bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural modeling for Oxford histological classifications of immunoglobulin A nephropathy
Authors: Joh Kensuke , Nakazato Takashi , Hashiguchi Akinori , Shimizu Akira , Katafuchi Ritsuko , Okonogi Hideo , Koike Kentaro , Hirano Keita , Tsuboi Nobuo , Kawamura Tetsuya , Yokoo Takashi , Narita Ichiei , Suzuki Yusuke
Published: May 2022

In immunoglobulin A nephropathy (IgAN), Cox regression analysis can select independent prognostic variables for renal functional decline (RFD). However, the correlation of the selected histological variables with clinical and/or treatment variables is unknown, thereby making histology-based treatment decisions unreliable. We prospectively followed 946 Japanese patients with IgAN for a median of 66 mo. and applied structural equation modeling (SEM) to identify direct and indirect effects of histological variables on RFD as a regression line of estimated glomerular filtration rate (eGFR) via clinical variables including amount of proteinuria(UPE), eGFR, mean arterial pressure(MAP) at biopsy, and treatment variables such as steroid therapy with/without tonsillectomy(ST) and renin-angiotensin system blocker (RASB). Multi-layered correlations between the variables and RFD were identified by multivariate linear regression analysis and the model’s goodness of fit was confirmed. Only tubular atrophy/interstitial fibrosis (T) had an accelerative direct effect on RFD, while endocapillary hypercellularity (E) and active crescent (C) had an attenuating indirect effect via ST. S had an attenuating indirect effect via eGFR. M had accelerative indirect effect for RFD via UPE. Moreover, M and C had accelerative indirect effect via UPE, which can be controlled by ST. However, both T and S had additional indirect accelerative effects via eGFR0c or MAP, which cannot be controlled by ST. SEM identified a systemic path links between histological variables and RFD via dependent clinical and/or treatment variables. These findings lead to clinically applicable novel methodologies that can contribute to predict treatment outcomes using the Oxford classifications.
Mental health challenges and the associated factors in HIV-positive women who have children living with HIV in Indonesia: A qualitative study
Authors: Fauk Nelsensius Klau , Maria Silvia Merry , Mwanri Lillian , Hawke Karen , Ward Paul Russell
Published: May 2022

Women living with HIV (WLHIV) are vulnerable to various mental health challenges. However, there is a paucity of studies globally and in the Indonesian context that have specifically explored mental health challenges among HIV-positive mothers who also have children living with HIV (CLHIV). This qualitative study explored mental health challenges and the associated factors in HIV-positive mothers with CLHIV in Yogyakarta, Indonesia. In-depth interviews were employed to collect data from the participants (n=23) who were recruited using the snowball sampling technique. A qualitative data analysis framework was used to guide the analysis of the findings. The findings showed that the mothers experienced a range of mental health issues due to their own, and their child’s diagnosis; stress, depression, anxiety, fear, sadness, and guilt. Lack of knowledge about HIV, fear of death, shame, not knowing whom to talk with and what to do after their own HIV diagnosis, and the HIV diagnosis of their children were factors that challenged their mental health. Difficulties in dealing with daily life or social activities of their CLHIV, dilemma in addressing questions and complaints of their CLHIV about HIV treatment, and concerns about the health condition of their CLHIV and how their children cope with any potential negative social impacts also impacted the mothers’ mental health. Social factors such as unsympathetic expressions from friends towards them and their CLHIV and negatively worded religious-related advice from parents and relatives also contributed to their poor mental health. Our findings indicate the need for intervention programs that support HIV-positive mothers and their CLHIV. Future large-scale studies involving HIV-positive mothers with CLHIV in Indonesia and other settings globally are needed to obtain a comprehensive understanding of mental health challenges and the associated factors they face.
Performance of the SD Bioline rapid diagnostic test as a good alternative to the detection of Human African Trypanosomiasis in Cameroon
Authors: Deutou Wondeu Andrillene Laure , Okoko Aline , Djeunang Dongho Ghyslaine Bruna , Doll Christian , Bahebegue Samuel , Mpeli Mpeli Ulrich Stéphane , Ninko Christian Chouamou , Montesano Carla , Dologuele Nicolas Félicien , Awono Ambene Herman Parfait
Published: May 2022

Background

The management of human African trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense relies on case detection. As part of this, the routine screening by the card agglutination test for trypanosomiasis (CATT) is the critical step before parasitological confirmation. Individual rapid diagnostic tests (RDTs) have recently been developed for the serodiagnosis of HAT.

Objective

The objective of the current study was to assess the input of SD Bioline HAT on the serological screening of human African trypanosomiasis in Cameroonian foci.

Methods

Blood samples were collected during the surveys in the foci of Campo, Yokadouma and Fontem between June 2014 and January 2015. Diagnostic performance indicators such as sensitivity (Se) and specificity (Sp) of SD Bioline HAT was determined from the CATT, used as gold standard for the detection of specific antibodies of Trypanosoma brucei gambiense.

Results

A total of 88 samples were tested in Campo 59.1% (n=52), Yokadouma 31.8% (n=28) and Fontem 9.1% (n=8). The gender distribution was 61.4% (n=54) male and 38.4% (n=34) female, with an average age of 35.4 ± 19.0 years. The overall seroprevalence was 11.4% (95% CI: 6.3- 19.7) with the CATT method and 18.2% (95% CI: 11.5- 27.5) with the SD Bioline HAT RDT method in probed foci. The Se and Sp were 80.0% and 89.7% respectively for the SD Bioline HAT.

Conclusion

This study showed that the overall performance of the SD Bioline HAT was close to that of the CATT, with significant specificity in the serological detection of HAT.
Two phenotypes of Chronic Recurrent Multifocal Osteomyelitis with different patterns of bone involvement
Authors: Cebecauerová Dita , Malcová Hana , Koukolská Veronika , Kvíčalová Zuzana , Souček Ondřej , Wagenknecht Lukáš , Bronský Jiří , Šumník Zdeněk , Kynčl Martin , Cebecauer Marek , Horváth Rudolf
Published: May 2022

Introduction

Chronic Recurrent Multifocal Osteomyelitis (CRMO) is an autoinflammatory bone disorder with predominantly paediatric onset. Children present with multifocal osteolytic lesions accompanied by bone pain and soft tissue swelling. Patients often exhibit extraosseous co-morbidities such as psoriasis, inflammatory bowel disease, and arthritis.

Objectives

Comparison of children with two different phenotypes of CRMO defined by presence or absence of extraosseous co-morbidities.

Methods

Children diagnosed with CRMO at the Motol University Hospital between 2010-2020 were retrospectively reviewed, and according to the absence or presence of extraosseous manifestations divided into two cohorts – osteolytic CRMO and complex CRMO. The two groups were compared in terms of demographic data, age at disease onset, number and site of bone lesions, laboratory biomarker values, and need of escalation to a second-line therapy

Results

Thirty-seven children (30 female, 7 male) with confirmed CRMO were included in the analysis. The mean age at disease onset was ten years. All but 3 patients presented with multifocal disease. Twenty-three children (62%) had at least one extraosseous manifestation (13 sacroiliitis, 8 inflammatory bowel disease, 6 skin disease [acne, pustulosis, or psoriasis], 7 arthritis). Complex CRMO was associated with a significantly higher ESR rate (p=0.0064) and CRP level (p=0.018). The groups did not differ in number of foci or in age at disease onset. Bone lesion distribution differed between the two groups with significantly more frequent involvement of clavicle (p=0.011) and pelvis (p=0.038) in patients with complex CRMO. Children with complex CRMO more often needed escalation of therapy to DMARDs and biologic agents.

Conclusion

Our data suggest that CRMO affecting solely the skeleton has milder course compared to complex CRMO with extraskeletal features. Further studies are needed to explore the clinical as well as the patient reported outcomes and promote individually tailored therapeutic strategies in both CRMO phenotypes.
Elevated liver enzymes and bilirubin following SARS-CoV-2 infection in children under 10
Authors: Kendall Ellen K. , Olaker Veronica R. , Kaelber David C. , Xu Rong , Davis Pamela B.
Published: May 2022

Recently, the Centers for Diseases and Control released a nationwide health alert about an increase in hepatitis cases of unknown origin in children, raising concern about potential sequelae of COVID-19 infection. In this study, we test whether there was increased risk of elevated serum liver enzymes and bilirubin following COVID-19 infection in children. We performed a retrospective cohort study on a nation-wide database of patient electronic health records (EHRs) in the US. The study population comprise 796,369 children between the ages of 1-10 years including 245,675 who had contracted COVID-19 during March 11, 2020 - March 11, 2022 and 550,694 who contracted non-COVID other respiratory infection (ORI) during the same timeframe.

Compared to children infected with other respiratory infections, children infected with COVID-19 infection were at significantly increased risk for elevated AST or ALT (hazard ratio or HR: 2.52, 95% confidence interval or CI: 2.03-3.12) and total bilirubin (HR: 3.35, 95% CI: 2.16-5.18). These results suggest acute and long-term hepatic sequelae of COVID-19 in pediatric patients. Further investigation is needed to clarify if post-COVID-19 related hepatic injury described in this study is related to the current increase in pediatric hepatitis cases of unknown origin.
Unrealistic optimism in the eye of the storm: Positive bias towards the consequences of COVID-19 during the second and third waves of the pandemic
Authors: Maksim Ada , Śpiewak Sławomir , Lipp Natalia , Dużmańska-Misiarczyk Natalia , Gustaw Grzegorz , Rębilas Krzysztof , Strojny Paweł
Published: May 2022

Research conducted at the outset of the pandemic shows that people are vulnerable to unrealistic optimism (UO). However, the Weinstein model suggests that this tendency may not persist as the pandemic progresses. Our research aimed at verifying whether UO persists during the second (Study 1) and the third wave (Study 2) of the pandemic in Poland, whether it concerns the assessment of the chances of COVID-19 infection (Study 1 and Study 2), the chances of severe course of the disease and adverse vaccine reactions (Study 2). We show that UO towards contracting COVID-19 persists throughout the pandemic. However, in situations where we have little influence on the occurrence of the event, the participants do not show UO. The exceptions are those who have known personally someone who has died from a coronavirus infection. These results are discussed in terms of self-esteem protection and the psychological threat reduction mechanism.
Action selection in early stages of psychosis: an active inference approach
Authors: Knolle Franziska , Sterner Elisabeth , Moutoussis Michael , Adams Rick A , Griffin Juliet D. , Haarsma Joost , Taverne Hilde ,   NSPN Consortium, Goodyer Ian M. , Fletcher Paul C. , Murray Graham K
Published: May 2022

Background and Hypothesis

In order to interact successfully with our environment, we need to build a model, to make sense of noisy and ambiguous inputs. An inaccurate model, as suggested to be the case in psychosis, disturbs optimal action selection. Recent computational models, such as active inference (AI), have emphasized the importance of action selection, treating it as a key part of the inferential process. Based on an AI-framework, we examined prior knowledge and belief precision in an action-based task, given that alterations in these parameters have been linked to the development of psychotic symptoms. We further sought to determine whether task performance and modelling parameters would be suitable for classification of patients and controls.

Study Design

23 at-risk-mental-state individuals, 26 first-episode psychosis patients and 31 controls completed a probabilistic Go/NoGo task in which action choice (Go/ NoGo) was dissociated from outcome valence (gain/ loss). We examined group differences in performance and AI-model parameters, and then performed receiver operating characteristic (ROC) analyses to assess group-classification.

Study Results

We found reduced overall performance in patients. AI-modelling revealed that patients showed increased forgetting, reduced confidence in policy selection and less optimal general choice behavior, with poorer action-state associations. Importantly, ROC-analysis revealed fair-to-good classification performances of all groups, when combining modelling parameters and performance measures.

Conclusion

Findings show that AI-modelling of this task not only provides further explanation for dysfunctional mechanisms underlying decision making in psychosis, but may also be highly relevant for future research on the development of biomarkers for early identification.
Social clustering of unvaccinated children: measles-mumps-rubella vaccination coverage in schools in the Netherlands
Authors: Klinkenberg Don , van Hoek Albert Jan , Veldhuijzen Irene , Hahné Susan , Wallinga Jacco
Published: May 2022

Background

For the measles-mumps-rubella (MMR) vaccine, the WHO-recommended coverage for herd protection is 95% for measles and 80% for rubella and mumps. However, a national vaccine coverage does not reflect social clustering of unvaccinated children, e.g. in schools of Orthodox Protestant or Anthroposophic identity in The Netherlands. To fully characterise this clustering, we estimated one-dose MMR vaccination coverages at all schools in the Netherlands.

Methods

By combining postcode catchment areas of schools and school feeder data, each child in the Netherlands was characterised by residential postcode, primary and secondary school (referred to as school career). Postcode-level vaccination data were used to estimate vaccination coverages per school career. These were translated to coverages per school, stratified by school identity.

Results

Most schools had vaccine coverages over 99%, but major exceptions were Orthodox Protestant schools (63% in primary and 58% in secondary schools) and Anthroposophic schools (67% and 78%).

Conclusions

School-level vaccine coverage estimates reveal strong clustering of unvaccinated children. The school feeder data reveal strongly connected Orthodox Protestant and Anthroposophic communities, but separated from one another. This suggests that even at a national one-dose MMR coverage of 97.5%, thousands of children per cohort are not protected by herd immunity.
Pro-inflammatory innate-like T cells are expanded in the blood and inflamed intestine in Crohn’s Disease
Authors: Chiarolla Cristina M. , Schulz Axel R. , Meir Michael , Reu-Hofer Simone , Romero-Olmedo Addi J. , Lohoff Michael , Rosenwald Andreas , Chang Hyun-Dong , Schlegel Nicolas , Mei Henrik E. , Berberich-Siebelt Friederike
Published: May 2022

A complex and tissue-specific network of cells including T lymphocytes maintains intestinal homeostasis. To address disease and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with Crohn’s disease (CD) and healthy donor PBMCs. We compared inflamed and not inflamed tissue areas of bowel resections. Chronic inflammation enforced activation, exhaustion and terminal differentiation of CD4+and CD8+T cells and an enrichment of CD4+Foxp3+cells (Tregs) in inflamed intestine. However, tissue-repairing Tregs decreased, while enigmatic rare Foxp3+T-cell subsets appeared upon inflammation. In vitro assays revealed that those subsets, e.g. CD4+Foxp3+HLA-DR+TIGIT−and CD4+Foxp3+CD56+, express pro-inflammatory IFN-γ. Some T-conventional (Tcon) cells tended towards innateness. In blood of CD patients, not well studied CD4+and CD8+subsets of CD16+CCR6+CD127+T cells appeared anew, a phenotype reproducible by incubation of healthy blood T cells with patient blood plasma. Together, these findings suggest a bias towards innate-like pro-inflammatory Tregs and innate-like Tcon, which act with less specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.

Graphical Abstract
Real-world comparative effectiveness of mRNA-1273 and BNT162b2 vaccines among immunocompromised adults in the United States
Authors: Mues Katherine E. , Kirk Brenna , Patel Deesha A. , Gelman Alice , Chavers Scott , Talarico Carla , Esposito Daina B. , Martin David , Mansi James , Chen Xing , Gatto Nicolle M. , Van de Velde Nicolas
Published: May 2022

Introduction

Head-to-head studies comparing COVID-19 mRNA vaccine effectiveness in immunocompromised individuals, who are vulnerable to severe disease are lacking, as large sample sizes are required to make meaningful inferences.

Methods

This observational comparative effectiveness study was conducted in closed administrative claims data from the US HealthVerity database (December 11, 2020-January 10, 2022, before omicron). A 2-dose mRNA-1273 versus BNT162b2 regimen was assessed for preventing medically-attended breakthrough COVID-19 diagnosis and hospitalizations among immunocompromised adults. Inverse probability of treatment weighting was applied to balance baseline characteristics between vaccine groups. Incidence rates from patient-level data and hazard ratios (HRs) using weighted Cox proportional hazards models were calculated.

Results

Overall, 57,898 and 66,981 individuals received a 2-dose regimen of mRNA-1273 or BNT161b2, respectively. Among the weighted population, mean age was 51 years, 53% were female, and baseline immunodeficiencies included prior blood transplant (8%-9%), prior organ transplant (7%), active cancer (12%-13%), primary immunodeficiency (25%-26%), HIV (20%-21%), and immunosuppressive therapy use (60%-61%). Rates per 1,000 person-years (PYs; 95% confidence intervals [CI]s) of breakthrough medically-attended COVID-19 were 25.82 (23.83-27.97) with mRNA-1273 and 30.98 (28.93, 33.18) with BNT162b2 (HR, 0.83; 95% CI, 0.75-0.93). When requiring evidence of an antigen or polymerase chain reaction test before COVID-19 diagnosis, the HR for medically-attended COVID-19 was 0.78 (0.67-0.92). Breakthrough COVID-19 hospitalization rates per 1,000 PYs (95% CI) were 3.66 (2.96-4.51) for mRNA-1273 and 4.68 (3.91-5.59) for BNT162b2 (HR, 0.78; 0.59-1.03). Utilizing open and closed claims for outcome capture only, or both cohort entry/outcome capture, produced HRs (95% CIs) for COVID-19 hospitalization of 0.72 (0.57-0.92) and 0.66 (0.58-0.76), respectively.

Conclusions

Among immunocompromised adults, a 2-dose mRNA-1273 regimen was more effective in preventing medically-attended COVID-19 in any setting (inpatient and outpatient) than 2-dose BNT162b2. Results were similar for COVID-19 hospitalization, although statistical power was limited when using closed claims only.

Study Registration

NCT05366322
Fear of Infection and Sufficient Vaccine Reservation Information Might Drive Rapid Coronavirus Disease 2019 Vaccination in Japan: Evidence from Twitter Analysis
Authors: Niu Qian , Liu Junyu , Kato Masaya , Aoyama Tomoki , Nagai-Tanima Momoko
Published: May 2022

Background

The global public health and socioeconomic impacts of coronavirus disease 2019 (COVID-19) have been substantial, making herd immunity by COVID-19 vaccination an important factor for protecting people and retrieving the economy. Among all the countries, Japan became one of the countries with the highest COVID-19 vaccination rate in several months, although the vaccine confidence in Japan is the lowest worldwide.

Objective

We attempted to find the reasons for the rapid coronavirus disease 2019 (COVID-19) vaccination in Japan under the lowest vaccine confidence in the world by Twitter analysis.

Materials and methods

We downloaded COVID-19 related Japanese tweets from a large-scale public COVID-19 Twitter chatter dataset within the timeline of February 1, 2021 and September 30, 2021. The daily number of vaccination cases was collected from the official website of the Prime Minister’s Office of Japan. After preprocessing, we applied unigram and bigram token analysis, then calculated the cross correlation and Pearson correlation coefficient (r) between the term frequency and daily vaccination cases. Then we identified vaccine sentiments and emotions of tweets and used the topic modeling to look deeper into the dominant emotions.

Results

We selected 190,697 vaccine-related tweets after filtering. By n-gram token analysis, we discovered the top unigrams and bigrams over the whole period. In all the combinations of the top six unigrams, tweets with both keywords “reserve” and “venue” showed the largest r = 0.912 (P < 0.001) with the daily vaccination cases. In sentiment analysis, negative sentiment overwhelmed positive sentiment, and fear was the dominant emotion across the period. For the latent Dirichlet allocation model on tweets with fear emotion, the two topics were identified as “infect” and “vaccine confidence”. The expectation of the number of tweets generated from topic “infect” was larger than “vaccine confidence.”

Conclusion

Our work indicated that awareness of the danger of COVID-19 might increase the willingness to get vaccinated; With sufficient vaccine supply, effective vaccine reservation information delivery may be an important factor for people to get vaccinated; We didn’t find evidence for increased vaccine confidence in Japan during the period in our research. We recommend policymakers to share fair and prompt information about the infectious diseases and vaccination, and make efforts on smoother delivery of vaccine-reservation information.
Mapping the Regional Distribution of Molecular Tumor Board Patients and Identifying White Spots in our Catchment Area – a Joint Approach of the CCC WERA Alliance
Authors: Lüke Florian , Haller Florian , Utpatel Kirsten , Krebs Markus , Meidenbauer Norbert , Scheiter Alexander , Spörl Silvia , Heudobler Daniel , Keil Felix , Schubart Christoph , Tögel Lars , Einhell Sabine , Dietmaier Wolfgang , Huss Ralf , Dintner Sebastian , Sommer Sebastian , Jordan Frank , Goebeler Maria-Elisabeth , Metz Michaela , Haake Diana , Scheytt Mithun , Gerhard-Hartmann Elena , Maurus Katja , Brändlein Stephanie , Rosenwald Andreas , Hartmann Arndt , Märkl Bruno , Einsele Hermann , Mackensen Andreas , Herr Wolfgang , Kunzmann Volker , Bargou Ralf , Beckmann Matthias W. , Pukrop Tobias , Trepel Martin , Evert Matthias , Claus Rainer , Kerscher Alexander
Published: May 2022

Background

Molecular Tumor Boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs.

Methods

We analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities.

Results

Highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed us to identify regions within our catchment area relatively underrepresented in WERA MTBs.

Conclusion

Investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in precision oncology and establishing a joint WERA-wide outreach strategy.
Clinical validation of 3D-printed nasopharyngeal and oropharyngeal swabs for SARS-CoV-2 RT-PCR
Authors: Riis Åse Garløv , Røssland Tonje Merethe , Høyland Löhr Iren , Dalen Ingvild , Kåre Kleppe Lars , Sundal Jon , Berg Åse , Vadla May Sissel , Lenning Ole Bernt , Syre Heidi
Published: May 2022

Due to limited access to commercially available flocked nasopharyngeal (NP) and oropharyngeal (OP) swabs during the SARS-COV-2 pandemic, we have evaluated the sensitivity of 3D-printed swabs compared to commercial swabs in a clinical setting. We included 35 subjects with known exposure to SARS-CoV-2. Participants were tested with commercial and prototype NP/OP swab pairs 8 and 22 days after exposure. At day 8, the sensitivity of the prototype was 96% for NP-samples (CI 81-99%) and 91% for OP-samples (CI 72-97%). The sensitivity of the commercial swab was 92% for NP-samples (CI 76-98%) and 91% for OP-samples (CI 72-97%). At day 22, the sensitivities of the commercial swab were 100% for NP-samples (CI 82-100%) and OP-samples (CI 77-100%), whereas sensitivity of the prototype was 61% for NP-samples (CI 39-80%) and 54% for OP-samples (CI 29-77%). In conclusion, the prototype might be an alternative to commercial swabs when used early in the course of infection.
Informing Variant Assessment using Structured Evidence from Prior Classifications (PS1, PM5, and PVS1 Sequence Variant Interpretation Criteria)
Authors: Bhat Vineel , Adzhubei Ivan A. , Fife James D. , Lebo Matthew , Cassa Christopher A.
Published: May 2022

Purpose

To explore whether evidence of pathogenicity from prior variant classifications in ClinVar could be used to inform variant interpretation using the ACMG/AMP clinical guidelines.

Methods

We identify distinct SNVs which are either similar in location or in functional consequence to pathogenic variants in ClinVar, and analyze evidence in support of pathogenicity using three interpretation criteria.

Results

Thousands of variants, including many in clinically actionable disease genes (ACMG SFv3.0), have evidence of pathogenicity from existing variant classifications, accounting for 2.5% of non-synonymous SNVs within ClinVar. Notably, there are many variants with uncertain or conflicting classifications which cause the same amino acid substitution as other pathogenic variants (PS1, N=323), variants which are predicted to cause different amino acid substitutions in the same codon as pathogenic variants (PM5, N=7,692), and LOF variants which are present in genes where many LOF variants are classified as pathogenic (PVS1, N=3,635). The majority of these variants have similar computational predictions of pathogenicity and splicing impact as their associated pathogenic variants.

Conclusion

Broadly, over 1.4 million SNVs exome-wide could make use of information from previously classified pathogenic variants. We have developed a pipeline to identify variants meeting these criteria, which may inform interpretation efforts.
Coding of Obesity-related Mortality Impacts Estimates of Obesity on U.S. Life Expectancy
Authors: Tilstra Andrea M. , Aburto José Manuel , Gutin Iliya , Dowd Jennifer Beam
Published: May 2022

Background

High levels of obesity remain an important population health problem in the U.S. and a possible contributor to stalling life expectancy. However, reliable estimates of the contribution of obesity to mortality in the U.S. are lacking, because of inconsistent coding of obesity-related causes of death.

Methods

We compare five International Classification of Diseases version 10 (ICD-10) coding schemes for obesity-related mortality used in the literature and examine how the magnitude of obesity-related mortality burdens varies across different schemes. We use U.S. multiple cause of death data and population estimates for the Black, white, and Latino population in the years 2010, 2015, and 2020. In sex- and race/ethnic-stratified analyses, we estimate the potential years of life expectancy gained if obesity-related mortality had not occurred as measured by each coding scheme.

Results

We estimate that obesity-related mortality contributes to up to 78 months (6.5 years) of lost U.S. life expectancy, though estimates range from as low as 0 months, with a median contribution across ICD-10 coding schemes of about 20 months (1.7 years). Despite substantial variation across coding schemes, obesity-related mortality consistently contributes more to life expectancy deficits for Black Americans compared to white and Latino Americans. Across all ICD-10 coding schemes, the age pattern of obesity follows a J-shaped curve, suggesting exponential increases in obesity-related mortality after age 25.

Conclusions

The estimation of the burden of obesity-related mortality on life expectancy in the United States varies widely depending on the causes of death used in analyses. This inconsistency may obscure our understanding of the contribution of obesity-related mortality to trends in life expectancy. We propose a standardization of the coding of obesity-related mortality for future studies and outline which causes should be included.
Performance and validation of an adaptable multiplex assay for detection of serologic response to SARS-CoV-2 infection or vaccination
Authors: Kenny Grace , Negi Riya , O’Reilly Sophie , Garcia-Leon Alejandro , Alalwan Dana , Gaillard Colette Marie , Saini Gurvin , Inzitari Rosana , Feeney Eoin R. , Yousif Obada , Cotter Aoife , de Barra Eoghan , Sadlier Corinna , Crispie Fiona , Doran Peter , Gautier Virginie , Mallon Patrick WG
Published: May 2022

Measurement of quantitative antibody responses are increasingly important in evaluating the immune response to infection and vaccination. In this study we describe the validation of a quantitative, multiplex serologic assay utilising an electrochemiluminescence platform, which measures IgG against the receptor binding domain (RBD), spike S1 and S2 subunits and nucleocapsid antigens of SARS-CoV-2. The assay displayed a sensitivity ranging from 73-91% and specificity from 90 to 96% in detecting previous infection with SARS-CoV-2 depending on antigenic target and time since infection, and this assay highly correlated with commercially available assays. The within-plate coefficient of variation ranged from 3.8-3.9% and the inter-plate coefficient of variation from 11-13% for each antigen.
Interrogating the causal effects of maternal circulating CRP on gestational duration and birth weight
Authors: Chen Jing , Navais Pol Sole , Xu Huan , Flatley Christopher , Bacelis Jonas , Monangi Nagendra , Kacerovsky Marian , Hallman Mikko , Teramo Kari , Lawlor Deborah A. , Murray Jeffrey C. , Jacobsson Bo , Muglia Louis J. , Zhang Ge
Published: May 2022

Background

C-reactive protein (CRP) is an acute-phase marker of inflammation. Previous epidemiological studies have associated elevated maternal CRP levels during pregnancy with preterm birth risk and lower birth weight. However, the causal relationships behind these observed associations are not clear.

Methods and Findings

We utilized phenotype and genotype data on 10,734 mother/child pairs of European ancestry collected from six birth cohorts. We performed two-sample multivariate Mendelian Randomization (MR) using maternal non-transmitted alleles to interrogate the causal effect of maternal CRP on gestational duration and birth weight. Based on the non-transmitted alleles of 55 CRP associated single nucleotide polymorphisms (SNPs), a unit increase in log-transformed maternal CRP level was associated with a reduction of 1.58 days (95% CI: 0.23, 2.94, P = 0.022) in gestational duration and a reduction of 76.3g (95% CI: 18.2, 134.4, P = 0.010) in birth weight. The magnitude of the association between genetically increased CRP and birth weight was reduced after adjusting for gestational age. Utilizing the effect estimates of CRP-associated SNPs on birth weight from the UK Biobank genome-wide association (GWA) summary results, our results suggested one unit of genetically increased maternal CRP was associated with a decrease of 50.1g (95% CI: 24.7, 75.5, P = 9.6E-5) of birth weight (unadjusted by gestational age). We validated the results using a single genetic variant (rs2794520) near the CRP gene, which is less prone to horizontal pleiotropy bias.

Conclusions

Increased maternal CRP levels appear to causally reduce gestational duration and birth weight. The effect of maternal CRP on birth weight is partially due to its effect on gestational duration. The estimated causal effect sizes are consistent with previous epidemiological reports and this triangulation increases confidence in these results being causal.
Metabolomic Risk Predictors of Diabetic Foot Complications: a longitudinal observational study in Type 1 Diabetes
Authors: Andersen Jonas A. , Suvitaival Tommi , Trošt Kajetan , Romero-Lado María José , Theilade Simone , Mattila Ismo , Frimodt-Møller Marie , Rasmussen Anne , Rossing Peter , Legido-Quigley Cristina , Ahluwalia Tarunveer S.
Published: May 2022

Diabetic foot complications (DFCs) comprising diabetic foot ulcer (DFU), charcot’s neuroarthropathy and amputations are a collective term used for the ailments of the foot that individuals with diabetes incur. Despite implementation of national and international guidelines, DFCs are still a growing challenge to the individual and society. Novel markers for the treatment and prevention of DFCs are thus needed. The aim of this study was to investigate circulating metabolites associated with the prevalence and incidence of DFCs in persons with type 1 diabetes (T1D). A panel of non-targeted serum metabolites (n=75) were analyzed using mass spectrometry in 637 individuals with T1D with a median follow up time of 10 years. Cross sectional associations between metabolites and DFCs were analysed by linear regression models at baseline, Cox proportional hazards model at follow-up and adjusted for relevant confounders (age, sex, HbA1c, systolic blood pressure, bmi, smoking, statin use, total cholesterol, plasma triglycerides, and renal function). The median (interquartile range) age was 55 (47, 64) years, diabetes duration of 35 (25, 44) years and HbA1clevels 64 (8%) (56, 72(7.3%, 8.7%)) mmol/mol. In the adjusted model, four amino acids (Proline, Threonine, Valine, and Leucine) were associated with a decreased incidence of Charcot’s arthropathy at baseline (p<0.05). In addition, circulating ribonic acid levels were associated with an increased risk of DFUs during follow-up (HR 1.38(1.06-1.8); p<0.05) which were validated in an independent cross-sectional T1D cohort (p<0.05). This study identifies novel circulating metabolites, as potential biomarkers for risk stratification of diabetic foot complications.
Assessment of psychological distress, coping, and spirituality in patients with resected, non-metastatic vs unresectable advanced cancer. Data from the NEOcoping and NEOetic_SEOM studies
Authors: Velasco Veronica , Cruz-Castellanos Patricia , Hernandez Raquel , Rodriguez-Gonzalez Adan , Montes Ana Fernandez , Gallego Alejandro , Manzano-Fernandez Aranzazu , Sorribes Elena , Zafra Marta , Carmona-Bayonas Alberto , Calderon Caterina , Jiménez-Fonseca Paula
Published: May 2022

Background

Cancer negatively affects patients’ physical and mental health. This work sought to analyze the sociodemographic and clinical variables that modulate psychological distress in individuals with resected vs unresectable cancer before and after receiving systemic antineoplastic treatment, and to evaluate how different coping strategies and spiritual well-being influence psychological distress in these subjects.

Methods

Observational, prospective, consecutive study performed in 15 hospitals in Spain. The study consists of two cohorts: patients with resected locally and locally advanced cancer receiving adjuvant chemotherapy (NEOcoping study, 2016 and 2018) and those with unresectable locally advanced and advanced cancer, eligible for systemic treatment (NEOetic study, 2020 and 2021). Participants completed the following scales: BSI-18 (psychological distress) at baseline and after antineoplastic treatment; MINI-MAC (coping), and FACIT-sp (spirituality), before initiating systemic treatment.

Results

Fourteen hundred and fifty patients were recruited; 941 had resected cancer and 509 had advanced cancer. The advanced cancer sample included more males, older, less educated, and more unemployed individuals. Before starting systemic treatment, the advanced, unresectable disease group suffered more psychological distress than those with resected cancer (66.9 vs. 63.7, p=0.001) and used more coping strategies, especially positive attitude (79.1 vs. 75.6, p=0.001) and cognitive avoidance (64.3 vs. 53.6, p=0.001). Participants with resected cancer displayed greater spiritual well-being (36.5 vs 33.2, p=0.001). After receiving systemic treatment, psychological distress decreased in cases of advanced cancer and increased in resected cancer, albeit still higher in subjects with advanced cancer, particularly anxiety (61.4 vs 60.9) and depression (61.0 vs 60.6), (p=0.001 in both cases).

Conclusion

Patients with advanced cancer exhibit greater psychological distress, use more coping strategies, and have less spiritual well-being, but their psychological distress improves with antineoplastic treatment.
Increasing the Value of Digital Phenotyping Through Reducing Missingness: A Retrospective Analysis
Authors: Currey Danielle , Torous John
Published: May 2022

Objectives

Digital phenotyping methods present a scalable tool to realize the potential of personalized medicine. But underlying this potential is the need for digital phenotyping data to represent accurate and precise health measurements. This requires a focus on the data quality of digital phenotyping and assessing the nature of the smartphone data used to derive clinical and health-related features.

Design

Retrospective cohorts. Representing the largest combined dataset of smartphone digital phenotyping, we report on the impact of sampling frequency, active engagement with the app, phone type (Android vs Apple), gender, and study protocol features may have on missingness / data quality.

Setting

mindLAMP smartphone app digital phenotyping studies run at BIDMC between May 2019 and March 2022

Participants

1178 people who partook in mindLAMP studies

Main outcome measures

Rates of missing digital phenotyping data.

Results

Missingness from sensors in digital phenotyping is related to active user engagement with the app. There are small but notable differences in missingness between phone models and genders. Datasets with high degrees of missingness can generate incorrect behavioral features that may lead to faulty clinical interpretations.

Conclusions

Digital phenotyping data quality is a moving target that requires ongoing technical and protocol efforts to minimize missingness. Adding run-in periods, education with hands-on support, and tools to easily monitor data coverage are all productive strategies studies can utilize today.

Strengths and Limitations of this Study

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Methods are informed by a large sample of participants in digital phenotyping studies.

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Methods can be replicated by others given the open-source nature of the app and code.

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Methods are informed by only mindLAMP studies from one team which is a limitation.
Parameter Estimation for a Modified SEIR Model of the COVID-19 Dynamics in the Philippines using Genetic Algorithm
Authors: Santos Gabriel Lorenzo I.
Published: May 2022

The Philippines has been under a series of different levels of community quarantine and this affected the dynamics of the COVID-19 spread in the country. Predicting the trajectory has been an interest of various research groups. To provide a more efficient method to estimate the parameters of the Age-Stratified, Quarantine-modified SEIR model with Nonlinear Incidence Rates (ASQ-SEIR-NLIR) other than the shooting method, a genetic algorithm approach is explored. By defining constraints for each parameter, the algorithm arrived at an acceptable optimal value for each parameter. The experiment is done on two regions of interest: the Philippines (country-level) and Quezon City, Metro Manila (city-level). The ASQ-SEIR-NLIR model, using the parameters generated by the genetic algorithm, is able to produce an average trajectory compared to the actual data, which may be deemed noisy. The dynamics of the COVID-19 spread between Quezon City and average country level is compared, showing that the city population is being exposed to the virus at a much faster rate than the country average and may have more asymptomatics not getting tested than the country average. Given the average trajectory, the peak daily infection projection is way lower at 0.0823% of the country population for the country projection and 0.1494% of the Quezon City population for the city projection, which is below than previous literature estimates of 3-10%.
COMPARISON OF SARS-COV-2 WUHAN AND ALPHA VARIANTS: CLINICAL AND LABORATORY HIGHLIGHTS
Authors: Timur Demet , Demirpek Uğur , Ertek Engin , Çetinkaya Aydın Özlem , Karabıyık Talha , Kayadibi Hüseyin
Published: May 2022

Since December 2019, after the declaration of new cases regarding novel coronavirus disease, many variants have emerged as a consequence of the viral evolution. Though the SARS-CoV-2 variants have been studied for molecular basis, the clinical and pathologic disparities of them have been understood inadequately. The aim of this research was to figure out the differences between the SARS-CoV-2 Alpha (B1.1.7) variant and the classical Wuhan groups on the clinical basis and laboratory results of the COVID-19 patients who had positive PCR test.The study was done retrospectively inclusive of epidemiological, laboratory data and clinical symptoms of patients who were admitted to the emergency service between February 15 and March 15, 2021 and had positive COVID-19 PCR test results. Though there was no statistically significant difference in symptoms between SARS-CoV-2 Alpha variant and classical variant (Wuhan type) groups; C-reactive protein (CRP), lymphocyte and leukocyte counts were statistically significantly higher in the Wuhan type group; prothrombin time (PT), International Normalized Ratio (INR) and serum creatinine values were statistically significantly higher in the Alpha group. Studies such as ours that investigate both the clinical features and laboratory data of SARS-CoV-2 variants will close the knowledge gaps, so better decisions may be made by health policy makers. Additional studies in this area will increase the understanding of the topic.
A hybrid approach to predict COVID-19 cases using neural networks and inverse problem
Authors: Paul Subhendu , Lorin Emmanuel
Published: May 2022

We derive a novel hybrid approach, a combination of neural networks and inverse problem, in order to forecast COVID-19 cases, and more generally any infectious disease. For this purpose, we extract a second order nonlinear differential equation for the total confirmed cases from a SIR-like model. That differential equation is the key factor of the present study. The neural network and inverse problems are used to compute the trial functions for total cases and the model parameters, respectively. The number of suspected and infected individuals can be found using the trial function of total confirmed cases. We divide the time domain into two parts, training interval (first 365/395 days) and test interval (first 366 to 395/ 396 to 450 days), and train the neural networks on the preassigned training zones. To examine the efficiency and effectiveness, we apply the proposed method to Canada, and use the Canadian publicly available database to estimate the parameters of the trial function involved with total cases. The trial functions of model parameters show that the basic reproduction number was closed to unity over a wide range, the first from 100 to 365 days of the current pandemic in Canada. The proposed prediction models, based on influence of previous time and social economic policy, show excellent agreement with the data. The test results revel that the single path prediction can forecast a period of 30 days, and forecasting using previous social and economical situation can forecast a range of 55 days.
Sequence Proven Reinfections with SARS-CoV-2 at a Large Academic Center
Authors: Morris C. Paul , Eldesouki Raghda E. , Fall Amary , Gaston David C. , Norton Julie M. , Gallagher Nicholas , Luo Chun Huai , Abdullah Omar , Klein Eili Y. , Mostafa Heba H.
Published: May 2022

Background

Increased reinfection rates with SARS-CoV-2 have recently been reported, with some locations basing reinfection on a second positive PCR test at least 90 days after initial infection.

Methods

We identified cases where patients had two positive tests for SARS-CoV-2 and evaluated which of these had been sequenced as part of our surveillance efforts, and evaluated sequencing and clinical data.

Results

750 patients (920 samples) had a positive test at least 90 days after the initial test. The median time between tests was 377 days, and 724 (79%) of the post 90-day positives were collected after the emergence of the Omicron variant in November 2021. Sequencing was attempted on 231 samples and successful in 127. Successful sequencing spiked during the Omicron surge and showed higher median days from initial infection compared to failed sequences (median 398 days compared to 276 days, p<0.0005). A total of 122 (98%) patients showed evidence of reinfection, 45 of which had sequence proven reinfection and 77 had inferred reinfections (later sequence showed a clade that was not circulating when the patient was initially infected). Children accounted for only 4% of reinfections. 43 (96%) of 45 infections with sequence proven reinfection were caused by the Omicron variant, 41 (91%) were symptomatic, 32 (71%), were vaccinated prior to the second infection, and 6 (13%) were Immunosuppressed. Only 2 (4%) were hospitalized, and both had underlying conditions.

Conclusion

Sequence proven reinfections increased with the Omicron variant but generally caused mild infections.
Health Technology Assessment of Diagnostic Tests: A state of the art review of methods guidance from international organisations
Authors: Ferrante di Ruffano Lavinia , Harris Isobel M , Zhelev Zhivko , Davenport Clare , Mallett Sue , Peters Jamie , Takwoingi Yemisi , Deeks Jon , Hyde Chris
Published: May 2022

Objectives

To identify which international HTA agencies are undertaking evaluations of medical tests, summarise commonalities and differences in methodological approach, and highlight examples of best practice.

Methods

A methodological review incorporating: systematic identification of HTA guidance documents mentioning evaluation of tests; identification of key contributing organisations and abstraction of approaches to all essential HTA steps; summary of similarities and differences between organisations; and identification of important emergent themes which define the current state of the art and frontiers where further development is needed.

Results

Seven key organisations were identified from 216 screened. The main themes were: elucidation of claims of test benefits; attitude to direct and indirect evidence of clinical effectiveness (including evidence linkage); searching; quality assessment; and health economic evaluation. With the exception of dealing with test accuracy data, approaches were largely based on general approaches to HTA with few test-specific modifications. Elucidation of test claims and attitude to direct and indirect evidence are where we identified the biggest dissimilarities in approach.

Conclusions

There is consensus on some aspects of HTA of tests, such as dealing with test accuracy, and examples of good practice which HTA organisations new to test evaluation can emulate. The focus on test accuracy contrasts with universal acknowledgement that it is not a sufficient evidence base for test evaluation. There are frontiers where methodological development is urgently required, notably integrating direct and indirect evidence and standardising approaches to evidence linkage.