralizing antibody titers against all variants for vaccinated individuals after BA.1 breakthrough infection or for individuals after infection with a pre-omicron variant followed by BA.1 infection. In contrast, samples from naive unvaccinated individuals after BA.1 infection mainly contained neutralizing antibodies against BA.1 but only occasionally against the other variants.


title: The public views of and reactions to the COVID-19 pandemic in England- a qualitative study with diverse ethnicities

abstract:
ObjectivesTo explore public reactions to the COVID-19 pandemic across diverse ethnic groups.

DesignRemote qualitative interviews and focus groups in English or Punjabi. Data were transcribed and analysed through inductive thematic analysis.

SettingEngland and Wales June-October 2020.

Participants100 participants from 19 diverse  self-identified ethnic groups.

ResultsDismay, frustration and altruism were reported across all ethnic groups during the first six to nine months of the COVID-19 pandemic. Dismay was caused by participants reported individual, family and community risks, and loss of support networks. Frustration was caused by reported lack of recognition of the efforts of minority ethnic groups (MEGs), inaction by government to address COVID-19 and inequalities, rule breaking by government advisors, changing government rules around: border controls, personal protective equipment, social distancing, eating out, and perceived poor communication around COVID-19 and the Public Health England (PHE) COVID-19 disparities report (leading to reported increased racism and social isolation). Altruism was felt by all, in the resilience of NHS staff and their communities and families pulling together. Data, participants suggested actions, and the Behaviour Change Wheel informed suggested interventions and policies to help control COVID-19.

ConclusionTo maintain public trust, it is imperative that governmental bodies consider vulnerable groups, producing clear COVID-19 control guidance with contingency, fiscal, service provision and communication policies for the next rise in COVID-19 cases. This needs to be combined with public interventions including information, education, modelling and enablement of infection prevention through local community involvement and persuasion techniques or incentivisation. Government policy needs to review and include town and social planning leading to environmental restructuring that facilitates infection prevention control. This includes easy access to hand-washing facilities in homes, work, all food providers and shopping centres; toilet facilities as our Travellers mentioned, and adequate living accommodation and work environment facilitating IPC for all.

Strengths and limitationsO_LIThis is amongst the largest qualitative studies on attitudes to the COVID-19 pandemic in the UK general public across ethnic groups, ages and religions, adding insights to previous smaller qualitative studies, from a broader range of participants.
C_LIO_LIThe qualitative methodology allowed us to discuss participants responses around the COVID-19 pandemic, probing their answers to obtain detailed data to inform needs across ethnic groups.
C_LIO_LIMost data collection was undertaken in English and therefore excludes non-English speaking sectors of the population who may have experienced the COVID-19 pandemic differently.
C_LIO_LIWe did not obtain the views of older members of the population over 70 years, who were most at risk.
C_LIO_LIThe data reflect public perceptions six to nine months into the pandemic when some of the social distancing rules had been relaxed in England; as the pandemic progresses attitudes and needs may well change.
C_LI


title: High Rates of Rapid Antigen Test Positivity After 5 Days of Isolation for COVID-19

abstract:
BackgroundThe emergence of the highly transmissible COVID-19 variant, omicron, has resulted in high numbers of breakthrough infections, including among healthcare workers (HCW). Recent CDC recommendations now allow healthcare workers to return to work after day 5 if symptoms have improved, without a requirement for a negative rapid antigen test (RAT).

MethodsFully vaccinated and non-immunocompromised HCW at a large, urban, academic medical center who tested positive for COVID-19 starting in late December, 2021 (when omicron was the predominant circulating strain) were allowed to return to work early if all symptoms had resolved excepting mild, intermittent cough and/or lingering loss of taste/smell, provided a rapid antigen test was negative upon return. Those with negative tests were allowed to return to work with the stipulations that they wear an N95 at all times and take breaks and eat meals apart from others. Those with positive tests on first attempt could return 24-48 hours later to test again for as many days as needed to achieve a negative result or until they completed 10 days of restriction from work.

ResultsBetween January 2, 2022 and January 12, 2022 there were 309 total RAT done on 260 separate HCW on day 5-10 of illness. Overall, 43% (134 of 309) of all RAT were positive between days 5-10. The greatest percent positive RAT was noted among HCW returning for their first test on day 6 (58%). The rate of positivity was greatest (58%) among HCW returning for their first test on day 6. HCW returning on day 8 and 9 were less likely to have a positive test (26%, 19/74). In RAT positive HCW returning for their first test on days 5 or 6 (and for which line intensity was recorded) 49% (25/51) were recorded as having the darkest intensity on their RAT. HCW who test positive on their first test most often remained positive on their second test, with 56% of second tests, aggregated across all days 6-10, remaining positive. Over all first tests performed on days 5-10, boosted HCW were nearly twice as likely to test RAT positive: 53% (75 out of 141) of boosted HCW tested positive.

DiscussionMore than 40% of vaccinated HCW who felt well enough to work still had positive RAT tests when presenting for a first test between days 5 and 10. Boosted individuals were nearly 3x as likely to result positive on day 5, their first day eligible for return, and [~]2x as likely to result positive on first RAT overall. New guidance provides clearance to exit isolation after 5 days from symptom onset, without the need for a negative rapid antigen test to exit, as long as symptoms are beginning to resolve. Per CDC, the guidance was driven by prior studies, mostly collected before Omicron and before most people were vaccinated or infected, that reported on symptom onset beginning one or more days after peak virus loads. In such an instance, where isolation based on symptom onset often did not begin until peak virus load was already attained, then release from isolation at 5 days would be appropriate. However, reports showing much earlier onset of symptoms, coupled with our own results here demonstrate that the relationship between symptom onset and peak virus load has changed, and 5 days from symptom onset may no longer be an appropriate window to end isolation without a negative rapid antigen test to support safe exit.

ConclusionThese results indicate that a substantial proportion of individuals with COVID-19 are likely still contagious after day 5 of illness regardless of symptom status. Early liberation from isolation should be undertaken only with the understanding that inclusion of individuals on day 6-10 of illness in community or work settings may increase the risk of COVID-19 spread to others which, in turn, may undermine the intended benefits to staffing by resulting in more sick workers.


title: Integrating Multiple Imaging Modalities does not Boost Prediction of Carotid Artery Intima-Media Thickness in Midlife Adults

abstract:
BackgroundHuman neuroimaging evidence suggests that cardiovascular disease (CVD) risk may relate to functional and structural features of the brain. The present study tested whether combining functional and structural (multimodal) brain measures, derived from magnetic resonance imaging (MRI), would yield a multivariate brain biomarker that reliably predicts a subclinical marker of CVD risk, carotid-artery intima-media thickness (CA-IMT).

MethodsNeuroimaging, cardiovascular, and demographic data were assessed in 324 midlife and otherwise healthy adults who were free of (a) clinical CVD and (b) use of medications for chronic illness (aged 30-51 years, 49% female). We implemented a prediction stacking algorithm that combined multimodal brain imaging measures and Framingham Risk Scores (FRS) to predict CA-IMT. We included imaging measures that could be easily obtained in clinical settings: resting state functional connectivity and structural morphology measures from T1-weighted images.

ResultsOur models reliably predicted CA-IMT using FRS, as well as for several individual MRI measures; however, none of the individual MRI measures outperformed FRS. Moreover, stacking functional and structural brain measures with FRS did not boost prediction accuracy above that of FRS alone.

ConclusionsCombining multimodal functional and structural brain measures through a stacking algorithm does not appear to yield a reliable brain biomarker of subclinical CVD, as reflected by CA-IMT.

category: cardiovascular medicine


title: Nucleocapsid and spike antibody responses post virologically confirmed SARS-CoV-2 infection: An observational analysis in the Virus Watch community cohort

abstract:
IntroductionSeroprevalence studies can provide a measure of cumulative incidence of SARS-CoV-2 infection, but a better understanding of antibody dynamics following infection is needed to assess longevity of detectability. Infection is characterised by detection of spike (anti-S) and nucleocapsid (anti-N) antibodies, whereas vaccination only stimulates anti-S. Consequently, in the context of a highly vaccinated population, presence of anti-N can be used as a marker of previous infection but waning over time may limit its use.

MethodsAdults aged [≥]18 years old, from households enrolled in the Virus Watch prospective community cohort study in England and Wales, provided monthly capillary blood samples which were tested for anti-S and anti-N. Participants self-reported vaccination dates and past medical history. Prior polymerase chain reaction (PCR) swabs were obtained through Second Generation Surveillance System (SGSS) linkage data. Primary outcome variables were seropositivity (antibodies at or above the manufacturers cut-off for positivity) and total anti-N and anti-S levels after PCR confirmed infection. Outcomes were analysed by days since infection, self-reported demographic and clinical factors.

ResultsA total of 13,802 eligible individuals, median age 63, provided 58,770 capillary blood samples. 537 of these had a prior positive PCR confirmed SARS-CoV-2 infection 0-269 days before the antibody sample date. 432 out of the 537 (80.44%) were anti-N positive and detection remained stable through-out follow-up. Median anti-N levels peaked between days 90 and 119 post PCR results and then began to decline. Logistic regression models, both univariable and multivariable, only showed higher odds of positive anti-N result between 0-269 days for 35-49 year olds, compared to 18-34 year olds. There is evidence of anti-N waning from 120 days onwards, with earlier waning for females and younger age categories.

DiscussionApproximately 4 in 5 participants with prior PCR-confirmed infection were anti-N positive, and this remained stable through follow-up for at least 269 days. However, median antibody levels began to decline from about 120 days post-infection. This suggests that anti-N have around 80% sensitivity for identifying previous COVID-19 infection and that this sensitivity is maintained through 269 days of follow up.

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

category: epidemiology


title: The clinical impact of maternal COVID-19 on mothers, their infants, and placentas with an analysis of vertical transfer of maternal SARS-CoV-2-specific IgG antibodies

abstract:
IntroductionThe effect of SARS-CoV-2 infection on pregnant mothers, the placenta, and infants is not fully understood and sufficiently characterized.

MethodsWe performed a retrospective, observational cohort study in Chapel Hill, NC of 115 mothers with SARS-CoV-2 and singleton pregnancies from December 1, 2019 to May 31, 2021. We performed a chart review to document the infants weight, length, head circumference, survival, congenital abnormalities, and hearing loss, maternal complications, and placental pathology classified by the Amsterdam criteria.

ResultsThe average infant weight, length, and head circumference were all within the normal range for gestational age, the infants had no identifiable congenital abnormalities, and all infants and mothers survived. Only one infant (0.870%) became infected with SARS-CoV-2. Moderate and severe maternal COVID-19 were associated with increased caesarean section, premature delivery, infant NICU admission, and maternal respiratory failure, and were more likely in Type 1 (p=0.0055) and Type 2 (p=0.0285) diabetic mothers. Most placentas (n=63, 54.8%) showed normal or non-specific findings, while a subset had mild maternal vascular malperfusion (n=26, 22.6%) and/or mild microscopic ascending intrauterine infection (n=28, 24.3%).

DiscussionMost mothers with SARS-CoV-2 and their infants had a routine clinical course. Maternal SARS-CoV-2 infection was not associated with intrauterine fetal demise, infant death, congenital abnormalities, or hearing loss. Infant infection with SARS-CoV-2 was rare and not via the placenta. Most placentas had non-specific findings and a subset showed mild maternal vascular malperfusion and/or mild microscopic ascending intrauterine infection, which were not associated with maternal COVID-19 severity.

category: pathology


title: Moment-to-moment fluctuations of hemodynamic responses in posterior default mode networks differentially predict level of attentional lapses in adolescents with Attention-Deficit/Hyperactivity Disorder

abstract:
BackgroundThe neurobiological underpinnings of the characteristically higher intra-individual variability of reaction times (IIVRT) in patients with ADHD remain poorly understood. The aim of the current study was to characterize the role of the default mode and other canonical brain networks measured by functional magnetic resonance imaging (fMRI) to task performance fluctuations measured by IIVRT. To our knowledge, no prior fMRI study has shown the involvement of posterior default mode network (DMN) in ADHD IIVRT. We expected that moment-to-moment fluctuations in hemodynamic responses in posterior DMN would predict higher IIVRT in ADHD.

MethodsAdolescents (12 to 19 years old) with ADHD (n= 55) and healthy controls (n= 55) performed a fMRI Go/NoGo task. Whole-brain independent component analysis (ICA) segregated hemodynamic responses into functional brain networks, then further decomposed into individual trial-specific estimates of hemodynamic response amplitude. Mean and variability metrics of these amplitudes were tested in stepwise linear regression analyses to identify which functional brain networks predicted high IIVRT.

ResultsAs hypothesized, variability in hemodynamic responses in posterior DMN regions predicted level of IIVRT. In posterior cingulate cortex this variability predicted higher IIVRT only in ADHD, whereas in precuneus variability in hemodynamic responses predicted lower IIVRT. Average hemodynamic responses in a bilateral superior temporal cortex network predicted higher IIVRT only in ADHD.

ConclusionOur findings suggest that estimating variability in hemodynamic responses is crucial to understand the involvement of the intrinsic default mode in attentional lapses in ADHD. The parcellation into subnetworks showed the differentiating role of default mode in attentional lapses in ADHD.

category: psychiatry and clinical psychology


title: Zero-COVID Policies: Melbourne's 112-Day Hard Lockdown Experiment Harmed Mostly Mothers

abstract:
Lockdowns were used worldwide to mitigate the spread of SARS-CoV-2. We demonstrate that the 112-day hard lockdown in Melbourne, Australia, the longest among OECD jurisdictions, exclusively penalized families with young children. To identify the causal impact of lockdown, we interrogated nationally-representative longitudinal survey data and exploited quasi- experimental variation in Melbournes lockdown, one that left other jurisdictions unaffected. Using difference-in-differences estimation, we found that, surprisingly, most vulnerable groups (the young, poor, lonely and those with previous mental health conditions) were left unscathed. However, we found mothers experienced significant, sizable declines in health and work hours, and increases in loneliness, despite feeling safer and being more active. Zero-COVID policies are not as harmful as may have been expected but came at high cost to mothers in society.

One-Sentence SummaryMelbournes hard lockdown left most vulnerable groups unscathed but led to greater ill- health and loneliness in mothers.

category: public and global health


title: The Investigation of Pulmonary Abnormalities using Hyperpolarised Xenon Magnetic Resonance Imaging in Patients with Long-COVID.

abstract:
BackgroundLong-COVID is an umbrella term used to describe ongoing symptoms following COVID-19 infection after four weeks. Symptoms are wide-ranging but breathlessness is one of the most common and can persist for months after the initial infection. Investigations including Computed Tomography (CT), and physiological measurements (lung function tests) are usually unremarkable. The mechanisms driving breathlessness remain unclear, and this may be hindering the development of effective treatments.

MethodsEleven non-hospitalised Long-COVID (NHLC, 4 male), 12 post-hospitalised COVID-19 (PHC, 10 male) patients were recruited from a Post-COVID Assessment clinic, and thirteen healthy controls (6 female) were recruited to undergo Hyperpolarized Xenon Magnetic Resonance Imaging (Hp-XeMRI). NHLC and PHC participants underwent contemporaneous CT, Hp-XeMRI, lung function tests, 1-minute sit-to-stand test and breathlessness questionnaires. Statistical analysis included group and pair-wise comparisons between patients and controls, and correlations between patient clinical and imaging data.

ResultsNHLC and PHC patients were 287 {+/-} 79 [range 190-437] and 149 {+/-} 68 [range 68-269] days from infection, respectively. All NHLC patients had normal CT scans, and the PHC had normal or near normal CT scans (0.3/25 {+/-} 0.6 [range 0-2] and 7/25 {+/-} 5 [range 4-8], respectively). There was a significant difference in TLco (%) between NHLC and PHC patients (76 {+/-} 8 % vs 86 {+/-} 8%, respectively, p = 0.04) but no differences in other measurements of lung function. There were significant differences in RBC:TP mean between volunteers (0.45 {+/-} 0.07, range [0.33-0.55]) and PHC (0.31 {+/-} 0.11, [range 0.16-0.37]) and NHLC (0.35 {+/-} 0.09, [range 0.26-0.58]) patients, but not between NHLC and PHC (p = 0.26).

ConclusionThere are RBC:TP abnormalities in NHLC and PHC patients, with NHLC patients also demonstrating lower TLco than PHC patients despite their having normal CT scans. These abnormalities are present many months after the initial infection.

Summary statementHyperpolarized Xenon MRI and TLco demonstrate significantly impaired gas transfer in non-hospitalised long-COVID patients when all other investigations are normal.

Key resultsO_LIThere are significant differences in RBC:TP mean between healthy controls and PHC/NHLC patients (0.45 {+/-} 0.07, range [0.33-0.55], 0.31 {+/-} 0.11, [range 0.16-0.37], 0.35 {+/-} 0.09, [range 0.26-0.58], respectively, p < 0.05 after correction for multiple comparisons) indicating a change in lung compartment volumes between groups.
C_LIO_LIThere was a significant difference in TLco (%) between NHLC and PHC patients (76 {+/-} 8 % vs 86 {+/-} 8%, respectively, p = 0.04), despite normal or near normal FEV (%) (100 {+/-} 13% [range 72-123%] and 88 {+/-} 21% [range 62-113%], p>0.05.
C_LIO_LIThere were significant differences in CT abnormalities between NHLC and PHC patients (0.3/25 {+/-} 0.6 [range 0-2] and 7/25 {+/-} 5 [range 4-8], respectively) despite similarly impaired RBC:TP.
C_LI

category: radiology and imaging


title: Modern contraceptive Use and its associated factors among married women in Senegal: Based on the recent National Demographic and Health Survey Data

abstract:
ObjectiveThis study aimed to assess the prevalence and associated factors of modern contraceptive use among married women in Senegal.

MethodThe most recent Demographic and Health Survey (DHS), which was conducted in 2019 in Senegal was used. For this study 5,659 women were included. Multivariable binary Logistic regression analysis was used to identify factors associated with womens contraceptive use.

ResultAccording to the study, 25.5% (95%CI (24.4, 26.7)) of married women in Senegal uses modern contraceptive methods. Being currently working (AOR=1.27, 95% CI (1.11, 1.46)), husband educational level (primary educational level (AOR=1.32, 95% CI (1.07,1.61), higher educational levels (AOR= 1.83, 95% CI (1.32, 2.54)), wealth index (middle (AOR=1.37,95% CI (1.15,1.63) and rich (AOR=1.34,95% CI (1.11,1.62)), exposure to family planning messages (AOR=1.29,95% CI (1.13,1.48)), having ANC visits(AOR=2.01, 95% CI(1.13,3.57)) and not wanting a child (AOR=2.35, 95%CI (1.90,2.95)) were positively and significantly with womens contraceptives use. On the other hand, number of children (having no child (AOR=0.03, 95% CI (0.01,0.06)), 1-2 children (AOR=0.47,95% CI(0.38,0.59) and 3-4 children (AOR=0.79, 95% CI(0.67,0.96)), women who thought [≥]5 children are ideal (AOR=0.73,95% CI(0.61,0.88)), and had a desire for more children after 2 years (AOR=2.19, 95% CI(1.82,2.64) were negatively and significantly with womens contraceptives use.

Conclusioncontraceptive utilization was low among married women in Senegal. Womens contraceptive use was affected by family planning messages exposure, sociodemographic, and obstetric factors. Thus, a tailored behavior change intervention is required to increase contraceptive utilization among married women in Senegal.

O_TEXTBOXStrengths and limitations of this studyO_LIThe inclusion of nationally representative data and a large sample size, which strengthened the generalizability of the findings, was the studys key strength.
C_LIO_LISample weighing was employed to compensate unequal sample allocations and non-responses.
C_LIO_LIIt may not be possible to establish causal links due to the cross-sectional nature of the data.
C_LIO_LIIts possible that crucial factors that influence womens use of modern contraceptives might be neglected because the study relied on secondary data.
C_LI

C_TEXTBOX

category: sexual and reproductive health


title: Diagnostic Utility of Exome Sequencing for Polycystic Kidney Disease

abstract:
BackgroundLarge clinical cohorts with electronic health records (EHR) and genetic data allow estimating population prevalence of rare genetic disorders like polycystic kidney disease (PKD) and deciphering their genetics, allowing more precise diagnosis and management.

MethodsWe performed genotype- and phenotype-based analyses to gain insight into the prevalence and genetic basis of PKD in an unselected health system-based cohort of 173,954 patients with EHR and exome sequencing data. We determined the diagnostic rate of PKD amongst patients with PKD1/2 variants, reviewed EHR data including imaging and family history when available to phenotype PKD cases of various severity, determined disease prevalence, and identified the genetic basis for most of these cases.

ResultsIn genotype-first analyses, individuals with a protein-truncating (PTV) or copy number variant deletion (CNV) in PKD1 and PKD2 had ADPKD rates of 94.3% (66/70) and 97.7% (43/44) respectively. For individuals with missense or in-frame deletion variants previously classified as likely pathogenic (LP) or hypomorphic, ADPKD diagnosis was infrequent (34/425 for PKD1 and 0 /12 for PKD2). Phenotype-first analyses identified 235 ADPKD cases (1.35/1,000), which were further subclassified by imaging findings (196 moderate/severe typical ADPKD, 16 mild typical ADPKD, 23 atypical ADPKD). The genetic diagnostic rate for moderate/severe typical ADPKD was 69% (135/196) and significantly lower for mild typical and atypical ADPKD (25.0% and 21.7% respectively). Specifically, for typical ADPKD, 125/196 (63.7%) had a diagnostic (CNV/PTV/LP) variant in PKD1 or PKD2, two had PKD1 missense variants previously classified as VUS, and 24 had novel PKD1 or PKD2 missense variants, 8 of which segregated with ADPKD in pedigree analysis. Genetic diagnostic yield was much higher in those with a family history of ADPKD than those without a family history.

ConclusionsData from a large carefully phenotyped clinical cohort provides the population-based prevalence of PKD and establishes the utility of exome sequencing in ADPKD diagnosis which should lead to earlier diagnosis and improved care for PKD.

category: nephrology


title: SARS-CoV-2 antibody seroprevalence in cancer patients on systemic antineoplastic treatment in the first wave of the COVID-19 pandemic in Portugal

abstract:
At the time of the first wave of the COVID-19 pandemic cancer patients were considered to be at high risk of serious illness and had a higher exposure risk since they needed frequent and non- deferrable hospital visits. Serologic tests were not routinely used and seroprevalence in this population was unknown.

A single-center cross-sectional study was developed to determine the seroprevalence of anti- SARS-CoV-2 antibodies (Abs) in cancer patients undergoing systemic antineoplastic treatment. One hundred patients were consecutively recruited in a two-week period (6th to 20th May, 2020) and serum samples were tested for the presence of IgM and IgG Abs directed against both spike and nucleocapsid SARS-CoV-2 proteins in two distinct timepoints (at recruitment and four to eight weeks later). IgG positive results were subject to confirmation, in the same serum sample, using two distinct assays.

At the time of the first study visit, no patient had a previously confirmed diagnosis of COVID-19, one reported previous contact with a COVID-19 patient and all had a baseline SARS-CoV-2 negative RT-PCR. Two patients tested positive for SARS-CoV-2 IgG in the first study visit, which was not confirmed in either of the two confirmatory assays. Seventy-two patients were tested at the second study visit, all with negative IgG test. IgM was persistently positive at both study visits in one patient and was positive in another patient at the second study visit, both with negative RT-PCR and serum IgG. No patient tested RT-PCR positive within the study timeframe.

No evidence of prior or acute SARS-CoV-2 infection was documented in this cohort of cancer patients undergoing systemic treatment and no additional exposure risk was documented compared to general population seroprevalence studies. The study was inconclusive regarding the role of SARS-CoV-2 serology in cancer patients in the early phase of the pandemic. This study did show that, with adherence to recommended preventive measures, it was safe to maintain systemic cancer therapy.

category: oncology


title: Non-targeted metabolomics analysis reveals distinct metabolic profiles between positive and negative emotional tears of humans

abstract:
BACKGROUNDAlthough the chemical components of basal, reflex, and emotional tears are different, the presence of distinctions in the tears of different emotions is still unknown. The present study aimed to address the biochemical basis behind emotional tears through non-targeted metabolomics analysis between positive and negative emotional tears of humans.

METHODSSamples of reflex (C), negative (S), and positive (M) emotional tears were collected from healthy college participants. Untargeted metabolomics was performed to identify the metabolites in the different types of tears. The differentially altered metabolites were screened and assessed using univariate and multivariate analyses.

RESULTSThe global metabolomics signatures classified the C, S, and M emotional tears. A total of 133 significantly differential metabolites of ESI-mode were identified between negative and positive emotional tears. The top 50 differential metabolites between S and M were highly correlated. The significantly altered pathways included porphyrin & chlorophyll metabolism, bile secretion, biotin metabolism, arginine & proline metabolism and among others.

CONCLUSIONThe metabolic profiles between reflex, positive, and negative emotional tears of humans are distinct. Secretion of positive and negative emotional tears are distinctive biological activities. Therefore, the present study provides a chemical method to detect human emotions which may become a powerful tool for diagnosis of mental disease and identification of fake tears.

category: ophthalmology


title: Humoral response, associated symptoms and profile of patients infected by SARS-CoV-2 with taste or smell disorders in the SAPRIS multicohort study.

abstract:
ObjectivesTaste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and humoral response intensity associated with taste or smell disorders.

Patients and methodsWe used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave.

ResultsThe analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05-1.58] for women), smoking (OR = 1.54 [95% CI 1.13-2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06-1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26-1.36], OR = 1.37 [95% CI 1.33-1.42] and OR = 1.34 [95% CI 1.29-1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea.

ConclusionAmong patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with a humoral response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms.


title: SARS-CoV-2 RT-qPCR testing of pooled saliva samples: a case study of 824 asymptomatic individuals and a questionnaire survey in Japan

abstract:
From the beginning of the COVID-19 pandemic, the demand for diagnostic and screening tests has exceeded supply. Although the proportion of vaccinated people has increased in wealthier countries, breakthrough infections have occurred amid the emergence of new variants. Pooled-sample COVID-19 testing using saliva has been proposed as an efficient, inexpensive, and non-invasive method to allow larger-scale testing, especially in a screening setting. In this study, we aimed to evaluate pooled RT-qPCR saliva testing and to compare the results with individual tests.

Employees of Philips Japan, Ltd. were recruited to participate in COVID-19 screening from October to December 2020. Asymptomatic individuals (n=824) submitted self-collected saliva samples. Samples were tested for the presence of SARS-CoV-2 by RT-qPCR in both 10-sample pools and individual tests. We also surveyed participants regarding their thoughts and behaviors after the PCR screening project.

Two of the 824 individuals were positive by RT-qPCR. In the pooled testing, one of these two had no measurable Ct value, but showed an amplification trend at the end of the PCR cycle. Both positive individuals developed cold-like symptoms, but neither required hospitalization. Of the 824 participants, 471 responded to our online questionnaire. Overall, while respondents agreed that PCR screening should be performed regularly, the majority were willing to undergo PCR testing only when it was provided for free or at low cost.

In conclusion, pooled testing of saliva samples can support frequent large-scale screening that is rapid, efficient, and inexpensive.


title: Durability of Omicron-neutralizing serum activity following mRNA booster immunization in elderly individuals

abstract: Elderly individuals are at high risk for severe COVID-19. Due to modest vaccine responses compared to younger individuals and the time elapsed since prioritized vaccinations, the emerging immune-evasive Omicron variant of SARS-CoV-2 is a particular concern for the elderly. Here we longitudinally determined SARS-CoV-2-neutralizing serum activity against different variants in a cohort of 37 individuals with a median age of 82 years. Participants were followed for 10 months after an initial two-dose BNT162b2 vaccination and up to 4.5 months after a BNT162b2 booster. Detectable Omicron-neutralizing activity was nearly absent after two vaccinations but elicited in 89% of individuals by the booster immunization. Neutralizing titers against the Wu01, Delta, and Omicron variants showed similar post-boost declines and 81% of individuals maintained detectable activity against Omicron. Our study demonstrates the mRNA booster effectiveness in inducing Omicron neutralizing activity and provides critical information on vaccine response durability in the highly vulnerable elderly population.


title: Logistic regression with machine learning sheds light on the problematic sexual behavior phenotype

abstract:
There has been a longstanding debate about whether the mechanisms involved in problematic sexual behavior (PSB) are similar to those observed in addictive disorders, or related to impulse control or compulsivity. The aim of this report was therefore to contribute to this debate by investigating the association between PSB, addictive disorders (internet addiction, compulsive buying), other measures associated with the construct known as reward deficiency (attention deficit disorder and personality disorder), and obsessive-compulsive disorder (OCD) in young adults in post-secondary education.

A Canadian University Office of the Registrar invited 68846 eligible students and postdoctoral fellows. Out of 4710 expressing interest in participating, 3359 completed on-line questionnaires and 1801 completed the Mini-International Neuropsychiatric Interview (MINI). PSB was measured by combining those screening positive ([≥]6) on the Sexual Addiction Screening Test-Revised (SAST-R) Core with those self-reporting monthly PSB. Current mental health condition(s) and childhood trauma were measured by self-report. OCD was assessed by a combination of self-report and MINI data.

12.18% (407/3341) of participants screened positive on the SAST-R Core. On logistic regression analysis (conventional and by machine learning), OCD, attention deficit, internet addiction, a family history of PSB, childhood trauma, compulsive buying and male gender were associated with PSB. On multiple correspondence analysis (MCA), OCD appeared to cluster separately from the other measures, and the pattern of data differed by gender.

In summary, factors that have previously been associated with the construct known as RDS and OCD are both associated with increased odds of PSB. The factors associated with RDS appear to contribute to a separate data cluster from OCD, and to lie closer to PSB.

category: addiction medicine


title: Pediatric Nemaline Myopathy: A systematic review using individual patient data

abstract:
ContextNemaline myopathy (NM) is a skeletal muscle disease that affects 1 in 50,000 live births.

ObjectiveDevelop a narrative synthesis of the findings of a systematic review of the latest case descriptions of patients with nemaline myopathy.

Data SourcesA systematic search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using the keywords pediatric, child, nemaline myopathy, nemaline rod, rod myopathy.

Study SelectionCase studies focused on pediatric NM and published in English between January 1, 2010 and December 31, 2020 in order to represent the most recent findings.

Data ExtractionInformation was collected about the age of first signs, earliest presenting neuromuscular signs and symptoms, systems affected, progression, death, pathological description, and genetic changes.

ResultsOf a total of 385 records, 55 case reports or series were reviewed, covering 101 pediatric patients from 23 countries. We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with nemaline myopathy.

LimitationsThe results are limited by findings shared in the literature, which varied in their detail and sometimes lacked histological or genetic results. Trends and correlations may be altered by information available.

ConclusionsThis review synthesizes genetic, histopathologic, and disease presentation findings from pediatric nemaline myopathy case reports. These data strengthen our understanding of the wide spectrum of disease seen in nemaline myopathy. Future studies are needed to identify the underlying molecular mechanism of pathology, to improve diagnostics, and to develop better methods to improve quality of life for these patients.

category: pediatrics


title: Genetic and phenotypic associations between brain imaging, psychopathology and educational attainment in children aged 9-11

abstract:
BackgroundPsychiatric disorders are highly heritable and polygenic, and many have their peak onset in late childhood and adolescence, a period of tremendous changes. Although the neurodevelopmental antecedents of mental illness are widely acknowledged, research in youth population cohorts is still scarce, preventing our progress towards the early characterization of these disorders.

MethodsWe included 7,124 children (9-11 years old) from the Adolescent Brain and Cognitive Development Study to map the associations of structural brain imaging with common genetic variants and polygenic scores for psychiatric disorders and educational attainment. We used principal component analysis to derive imaging components, and calculated their heritability. We then assessed the relationship of imaging components with genetic and clinical psychiatric risk with univariate models and Canonical correlation analysis (CCA).

ResultsMost imaging components had moderate heritability. Univariate models showed limited evidence and small associations of polygenic scores with brain structure at this age. CCA revealed two significant modes of covariation. The first linked higher polygenic scores for educational attainment with less externalizing problems and larger surface area. The second mode related higher polygenic scores for schizophrenia, bipolar disorder, and autism spectrum disorder to higher global cortical thickness, smaller white matter volumes of the fornix and cingulum, larger medial occipital surface area and smaller surface area of lateral and medial temporal regions.

ConclusionWhile cross-validation suggested limited generalizability, our results highlight the potential of multivariate models to better understand the transdiagnostic and distributed relationships between mental health and brain structure in late childhood.


title: Recommendations for an Optimal Model of integrated case detection, referral, and confirmation of Neglected Tropical Diseases: A case study in Bong County, Liberia

abstract:
BackgroundPeople affected by Neglected Tropical Diseases (NTDs), specifically leprosy, Buruli ulcer (BU), yaws, and lymphatic filariasis, experience significant delays in accessing health services, often leading to catastrophic physical, psychosocial, and economic consequences. Global health actors have recognized that Sustainable Development Goal 3:3 is only achievable through an integrated inter and intra-sectoral response. This study evaluated existing case detection and referral approaches in Liberia, utilizing the findings to develop and test an Optimal Model for integrated community-based case detection, referral, and confirmation. Finally, this study evaluates the efficacy of implementing the Optimal Model in improving the early diagnosis of NTDs.

Methodology/Principal FindingsThe study used mixed methods, including key informant interviews, focus group discussions, participant observation, quantitative analysis, and reflexive sessions to evaluate the implementation of an Optimal Model developed through this study. The quantitative results from the testing of the optimal model are of limited utility. The annual number of cases detected increased in the twelve months of implementation in 2020 compared to 2019 (pre-intervention) but will require observation over a more extended period to be of significance. Qualitative data revealed essential factors that impact the effectiveness of integrated case detection. Data emphasized the gendered dynamics in communities that shape the case identification process, such as men and women preferring to see health workers of the same gender. Furthermore, the qualitative data showed an increase in knowledge of the transmission, signs, symptoms, and management options amongst CHW, which enabled them to dispel misconceptions and stigma associated with NTDs.

Conclusion/SignificanceThis study demonstrates the opportunity for greater integration in training, case detection, rereferral, and confirmations. However, the effectiveness of this approach depends on a high level of collaboration, joint planning, and implementation embedded within existing health systems infrastructure. Together, these approaches improve access to health services for NTDs.

Author SummaryGlobal health professionals and stakeholders have advocated for integration across diseases and sectors to improve the success of public health interventions. This advocacy has also impacted NTDs programs globally. NTDs interventions are becoming more integrated than disease-specific activities to maximize limited resources, improve coverage and access to healthcare services. However, documentation on the effectiveness of integrated approaches to improve access to healthcare services is minimal. This study evaluated existing case detection and referral approaches in Liberia, utilizing the findings to develop and test an Optimal Model for integrated community-based case detection, referral, and confirmation. Finally, this study evaluates the efficacy of implementing the Optimal Model in improving the early diagnosis of NTDs. The results provide evidence of the benefits of an integrated approach and the programmatic challenges to achieve the goal of improving access to health services for persons affected by NTDs.


title: Toward a phenome-wide view of Parkinson's disease

abstract:
Background and ObjectivesMany studies have examined the relation between PD and environmental variables serially --- one candidate association at a time. In the real world however, both environmental exposures and patients are much more complex, including correlated environmental exposures, polypharmacy, and complex comorbidities. Here we begin to characterize a holistic view of environmental, health, and pharmacological traits linked to patients with PD.

MethodsThe Harvard Biomarkers Study (HBS) is a large case-control study of PD patients and healthy controls that includes an extensive questionnaire covering past medical and social history data and is thus well-suited for such an exploratory study. Sixty-four environmental, pharmacological, and clinical features were evaluated for associations with PD using logistic regression analysis with backward elimination.

ResultsMale gender, coronary artery disease, depression, anxiety, restless leg syndrome, head trauma, ibuprofen use, co-enzyme Q10 use, and vitamin D supplementation were significantly positively associated with PD. By contrast, asthma/chronic obstructive pulmonary disease (COPD), naproxen, ezetimibe, and smoking were significantly negatively associated with PD.

DiscussionThis study shows that unbiased, data-rich exploration of the Parkinson phenome has the promise to uncover, prioritize, and clarify associations between environment, multi-system health phenotypes, and PD in a patient-centric manner. Associations with coronary artery disease, mood disorders, and the cholesterol-absorption inhibitor ezetimibe were revealed that have been largely neglected in traditional hypothesis-driven investigations. Interestingly, asthma/COPD was inversely associated with PD, and this was independent of smoking history. Furthermore, well-established associations were confirmed for male gender, smoking, head trauma, and restless legs syndrome.

category: neurology


title: Effectiveness and safety of acupuncture for insulin resistance in women with polycystic ovary syndrome : A systematic review and meta-analysis

abstract:
ObjectiveTo perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate acupunctures clinical effect of on insulin resistance (IR) in women with polycystic ovary syndrome (PCOS).

MethodsPubMed, Cochrane Library, Embase databases, and Chinese databases, including China National Knowledge Infrastructure (CNKI), Technology Journal Database (VIP), and Wanfang Database, were searched without language restrictions from inception to 20 December 2021. Only RCTs in which acupuncture had been examined as the sole or adjunctive PCOS-IR treatment were included. Additionally, only studies in Chinese databases that had been published in core journals of Peking University were included. Our primary endpoint was homeostasis model assessment of insulin resistance (HOMA-IR). The secondary outcomes were fasting blood glucose (FBG), 2-h postprandial blood glucose (2h-PBG), fasting insulin (FINS), body mass index (BMI), and adverse events. A random-effects model enabled reporting of differences between groups as mean differences, thus minimizing the effects of uncertainty associated with inter-study variability on the effects of different interventions.

ResultsOur analysis included seven eligible RCTs (N=728 participants). Compared with other treatments, acupuncture therapy yielded a greater mean reduction in BMI (-1.21; 95% CI, -2.41 to -0.02; P=0.05). No significant differences existed between acupuncture and other studied treatments for changes in HOMA-IR (-0.33; 95% CI, -0.87 to 0.22; P>0.05), FBG (-0.43; 95% CI, -0.88 to 0.03; P=0.07), 2h-PBG (-0.40;95% CI, -0.90 to 0.10; P>0.05), and FINS (-0.65; 95% CI, -2.18 to 0.89; P>0.05). Furthermore, compared with medication alone, a combination of acupuncture and medication yielded a mean reduction in HOMA-IR of -0.63 (95% CI, -1.12 to -0.14; P=0.01) and BMI of -1.36 (95% CI, -2.07 to -0.66; P<0.01).

ConclusionAlthough acupuncture is not more effective than metformin, the former could be an adjuvant strategy for improving PCOS-IR. Further large-scale, long-term RCTs with strict methodological standards are justified.

category: obstetrics and gynecology


title: Cost effective sequencing enables longitudinal profiling of clonal hematopoiesis

abstract: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to its high cost, most population studies have been cross-sectional, sequencing only a single timepoint. Here we describe a cost-effective sequencing assay for detecting CHIP. We validate this technology on a set of 548 longitudinal and multi-timepoint samples from 182 participants in the Womens Health Initiative cohort over median 16 years, including 85 participants with [≥]3 timepoints assayed. The majority (52.1%) of clonal mutations expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. This assay provides a cost-effective and sensitive platform for investigating the associations between CHIP dynamics and health outcomes at a biobank scale.

category: genetic and genomic medicine


title: The role of CYP2C19 gene polymorphisms on antiplatelet activity of clopidogrel among Arabs: systematic review and meta-analysis

abstract: This study aimed to predict the preventive effect of clopidogrel against recurrent cardiovascular events (CVEs) among the Arab population carrying different CYP2C19 mutations and to determine the frequency of polymorphic alleles and genotypes of CYP2C19 among them. The review included all the studies that reported data related to the CYP2C19 polymorphisms among Arab populations. The review included Arab CVDs patients who are categorized into carriers (cases) and non-carriers (controls) of CYP2C19 alleles and used clopidogrel as secondary prophylaxis. The patients who had recurrent CVEs or had high on-treatment platelet reactivity (HTPR) while using clopidogrel treatment were described as (events). The results showed a significantly increased risk of recurrent CVDs events by about three folds was associated with carriers of CYP2C19*2 and CYP2C19*3 mutations compared to non-carriers (OR= 3.32, CI=1.94-5.67, and OR=3.53, CI=1.17-10.63 respectively). However, no significant difference was recorded between both studied groups regarding the presence of CYP2C19*17 mutation (OR=0.80, (CI=0.44-1.44). The results also revealed that 59 (4.16%) of Arabs carrying two CYP2C19*2 alleles (homozygous), and 356 (25.12%) have one CYP2C19*2 allele and one CYP2C19*1 allele (heterozygous). Moreover, 42 (2.96%) were carrying two CYP2C19*17 alleles (homozygous), and 262 (18.49%) were carrying one CYP2C19*17 allele and one wild-type allele of CYP2C19 (heterozygous). The most common CYP2C19 genotypes reported among Arabs was the wild-type *1/*1, of which 49.26% of them had the homozygous form of the CYP2C19*1 allele. The frequency of the CYP2C19*1 allele was 71.07%, followed by the CYP2C19*2 allele (16.73%) and CYP2C19*17 (12.21%), respectively. The CYP2C19*3 allele was detected rarely among Arabs (<1%) compared to CYP2C19*1, *2, and *17 alleles. The present study revealed that Arabs carrying CYP2C19*2 and CYP2C19*3 alleles may not respond to clopidogrel and may put those patients at risk of recurrent CVEs. Carriers of the CYP2C19*17 allele, on the other hand, did not show a significant role either in increasing or decreasing the antiplatelet efficacy of clopidogrel. The CYP2C19 genotypes including *1/*1, *1/*2, *1/*17, *2/*2, and *17/*17 are commonly distributed among the Arabs.


title: Rapid, high throughput, automated detection of SARS-CoV-2 neutralizing antibodies against native-like vaccine and delta variant spike trimers

abstract: Traditional cellular and live-virus methods for detection of SARS-CoV-2 neutralizing antibodies (nAbs) are labor- and time-intensive, and thus not suited for routine use in the clinical lab to predict vaccine efficacy and natural immune protection. Here, we report the development and validation of a rapid, high throughput method for measuring SARS-CoV-2 nAbs against native-like trimeric spike proteins. This assay uses a blockade of hACE-2 binding (BoAb) approach in an automated digital immunoassay on the Quanterix HD-X platform. BoAb assays using vaccine and delta variant viral strains showed strong correlation with cell-based pseudovirus and live-virus neutralization activity. Importantly, we were able to detect similar patterns of delta variant resistance to neutralization in samples with paired vaccine and delta variant BoAb measurements. Finally, we screened clinical samples from patients with or without evidence of SARS-CoV-2 exposure by a single-dilution screening version of our assays, finding significant nAb activity only in exposed individuals. In principle, these assays offer a rapid, robust, and scalable alternative to time-, skill-, and cost-intensive standard methods for measuring SARS-CoV-2 nAb levels.


title: The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis

abstract:
Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both may induce indoleamine-2,3- dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of the current study was to systematically review and meta-analyze the TRYCAT pathway status including levels of TRP and kynurenine (KYN) and IDO activity, as assessed using the KYN/TRP ratio. This systematic review was performed in December 2021 and searched data in PubMed, Google Scholar, and Web of sciences. In our meta-analysis we included 14 articles which examine TRP and TRYCATs in COVID-19 patients versus non-COVID-19 controls, and severe/critical versus mild/moderate COVID-19. Overall, the analysis was performed on 1269 individuals, namely 794 COVID-19 patients and 475 controls. The results show a significant (p <0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD=1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD= 1.123, 95% CI: 0.730;1.516) and significantly lower TRP ((SMD= - 1.002, 95%CI: -1.738; -0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD= 0.945, 95%CI: 0.629; 1.262) and KYN (SMD= 0.806, 95%CI: 0.462; 1.149) were also significantly (p <0.001) higher and TRP lower (SMD= -0.909, 95% CI: -1.569; -0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in the kynurenic acid (KA)/KYN ratio and KA between COVID-19 patients and controls. Our results indicate increased activity of the IDO enzyme in COVID-19 and in severe/critical patients. The TRYCAT pathway is probably implicated in the pathophysiology and progression of COVID-19 and may signal a worse outcome of the disease.

One-sentence summaryThe current meta-analysis study revealed a significant increase in peripheral blood IDO activity and kynurenine levels and a significant reduction in tryptophan in COVID-19 versus controls and in severe/critical COVID-19 versus mild/moderate COVID-19.


title: Predicting Respiratory Decompensation in Mechanically Ventilated Adult ICU Patients

abstract:
BackgroundMechanical ventilation is a life-saving treatment in the Intensive Care Unit (ICU), but often causes patients to be at risk of further respiratory complication. We created a statistical model utilizing electronic health record and physiologic vitals data to predict the Center for Disease Control and Prevention (CDC) defined Ventilator Associated Complications (VACs).

MethodsWe constructed a random forest model to predict occurrence of VACs using health records and chart events from adult patients in the Medical Information Mart for Intensive Care III (MIMIC-III) database. We trained the machine learning models on two patient populations of 1921 and 464 based on low and high frequency data availability. Model features were generated using both basic statistical summaries and tsfresh, an automated python feature generation library. Classification to determine whether a patient will experience VAC one hour after 36 hours of ventilation was performed using a random forest classifier. Two different sample spaces conditioned on five varying feature extraction techniques were evaluated to identify the most optimal selection of features resulting in the best VAC discrimination. Each dataset was assessed using K-folds cross-validation (k = 10), giving average area under the receiver operating curves (AUROC) s and accuracies.

FindingsAfter feature selection, hyperparameter tuning, and feature extraction, the best performing model used automatically generated features on high frequency data and achieved an average Area Under Receiver Operating Characteristic Curve (AUC) of 0{middle dot}83 {+/-} 0{middle dot}11 and an average accuracy of 0{middle dot}69 {+/-} 0{middle dot}10.

InterpretationWe constructed a promising model to predict VACs 1 hour prior to occurrence with 36 hours of ICU patient data. The model provides early warnings of VACs, which may allow actionable therapies to prevent or mitigate ventilator associated complications.

FundingN/A

category: intensive care and critical care medicine


title: Understanding of and Trust in the Centers for Disease Control and Prevention's Revised COVID-19 Isolation and Quarantine Guidance Among US Adults

abstract: On December 27, 2021 the Centers for Disease Control and Prevention (CDC) announced changes to their guidance for individuals who are exposed to or test positive for COVID-19. The revised recommendations have prompted widespread discussion of both the scientific rationale and communication strategy, including criticism from the American Medical Association.1,2 In this survey study, we assessed understanding of and trust in the CDCs initial public statement about the new guidance among US adults.


title: Reliability and validity of the Japanese version of the Mental Health Literacy Scale (MHLS) among undergraduate and graduate students in the medical field

abstract:
ObjectiveMental health literacy (MHL) is a fundamental basis of reducing stigma towards mental disorders and promoting early help-seeking. However, there is no internationally standardized scale covering all the attributes of MHL available in Japan. This study aimed to examine the reliability and validity of the Japanese version of the Mental Health Literacy Scale (MHLS) developed by OConnor et al. (2015).

MethodsThe MHLS was translated in accordance with international guidelines. Japanese students in the medical field were invited to complete an online questionnaire twice at baseline and two-week follow-up. Using the data, Cronbachs alphas, intra-class correlation coefficient (ICC), and measurement errors were calculated for internal consistency and test-retest reliability. Correlations with mental health-related behavior (RIBS), accurate knowledge about mental disorders (MIDUS), intentions to seek help (GHSQ), and psychological distress (K6) were used to examine the convergent validity. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were performed to test structural validity.

ResultsA total of 183 and 150 students responded at baseline and follow-up. Cronbachs alpha coefficient was 0.76 and the ICC was 0.77 for the total score. The MHLS had a strong positive correlation with RIBS and moderate positive correlations with MIDUS and GHSQ. The CFA did not show a good fit either for one-or six-factor models, and the EFA yielded a four-factor structure.

ConclusionsThe Japanese version of the MHLS demonstrated adequate reliability and validity, while the factor structure did not fit previously proposed models. This scale may be useful for assessing the degree of MHL among medical field students in Japan.


title: Towards increasing equity in healthcare among transgender women: a cross-sectional analysis of self-reported needs and health service utilization in Lima, Peru

abstract: Globally, transgender women experience wide-ranging barriers to health and care, with disproportionately high risks of infectious and chronic diseases, mental illness, violence, and substance abuse. Despite these vulnerabilities, research on transgender populations in low- and middle-income countries is extremely limited. Furthermore, existing studies have primarily focused on HIV/AIDS, with less emphasis on transgender womens broader health needs. This cross-sectional study conducted in Lima, Peru aimed to analyze patterns of morbidity and health service uptake to identify subgroups that be especially in need of health interventions to improve access. We identified suboptimal levels of health coverage and access to care, with less education and older age as important risk factors for self-reported illness and HIV and tuberculosis (TB) testing, and differential HIV testing and pre-exposure prophylaxis (PrEP) usage among gender identity subgroups within Perus broader community of transgender women. Both awareness of and interest in PrEP were suboptimal, and usage was low among those who were interested in taking PrEP. Future public health efforts should be tailored to the diverse needs of transgender women, bridge the gap between PrEP interest and use, and increase insurance coverage and access to trans-friendly services to promote improved health outcomes and equity.


title: Aberrant naive CD4+ T Cell differentiation in systemic juvenile idiopathic arthritis is committed to B cell help

abstract:
ObjectiveSystemic juvenile idiopathic arthritis (sJIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. Previous work indicated decreased IFN{gamma}-expression by T helper (Th) cells in sJIA. Here, we hypothesized this to result from aberrant or incomplete Th cell polarization.

MethodsCells or sera were obtained from healthy controls (HC, n=26) and sJIA patients (n=61). Isolated naive Th cells were cultured under Th1, Th17, and T follicular or T peripheral helper (Tf/ph) polarizing conditions and were partly co-cultured with allogenic memory B cells. Surface marker, transcription factor, and/or cytokine expression in peripheral or polarized Th cells or sera as well as B cellular plasma blast generation were studied by flow cytometry, multiplexed bead array assays, ELISA and retrospective RNA profiling analyses.

ResultsSJIA naive Th cell differentiation towards Th1 resulted in low IFN{gamma} and Eomesodermin expression. Instead, developing sJIA Th1 cells revealed elevated IL-21 release that negatively correlated with cellular IFN{gamma} and Eomesodermin expression. Both In vitro and ex vivo, IL-21 together with PD-1, ICOS and CXCR5 expression indicated naive sJIA Th cell differentiation to rather polarize towards a Tf/ph phenotype. Retrospective analysis of whole blood RNA sequencing data demonstrated sJIA-specific overexpression of Bcl-6 as respective master transcription factor. Compared to controls, in vitro generated sJIA Tf/ph cells promoted enhanced B cellular plasma-blast generation.

ConclusionIn sJIA pathogenesis skewing of sJIA naive Th cell differentiation towards a Tf/ph phenotype may represent an echo of autoimmunity, which could shed light on the mechanisms driving the progression towards chronic destructive arthritis.

category: rheumatology


title: Neutrophil Extracellular Trap Biomarker Titers and Delayed Cerebral Ischemia in Patients With Aneurysmal Subarachnoid Hemorrhage

abstract:
BackgroundMyeloperoxidase (MPO)-DNA complexes, biomarkers of neutrophil extracellular traps, have been associated with arterial and venous thrombosis. Their role in patients with aneurysmal subarachnoid hemorrhage (aSAH) is unknown. Here, we sought to explore whether serum MPO-DNA-complexes are present in patients with aSAH, and whether these levels are associated with delayed cerebral ischemia (DCI).

MethodsWe performed a post-hoc analysis of a prospective, blinded, observational single-center biomarker study that enrolled consecutive patients with spontaneous SAH between July 2018 and September 2020. Serum samples obtained on admission and on hospital day 4 were analyzed for concentrations of MPO-DNA complexes. The primary outcome was the occurrence of DCI defined as new infarction on brain CT-scan. The secondary outcome was clinical vasospasm, a composite of clinical and transcranial doppler parameters. We used Wilcoxons signed-rank-test to assess for differences between paired measures.

ResultsAmong 100 patients with spontaneous SAH, mean age 59 (SD+13) years, 55% women, 78 patients had an aneurysmal SAH and complete DCI information. Among these, 29 (37%) developed DCI. MPO-DNA complexes were detected in all samples. The median MPO-DNA level was 33 ng/ml (IQR, 18-43 ng/ml) on admission, and 22 ng/ml (IQR, 11-31 ng/ml) on day 4 (Mann-Whitney test: p=0.015). In the primary outcome analysis, we found a significant reduction in MPO-DNA levels from admission to day 4 in patients with DCI (paired test, p=0.036) but not in those without DCI (p=0.171). The secondary analysis showed a similar reduction in MPO-DNA levels between admission and day 4 in patients with (p=0.006), but not in those without clinical vasospasm (p=0.473).

ConclusionsMPO-DNA-complexes are detectable in peripheral serum samples of patients with aSAH. A pronounced reduction in MPO-DNA levels over the first days after aSAH might herald DCI. The potential of MPO-DNA levels to serve as a biomarker of DCI requires further exploration.


title: An image processing protocol to extract variables predictive of human embryo fitness for assisted reproduction

abstract:
OBJECTIVETo study the application of image processing for segmentation of blastocysts images and extraction of potential variables for prediction of embryo fitness.

DESIGNRetrospective study.

SETTINGSingle reproductive medical center. IVI-RMA (Valencia, Spain) between 2017 and 2019.

PATIENTSAn initial dataset including 353 images from EmbryoScope(R) and 474 images from Geri(R) incubators was acquired, of which 320 images from EmbryoScope(R) and 309 images from Geri(R) incubators were used in this study.

INTERVENTION(S)None.

MAIN OUTCOME MEASURE(S)Successful segmentation of images into trophectoderm (TE), blastocoel, and inner cell mass (ICM) using the proposed processing steps.

RESULTSA total of 33 variables were automatically generated by digital image processing, each representing a different aspect of the embryo and describing a different characteristic of the expanding blastocyst (EX), ICM, or TE. These variables can be categorized into texture, gray level average, gray level standard deviation, modal value, relations, and light level. The automated and directed steps of the proposed processing protocol exclude spurious results, except when image quality (e.g., focus) prevents correct segmentation.

CONCLUSIONSThe proposed image processing protocol that can successfully segment human blastocyst images from two distinct sources and extract 33 variables with potential utility in embryo selection for ART.


title: Anterior Segment Parameters on Optical Coherence Tomography in Healthy Children

abstract:
PurposeTo assess the anterior segment parameters in healthy children, using high resolution spectral domain optical coherence tomography (SD-OCT).

DesignProspective, observational study

Methods108 eyes of 54 healthy children [≤]16 years were included after a thorough eye examination. Significant refractive error (>{+/-}5 DS), history of previous glaucoma, ocular pathology, intraocular surgery, trauma or systemic ailments were excluded. The anterior segment analysis was done by Optopol Revo 80(R) high resolution SD-OCT. Central corneal thickness (CCT), Angle opening distance (AOD), Anterior chamber (AC) angle, Trabecular iris space area (TISA), Trabecular iris angle (TIA), iris thickness at 2 mm, internal AC diameter and lens vault were evaluated.

ResultsMean age was 11.38{+/-}3.18 years with a female predominance; 29 (53.7%). Mean IOP was 13.63{+/-}2.90 mmHg, mean axial length was 22.82{+/-}0.89 mm, mean spherical equivalent was -0.14{+/-}1.28 D, mean CCT was 532.6{+/-}46.09mm and mean CDR was 0.31{+/-}0.19. The mean internal AC diameter was 11609.15{+/-}2354 {micro}m. The nasal AC angle was 53.54{+/-}11.82{degrees} and significantly wider than the temporal AC angle; 50.37{+/-}10.26{degrees} [p=0.008]. The nasal AOD500 was 0.9{+/-}0.33 mm and not significantly greater than the temporal AOD500, 0.85{+/-}0.28 mm [p=0.09]. The nasal AOD750 was 1.21{+/-}0.45 mm, significantly greater than the temporal AOD750, 1.06{+/-}0.32 mm [p=0.001]. The nasal TIA was 41.75{degrees}; not significantly greater than the temporal TIA, 40.24{degrees} [p=0.246]. The nasal TISA500 was 0.33{+/-}0.15 mm2; not significantly wider than the temporal TISA500, 0.31{+/-}0.10 mm2 [p=0.056]. The nasal TISA750 was 0. 59{+/-}0.22 mm2; not significantly wider than the temporal TISA750, 0.56{+/-}0.21 mm2 [p=0.14]. The nasal iris thickness at 2 mm from pupil was 483.54{+/-}129.56 {micro}m; not significantly different from the temporal iris thickness, 505.8{+/-}138.85 {micro}m [p=0.08]. The mean lens vault was - 519.58{+/-}359{micro}m.

ConclusionsOur study data depicts the normal anterior segment parameters in healthy children. This will be useful in diagnosing and managing ocular pediatric pathology.

Key MessagesO_LIAnterior segment OCT is still an emerging technique especially in pediatric eye assessment
C_LIO_LIAnterior segment evaluation via OCT has not been reported in our pediatric population
C_LIO_LIOur study describes a detailed assessment of anterior segment in pediatric eyes
C_LIO_LIReporting results of normative data helps in diagnosing ocular pathology
C_LI


title: Frequency of FLCN Loss of Function Variants and Birt-Hogg-Dube-Associated Phenotypes in a Healthcare System Population

abstract:
PurposeCurrent penetrance estimates of Birt-Hogg-Dube (BHD)-associated cutaneous, pulmonary, and renal manifestations are based on clinically ascertained families. In a healthcare system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) variants in the FLCN gene, which cause BHD, and the penetrance of BHD-related phenotypes.

MethodsExomes from 135,990 patient-participants in Geisingers MyCode(R) cohort were assessed for P/LP FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between FLCN P/LP variants and BHD-related phenotypes were assessed by Firths logistic regression.

ResultsP/LP FLCN variants were identified in 35 (1 in 3,234) individuals, 68.6% of whom had BHD-related phenotype(s) including: cystic lung disease (65.7%); pneumothoraces (17.1%); cutaneous manifestations (8.6%); and renal cancer (2.9%). Only four (11.4%) were clinically diagnosed with BHD.

ConclusionIn this healthcare population, the frequency of P/LP FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes in the EHR, a minority were clinically diagnosed with BHD, likely because cutaneous manifestations, pneumothoraces, and renal cancer were observed at lower frequencies than clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.


title: Personalized structural biology reveals the molecular mechanisms underlying heterogeneous epileptic phenotypes caused by de novo KCNC2 variants

abstract:
BackgroundNext-generation whole exome sequencing (WES) is ubiquitous as an early step in the diagnosis of rare diseases and the interpretation of variants of unknown significance (VUS). Developmental and epileptic encephalopathies (DEE) are a group of rare devastating epilepsies, many of which have unknown causes. Increasing WES in the clinic has identified several rare monogenic DEEs caused by ion channel variants. However, WES often fails to provide actionable insight, due to the challenges of proposing functional hypotheses for candidate variants. Here, we describe a "personalized structural biology" (PSB) approach that addresses this challenge by leveraging recent innovations in the determination and analysis of protein 3D structures.

ResultsWe illustrate the power of the PSB approach in an individual from the Undiagnosed Diseases Network (UDN) with DEE symptoms who has a novel de novo VUS in KCNC2 (p.V469L), the gene that encodes the Kv3.2 voltage-gated potassium channel. A nearby KCNC2 variant (p.V471L) was recently suggested to cause DEE-like phenotypes. We find that both variants are located in the conserved hinge region of the S6 helix and likely to affect protein function. However, despite their proximity, computational structural modeling suggests that the V469L variant is likely to sterically block the channel pore, while the V471L variant is likely to stabilize the open state. Biochemical and electrophysiological analyses demonstrate heterogeneous loss-of-function and gain-of-function effects, respectively, as well as differential inhibition in response to 4-aminopyridine (4-AP) treatment. Using computational structural modeling and molecular dynamics simulations, we illustrate that the pore of the V469L variant is more constricted increasing the energetic barrier for K+ permeation, whereas the V471L variant stabilizes the open conformation

ConclusionsOur results implicate KCNC2 as a causative gene for DEE and guided the interpretation of a UDN case. They further delineate the molecular basis for the heterogeneous clinical phenotypes resulting from two proximal pathogenic variants. This demonstrates how the PSB approach can provide an analytical framework for individualized hypothesis-driven interpretation of protein-coding VUS suspected to contribute to disease.


title: Factors associated with iron deficiency and how they can be used in blood donor selection processes

abstract:
Background and objectivesIn an effort to improve donor health, we set out to investigate determinants other than blood donation that increase risk of ID in a healthy population and if they should be implemented into current blood donor selection processes.

MethodsWe systematically searched the PubMed, Ovid Medline and Scopus for articles related to ID.

ResultsCurrent evidence suggests that several determinants, including biological, environmental, lifestyle and socioeconomic factors increase the risk for ID.

ConclusionsHeavy menstruation, use of some medications and dietary factors could potentially be implemented in donor selection, however further study is needed.

category: hematology


title: Case-control investigation of invasive Salmonella disease in Africa - comparison of human, animal and household environmental isolates find no evidence of environmental or animal reservoirs of invasive clades/strains

abstract:
BackgroundInvasive Salmonella infections are a major cause of morbidity and mortality in Sub-Saharan Africa (SSA). However, the sources and modes of transmission are uncertain. To shed light on potential transmission routes of invasive Salmonellosis, we obtained Salmonella isolates from healthy people, animals, and the environment of index-cases and geographically-matched control households.

MethodologySixty index cases of human invasive Salmonella infection were recruited. Twenty eight invasive Non-Typhoidal Salmonella (iNTS) disease and 32 typhoid patients consented to household sampling. Each index-case household was geographically matched to a control household. Extensive microbiological sampling included stool sampling from healthy household members, stool or rectal swabs from household-associated animals and boot-sock sampling of the household environment.

Findings1203 samples were taken from 120 households, yielding 43 non-Typhoidal Salmonella (NTS) isolates from 25 households (overall sample positivity 3.6%). In the 28 iNTS patients, disease was caused by 3 STs of Salmonella Typhimurium, mainly ST313. In contrast, the isolates from households spanned 15 sequence types (STs). Two S. Typhimurium isolates from index cases closely matched isolates from their respective asymptomatic household members (2 and 3 SNP differences respectively). Despite the recovery of a diverse range of NTS, there was no overlap between the STs causing iNTS disease and any environmental or animal isolates,

ConclusionsThe finding of NTS strains from index cases that matched household members, coupled with lack of related animal or environmental isolates, supports a hypothesis that healthy humans were the source of iNTS infections in the household. The breadth of NTS strains found in the household environment across all sites demonstrated the robustness of NTS sampling methodology, and suggests a diverse ecology of Salmonella in this setting. The lack of S. Typhi isolates from the household environment suggests that further methodological development may be needed to culture S. Typhi from the environment.

Author summaryInvasive Salmonella infections cause the loss of millions of disability adjusted life years (DALYs) every year globally. The two main types of invasive Salmonella infections in Africa are i) typhoid fever, caused by Salmonella Typhi, and ii) invasive Non-Typhoidal Salmonella (iNTS) disease, primarily caused in our setting by Salmonella Typhimurium. Despite the high disease burden, and the observed differences between the epidemiology of typhoid and iNTS disease, we lack an understanding of the reservoirs and transmission routes of iNTS. Therefore, we carried out extensive microbiological sampling of the household members and living environments of patients with invasive Salmonella infections, and of geographically-matched control households, and investigated the genetic relationships between household Salmonella and index-case blood-stream isolates by whole genome sequencing (WGS). We only identified Salmonella that matched iNTS-associated strains in the stool of healthy people from the same households. Our findings suggest that either iNTS-associated strains are spread person-to-person, or the infections arose from a common source. Boot-sock sampling of the household environment gave the highest yield of Salmonella of any of our sampling strategies. None of the 41 environmental Salmonella isolates from non-human sources, including 4 domestic animal-associated isolates, matched the disease-causing sequence types. Our findings are consistent with the reservoir of Typhimurium iNTS infections being the human gastrointestinal tract, and transmission occurring within households.

category: infectious diseases


title: Adjustment for Unmeasured Spatial Confounding in Settings of Continuous Exposure Conditional on the Binary Exposure Status: Conditional Generalized Propensity Score-Based Spatial Matching

abstract: Propensity score (PS) matching to estimate causal effects of exposure is biased when unmeasured spatial confounding exists. Some exposures are continuous yet dependent on a binary variable (e.g., level of a contaminant (continuous) within a specified radius from residence (binary)). Further, unmeasured spatial confounding may vary by spatial patterns for both continuous and binary attributes of exposure. We propose a new generalized propensity score (GPS) matching method for such settings, referred to as conditional GPS (CGPS)-based spatial matching (CGPSsm). A motivating example is to investigate the association between proximity to refineries with high petroleum production and refining (PPR) and stroke prevalence in the southeastern United States. CGPSsm matches exposed observational units (e.g., exposed participants) to unexposed units by their spatial proximity and GPS integrated with spatial information. GPS is estimated by separately estimating PS for the binary status (exposed vs. unexposed) and CGPS on the binary status. CGPSsm maintains the salient benefits of PS matching and spatial analysis: straightforward assessments of covariate balance and adjustment for unmeasured spatial confounding. Simulations showed that CGPSsm can adjust for unmeasured spatial confounding. Using our example, we found positive association between PPR and stroke prevalence. Our R package, CGPSspatialmatch, has been made publicly available.

category: epidemiology


title: Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study

abstract: Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. Here we assess cerebrovascular health in 45 hospitalised patients using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode, as indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. Exploratory analysis suggests that the level of cerebrovascular dysfunction is associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.


title: Random effects modelling vs logistic regression for the inclusion of cluster level covariates in propensity scores for medical device and surgical epidemiology

abstract:
PurposeSurgeon and hospital related features such as surgeries volume can be associated with treatment choices and treatment outcomes. Accounting for these covariates with propensity score (PS) analysis can be challenging due to clustered nature of the data. Previous studies have not focused solely on the PS estimation strategy when treatment effects are estimated using random effects model(REM). We studied PS estimation for clustered data using REM compared with logistic regression.

MethodsSix different PS estimation strategies were tested using simulations with variable cluster-level confounding intensity (odds ratio(OR)=1.01 to OR=2.5): i) logistic regression PS excluding cluster- level confounders; ii) logistic regression PS including cluster-level confounders; iii) same as ii) but including cross-level interactions; iv), v) and vi), similar to i), ii) and iii) respectively but using REM instead of logistic regression PS. Same analysis were tested in a randomised controlled trial emulation of partial vs total knee replacement surgery. Simulation metrics included bias and mean square error (MSE). For trial emulation, we compared observational vs trial-based treatment effect estimates.

ResultsIn most simulated scenarios, logistic regression including cluster-level confounders gave more accurate estimates with the lowest bias and MSE. E.g. with 50 clusters x 200 individuals and confounding intensity OR=1.5, the relative bias= 10% and MSE= 0.003 for (i), compared to 21% and, 0.010 for (iv). In the Trial emulation, all 6 PS strategies gave similar treatment effect estimates.

ConclusionsLogistic regression including patient and surgeon/hospital-level confounders appears to be the preferred strategy for PS estimation. Further investigation with more complex clustered structure is suggested.

Competing interestsProf. Prieto-Alhambras research group has received grant support from Amgen, Chesi-Taylor, Novartis, and UCB Biopharma. His department has received advisory or consultancy fees from Amgen, Astellas, AstraZeneca, Johnson, and Johnson, and UCB Biopharma and fees for speaker services from Amgen and UCB Biopharma. Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programs organised by DPAs department and open for external participants organized by his department outside submitted work.

Ethics Approval and Informed ConsentThis study was approved by the secretary of state, having considered the recommendation from the Confidentiality Advisory Group (CAG reference: 17/CAG/0174). Informed ethical approval was given on the use of pseudonymised patients data included in the study.


title: Doxycycline for the prevention of progression of COVID-19 to severe disease requiring intensive care unit (ICU) admission: a randomized, controlled, open-label, parallel group trial (DOXPREVENT.ICU)

abstract:
BackgroundAfter admission to hospital, COVID-19 progresses in a substantial proportion of patients to critical disease that requires intensive care unit (ICU) admission.

MethodsIn a pragmatic, non-blinded trial, 387 patients aged 40-90 years were randomised to receive treatment with SoC plus doxycycline (n=192) or SoC only (n=195). The primary outcome was the need for ICU admission as judged by the attending physicians. Three types of analyses were carried out for the primary outcome: "Intention to treat" (ITT) based on randomisation; "Per protocol" (PP), excluding patients not treated according to randomisation; and "As treated" (AT), based on actual treatment received. The trial was undertaken in six hospitals in India with high-quality ICU facilities. An online application serving as the electronic case report form was developed to enable screening, randomisation and collection of outcomes data.

ResultsAdherence to treatment per protocol was 95.1%. Among all 387 participants, 77 (19.9%) developed critical disease needing ICU admission. In all three primary outcome analyses, doxycycline was associated with a relative risk reduction (RRR) and absolute risk reduction (ARR): ITT 31.6% RRR, 7.4% ARR (P=0.063); PP 40.7% RRR, 9.6% ARR (P=0.017); AT 43.2% RRR, 10.8% ARR (P=0.007), with numbers needed to treat (NTT) of 13.4 (ITT), 10.4 (PP), and 9.3 (AT), respectively. Doxycycline was well tolerated with not a single patient stopping treatment due to adverse events.

ConclusionsIn hospitalized COVID-19 patients, doxycycline, a safe, inexpensive, and widely available antibiotic with anti-inflammatory properties, reduces the need for ICU admission when added to SoC.


title: Human germline biallelic complete NFAT1 deficiency causes the triad of progressive joint contractures, osteochondromas, and susceptibility to B cell malignancy

abstract: Discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs*18) and presented with joint contractures, osteochondromas, and B cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in pro-survival and inflammatory genes. Systematic single-cell-omic analyses revealed an environment that promotes lymphomagenesis with accumulation of naive B cells (with oncogenic signatures - MYC, JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further define detrimental effects a long-term use of calcineurin inhibitors.