title: EXTRACELLULAR MATRIX REMODELING IN ATOPIC DERMATITIS HARNESSES THE ONSET OF AN ASTHMATIC PHENOTYPE AND IS A POTENTIAL CONTRIBUTOR TO THE ATOPIC MARCH

abstract:
The development of atopic dermatitis (AD) in infancy, and subsequent allergic rhinitis, food allergies, and asthma in later childhood, is known as the atopic march. The mechanism is largely unknown, yet the course of disease indicates the contribution of inter-epithelial crosstalk, through to the onset of inflammation in the skin and progression to another mucosal epithelium.

Here, we investigated if and how skin-lung epithelial crosstalk could contribute to the development of the atopic march. First, we emulated this inter-epithelial crosstalk through indirect co-culture of bioengineered atopic-like skin disease models and three-dimensional bronchial epithelial models triggering an asthma-like phenotype in the latter. A subsequent secretome analysis identified throm-bospondin-1, CD44, complement factor C3, fibronectin, and syndecan-4 as potentially relevant skin-derived mediators. As these mediators are extracellular matrix (ECM)-related proteins, we then studied the involvement of the ECM, unveiling distinct proteomic, transcriptomic, and ultrastructural differences in atopic samples. The latter indicated ECM remodeling triggering the release of the above-mentioned mediators. In addition to pro-inflammatory effects in lung tissue, the ECM mediators also exert distinct effects on CD4+ T cells. In vivo mouse data showed that exposure to these mediators over seven days dysregulated activated circadian clock genes which have been previously discussed in the context of atopic diseases and asthma development.

We hypothesize the existence of a skin-lung axis that could contribute to the atopic march driven by skin ECM remodeling.

One Sentence SummaryAtopic skin harbors the progression of atopic diseases to lung tissue through a skin-lung axis that contributes to the atopic march via extracellular matrix remodeling.


title: An adaptive testing strategy for efficient utilization of healthcare resources during an epidemic

abstract: Stringent lockdowns imposed as a preventive measure against rapidly spreading epidemics like COVID-19 adversely affect the economy. They also prolong the duration of the epidemic, making the hardship on the economy two-fold. The extended duration observed in strategies rooted in social distancing and lockdowns is often due to the under-utilization of medical facilities. Even though an under-utilized health care system is preferred over an overwhelmed one, an alternate and optimal strategy is to maintain medical facilities close to their capacity. We show that such a control strategy can be achieved by varying the testing rate and we present an algorithm to calculate the number of tests per day to achieve this. We illustrate the efficacy of our strategy by showing that it reduced the epidemic duration by 40% in comparison to lockdown-based strategies. Our strategy helps in managing the epidemic without high fatalities and the crippling effects of lockdowns.

category: epidemiology


title: Systematic recovery of building plumbing-associated microbial communities after extended periods of altered water demand during the COVID-19 pandemic.

abstract: Building closures related to the coronavirus disease (COVID-19) pandemic resulted in increased water stagnation in commercial building plumbing systems that heightened concerns related to the microbiological safety of drinking water post re-opening. The exact impact of extended periods of reduced water demand on water quality is currently unknown due to the unprecedented nature of widespread building closures. We analyzed 420 tap water samples over a period of six months, starting the month of phased reopening (i.e., June 2020), from sites at three commercial buildings that were subjected to reduced capacity due to COVID-19 social distancing policies and four occupied residential households. Direct and derived flow cytometric measures along with water chemistry characterization were used to evaluate changes in plumbing-associated microbial communities with extended periods of altered water demand. Our results indicate that prolonged building closures impacted microbial communities in commercial buildings as indicated by increases in microbial cell counts, encompassing greater proportion cells with high nucleic acids. While flushing reduced cell counts and increased disinfection residuals, the microbial community composition in commercial buildings were still distinct from those at residential households. Nonetheless, increased water demand post-reopening enhanced systematic recovery over a period of months, as microbial community fingerprints in commercial buildings converged with those in residential households. Overall, our findings suggest that sustained and gradual increases in water demand may play a more important role in the recovery of building plumbing-associated microbial communities as compared to short-term flushing, after extended periods of altered water demand that result in reduced flow volumes.

category: public and global health


title: A Phase 2 open-label study to determine the safety and efficacy of weekly dosing of ATL1102 in patients with non-ambulatory Duchenne muscular dystrophy

abstract:
BackgroundATL1102 is a 2MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4. ATL1102 inhibits expression of CD49d on lymphocytes, thereby reducing their survival, activation and migration to sites of inflammation. Children with Duchenne muscular dystrophy (DMD) have dystrophin deficient muscles. These are susceptible to contraction induced injury which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment.

MethodsThis Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10-18 years. Participants receiving corticosteroid therapy were allowed into the study if on a stable dose for at least 3 months. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline.

ResultsATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week eight (mean change -0.56x109/L 95%CI -1.52, 0.40), week twelve (mean change -0.53x109/L 95%CI -1.65, 0.58) or week twenty-four (mean change -0.28x109/L 95%CI -1.10, 0.55) of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p=0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period.

ConclusionATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD.

category: neurology


title: Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans

abstract: Genome-wide association studies (GWAS) in admixed populations such as African American (AA) have limited sample sizes, resulting poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within boundaries of these genes, we proposed a novel gene-based PRS method (PRSgene) by using variants located in these shared disease-causing genes. Using AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and EA GWAS of problematic alcohol use as the discovery datasets, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA cohorts (P-values: 7.61E-05-6.27E-03; Betas: 0.15-0.21) and outperformed PRS calculated using all variants (P-values: 7.28E-03-0.16; Betas: 0.06-0.18). PRSgene was also associated with AUD in an EA cohort (P-value=0.02, Beta=0.11). In AA, individuals in the highest PRSgene decile had an Odds Ratio of 1.76 (95% CI: 1.32-2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving synaptic system, which are known to be AUD-related. Additionally, 26 genes were targets of drugs to treat AUD or other diseases, but may be repurposed to treat AUD. Our study demonstrated that our gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into identification of AUD genes.

category: addiction medicine


title: A residual marker of cognitive reserve is associated with resting-state intrinsic functional connectivity along the Alzheimer's disease continuum

abstract:
BackgroundCognitive reserve (CR) explains interindividual differences in the impact of neurodegenerative burden on cognitive and daily functioning. A residual model was proposed to estimate CR more accurately compared to static measures, such as years of education. However, the functional brain correlates of residual CR markers (CRM) remain unexplored.

MethodsFrom the DELCODE cohort, 318 participants with resting-state functional and structural MRI data were included and stratified using cerebrospinal fluid (CSF) biomarkers according to the A(myloid-{beta}, A{beta})/T(au)/N(eurodegeneration) classification scheme, resulting in 112 A{beta}-negative healthy controls and 206 A{beta}-positive patients in the Alzheimers disease (AD) spectrum.. CRM was calculated utilizing residuals obtained from a multilinear regression model using global cognition as dependent variable and demographic and disease burden measures as predictors. Associations between the CRM and intrinsic network connectivity (INC) in resting-state networks associated with cognition were explored, including the default mode network (DMN), frontoparietal network (FPN), salience network (SAL) and dorsal attention network (DAN). Moreover, the association between memory performance-associated regional INC and CRM was assessed.

ResultsCRM was positively associated with INC in the DMN in the entire cohort. In a subgroup analysis, the A+T+N+ group revealed an anti-correlation between SAL and DMN. Furthermore, CRM was positively associated with the anti-correlation between the memory-related regions in the FPN and the DMN in the A+ and A+T/N+ subgroups.

ConclusionsCRM is associated with alterations of functional connectivity in resting-state networks of cognitive function, particularly the DMN and the FPN. Our results provide evidence on individual functional network differences associated with CRM in the AD continuum.

category: psychiatry and clinical psychology


title: Mechanisms linking physical activity with psychiatric symptoms: a protocol for a systematic review.

abstract:
IntroductionPersistent psychiatric symptomatology during childhood and adolescence predicts vulnerability to experience mental illness in adulthood. Physical activity is well-known to provide mental health benefits across the lifespan. However, the underlying mechanisms linking physical activity and psychiatric symptoms remain underexplored. In this context, we aim to systematically synthesize evidence focused on the mechanisms through which physical activity might reduce psychiatric symptoms across all ages.

Methods and analysisWith the aid of a biomedical information specialist, we will develop a systematic search strategy based on the predetermined research question in the following electronic databases: MEDLINE, Embase, Web of Science, Cochrane, and PsycINFO. Two independent reviewers will screen and select studies, extract data, and assess the risk of bias. In case of inability to reach a consensus, a third person will be consulted. We will not apply any language restriction, and we will perform a qualitative synthesis of our findings as we anticipate that studies are scarce and heterogeneous.

Ethics and disseminationOnly data that has already been published will be included. Then, ethical approval is not required. Findings will be published in a peer-reviewed journal and presented at conferences. Additionally, we will communicate our findings to healthcare providers and other sections of society (e.g., through regular channels, including social media).

PROSPERO registration numberCRD42021239440

Strengths and limitations of this studyO_LIThis protocol has been designed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses for Protocols (PRISMA-P) guidelines and guidelines of the Cochrane Effective Practice and Organisation of Care.
C_LIO_LIThis protocol presents a cautiously designed search strategy, inclusion and exclusion criteria, and timespan and age-range coverage.
C_LIO_LIA possible limitation is that included studies might be heterogeneous in the study design, data collection methods, and data analysis which might limit the ability to synthesize the results using a meta-analysis.
C_LIO_LIThe value of this systematic review depends on the quality and availability of the evidence on the topic.
C_LI

category: sports medicine


title: ELF5 is a respiratory epithelial cell-specific risk gene for severe COVID-19

abstract: Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis and severe course of COVID-19 infection remain poorly understood. Here, we identified eight candidate protein mediators of COVID-19 outcomes by establishing a shared genetic architecture at protein-coding loci using large-scale human genetic studies. The transcription factor ELF5 (ELF5) showed robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.85; 95%-CI: 2.65-8.89; p-value<3.1x10-7) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. We also observed a 25% reduced risk of severe COVID-19 per 1 s.d. higher genetically predicted plasma G-CSF, a finding corroborated by a clinical trial of recombinant human G-CSF in COVID-19 patients with lymphopenia reporting a lower number of patients developing critical illness and death. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a novel risk gene for COVID-19 prognosis, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.

category: genetic and genomic medicine


title: Serum extracellular vesicles trace COVID-19 progression and immune responses

abstract: Coronavirus disease 2019 (COVID-19) has transformed very quickly into a world pandemic with severe and unexpected consequences on human health. Concerted efforts to generate better diagnostic and prognostic tools have been ongoing. Research, thus far, has primarily focused on the virus itself or the direct immune response to it. Here, we propose extracellular vesicles (EVs) from serum liquid biopsies as a new and unique modality to unify diagnostic and prognostic tools for COVID-19 analyses. EVs are a novel player in intercellular signaling particularly influencing immune responses. We herein show that innate and adaptive immune EVs profiling, together with SARS-CoV-2 Spike S1+ EVs provide a novel signature for COVID-19 infection. It also provides a unique ability to trace the co-existence of viral and host cell signatures to monitor affected tissues and severity of the disease progression. And provide a phenotypic insight into COVID-associated EVs.

category: infectious diseases


title: Cross-sectional study to assess the efficacy of SARS-CoV-2 vaccination in patients with monoclonal gammopathies

abstract: SARS-CoV-2 vaccination is the most effective strategy to protect patients with haematologic malignancies against severe COVID-19, but primary vaccine responses are less effective in this population. Here, we characterized the humoral responses following 3 months after mRNA-based vaccines in patients at different stages of the same plasma cell diseases, including monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and multiple myeloma on first line therapy (MM), compared to a healthy control population matched by sex and age. We observed that plasmas from uninfected MM patients after 3 months post-vaccine have lower SARS-CoV-2 specific IgG and IgA antibodies and decreased neutralization capacity compared with MGUS and SMM individuals, and a group of healthy controls. Importantly, we detected significantly higher plasma neutralization capacity in MM individuals who recovered from COVID-19 compared to their uninfected counterparts, highlighting that hybrid immunity elicit stronger immune responses even in this immunocompromised population. In contrast to MM group, no differences in the vaccine-induced humoral response were observed between uninfected MGUS, SMM and healthy individuals. In conclusion, a booster vaccine dose is recommended in uninfected MM patients to develop an adequate and effective humoral response to SARS-CoV-2 vaccine.


title: Psychological flexibility and the moderating role of the therapeutic working alliance in Acceptance and Commitment Therapy in Daily Life (ACT-DL) in an early psychosis sample.

abstract:
BackgroundWe investigated treatment effects of Acceptance and Commitment Therapy in Daily Life (ACT-DL) on psychological flexibility (PF) and the moderating role of the therapeutic working alliance on these effects in patients with early psychosis.

MethodsACT-DL is an ecological momentary intervention (EMI) combining face-to-face ACT with a smartphone app. In the multi-center INTERACT randomized controlled trial, n=148 early psychosis individuals were randomized to either treatment as usual (TAU as the control condition, n=77) or to ACT-DL in addition to TAU (ACT-DL + TAU as the experimental condition, n=71). We assessed global PF and the therapeutic alliance with self-report questionnaires. In addition, we used the experience sampling methodology (ESM) to assess PF with a momentary (in-the-moment and since-the-previous-beep openness) and an evening (daily PF) questionnaire. Assessments took place at baseline, post-intervention (POST), six (FU6), and twelve months (FU12) follow-up.

ResultsGlobal (B=19.49 to 33.14; all P-values<.001) and daily PF (B=0.68; P-value<.001) improved equally in both conditions at each time point. Individuals in the ACT-DL condition improved more than those in TAU on momentary openness (in-the-moment openness at POST (B=0.32; P-value=0.007) and since-the-previous-beep openness at POST (B=0.33; P<.001) and FU6 (B=0.23; P-value=0.025). Client-perceived working alliance moderated in-the-moment openness such that larger improvements in openness at POST (B=0.05; P-value<.001) were found in ACT-DL in individuals with higher working alliance scores.

ConclusionOur results provide partial support for the capability of ACT-DL to improve daily life measures of openness, and emphasize the importance of the therapeutic relationship in supporting processes of change.


title: Subsequent hip fractures in patients identified by an Fracture Liaison Service (FLS) in England and Wales: linkage of the national FLS and Hip Fracture databases

abstract:
Fracture Liaison Services (FLSs) are recommended healthcare models to deliver secondary fracture prevention and reduce the risk of subsequent fractures. Several studies have demonstrated the cost and clinical effectiveness of FLSs, but there is little real-world data on the impact of FLSs on subsequent hip fracture rates.

A cohort of 50,214 patients from the national FLS database with an index fracture of the hip, spine, or other in 2017 was linked to the National Hip Fracture Database from 2017 to 2020 to identify those patients who went on to have a subsequent hip fracture.

One in twenty (5.1%) of the 9,888 people in whom the index fracture was at the hip went on to suffer a second hip fracture within 3-4 years, despite receiving the support of an FLS. The risk of hip fracture was similar (4.7%) if the index fracture was at the spine, but lower at other sites (2.8%, p<0.001) and the interval shortest after an index hip fracture (1.1 years (0.4,2.0) p<0.001). The proportion of patients with a subsequent hip fracture was not lower by types of anti-osteoporotic medication.

This work highlights the need for alternative anti-osteoporotic management strategies to rapidly decrease the risk of subsequent hip fractures for people seen by an FLS setting with levels of risk that are even higher for patients in areas which are still not served by an FLS.

category: rheumatology


title: Loss of Y in leukocytes as a risk factor for critical COVID-19 in men

abstract: COVID-19 shows an unexplained, strong male bias for severity and mortality. Loss of Y (LOY) in myeloid cells is a risk factor candidate in COVID-19 because of associations with many age-related diseases and its effect on transcription of immune genes. We report the highest levels of LOY in cells that are crucial for the development of severe COVID-19 phenotype, such as low-density neutrophils, granulocytes, and monocytes reaching 46%, 32%, and 29%, respectively, from men with critical COVID-19 (n=139). LOY in sorted subpopulations of leukocytes correlated with increased thrombocyte count, thromboembolic events, invasive mechanical ventilation and a history of vessel disease. In recovered patients, LOY decreased in whole blood and peripheral blood mononuclear cells. Moreover, sc-RNA-seq analysis of CD14+ monocytes from 30 COVID-19 males and 34 controls revealed pervasive transcriptional downregulation in LOY-cells, notably affecting HLA class I and II genes important for antigen presentation. The data support a link between LOY and emergency myelopoiesis as well as the role of LOY in modulation of COVID-19 severity. Our results might also be relevant for other viral infections showing similar male bias.


title: Long-Term Persistence of IgG Antibodies in recovered COVID-19 individuals at 18 months and the impact of two-dose BNT162b2 (Pfizer-BioNTech) mRNA vaccination on the antibody response

abstract: This era of emerging variants needs a thorough evaluation of data on the long-term efficacy of immune responses in vaccinated as well as recovered individuals, to understand the overall evolution of the pandemic. In this study, we aimed to assess the dynamics of IgG titers over 18 months in n=36 patients from the Umbria region in Italy, who had a documented history of COVID-19 infection in March 2020, and then compared the impact of two-dose BNT162b2 (Pfizer-BioNTech) vaccination on the antibody titers of these patients with the ones who did not receive any dose of vaccine. This is the longest observation (March 2020-September 2021) for the presence of antibodies against SARS-CoV-2 in recovered individuals along with the impact of 2 dose-BNT162b2 vaccination on the titers. Fixed-effect regression models were used for statistical analysis which could be also used to predict future titer trends. At 18 months, 97% participants tested positive for anti-NCP hinting towards the persistence of infection-induced immunity even for the vaccinated individuals. Our study findings demonstrate that while double dose vaccination boosted the IgG titers in recovered individuals 161 times, this "boost" was relatively short-lived. The unvaccinated recovered individuals, in contrast, continued to show a steady decline but detectable antibody levels. Further studies are required to re-evaluate the timing and dose regimen of vaccines for an adequate immune response in recovered individuals.


title: Retention of Neutralizing response against SARS-CoV-2 Omicron variant in Sputnik V vaccinated individuals

abstract:
The new variant Omicron (B.1.1.529) of SARS-CoV-2, first identified in November 2021, is rapidly spreading all around the world. The Omicron becomes the dominant variant of SARS-CoV-2. There are many ongoing studies evaluating the effectiveness of existing vaccines. Studies on neutralizing activity of vaccinated sera against Omicron variant are currently being carried out in many laboratories.

In this study, we have shown the neutralizing activity of sera against SARS-CoV-2 Omicron (B.1.1.529) variant compared to the reference Wuhan D614G (B.1) variant in individuals vaccinated with 2 doses of Sputnik V or BNT162b2 in different time points up to 6 months after vaccination. We performed analysis on sample pools with comparable NtAb to Wuhan D614G variant. The decrease in neutralizing antibody (NtAb) to the Omicron variant was 8.1 folds for group of Sputnik V-vaccinated and 21.4 folds for group of BNT162b2-vaccinated. Analysis showed that 74.2% of Sputnik V- and 56.9% of BNT162b2-vaccinated sera had detectable NtAb to SARS-CoV-2 Omicron variant.

The decrease in NtAb to SARS-CoV-2 Omicron variant compared to Wuhan variant has been shown for many COVID-19 vaccines in use, with some showing no neutralization at all. Today the necessity of third booster vaccination is obvious. And the most effective approach, already shown in several studies, is the use of heterologous booster vaccination pioneered in COVID-19 vaccines by Sputnik V.


title: High prevalence of olfactory disorders 18 months after contracting COVID-19

abstract: Reduced olfactory function is the symptom with the highest prevalence in COVID-19 with nearly 70% of individuals with COVID-19 experiencing partial or total loss of their sense of smell at some point during the disease. Recent reports suggest that more than 7 months after recovering from COVID-19, a large proportion of these individuals still have olfactory dysfunction of some form. To establish the prevalence of olfactory dysfunction 18 months and beyond, we tested 100 individuals with established COVID-19 in the first wave of the pandemic using psychophysical full-scale testing of smell and taste functions as well as assessments of parosmia. Participants were recruited from an ongoing study, comprising healthcare workers at a hospital in Stockholm, Sweden, that are regularly tested for SARS-CoV-2 IgG antibodies since the start of the pandemic in Sweden. To assess potential skewed recruitment of individuals with prior olfactory dysfunction and assess normal rate of dysfunctions in the used population, 44 SARS-CoV-2 IgG naive individuals were also tested as a control group. One and a half year after COVID-19, more than one third of individuals recovered from COVID-19 demonstrated a clinical reduction in their sense of smell. Critically, nearly half of COVID-19-recovered individuals complaint about parosmia. Prevalence of gustatory dysfunction was, however, low (3%). In summary, a full 65% of individuals recovered from COVID-19 experience olfactory dysfunction of some form 18 months later. Given the amount of time since initial insult to the olfactory system, it is likely that these olfactory problems are permanent.

category: otolaryngology


title: Detection and upsurge of SARS-CoV-2 Omicron variant in Islamabad Pakistan

abstract: The SARS-CoV-2 omicron variant was first detected in South Africa in November, 2021 and has rapidly spread to more than 90 countries. The emergence of Omicron variant demands for enhanced genomic surveillance to track the mutation profile and spread of virus. In the current study, we have sequenced 15 whole-genome sequences of SARS-CoV-2 Omicron variant from Islamabad region of Pakistan. Among the 15 isolates, 66% were from Islamabad whereas 33% of cases had international travel history of United Kingdom, Maldives, South Africa, and Oman. The detection of Omicron in local community and in travelers highlights the need for rigorous screening at national level and at entry points in order to contain the spread of variant.


title: The association between high ambient temperature and mortality in the Mediterranean basin: a systematic review and meta-analysis

abstract:
BackgroundThe effect of hot ambient temperature on mortality differs between geographical locations. The Mediterranean basin has been identified as one of the most prominent "hot-spots" in the world in terms of vulnerability to climate change. No recent, large synthesis of the estimated effects in the Mediterranean basin has been conducted.

MethodsA systematic review was conducted across three major databases to retrieve effect estimates from time-series or case-crossover studies on temperature and mortality performed in the Mediterranean basin countries, between 2000-2021. Of all reviewed studies, n=16 were eligible for inclusion in the meta-analysis. Estimates were pooled using a random-effects model. Subgroup analyses were performed for death-cause, age-group, region, and climate type. Meta-regression was performed with respect to national Gross Domestic Product (GDP) per capita, latitude and longitude, and local temperature thresholds.

ResultsWe found an increased risk of all-cause mortality due to ambient heat exposure in the Mediterranean basin, with a pooled RR=1.035 (95%CI 1.028-1.041) per 1{degrees}C increase in temperature above local thresholds (I2=79%). Risk was highest for respiratory (RR=1.063, 95% CI 1.052-1.074) and cardiovascular (RR=1.046, 95% CI 1.036-1.057) mortality.

ConclusionsHot ambient temperatures increase the mortality risk across the Mediterranean basin. This is increasingly important for public health processes in the Mediterranean basin countries in light of the climate changes already noticed in this area. Further high-quality studies, especially in North African, Asian Mediterranean, and eastern European countries, are needed to bolster regional preparedness against future heat-related health burdens.

Key MessagesO_LIHigh ambient temperatures affect short-term mortality across the Mediterranean basin countries.
C_LIO_LIRisk is highest for respiratory and cardiovascular mortality.
C_LIO_LIIn light of climate change, this is an increasingly important public health concern. Further high-quality studies, especially in North African, Asian Mediterranean and eastern European countries, are needed to help regions prepare for future heat-related health burdens.
C_LI


title: Auto-Detection and Segmentation of Involved Lymph Nodes in HPV-Associated Oropharyngeal Cancer Using a Convolutional Deep Learning Neural Network

abstract:
PurposeSegmentation of involved lymph nodes on head and neck computed tomography (HN-CT) scans is necessary for the radiotherapy treatment planning of human papilloma virus (HPV) associated oropharynx cancers (OPC). We aimed to train a deep learning convolutional neural network (DL-CNN) to identify and segment involved lymph nodes on contrast-enhanced HN-CT scans.

Methods90 patients who underwent levels II-IV neck dissection for newly diagnosed, clinically node-positive, HPV-OPC were identified. Ground-truth segmentation of all radiographically and pathologically involved nodes was manually performed on pre-surgical HN-CT scans, which were randomly divided into training/validation dataset (n=70) and testing dataset (n=20). A 5-fold cross validation was used to train 5 separate DL-CNN sub-models based on a residual U-net architecture. Validation and testing segmentation masks were compared to ground-truth segmentation masks using overlap-based, volume-based, and distance-based metrics. A lymph auto-detection model was developed by thresholding segmentation model outputs, and 20 node-negative HN-CT scans were added to the test set to further evaluate auto-detection capabilities. Model discrimination of lymph node "positive" and "negative" HN-CT scans was evaluated using the area under the receiver operating characteristic curve (AUC).

ResultsIn the DL-CNN validation phase, all sub-models yielded segmentation masks with median DSC [≥] 0.90 and median volume similarity score of [≥] 0.95. In the testing phase, the DL-CNN produced consensus segmentation masks with median Dice of 0.92 (IQR, 0.89-0.95), median volume similarity of 0.97 (IQR, 0.94-0.99), and median Hausdorff distance of 4.52 mm (IQR, 1.22-8.38). The detection model achieved an AUC of 0.98.

ConclusionThe results from this single-institution study demonstrate the successful automation of lymph node segmentation for patients with HPV-OPC using a DL-CNN. Future studies, including external validation using a larger dataset, are necessary to clarify the role of the DL-CNN in the routine radiation oncology treatment planning workflow.

category: radiology and imaging


title: Whole-exome Sequencing Study of Hypospadias

abstract:
While hypospadias is one of the most common male congenital disorders, the missing heritability contributed by rare variants with larger effects is poorly understood. To systematically explore the variant patterns in the developing of hypospadias, we performed whole exome sequencing (WES) in 191 severe hypospadias cohort and three trios. Subsequent RNA sequencing of 12 severe hypospadiac foreskins and 6 non-hypospadiac foreskins were conducted. Among previous reported hypospadias risk associated genes, we found that NR5A1, SRD5A2 and AR genes are mutational hotspots in the etiology of severe hypospadias. Additionally, rare damaging variants in novel identified outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, and DNAH17) (p = 4.8x10-17) were significantly enriched in 191 sporadic severe hypospadias compared with 208 controls. The following transcriptomic analysis further demonstrated that the mutations in the DNAH8 and DNAH17 genes might affect the network regulation of testosterone (T)-dihydrotestosterone-androgen receptor (T-DHT-AR) signaling. We also identified a novel rare damaging variant of DNAH8 in a severe hypospadias case which was transmitted from the mother. Overall, a panel of ODNAH genes with rare damaging variants were identified in 22.5% of severe hypospadias patients. This study provides unequivocal evidence for association of ODNAH genes and hypospadias. This knowledge may guide the genetic counseling for hypospadias.

One Sentence SummaryRare damaging variants in outer DNAH genes were identified in 22.5% of severe hypospadias patients, which may guide the genetic counseling of families facing familial hypospadias.


title: One vaccine to counter many diseases? Modelling the economics of oral polio vaccine against child mortality and COVID-19

abstract:
BackgroundRecent reviews summarize evidence that some vaccines have heterologous or non-specific effects (NSE), potentially offering protection against multiple pathogens. Numerous economic evaluations examine vaccines pathogen-specific effects, but we have found only two economic evaluations of NSE. This paper starts to fill this gap by reporting economic evaluations of the NSE of oral polio vaccine (OPV) against under-five mortality and COVID-19.

MethodsWe studied two settings: (1) reducing child mortality in a high-mortality setting (Guinea-Bissau) and (2) preventing COVID-19 in India. In the former, the intervention involves three annual campaigns in which children receive OPV incremental to routine immunization. In the latter, a susceptible-exposed-infectious-recovered model was developed to estimate the population benefits of two scenarios, in which OPV would be co-administered alongside COVID-19 vaccines. Incremental cost-effectiveness and benefit-cost ratios were modelled for ranges of intervention effectiveness estimates to supplement the headline numbers and account for heterogeneity and uncertainty.

ResultsFor child mortality, headline cost-effectiveness was $650 per child death averted. For COVID-19, assuming OPV had 20% effectiveness, incremental cost per death averted was $23,000-65,000 if it were administered simultaneously with a COVID-19 vaccine less than 200 days into a wave of the epidemic. If the COVID-19 vaccine availability were delayed, the cost per averted death would decrease to $2600-6100. Estimated benefit-to-cost ratios vary but are consistently high.

ConclusionEconomic evaluation suggests the potential of OPV to efficiently reduce child mortality in high mortality environments. Likewise, within a broad range of assumed effect sizes OPV could play an economically attractive role against COVID-19.

category: health economics


title: Safety and immunogenicity of Pfizer/BioNTech SARS-CoV-2 mRNA third booster vaccine against SARS-CoV-2 Omicron variant in Japanese healthcare workers

abstract:
BackgroundThe Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Japan in November 2021. This variant contains up to 36 mutations in the spike protein, the target of neutralizing antibodies, and can escape vaccine-induced immunity. The third booster vaccination campaign began with healthcare workers and high-risk groups. The safety and immunogenicity of third booster vaccination against Omicrons remain unknown.

MethodsIn total, 272 healthcare workers were evaluated for their long-term safety and immunogenicity. Here, we established vaccine panels to evaluate the safety and immunogenicity against variants of concern (VOCs), including the Omicron variant, using a live virus microneutralization assay.

FindingsTwo-dose vaccination induced robust anti-spike antibodies and neutralization titers (NTs) against the ancestral strain WK-521, whereas NTs in VOCs were significantly decreased. Within 93-247 days of the second vaccine dose, NTs against Omicron were completely abolished in up to 80% of individuals among the vaccine panels. The third booster vaccination induced a robust increase in anti-spike antibodies and NTs against the WK-521, Delta, and Omicron variants. The breadth of humoral immunity and cross-reactivity with Omicron increased. The cytokine signature and adverse event rate remained unchanged after three-dose vaccination.

ConclusionsThe third vaccination dose is safe and effective against Omicron infection.

FundingThis study was supported by grants from AMED (Grant Number JP21fk0108104 and JP21mk0102146).


title: Cannabis Use and Sleep Quality in Daily Life: a Daily Diary Study of Adults Starting Cannabis for Health Concerns

abstract:
BackgroundLegalization of cannabis for medical uses has proceeded without well-controlled study of its efficacy and safety for most indications. Real world patterns of medical cannabis use are highly variable and rarely overseen by a physician. Pragmatic effectiveness studies with web-based and smartphone assessment methods, designed to understand ecologically valid patterns of medical cannabis use and health symptoms, can help clarify the risks and benefits of cannabis use for medical indications.

MethodsAs part of a larger, randomized trial (NCT03224468), adults (N=181) seeking medical cannabis for insomnia, pain, or anxiety or depressive symptoms were randomized to obtain a medical cannabis card immediately (MCC) or to a waitlist control (WLC) and subsequently completed 12-weeks of daily web-based surveys on cannabis use and three health outcomes: sleep, pain, and depressive symptoms.

ResultsCompletion rates of daily surveys in this long-term, web-based survey design were moderate to high across participants (median number of daily assessments completed: 72 out of 90 days). Daily reports of cannabis use were consistent with monthly interview assessments and urinalysis. The MCC group increased cannabis use frequency in the 12 weeks following randomization, while WLC did not. Within the MCC group, self-reported sleep quality was significantly higher on cannabis use days, compared to nonuse days. The MCC group displayed long-term sleep improvements, consistent with increased cannabis frequency rather than a sustained effect of any single cannabis use. Daily associations between cannabis use and self-reported pain or depressive symptoms were small and not significant.

ConclusionCannabis use is associated with same day improvements in self-reported sleep quality, but not pain or depressive symptoms, although sleep improvements occurred in the context of increased frequency of cannabis use, raising the risk for cannabis use disorder. Long-term, daily web-based assessments of cannabis appear valid and feasible in medical cannabis users, providing a robust method for future real-world effectiveness studies with expanded and objective measures.


title: Development of a core outcome set on traditional Chinese medicine (COS-TCM) for rheumatic heart disease (RHD): study protocol

abstract:
IntroductionRheumatic heart disease (RHD) is an important cause of acquired heart disease in children and adolescents globally. Clinical trials on RHD treatment with traditional Chinese medicine (TCM) are gradually increasing in China. However, because clinical trials are heterogeneous and report outcomes selectively, similar studies cannot be merged and compared, complicating assessing the effectiveness and safety of TCM, diminishes the value of clinical trials, and results in a waste of research resources. Therefore, there is an urgent need to develop a core outcome set of traditional Chinese medicine for rheumatic heart disease (COS-TCM-RHD). This study will report the protocol development process for COS-TCM-RHD.

Methods and analysisA multidisciplinary Steering Committee will lead the development of this protocol through four stages (1). Establishing a comprehensive and systematic outcomes checklist through a systematic review of previously published research, retrieval of clinical trial registration centers, patients semi-structured interviews, and clinicians questionnaire surveys; (2). Screen stakeholder groups from various fields to participate in the Delphi survey; (3). Two rounds of e-Delphi surveys will be conducted to determine the outcomes of various concerned stakeholder groups; (4). Hold a face-to-face consensus meeting to develop the COS-TCM-RHD.

Ethics and disseminationEthical approval has been granted by the Tianjin university of Traditional Chinese Medicine Ethics Committee. The findings will be published in peer-reviewed journals and the website of Chinese Clinical Trials for Core Outcome Set.

Trial registrationThis study protocol has been prospectively registered with the Core Outcome Measures in Effectiveness Trials (COMET):

http://www.comet-initiative.org/Studies/Details/1743.

Strengths and limitations of this study{blacksquare} This protocol is the first core outcomes set registered on the Core Outcome Measures in Effectiveness Trials (COMET) website for the treatment of rheumatic heart disease by Traditional Chinese medicine.
{blacksquare}This study is guided by the Core Outcome Set-STAndards for Development and Core Outcome Set-Standardized Protocol Items, with recommendations of the COMET.
{blacksquare}A multidisciplinary Steering Committee will supervise this research, and stakeholders from different fields including clinicians, patients, methodologists, and COS developers will be engaged.
{blacksquare}Systematic reviews, qualitative research (patients semi-structured interviews and clinicians questionnaire surveys), Delphi surveys, and consensus meetings will be used for core outcome set development.
{blacksquare}Traditional Chinese medicine is mainly used in China. Thus, the geographical distribution of stakeholders will be a limitation.

category: cardiovascular medicine


title: Joinpoint Regression to Determine the Impact of COVID-19 on Mortality in Europe: A Longitudinal Analysis From 2000 to 2020 in 27 Countries

abstract: The novel coronavirus disease 2019 (COVID-19) represented the most extensive health emergency in human history. However, to date, there is still a lot of uncertainty about the exact death toll the pandemic has claimed. In particular, the number of official deaths could be vastly underestimated. Despite this, many conspirationists speculate that COVID-19 is not a dangerous disease. Therefore, in this manuscript, we use joinpoint regression analysis to estimate the impact of COVID-19 in 27 European countries by comparing annual mortality trends from 2000 to 2020. Furthermore, we provide accessible evidence even for a non-expert audience. Siegel (A1) and Holm-Bonferroni (A2) approaches were employed to assess the significance of the results separately. In conclusion, these results estimate that COVID-19 increased the overall mortality in Europe by 10% (A1: P < .001, A2: Adjusted P = .001). In 16 out of 27 countries (59.3%), the excess mortality ranged from 7.4% to 18.5% (A1: P < .003, A2: Adjusted P < .040). Comparison of the excess mortalities distribution to the null counterfactual showed that the mortality increase was highly significant across Europe (Adjusted P < .001).


title: Monitoring SARS-CoV-2 genome evolution in a localized population

abstract: Despite seminal advances towards understanding its infection mechanism, SARS-CoV-2 continues to cause significant morbidity and mortality worldwide. Though mass immunization programs have been implemented in several countries, the viral transmission cycle has shown a continuous progression in the form of multiple waves. A constant change in the frequencies of dominant viral lineages, arising from the accumulation of nucleotide variations (NVs) through favourable selection, is understandably expected to be a major determinant of disease severity and possible vaccine escape. Indeed, worldwide efforts have been initiated to identify specific virus lineage(s) and/or NVs that may cause a severe clinical presentation or facilitate vaccination breakthrough. Since host genetics is expected to play a major role in shaping virus evolution, it is imperative to study role of genome-wide SARS-CoV-2 NVs across various populations. In the current study, we analysed the whole genome sequence of 3543 SARS-CoV-2 infected samples obtained from the state of Telangana, India (including 210 from our previous study), collected over an extended period from April, 2020 to October, 2021. We present a unique perspective on the evolution of prevalent virus lineages and NVs during this time period. We also highlight presence of specific NVs likely to be associated favourably with samples classified as vaccination breakthroughs. Finally, we report genome-wide intra-host variations (iSNVs) at novel genomic positions. The results presented here provide critical insights into virus evolution over an extended time period within a geographically restricted area and pave the way to rigorously investigate the role of specific NVs in vaccination breakthroughs.


title: Loneliness is associated with mentalizing and emotion recognition abilities in schizophrenia, but only in a cluster of patients with social cognitive deficits.

abstract:
BackgroundLoneliness is a concern for patients with schizophrenia (SCZ). However, the correlates of loneliness in SCZ are unclear; thus, the aim of the study is to investigate neuro- and social cognitive (SC) mechanisms associated with loneliness in SCZ.

MethodsData for the study were pooled from two cross-national samples (Poland/USA) and included 147 SCZ and 103 healthy controls (HC) overall. Data from clinical, neurocognitive, and SC assessments were examined as potential predictors of loneliness in HC and SCZ samples pooled across two sites. Furthermore, Latent Class Analysis (LCA) was used to cluster patients based on SC capacity. Next, the relationship between SC and loneliness was explored in each cluster of SCZ.

ResultsSCZ reported higher levels of loneliness than HC. Loneliness was linked to increased negative and affective symptoms in patients. A negative association between loneliness and mentalizing and emotion recognition abilities was found in the patients with social-cognitive impairments, but not in those who performed at normative levels.

ConclusionsWe have elucidated a novel mechanism which may explain previous inconsistent findings regarding the correlates of loneliness in SCZ. As decreased SC capacity may be linked with loneliness only in patients with observable SC impairments, SC heterogeneity in SCZ needs to be recognized while planning psychosocial interventions targeting loneliness in this group.


title: Prevalence of Specific Multimorbidity Combinations and Association with Medical Expenditures and Perceived Health among U.S. Adults, 2016-2019

abstract:
BackgroundMultimorbidity is common, but the prevalence and burden of the specific combinations of co-occurring disease has not been systematically examined at the population level in the U.S. The objective was to identify and measure the burden of highly prevalent combinations of chronic conditions treated among adults in the United States.

MethodsCross-sectional analysis of U.S. households in the Medical Expenditure Panel Survey (MEPS), 2016-2019, a large nationally-representative sample of the community-dwelling population. Association rule mining was used to identify the most common combinations of 20 chronic conditions that have high relevance, impact, and prevalence in primary care. The main measures and outcomes were annual treated prevalence, total medical expenditures, and perceived fair/poor health.

ResultsFrequent pattern mining yielded 259 unique combinations of chronic disease, including 77 two-way (dyad), 134 three-way (triad), 47 four-way, and one five-way combinations that are treated in one million or more U.S. adults. {Hypertension & Hyperlipidemia} was the most common two-way combination. The combination of {Diabetes & Arthritis & Cardiovascular disease} was associated with the highest median annual medical expenditures ($23,850, [Interquartile range: $11,593 - $44,616]), and the combination of {Diabetes & Arthritis & Asthma/COPD} had the highest age-race-sex adjusted odds ratio of fair/poor self-rated health (adjusted odd ratio: 6.9, [95%CI: 5.4 - 8.8]).

ConclusionThis study demonstrates that many multimorbidity combinations are highly prevalent among U.S. adults, yet most research and practice-guidelines remain single disease focused. Highly prevalent and burdensome multimorbidity combinations could be prioritized for evidence-based research on optimal prevention and treatment strategies.


title: Prevalence of multimorbidity combinations and their association with medical costs and poor health among U.S. adults


title: Microbial GWAS studies revealing combinations of Omicron RBD mutations existed and may contribute to antibody evasion and ACE2 binding

abstract: Since Omicron variant of SARS-CoV-2 was first detected in South Africa (SA), it has now dominated in United Kingdom (UK) of Europe and United State (USA) of North America. A prominent feature of this variant is the gathering of spike protein mutations, in particularly at the receptor binding domain (RBD). These RBD mutations essentially contribute to antibody resistance of current immune approaches. During global spillover, combinations of RBD mutations may exist and synergistically contribute to antibody resistance in fact. Using three geographic-stratified genome wide association studies (GWAS), we observed that RBD combinations exhibited a geographic pattern and genetical associated, such as five common mutations in both UK and USA Omicron, six or two specific mutations in UK or USA Omicron. Although the UK specific RBD mutations can be further classified into two separated sub-groups of combination based on linkage disequilibrium analysis. Functional analysis indicated that the common RBD combinations (fold change, -11.59) alongside UK or USA specific mutations significantly reduced neutralization (fold change, -38.72, -18.11). As RBD overlaps with angiotensin converting enzyme 2(ACE2) binding motif, protein-protein contact analysis indicated that the common RBD mutations enhanced ACE2 binding accessibility and were further strengthened by UK or USA-specific RBD mutations. Spatiotemporal evolution analysis indicated that UK-specific RBD mutations largely contribute to global spillover. Collectively, we have provided genetic evidence of RBD combinations and estimated their effects on antibody evasion and ACE2 binding accessibility.


title: Race-adjusted Lung Function Increases Inequities in Diagnosis and Prognosis and Should Be Abandoned

abstract:
BackgroundLung function assessment is essential for respiratory medicine and health. Recommended international reference values differ by race, which is controversial. We evaluated the effect of adjusting lung function for race on prevalence of lung function impairment, breathlessness and mortality in the US population.

MethodsPopulation-based analysis of the National Health and Nutrition Examination Survey (NHANES) 2007-2012. Race was analyzed as black, white, or other. Lung function was assessed as forced expired volume in one second (FEV1) and forced vital capacity (FVC). Predicted normal values were calculated for each person using the Global Lung Initiative (GLI)-2012 equations for 1) white; 2) black; and 3) other/mixed populations. Outcomes were compared for the different reference values in relation to: prevalence of lung function impairment (<lower limit of normal [LLN]), moderate/severe impairment (<50%pred); self-reported exertional breathlessness; and mortality up to 31 December, 2015.

FindingsWe studied 14,123 people (50% female); white (n=5,928), black (n=3,130), and other (n=5,065). Compared to those for white, black reference values identified markedly fewer cases of lung function impairment (FEV1) both in black people (9.3% vs. 36.9%) and other non-white races (1.5% vs. 9.5%); and prevalence of moderate/severe impairment was approximately halved. Outcomes among those impaired differed by reference value used: white (best outcomes), other/mixed (intermediate), and black (worst outcomes). Black people with FEV1 [≥]LLNblack but <LLNwhite had 48% increased rate of breathlessness and almost doubled mortality, compared to blacks [≥]LLNwhite. Lung function [≥]LLNwhite identified people with good outcomes, similarly in black and white people. Findings were similar when analyzing FEV1 or FVC.

InterpretationRace adjustment of lung function should be abandoned. White reference values are most sensitive and specific to identify impairment, and could be applied across the population for improved assessment and health equity.

FundingSwedish Research Council (Dnr: 2019-02081).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE and Embase using search terms including "race", "ethnicity", "pulmonary function", "spirometry", and "prediction equations" from database inception and January 10, 2022, for papers published in English. A total 33 papers related to lung function and race were identified. Race-adjusted lung function reference values were recommended by major guidelines for use internationally. Race-specific references assume a 10-15% lower lung function, such as the forced expired volume in one second (FEV1) and forced vital capacity (FVC), in black people and 4-6% lower in Asian people compared with in whites. Compared to not adjusting for race, race-adjusted lung function values have recently been questioned as they have been found to not improve prediction of outcomes in population-based studies or in people at risk of obstructive pulmonary disease. Concerns have been raised that, contrary to the intent, race-adjusted reference values may contribute to under diagnosis of disease in disadvantage minorities, with the largest differences reported in black (Afro-American) people, and may worsen race-related health inequalities. Data on the impact of race-adjusted lung function values across the ethnically diverse population are limited and data on how to decrease racial bias in lung function assessment are needed.

Added value of this studyWe analyzed the impact of using different race-specific (GLI-2012) reference equations for FEV1 and FVC across the US population in the National Health and Nutrition Examination Survey (NHANES) 2007-2012. Outcomes were prevalence of lung function impairment (value < lower limit of normal), breathlessness on exertion, and mortality up to December 31, 2015. Compared to using references for whites, black reference values were less likely to identify lung function impairment across all races but especially in blacks (9.3% vs. 36.9%); and those identified had lower lung function, more breathlessness, and worse prognosis. Black people with lung function normal by black standards but impaired by white standards had increased prevalence of breathlessness and mortality, compared to those normal also by white standards. Thus, race-adjusted reference values labeled black people as normal despite worse outcomes. White normal values identified people with similarly good lung function, and low rates of breathlessness and mortality across races groups.

Implications of all the available evidenceThe findings from this study support that race-adjusted reference values markedly under diagnose lung function impairment, and related breathlessness, and mortality in underprivileged groups across the US population. Normal values for whites were most sensitive to identify lung function impairment related to worsening outcomes and people classified as having normal lung function with similar good outcomes irrespective of race group. These findings suggest that lung function should not be adjusted for race. When applied across the population, white reference values were most sensitive to identify smaller or earlier impairment and most specific to identify people with normal lung function with similarly good outcomes across race groups. Given the large impact shown, abandoning the use of race-adjusted lung function values is likely to contribute to improved health equity.

category: respiratory medicine


title: Association between oral health and hyperuricemia in Korean adults: Korea National Health and Nutrition Examination Survey 2016-2019

abstract:
Hyperuricemia plays an essential role in the development of gout. Despite the clinical importance of hyperuricemia, a direct relationship between oral health and hyperuricemia has not been established. Therefore, we aim to investigate the association between oral health and hyperuricemia in Korean adults.

We selected 17,584 subjects from the Korea National Health and Nutrition Examination Survey 2016-2019 database. Oral health-related variables included the number of dental caries, regular tooth brushing, use of secondary oral products, and regular dental examination. The odds ratio (OR) and 95% confidence intervals (CIs) for hyperuricemia were calculated using a multivariable-adjusted logistic regression model.

In all subjects, oral health status with dental caries and oral health behaviors, including tooth brushing; secondary oral products; and regular dental examination, were significantly associated with hyperuricemia. The adjusted OR and 95% CIs for hyperuricemia comparing more than three dental caries with no dental caries were 1.28 (1.08-1.51). The adjusted OR and 95% CIs for hyperuricemia in regular tooth brushing, use of secondary oral products, and regular dental examination were 0.78 (0.67-0.91), 0.91 (0.82-1.00), and 0.86 (0.78-0.95), respectively. Notably, the association between oral health and hyperuricemia was more prominent in male subjects. In addition, when subjects were grouped by the scoring system regarding oral health, the prevalence of hyperuricemia was lower in groups with a better oral health score.

In conclusion, we demonstrated that oral health status and behaviors were associated with hyperuricemia, especially in males. Further complementary studies are needed to confirm the definite association between oral health and hyperuricemia.


title: Discrepancy review: A feasibility study of a novel peer review intervention to reduce undisclosed discrepancies between registrations and publications

abstract:
BackgroundUndisclosed discrepancies often exist between study registrations and their associated publications. Discrepancies can increase risk of bias, and when undisclosed, they disguise this increased risk of bias from readers. To remedy this issue, we developed an intervention called discrepancy review. We provided journals with peer reviewers specifically assigned to check for undisclosed discrepancies between registrations and manuscripts submitted to journals.

ObjectivesWe aimed to (1) evaluate the feasibility of incorporating discrepancy review as a regular practice at scientific journals and the feasibility of conducting a trial on discrepancy review; (2) explore the benefits and time required to incorporate discrepancy review as a regular practice at scientific journals; and (3) refine the discrepancy review process.

MethodWe performed discrepancy review on 18 manuscripts submitted to Nicotine and Tobacco Research and 3 manuscripts submitted to the European Journal of Personality. We iteratively refined the discrepancy review process based on feedback from discrepancy reviewers, editors, and authors. We then assessed whether revised manuscripts addressed recommendations from discrepancy reviewers and identified potential outcome measures for use in a future trial of discrepancy review.

ResultsRegistrations were generally too imprecise to be effectively evaluated by our original discrepancy review process so we developed a simplified, semi-structured process. Authors addressed the majority of discrepancy reviewer comments and there was no opposition to running a trial from authors, editors, or discrepancy reviewers. Clinical trial registrations were more precise but less comprehensive than registrations on the Open Science Framework, suggesting they should be evaluated in separate trials. Outcome measures for a trial of discrepancy review on clinical trial registration could include the presence of primary or secondary outcome discrepancies and whether publications that are not the primary report from a clinical trial registration are clearly described as such. Outcome measures for a trial on Open Science Framework registrations could include assessments of whether registrations are permanent, as well as an overarching subjective assessment of the impact of discrepancies.

ConclusionWe found that discrepancy review could feasibly be introduced as a regular practice at journals interested in this process. A full trial of discrepancy review would be needed to evaluate its impact on reducing undisclosed discrepancies.

category: health systems and quality improvement


title: Is trait mindfulness associated with lower pain reactivity and connectivity of the default mode network? A replication and extension study in healthy and episodic migraine participants

abstract:
Formal training in mindfulness-based practices promotes reduced experimental and clinical pain, which may be driven by reduced emotional pain reactivity and undergirded by alterations in the default mode network (DMN), implicated in mind-wandering and self-referential processing. Recent results published in this journal suggest that trait mindfulness (TM), or the day-to-day tendency to maintain a non-reactive mental state in the absence of training, associates with reduced pain reactivity, pain sensitivity, and resting-state DMN functional connectivity (FC) in healthy adults in a similar manner to trained mindfulness. The extent to which these findings extend to chronic pain samples and replicate in healthy samples is unknown. Using data from healthy adults (n = 36) and episodic migraine patients (n = 98) and replicating previously published methods, we observed no significant association between TM and pain sensitivity (r = -0.05, p = .80), intensity (r = .01, p = .94) or unpleasantness (r = .07, p = .67), or pain catastrophizing (PC; r = .30, p = .08) in healthy controls, or between TM and headache frequency (r = -.11, p = .26), severity (r = .03, p = .77), impact (r = -.17, p = .10) or PC (r = -0.09, p = .36) in patients. There was no association between DMN connectivity and TM in either sample when probed via seed-based FC analyses. In post-hoc whole brain exploratory analyses, meta-analytically derived DMN nodes (i.e., PCC and vmPFC) showed connectivity with regions unassociated with pain processing as a function of TM, such that healthy adults higher in TM showed greater PCC-cerebellum and vmPFC-parietal FC. Collectively, these findings suggest that the relationship between TM and DMN-FC may be nuanced or lacking in robustness, and cast doubt on TM as a clinically meaningful protective factor in migraine.

PerspectiveThis study tested relationships between trait mindfulness and pain, pain reactivity and default mode connectivity in healthy adults and migraine patients. Findings cast doubt on trait mindfulness as an individual difference marker of the ability to cope with pain in healthy adults, and as a protective factor in episodic migraine.

category: pain medicine


title: Performance of five metagenomic classifiers for virus pathogen detection using respiratory samples from a clinical cohort

abstract:
Viral metagenomics is increasingly being applied in clinical diagnostic settings for detection of pathogenic viruses. While a number of benchmarking studies have been published on the use of metagenomic classifiers for abundance and diversity profiling of bacterial populations, studies on the comparative performance of the classifiers for virus pathogen detection are scarce.

In this study, metagenomic data sets (N=88) from a clinical cohort of patients with respiratory complaints were used for comparison of the performance of five taxonomic classifiers: Centrifuge, Clark, Kaiju, Kraken2, and Genome Detective. A total of 1,144 positive and negative PCR results for a total of 13 respiratory viruses were used as gold standard. Sensitivity and specificity of these classifiers ranged from 83-100% and 90-99% respectively, and was dependent on the classification level and data pre-processing. Exclusion of human reads generally resulted in increased specificity. Normalization of read counts for genome length resulted in minor overall performance, however negatively affected the detection of targets with read counts around detection level. Correlation of sequence read counts with PCR Ct-values varied per classifier, data pre-processing (R2 range 15.1-63.4%), and per virus, with outliers up to 3 log10 reads magnitude beyond the predicted read count for viruses with high sequence diversity.

In this benchmarking study, sensitivity and specificity were within the ranges of use for diagnostic practice when the cut-off for defining a positive result was considered per classifier.

HighlightsO_LIThe performance of five metagenomic classifiers was assessed using datasets obtained from respiratory samples from a clinical cohort of patients
C_LIO_LI88 samples were characterized by means of 1,144 respiratory virus PCR results
C_LIO_LIUsing PCR as gold standard, sensitivity and specificity ranged from 83-100% and 90-99% respectively, with the overall highest scores resulting from amino-acid based classification by Kaiju classifier. Performance was dependent on classification level and exclusion of human reads prior to classification.
C_LIO_LINormalization of assigned read counts for corresponding genome lengths generally had minor effect on performance, but negatively affected the detection of target viruses with read counts around detection level.
C_LIO_LICorrelation between sequence read counts and PCR Ct-values varied per classifier (12.1-62.7% at species level), per data pre-processing, and per virus. Outliers were detected of up to 3 log10 reads the predicted read counts for viruses with high sequence diversity.
C_LIO_LISensitivity and specificity of the classifiers were within the range of use for diagnostic practice when combined with a determined cut-off for defining a positive result.
C_LI


title: Combination of Spironolactone and Sitagliptin Improves Clinical Outcomes of Outpatients with COVID-19: An Observational Study

abstract:
BackgroundCoronavirus disease 2019 (COVID-19) leads to hospitalization and death, especially in elderly and those with comorbidities. There are evidences showing that sitagliptin and spironolactone can potentially improve the clinical outcomes of COVID-19 cases. In this observational study on acutely symptomatic outpatient COVID-19 cases, we investigated the effects of spironolactone and sitagliptin on the outcomes of the disease.

MethodsThis prospective cohort study was conducted at Shiraz University of Medical Sciences Clinics during the fifth wave of the COVID-19 pandemic between July 2021 and September 2021. We followed mild to moderate symptomatic COVID-19 patients, who were treated with either combination (spironolactone 100 mg daily and sitagliptin 100 mg daily) or standard (steroid, antiviral and/or supportive care) therapy up to 30 days. Our primary outcome was hospitalization rate. The secondary outcomes included ER visit, duration of disease, and complications, such as hypoglycemia, low blood pressure or altered mental status.

ResultsOf the 206 patients referred to clinics, 103 received standard therapy and 103 treated with combination therapy. There were no significant differences in baseline characteristics, except for slightly higher clinical score in control group (6.92 {+/-} 4.01 control, 4.87 {+/-} 2.92 combination; P <0.0001). Treatment with combination therapy was associated with lower admission rate (5.8% combination, 22.3% control; P = 0.0011), ER visits (7.8% combination, 23.3% control; P = 0.0021) and average duration of symptoms (6.67 {+/-} 2.30 days combination, 18.71 {+/-} 6.49 days control; P =<0.0001).

ConclusionIn this prospective cohort study of acutely ill outpatients with COVID-19, the combination of sitagliptin and spironolactone reduced duration of COVID infection and hospital visits better than standard therapeutic approaches. The effects of combination of sitagliptin and spironolactone in COVID-19 patients should be further verified in a double blind, randomized, placebo-controlled trial.


title: Effectiveness of the EPA-based 'Toolbox Family Medicine' on students' learning satisfaction: study protocol for a controlled trial

abstract:
BackgroundFamily practices constitute an important learning environment for medical students. However, teaching situations markedly vary between practices, and students frequently find rotations underwhelming. Especially, students active participation in patient care varies profoundly, although it has a significant impact on students interest in primary care careers. To standardize and improve learning situations in practices, we developed the so-called  Toolbox Family Medicine (TFM) using the concept of entrustable professional activities. It provides standardized learning content appropriate for students levels and allows teaching adaptable to actual practice conditions.

MethodsUsing a controlled trial with a waiting list control arm, we will evaluate the effectiveness of the toolbox on students learning satisfaction. A total of 94 students will be allocated 1:1 to intervention and control practices. The teaching concept  Toolbox Family Medicine (TFM) comprises a didactic workshop for supervising physicians and a toolbox with practice-specific tasks for medical students. The primary outcome is students overall satisfaction with their learning progress after the rotation. Secondary outcomes include the kind and number of tasks performed, the entrusted level per task, the feasibility of implementing the toolbox in actual practice settings, and students motivation to pursue a career in primary care.

DiscussionWe assume an improvement in learning satisfaction with the intervention. The study will begin with the next practice rotations.

Administrative information

O_TBL View this table:
org.highwire.dtl.DTLVardef@1854ffborg.highwire.dtl.DTLVardef@1460a5eorg.highwire.dtl.DTLVardef@152d543org.highwire.dtl.DTLVardef@12f4f85org.highwire.dtl.DTLVardef@10dcc59_HPS_FORMAT_FIGEXP  M_TBL C_TBL

category: medical education


title: Pregnancy outcomes and long-term patient and graft survival after kidney transplantation

abstract:
IntroductionKidney transplant is considered the method of choice in the treatment of end-stage chronic kidney disease, improving survival and quality of life, and often allowing the recovery of fertility among woman. Objective: This study aims to assess the outcomes of post-transplant pregnancy, newborn and patient graft survival, compared to a control group of transplanted women who werent pregnant.

MethodsA retrospective case-control study was conducted at the Kidney Transplant Service of Santa Casa de Misericordia in Porto Alegre, among 1.253 female patients who underwent kidney transplantation and were of childbearing age between 1977 and 2016. They were compared to a control group matched for age, type of donor, date of transplant and immunological risk.

Results76 (6,1%) of the patients became pregnant, resulting in a total of 93 pregnancies. Compared to the control group, at 10 years after transplantation there was no significant difference in relation to graft loss (74% vs 66%, p=0.524), and the survival of pregnant patients was higher (97% vs 79%, p=0.018). We found that 40% pregnancies progressed to abortion, 30% of the deliveries were preterm, and 26% happened at term. Three pregnancies progressed to stillbirth. Of the 56 pregnancies that evolved, 23 (41%) resulted in pre-eclampsia, and one in eclampsia.

Conclusion6,1% of the women in the study became pregnant, and 56% of these pregnancies were successful. Compared to the control group, we found that those who got pregnant had similar graft survival outcomes and longer patient survival.

category: nephrology


title: The organisation of nurse staffing in intensive care units: a qualitative study

abstract:
AimsTo examine the organisation of the nursing workforce in intensive care units and identify factors that influence how the workforce operates.

BackgroundPre-pandemic UK survey data show that up to 60% of intensive care units (ICUs) did not meet locally agreed staffing numbers and 40% of ICUs were closing beds at least once a week because of workforce shortages, specifically nursing. Nurse staffing in ICUs is based on the assumption that sicker patients need more nursing resource than those recovering from critical illness. These standards are based on historical working, and expert professional consensus, deemed the weakest form of evidence.

MethodsFocus groups with health care professionals working in ICUs (n= 52 participants) and individual interviews with critical care network leads and policy leads (n= 14 participants) in England between December 2019 and July 2020. Data were analysed using framework analysis.

FindingsThree themes were identified: the constraining or enabling nature of ICU and hospital structures; whole team processes to mitigate nurse staffing shortfalls; and the impact of nurse staffing on patient, staff and ICU flow outcomes. Staff made decisions about staffing throughout a shift and were influenced by a combination of factors illuminated in the three themes.

ConclusionsWhilst nurse: patient ratios were clearly used to set the nursing establishment, it was clear that rostering and allocation/re-allocation during a shift took into account many other factors, such as patient and family nursing needs, staff wellbeing, ICU layout and the experience, and availability, of other members of the multi-professional team. This has important implications for future planning for ICU nurse staffing and highlights important factors to be accounted for in future research studies.

Implications for Nursing ManagementThe potential opportunities for different staffing models are likely to be highly dependent on other professions. Hence, any change to staffing models needs to take into account how different professions work together.

Factors such as ICU layout, reported to influence nurse staffing decisions, suggest that patient safety in ICU may not be best served by blanket  ratio approaches to nurse staffing, intended to apply uniformly across health services.

The findings have the potential to feed into discussions about funding tariffs for critical care and quality metrics to be included in commissioning contracts.

category: nursing


title: mRNA-COVID19 vaccination can be considered safe and tolerable for frail patients

abstract:
BackgroundFrail patients are considered at relevant risk of complications due to COVID-19 infection and, for this reason, are prioritized candidates for vaccination. As these patients were originally not included in the registration trials, fear related to vaccine side-effects and disease worsening was one of the reasons for vaccine hesitancy. Herein we report the safety profile of the prospective, multicenter, national VAX4FRAIL study (NCT04848493) to evaluate vaccines in a large trans-disease cohort of patients with solid or hematological malignancies, neurological and rheumatological diseases.

MethodsBetween March 3rd and September 2nd, 2021, 566 patients were evaluable for safety endpoint: 105 received the mRNA-1273 vaccine and 461 the BNT162b2 vaccine.

Frail patients were defined per protocol as patients under treatment with hematological malignancies (131), solid tumors (191), immune-rheumatological diseases (86), and neurological diseases (158), including multiple sclerosis and generalized myasthenia.

The impact of the vaccination on the health status of patients was assessed through a questionnaire focused on the first week after each vaccine dose.

ResultsThe most frequently reported moderate-severe adverse events were pain at the injection site (60.3% after the first dose, 55.4% after the second), fatigue (30.1% - 41.7%), bone pain (27.4% - 27.2%) and headache (11.8% - 18.9%).

Risk factors associated with the occurrence of severe symptoms after vaccine administration were identified through a multivariate logistic regression analysis: age was associated with severe fever presentation (younger patients vs. middle-aged vs. older ones), females presented a higher probability of severe pain at the injection site, fatigue, headache, and bone pain; the mRNA-1237 vaccine was associated with a higher probability of severe pain at the injection site and fever. After the first dose, patients presenting a severe symptom were at a relevant risk of recurrence of the same severe symptom after the second one.

Overall, 11 patients (1.9%) after the first dose and 7 (1.2%) after the second one required to postpone or suspend the disease-specific treatment. Finally, 2 fatal events occurred among our 566 patients. These two events were considered unrelated to the vaccine.

ConclusionsOur study reports that mRNA-COVID-19 vaccination is safe also in frail patients as expected side effects were manageable and had a minimum impact on patient care path.

ImportanceOur study reports the safety analysis of the trial VAX4FRAIL confirming that mRNA-COVID-19 vaccination is safe in frail immunocompromised patients: expected side effects were manageable and had a minimum impact on patient care path.

ObjectiveTo evaluate the safety of mRNA-COVID-19 vaccination in vulnerable patients.

DesignVAX4FRAIL is a national, multicentric, observational, prospective trial (start date March 3rd, 2021 - primary completion date September 2nd, 2021).

SettingMulticenter prospective trial.

ParticipantsFrail patients were defined per protocol as patients under treatment with solid tumors (191), immune-rheumatological diseases (86), hematological malignancies (131), and neurological diseases (158), including multiple sclerosis and generalized myasthenia.

ExposureOverall, 105 received the mRNA-1273 vaccine and 461 the BNT162b2 vaccine.

Main OutcomeThe occurrence of adverse events after 1st and 2nd m-RNA-COVID-19 vaccination was analyzed. Adverse events were collected through a questionnaire comprising both open and closed questions.

ResultsThe most frequently reported moderate-severe adverse events were pain at the injection site (60.3% after the first dose, 55.4% after the second), fatigue (30.1% - 41.7%), bone pain (27.4% - 27.2%) and headache (11.8% - 18.9%).

Risk factors associated with the occurrence of severe symptoms after vaccine administration were identified through a multivariate logistic regression analysis: age was associated with severe fever presentation (younger patients vs. middle-aged vs. older ones), females presented a higher probability of severe pain at the injection site, fatigue, headache, and bone pain; the mRNA-1237 vaccine was associated with a higher probability of severe pain at the injection site and fever. Patients presenting a severe symptom after the first dose were at a relevant risk of recurrence of the same severe symptom after the second one.

Overall, 11 patients (1.9%) after the first dose and 7 (1.2%) after the second one was required to postpone or suspend their disease-specific treatment. Finally, 2 fatal events occurred among our 566 patients, and these two events were due to disease progression and considered unrelated to the vaccine.

Conclusion and RelevanceOur study reports that mRNA-COVID-19 vaccination is safe also in frail patients as expected side effects were manageable and had a minimum impact on patient care path.

Study RegistrationA National, Multicentric, Observational, Prospective Study to Assess Immune Response to COVID-19 Vaccine in Frail Patients (VAX4FRAIL). NCT04848493 https://clinicaltrials.gov/ct2/show/NCT04848493

Key PointsO_ST_ABSQuestionC_ST_ABSCan m-RNA-COVID19 vaccination be considered safe for frail patients?

FindingsIn this national, multicentric, observational, prospective trial (NCT04848493) that included 566 frail patients, the occurrence of both local and systemic adverse events was manageable and did not negatively impact on the general treatment program.

MeaningmRNA-COVID19 vaccination is safe among frail immunocompromised patients.

category: oncology


title: Outcomes of the Advanced Visualization In Corneal Surgery Evaluation (ADVISE) trial; a non-inferiority randomized control trial to evaluate the use of intraoperative OCT during Descemet membrane endothelial keratoplasty

abstract:
PurposeTo evaluate if an intraoperative OCT (iOCT) optimized surgical protocol without prolonged overpressure is non-inferior to a standard protocol during Descemet membrane endothelial keratoplasty (DMEK).

DesignA multicenter international prospective non-inferiority randomized control trial

SubjectsSixty-five pseudophakic eyes of 65 patients with corneal endothelial dysfunction resulting from Fuchs endothelial corneal dystrophy were enrolled in 3 corneal centers in The Netherlands and Belgium.

MethodsThe study was powered to include 63 patients scheduled for routine DMEK. Subjects were randomized to the control arm (n=33) without iOCT-use and raising the intraocular pressure above normal physiological limits for 8 minutes (i.e., overpressure) or the intervention arm (n=32) with OCT-guidance to assess graft orientation and adherence while refraining from prolonged raising the intraocular pressure. The RD and 95% confidence intervals (95% CI) were calculated from a logistic regression model using 1,000 bootstrap samples. Secondary outcomes included the incidence of graft detachment, surgeon-reported iOCT-aided surgical decision making, surgical time, endothelial cell density (ECD), and corrected distance visual acuity (CDVA).

Main Outcome MeasuresThe primary outcome was the incidence of postoperative surgery-related adverse events, defined as rebubbling, graft failure, and iatrogenic acute glaucoma. The non-inferiority margin was set at a risk difference (RD) of 10%.

ResultsIn the control group, 13 adverse events were recorded in 10 subjects compared to 13 adverse events in 12 subjects in the intervention group. The mean unadjusted RD measured 0.38% (95%CI: - 9.64-10.64) and the RD adjusted for study site measured -0.32% (95%CI: -10.29-9.84). No significant differences in ECD and CDVA were found between the two groups 3 and 6 months postoperatively. Surgeons reported that iOCT aided surgical decision-making in 40% of cases. Surgical- and graft unfolding time were, respectively, 13% and 27% shorter in the iOCT-group.

ConclusionsiOCT-guided DMEK surgery with refraining from prolonged over-pressuring was non-inferior compared to conventional treatment. Surgery times were reduced considerably, and surgeons reported the iOCT aided surgical decision-making in 40% of cases. Refraining from prolonged overpressure did not affect postoperative ECD or CDVA.

category: ophthalmology


title: The SENSOR System: Using Standardized Data Entry and Dashboards for Review of Scientific Studies Using the Clinical Applications of Psychedelics as an Illustration

abstract:
IntroductionLiterature reviews are useful tools for communicating the breadth of scientific discovery for a given topic. Irrespective of the nature of the review, data should be communicated in effective, easy to understand ways. In trying to address these limitations of traditional scientific reviews, we propose using dynamic data driven displays that have been used in multiple other industries to improve communication and decision making. Given the recent interest in the clinical applications of psychedelics for various mental health issues, we chose to test the SENSOR System (Standardized Data Entry and Dashboards for Review of Scientific Studies) as an alternative for an existing review article.

MethodsTo validate the SENSOR System, an existing review with a topical, heterogenous, and growing set of studies was selected. In this case we chose the Wheeler et al. review on psychedelics in clinical practice where articles had already been preselected and reviewed. Detailed discussion of this review and the cited papers preceded designing the content and shared links for a Google Form for data intake, Google Drive for article access, and Google Sheets linked to the form intake data.

ResultsA total of 46 study entries were made by 2 team members, including 3 articles published since the review to demonstrate the ease of updating the system Various representations of the Google Forms intake data in the SENSOR System dashboard are presented.

DiscussionVisual representation of review studies using a dashboard proved feasible and advantageous for numerous reasons. As the technology and guidelines for these systems evolve there is an opportunity to standardize reporting, centralize legacy datasets, streamline the submission process, improve collaboration between researchers, measure relative contribution of participating authors, and improve patient involvement. For the use case of clinical applications of psychedelics, limitations of conveying data accurately includes heterogeneity of study design, dosing, indications, and outcome measures.

ConclusionCreation of a system for standardized data entry and dashboards for reviews of scientific studies is a feasible alternative and/or adjunct to the dissemination of summaries through traditional scientific review. There are numerous proposed advantages of the flexible, dynamic, and graphical display that requires further validation.

category: health informatics


title: Investigating sensitivity of nasal or throat (ISNOT): A combination of both swabs increases sensitivity of SARS-CoV-2 rapid antigen tests

abstract: The COVID-19 pandemic has been hallmarked by several waves of variants of concern (VoCs), each with novel challenges. Currently, the highly transmissible Omicron VOC is predominant worldwide, and sore throat is common among other cold-like symptoms. Anecdotes on social media suggested sampling ones throat can increase sensitivity for Omicron detection by antigen-based rapid testing devices (Ag-RDTs). This work determines whether the sensitivity of Ag-RDTs designed for nasal sampling is altered with use of self-administered throat swabs in self-perceived asymptomatic individuals. This investigation compared results of a common Ag-RDT (i.e. Abbott Panbio COVID-19 Ag Rapid Test Device) using three sampling sites: nasal swab; throat swab and; combined nasal/throat. All Ag-RDT results were confirmed with molecular testing. Compared to RT-PCR, samples from nasal or throat swabs each detected 64.5% of SARS-CoV-2 cases; however, combining the contributions of each swab increased sensitivity to 88.7%. This trend was also evident with the Rapid Response Ag-RDT (BTNX), which uses a more flexible swabs than Panbio. When nasal swab collection was compared to paired sampling of the nasal/throat using a single swab with the Panbio Ag-RDT, the sensitivity of each was 68.4% and 81.6%, respectively. No false-positive results were observed with nasal, throat, or combined nasal/throat sampling. Self-administered throat and nasal/throat swabs both had >90% acceptability. These findings support the use of self-collected combined nasal/throat sampling for Ag-RDT based SARS-CoV-2 detection in self perceived asymptomatic individuals.


title: An expanded high throughput RT-PCR assay to rapidly identify all known SARS-CoV-2 variants of concern using melting temperature coding.

abstract:
BackgroundThe rapid emergence of new vaccine-resistant SARS-CoV-2 variants of concern (VOC) requires an equally rapid deployment of diagnostic tests to specifically identify each VOC as soon as it arises. Here, we report an expanded version of our previously described sloppy molecular beacon (SMB) Alpha/Beta/Gamma RT-PCR melting temperature (Tm) signature-based assay, which now includes modifications that allow specific detection of Delta (B.1.617.2) and Omicron (B.1.529) VOCs.

MethodsWe developed a dual SMB assay (SMB-452), which targeted the T22917G (L452R) mutation in the SARS-CoV-2 spike protein to specifically detect the Delta VOC. We also identified a Tm profile in our existing SMB-501 and SMB-484 assays (which detect mutations in codons 501 and 484 of the SARS-CoV-2 spike protein, respectively) that differentiate the Omicron-specific N501Y (A23063T) and E484A (A23013C) mutations from both wild type (WT) and other VOCs. The entire six SMB three-codon assay was tested using reference SARS-CoV-2 RNAs. The assay was then validated using clinical samples from COVID-19 patients tested with a LightCycler 480 (LC480) (74 samples), Bio-Rad CFX96 (34 samples), Rotor-Gene Q (Qiagen) (34 samples) and an ABI-7500 (34 samples) RT-PCR instruments. Six SMB Tm results were then inputted into an Excel Analysis tool to generate specific VOC identifications.

ResultsThe limit of detection (LOD) for the new SMB-452 assay, which specifically identified the Delta variant was 1 genomic equivalent (GE) per reaction. The LODs of the SMB-501 and SMB-484 assays, which detect Omicron were 100 and 103 GE respectively. Clinical validation of the 3-codon assay in the LC480 instrument showed the assay detected 94% of the samples as WT or VOCs in clinical samples and 6% of the tests producing indeterminate results. None of the samples were incorrectly identified as WT or as a different VOC. Thus, excluding samples with indeterminant results, the assay was 100% sensitive and 100% specific compared to sequencing. There was also 100% concordance between the LC480, BioRad, ABI and Qiagen results, excluding negative or indeterminate results; however, the Qiagen assay had significantly more indeterminates than the other assays.

ConclusionThis new assay can serve as a robust diagnostic tool for selecting appropriate monoclonal antibody therapy and rapid VOC surveillance.


title: Testing behaviour may bias observational studies of vaccine effectiveness

abstract:
BackgrounRecent observational studies have suggested that vaccines for the omicron variant of SARS-Cov2 may have little or no effect in preventing infection. However, the observed effects may be confounded by patient factors and preventive behaviours or vaccine-related differences in testing behaviour. To assess the potential degree of confounding, we aimed to estimate differences in testing behaviour between unvaccinated and vaccinated populations.

MethodsWe recruited 1,526 Australian adults for an online randomised study about COVID testing between October and November 2021, and collected self-reported vaccination status and three measures of COVID-19 testing behaviour. We examined the association between testing intentions and vaccination status in the cross-sectional baseline data of this trial.

ResultsOf the 1,526 participants (mean age 31 years): 22% had a COVID-19 test in the past month and 61% ever; 17% were unvaccinated, 11% were partially vaccinated (1 dose), 71% were fully vaccinated (2+ doses). Fully vaccinated participants were twice as likely (RR 2.2; 95% CI 1.8 to 2.8) to report positive COVID testing intentions than those who were unvaccinated (p<.001). Partially vaccinated participants had less positive intentions than those fully vaccinated (p<.001) but higher intentions than those who were unvaccinated (p=.002).

DiscussionFor all three measures vaccination predicted greater COVID testing intentions. If the unvaccinated tested at half the rate of the vaccinated, a true vaccine effectiveness of 30% could appear to be a "negative" observed vaccine effectiveness of -40%. Assessing vaccine effectiveness should use methods to account for differential testing behaviours. Test negative designs are currently the preferred option, but its assumptions should be more thoroughly examined.


title: Effectiveness of BNT162b2 and mRNA-1273 COVID-19 boosters against SARS-CoV-2 Omicron (B.1.1.529) infection in Qatar

abstract:
BACKGROUNDWaning of COVID-19 vaccine protection and emergence of SARS-CoV-2 Omicron (B.1.1.529) variant have expedited efforts to scale up booster vaccination. This study compared protection afforded by booster doses of the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines, compared to the primary series of only two doses in Qatar, during a large, rapidly growing Omicron wave.

METHODSIn a population of 2,232,224 vaccinated persons with at least two doses, two matched, retrospective cohort studies were implemented to investigate effectiveness of booster vaccination against symptomatic SARS-CoV-2 infection and against COVID-19 hospitalization and death, up to January 9, 2022. Association of booster status with infection was estimated using Cox proportional-hazards regression models.

RESULTSFor BNT162b2, cumulative symptomatic infection incidence was 2.9% (95% CI: 2.8-3.1%) in the booster-dose cohort and 5.5% (95% CI: 5.3-5.7%) in the primary-series cohort, after 49 days of follow-up. Adjusted hazard ratio for symptomatic infection was 0.50 (95% CI: 0.47-0.53). Booster effectiveness relative to primary series was 50.1% (95% CI: 47.3-52.8%). For mRNA-1273, cumulative symptomatic infection incidence was 1.9% (95% CI: 1.7-2.2%) in the booster-dose cohort and 3.5% (95% CI: 3.2-3.9%) in the primary-series cohort, after 35 days of follow-up. The adjusted hazard ratio for symptomatic infection was 0.49 (95% CI: 0.43-0.57). Booster effectiveness relative to primary series was 50.8% (95% CI: 43.4-57.3%). There were fewer cases of severe COVID-19 in booster-dose cohorts than in primary-series cohorts, but cases of severe COVID-19 were rare in all cohorts.

CONCLUSIONSmRNA booster vaccination is associated with modest effectiveness against symptomatic infection with Omicron. The development of a new generation of vaccines targeting a broad range of variants may be warranted.

category: epidemiology


title: Thyroid hormone axis and anthropometric recovery of children/adolescents with overweight/obesity: a scoping review

abstract: Thyroid hormones play multiple physiological effects essential for the maintenance of basal metabolic rate (BMR), adaptive thermogenesis, fat metabolism, and appetite. The links between obesity and the hormones of the thyroid axis, i.e., triiodothyronine (T3), thyroxine (T4), thyrotropin-releasing hormone (TRH), and thyrotropin (TSH), are still controversial, especially when considering children and adolescents. This population has high rates of overweight and obesity and several treatment approaches, including nutritional, psychological, and physical exercise interventions have been used. Understanding the importance of the hormones of the thyroid axis in the recovery from overweight and obesity may help directing measures to the maintenance of a healthy body composition. The present scoping review was carried out to analyze studies evaluating these hormonal levels throughout interventions directed at treating overweight and obesity in children and adolescents. The main purpose was to ascertain whether the hormones levels vary during weight loss. We selected for analysis 16 studies published between 1999 and 2019. Most of the studies showed that the changes in body composition parameters in response to the multidisciplinary interventions correlated positively with free T3 (fT3)/ total T3 (TT3)/TSH. With respect to free T4 (fT4)/ total T4 (TT4), the most common finding was of unchanged levels and hence, no significant association with weight loss. Importantly, the response to the intervention has even been found to not be affected by fT4 supplementation. Further studies are necessary to elucidate the relevance of the variations in hormone levels to the establishment of overweight/obesity and to the recovery from these conditions in children/adolescents.

category: pediatrics