bluuebunny/crossref_metadata_2025 huggingface dataset:
Qualitative hepatitis C virus RNA assay identifies active infection with sufficient viral load for treatment among Phetchabun residents in Thailand
Authors: Pratedrat Pornpitra , Nilyanimit Pornjarim , Wasitthankasem Rujipat , Posuwan Nawarat , Auphimai Chompoonut , Hansoongnern Payuda , Pimsing Napaporn , Ngamnimit Saranya , Thongmai Chaiwat , Phaengkha Wijittra , Wanlapakorn Nasamon , Vongpunsawad Sompong , Poovorawan Yong
Published: May 2022

The World Health Organization envisions the elimination of viral hepatitis by 2030 through reducing prevalence and transmission, increasing diagnostic screening, and expanding treatment coverage. Efforts to micro-eliminate hepatitis in Phetchabun province in Thailand, a region where the prevalence of hepatitis C virus (HCV) infection and liver cancer is higher than elsewhere in the country, began with evaluating the province-wide burden of HCV. Here, we describe a feasibility study to assess active HCV infection by screening Phetchabun residents ages 35 to 69 years for anti-HCV antibodies by using a rapid diagnostic test (RDT) at the point of care. Positive anti-HCV results were further evaluated for active infection using qualitative HCV RNA assay, followed by quantitative HCV viral load determination in a subset of samples. Currently, we have identified 6.2% (10,621/170,163) anti-HCV positive individuals, of whom 74.9% (3,930/5,246) demonstrated detectable viral RNA. Quantitative test found that 97.5% (1,001/1,027) had HCV viral load ≥5,000 IU/mL. Thus, primary screening with anti-HCV RDT followed by qualitative HCV RNA evaluation could identify active and chronic HCV infection in almost all individuals with a viral load ≥5,000 IU/mL, which is the current threshold for the National Health Security Office treatment in Thailand. Our data suggest that qualitative HCV RNA evaluation may obviate the need for the more expensive quantitative HCV viral load test and reduce a significant barrier toward HCV elimination in a middle-income country.
Characterization of Childhood Trauma, Hippocampal Mediation and Cannabis Use in a Large Dataset of Psychosis and Non-Psychosis Individuals
Authors: del Re Elisabetta C. , Yassin Walid , Zeng Victor , Keedy Sarah , Alliey-Rodriguez Ney , Ivleva Elena , Hill Scott , Rychagov Nicole , McDowell Jennifer E. , Bishop Jeffrey R. , Mesholam-Gately Raquelle , Merola Giovanni , Lizano Paulo , Gershon Elliot , Pearlson Godfrey , Sweeney John A. , Clementz Brett , Tamminga Carol , Keshavan Matcheri
Published: May 2022

Background

Cannabis use (CA) and childhood trauma (CT) independently increase the risk of earlier psychosis onset; but their interaction in relation to psychosis risk and association with endocannabinoid-receptor rich brain regions, i.e. the hippocampus (HP), remains unclear. The objective was to determine whether lower age of psychosis onset (AgePsyOnset) is associated with CA and CT through mediation by the HP, and genetic risk, as measured by schizophrenia polygene scores (SZ-PGRS).

Methods

Cross- sectional, case-control, multicenter sample from 5 metropolitan US regions. Participants (n=1185) included 397 controls not affected by psychosis (HC); 209 participants with bipolar disorder type-1; 279 with schizoaffective disorder; and 300 with schizophrenia (DSM IV-TR). CT was assessed using the Childhood Trauma Questionnaire (CTQ); CA was assessed by self-reports and trained clinical interviewers. Assessment included neuroimaging, symptomatology, cognition and calculation of the SZ polygenic risk score (SZ-PGRS).

Outcomes

In survival analysis, low CT and CA are associated with lower AgePsyOnset. At high CT or CA, CT or CA are individually sufficient to affect AgePsyOnset. CT relation with AgePsyOnset is mediated in part by the HP in CA users before AgePsyOnset. CA before AgePsyOnset is associated with higher SZ-PGRS and correlated with younger age at CA usage.

Interpretation

CA and CT interact to increase risk when moderate; while severe CT and/or CA abuse/dependence are each sufficient to affect AgePsyOnset, indicating a ceiling effect. Probands with/out CA before AgePsyOnset differ on biological variables, suggesting divergent pathways to psychosis.

Funding

MH077945; MH096942; MH096913; MH077862; MH103368; MH096900; MH122759.

Research in context

Evidence before this study

Cannabis use (CA) and childhood trauma (CT) independently increase the risk of earlier development of psychosis. Scarce evidence exists on the interaction between CA and CT and the neurobiological substrate of their interaction.

Added value of this study

Analysis of a large transdiagnostic sample of psychosis probands and controls (N=1288) indicates synergy of CT and CA and small but significant contribution of the posterior hippocampus. Data further indicate existence of two populations of probands with psychosis, those with and those without CA after CT before psychosis onset. CT and CA before psychosis onset interact according to a stepwise increase up to reaching a ceiling effect.

Implications of all the available evidence

Clinically, youth with low, medium CT need to be targeted for intervention before CA onset.
Prevalence and risk factors of Pseudomonas aeruginosa colonization
Authors: Vy Tran Nguyen Bao , Truong Quang Minh , Anh Nguyen Lam Que , Huong Nguyen Ngoc My , Tran Quang Hung , Phuong Dinh Thi Tuyet , Hua Vinh Son , Lambert Peter A. , Nguyen Thi Thu Hoai
Published: May 2022

Pseudomonas aeruginosa (P. aeruginosa) is one of the most concerning pathogens due to its multidrug resistance. P. aeruginosa can be a part of the normal commensal flora of humans but can also cause a wide range of infections. In this study, we investigated the prevalence of commensal P. aeruginosa in 609 Vietnamese participants (310 females and 299 males, age range of 2 to 73 years) who had no acute infection or disease symptoms at the time of sample collection. Samples were taken from the throat, naris and outer ears. As a result, 19 were positive with P. aeruginosa (3.12%, 95% CI: 0.017-0.045) which came mostly from throat (11/19, 57.89%). Participants with a history of sinusitis were 11.57 times more likely to be colonized with P. aeruginosa than participants without a history of sinusitis (OR: 11.57, 95% CI: 4.08-32.76, p-value< 0.0001). Age and gender were not significantly associated with P. aeruginosa colonization. The commensal P. aeruginosa isolates were tested for biofilm formation, pyocyanin, siderophore, lipase, protease and gelatinase production. Among 16 P. aeruginosa isolates used for these tests, 100% (16/16) were positive for biofilm, pyocyanin and siderophores; 93.75% (15/16) isolates were positive for gelatinase and protease; and 50% (8/16) isolates were positive for lipase. There were no differences in the pattern and range of virulence factors of P. aeruginosa isolates taken from participants with and without sinusitis history. In summary, P. aeruginosa colonized 3.12% of participants, and its presence was clearly associated with sinusitis history. Most commensal P. aeruginosa isolates can produce biofilm, pyocyanin, siderophores, gelatinase and protease.

Author summary

P. aeruginosa is both a common opportunistic pathogen which causes various infections in humans, such as blood, lung, and skin infections and a commensal bacterium which can be found normal human flora. In this study, we showed that the P. aeruginosa colonized 3.12% participants and resided mostly in human throat. Interestingly, we found that people with sinusitis history were more likely to be P. aeruginosa carriers. On the other hand, age and gender did not significantly affect P. aeruginosa colonization. Most tested P. aeruginosa isolates expressed various virulence factors, including biofilm, siderophores, pyocyanin, gelatinase, protease, and lipase.
Tle4 controls both developmental acquisition and postnatal maintenance of corticothalamic projection neuron identity
Authors: Galazo Maria J. , Sweetser David , Macklis Jeffrey D.
Published: May 2022

Identities, circuitry, and function of distinct neuron subtypes are specified during embryonic development, then maintained during postnatal maturation and potential plasticity. Mechanisms that control early acquisition of neuron subtype identities, encompassing circuitry and function, in the cerebral cortex have become increasingly understood. However, mechanisms controlling maintenance of identity, and accompanying regulation of plasticity, are largely unexplored and unknown.

Here, we identify two novel functions of the co-repressor Tle4 in both acquisition and maintenance of neuron subtype identity of corticothalamic projection neurons. Embryonically, Tle4 promotes acquisition of corticothalamic molecular and cellular identity, and blocks emergence of core characteristics of subcerebral / corticospinal projection neuron identity, including morphology, gene expression, axonal connectivity, and circuitry. Postnatally, Tle4 is required to maintain corticothalamic molecular and projection identity during circuit maturation, avoiding potentially disruptive plasticity, but also limiting potentially beneficial plasticity.

We identify an epigenetic mechanism by which TLE4 controls the activation state of loci regulating the level of Fezf2 expression by corticothalamic neurons during embryonic and postnatal development. This mechanism contributes importantly to distinction of cortical output (corticofugal) subtypes, and ensures appropriate maturation and maintenance of CThPN.

Highlights

Tle4 promotes CThPN identity and blocks SCPN identity in early-born cortical neurons

Tle4 is necessary to maintain CThPN identity during circuit maturation

TLE4-FEZF2 complex epigenetically regulates Fezf2 expression in developing CThPN

TLE4-FEZF2 regulates corticofugal subtypes distinction and maturation of CThPN
Reduced contrast surround suppression associated with schizophrenia depends on visual acuity and scene context
Authors: Pokorny Victor J. , Schallmo Michael-Paul , Sponheim Scott R. , Olman Cheryl
Published: May 2022

Perceptual distortions are core features of psychosis. Weakened surround suppression has been proposed as a neural mechanism of such atypical perceptual experiences. While previous work has measured suppression by asking participants to report the perceived contrast of a low-contrast target surrounded by a high-contrast surround, it is possible to modulate perceived contrast solely by manipulating the orientation of a matched-contrast center and surround. Removing the bottom-up segmentation cue of contrast difference and isolating the orientation-dependent suppression may clarify the neural processes responsible for atypical surround suppression in psychosis. We examined surround suppression across a spectrum of psychotic psychopathology including people with schizophrenia (PSZ; N=31) and bipolar disorder (PBD; N=29), first-degree biological relatives of these patient groups (PBDrel, PSZrel; N=28, N=21, respectively), and healthy controls (N=29). Surround suppression deficits in PSZ, while observable under many stimulus conditions, were absent under the condition that produced the strongest suppression. PBD and PSZrel exhibited intermediate suppression, while PBDrel performed most similarly to controls. Intriguingly, group differences in surround suppression magnitude were moderated by visual acuity. We propose a potential model by which visual acuity and/or focal attention interact with untuned gain control that reproduces the observed pattern of results including the lack of group differences when orientation of center and surround are the same. Our findings further elucidate perceptual mechanisms of impaired center-surround processing in psychosis and provide insights into the effects of visual acuity on orientation-dependent suppression in PSZ.
Inhaled CO2 concentration while wearing face masks: a pilot study using capnography
Authors: Martellucci Cecilia Acuti , Flacco Maria Elena , Martellucci Mosè , Violante Francesco Saverio , Manzoli Lamberto
Published: May 2022

None of the available evaluations of the inhaled air carbon dioxide (CO2) concentration, while wearing face masks, used professional, real-time capnography with water-removal tubing. We measured the end-tidal CO2 using professional side-stream capnography, with water-removing tubing (Rad-97™ capnograph), at rest, (1) without masks, (2) wearing a surgical mask, and (3) wearing a FFP2 respirator, in 102 healthy volunteers aged 10-90 years, from the general population of Ferrara province, Italy. The inhaled air CO2 concentration was then computed as: ((mask volume × end-tidal CO2) + ((tidal volume - mask volume) × ambient air CO2)) / tidal volume).

The mean CO2 concentration was 4965±1047 ppm with surgical masks, and 9396±2254 ppm with FFP2 respirators. The proportion of the sample showing a CO2 concentration higher than the 5000 ppm acceptable exposure threshold recommended for workers was 40.2% while wearing surgical masks, 99.0% while wearing FFP2 respirators. The mean blood oxygen saturation remained >96%, and the mean end-tidal CO2 <33 mmHg. Adjusting for age, gender, BMI, and smoking, the inhaled air CO2 concentration significantly increased with increasing respiratory rate (with a mean of 10,143±2782 ppm among the participants taking 18 or more breaths per minute, while wearing FFP2 respirators), and was higher among the minors, who showed a mean CO2 concentration of 12,847±2898 ppm, while wearing FFP2 respirators. If these results will be confirmed, the current guidelines on mask-wearing could be updated to integrate recommendations for slow breathing and a more targeted use when contagion risk is low.
Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease
Authors: Hou Jiahui , Hess Jonathan L. , Armstrong Nicola , Bis Joshua C. , Grenier-Boley Benjamin , Karlsson Ida K. , Leonenko Ganna , Numbers Katya , O’Brien Eleanor K. , Shadrin Alexey , Thalamuthu Anbupalam , Yang Qiong , Andreassen Ole A. , Brodaty Henry , Gatz Margaret , Kochan Nicole A. , Lambert Jean-Charles , Laws Simon M. , Masters Colin L. , Mather Karen A. , Pedersen Nancy L. , Posthuma Danielle , Sachdev Perminder S. , Williams Julie ,   the Alzheimer’s Disease Neuroimaging Initiative, Fan Chun Chieh , Faraone Stephen V. , Fennema-Notestine Christine , Lin Shu-Ju , Escott-Price Valentina , Holmans Peter , Seshadri Sudha , Tsuang Ming T. , Kremen William S. , Glatt Stephen J.
Published: May 2022

Polygenic risk scores (PRSs) can boost risk-prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE)but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in 1) unaffected individuals having high PRSs for LOAD, and 2) unaffectedAPOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic-risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.
Loci on chromosome 12q13.2 encompassing ERBB3, PA2G4 and RAB5B are associated with polycystic ovary syndrome
Authors: Harris R. Alan , Archer Kellie J. , Goodarzi Mark O. , York Timothy P. , Rogers Jeffrey , Dunaif Andrea , McAllister Jan , Strauss Jerome F
Published: May 2022

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia of ovarian theca cell origin. Here we report the significant association of 15 single nucleotide polymorphisms (SNPs), identified by whole exome sequencing (WES). DNA was isolated from well-characterized theca cell preparations from women of European ancestry with PCOS (N=9) and elevated androgen production in vitro and from normal ovulatory women (N=7). Of the SNPs, 10 are located within 150 kb on chromosome 12q13.2. This region contains three plausible PCOS candidate genes (ERBB3/PA2G4/RAB5B), two of which (ERBB3 and RAB5B) have been identified in GWAS of PCOS. None of the SNPs individually had a significant association with PCOS or in vivo androgen levels when evaluated in an independent cohort (n=318) of families with one or more daughters with PCOS, but a haplotype consisting of the minor alleles of three of the SNPS (rs773121, rs773123 and rs812826) was found preferentially in women with PCOS and elevated androgen levels (p=0.0583). Moreover, the three minor alleles in this haplotype were significantly associated with anti-Mullerian Hormone (AMH) levels, a marker of follicular reserve and follicular maturation. Two of the three SNP minor alleles are predicted to have significant functional consequences (rs773123 a missense SNP in ERBB3, and rs812826, a SNP in the PA2G4 promoter). Notably, PA2G4 encodes a protein that interacts with the ERBB3 cytoplasmic domain, which is also the domain where the missense variant resides. These findings provide support for the contribution and probable functional significance of loci on chromosome 12q13.2 to the pathophysiology underlying PCOS.

Author Summary

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age. We identified 15 single nucleotide polymorphisms (SNPs) associated with androgen production in theca cells from normal ovulatory women and women with PCOS. Of these SNPs, 10 are within a 150 kbp region of chromosome 12 including 9 that form a haplotype. This region contains three PCOS candidate genes (ERBB3/PA2G4/RAB5B). These SNPs were further examined in an independent cohort of families with one or more daughters with PCOS. A haplotype consisting of the minor alleles of three of the SNPS was found preferentially in women with PCOS. Furthermore, the three minor alleles in this haplotype were significantly associated with anti-Mullerian Hormone (AMH) levels, a marker of follicular reserve and maturation. Two SNPs in the chromosome 12 haplotype were likely to have functional consequences based on genomic context, suggesting that they affect ERBB3 and PA2G4 interactions or PA2G4 expression.
Autism spectrum disorders and brain volume link through a set of mTOR-related genes
Authors: Arenella Martina , Mota Nina R. , Teunissen Mariel W.A. , Brunner Han G. , Bralten Janita
Published: May 2022

Background

Larger than average head and brain sizes are often observed in individuals with Autism Spectrum Disorders (ASDs). ASDs and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASDs and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include autism spectrum disorder features. Here we investigated whether variants in mTOR-related genes are also associated with ASDs and if they constitute a genetic link between large brains and ASDs.

Methods

We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N=2,258). Subsequently using Fisher’s exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASDs in the denovo-db database (N=23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASDs (N=46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASDs (N=46,350) and intracranial volume (N=25,974) globally using LD-score regression as well as mTOR-specific by restricting the genetic correlation to the mTOR-related genes using GNOVA.

Results

Our results show that both macrocephaly and ASDs occur above chance-level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASDs (p=0.0029) and an mTOR-stratified positive genetic correlation between ASDs and intracranial volume (p=0.027), despite the absence of a significant genome-wide correlation (p=0.81).

Conclusions

This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASDs and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASDs.
Accurate Screening for Early-Stage Breast Cancer by Detection and Profiling of Circulating Tumor Cells
Authors: Crook Timothy , Patil Darshana , Akolkar Dadasaheb , Ranade Anantbhushan , Limaye Sewanti , Page Raymond , Datta Vineet , Fulmali Pradip , Apurwa Sachin , Schuster Stefan , Srinivasan Ajay , Datar Rajan
Published: May 2022

BACKGROUND

Screening of asymptomatic women for early detection of Breast Cancer (BrC) is associated with improved survival. Presently, mammography is the standard of care (SoC) for BrC screening but has lower accuracy for invasive cancers as well as in women with higher breast tissue density.

METHODS

In this manuscript, we describe an accurate blood-based breast cancer detection test based on functional enrichment of breast adenocarcinoma associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, EpCAM, PanCK and CD45 status.

RESULTS

The test accurately detects BrAD-CTCs in breast cancers irrespective of age, ethnicity, disease stage, grade and hormone receptor status. Analytical validation established the high accuracy and reliability of the test under intended use conditions. A case-control study with samples from 9,632 healthy women and 548 known BrC cases established 100% specificity and 92.07% overall sensitivity; stage-wise sensitivities were 70.00% for Stage 0, 89.36% for Stage I, 95.74% for Stage II and 100% for Stage III and Stage IV cancers. In a prospective clinical study with 141 suspected cases of breast cancer who underwent a biopsy after blood collection, the test showed 93.1% specificity and 94.64% overall sensitivity in differentiating breast cancer cases (n = 112) from those with benign breast conditions (n = 29); stage-wise sensitivities were 87.50% for Stage 0, 95.83% for Stage I and Stage II, 95.00% for Stage III and 100% for Stage IV cancers.

CONCLUSION

The findings reported in this manuscript support the clinical potential of this test for blood based BrC detection.
Development and evaluation of an interoperable natural language processing system for identifying pneumonia across clinical settings of care
Authors: Chapman Alec B , Peterson Kelly S , Rutter Elizabeth , Nevers McKenna , Zhang Mingyuan , Ying Jian , Jones Makoto , Classen David , Jones Barbara
Published: May 2022

Objective

To evaluate the feasibility, accuracy, and interoperability of a natural language processing (NLP) system which extracts diagnostic assertions of pneumonia in different clinical notes and institutions.

Materials and Methods

An NLP system was designed to identify assertions of pneumonia in three types of clinical notes from electronic health records (EHRs): emergency department notes, radiology reports, and discharge summaries. The lexicon and classification logic were tailored for each note type. The system was first developed and evaluated using annotated notes from the Department of Veterans Affairs. Interoperability was assessed using data from the University of Utah.

Results

The NLP system was comprised of 782 rules and achieved moderate-to-high performance in all three note types in VA (precision/recall/f1: emergency=88.1/86.0/87.1; radiology=71.4/96.2/82.0; discharge=88.3/93.0/90.1). When applied to UU data, performance was maintained in emergency and radiology but decreased in discharge summaries (emergency=84.7/94.3/89.3; radiology=79.7/100.0/87.9; discharge=65.5/92.7/76.8). Customization with 34 additional rules increased performance for all note types (emergency=89.3/94.3/91.7; radiology=87.0/100.0/93.1; discharge=75.0/95.1/83.4).

Conclusion

NLP can be used to accurately identify the diagnosis of pneumonia in different clinical settings and institutions. A limited amount of customization to account for differences in lexicon, clinical definition of pneumonia, and EHR structure can achieve high accuracy without substantial modification.
Influencing factors of Anti-SARS-CoV-2-Spike IgG antibody titres in healthcare workers – A cross-section study
Authors: Reusch Julia , Wagenhäuser Isabell , Gabel Alexander , Eggestein Annika , Höhn Anna , Lâm Thiên-Trí , Frey Anna , Schubert-Unkmeir Alexandra , Dölken Lars , Frantz Stefan , Kurzai Oliver , Vogel Ulrich , Krone Manuel , Petri Nils
Published: May 2022

Background

Against the background of the current COVID-19 infection dynamics with the rapid spread of SARS-CoV-2 variants of concern (VOC), above all the Omicron VOC, the immunity of healthcare workers (HCWs) against SARS-CoV-2 continues to be of high importance. Vaccination plays a central role in reducing the severity and potentially the spread of the disease. In healthcare, this is important to prevent disease-related staff shortages. However, there is a lack of data on factors influencing the humoral immune response.

Aim

The aim of our study was to determine factors influencing the level of Anti-SARS-CoV-2-Spike IgG after SARS-CoV-2 infection or vaccination in healthcare workers.

Methods

1,750 study participants were recruited who met the following inclusion criteria: age ≥ 18 years, PCR-confirmed SARS-CoV-2 infection and/or at least one dose of COVID-19 vaccination, working in health care. Anti-SARS-CoV-2-Spike IgG titres were determined by SERION ELISA agile SARS-CoV-2 IgG.

Results

Mean Anti-SARS-CoV-2-Spike IgG levels increased significantly with the number of COVID-19 vaccinations (92.2 BAU/ml for single dose, 140.9 BAU/ml for two doses and 1,144.3 BAU/ml after threefold vaccination). Hybrid COVID-19 immunized respondents (after infection and vaccination) had significantly higher antibody titres compared with participants after infection only (525.4 BAU/ml vs. 105.7 BAU/ml). Anti-SARS-CoV-2-Spike IgG titres declined significantly with time after administration of the second vaccine dose. Smoking and high age were associated with lower titres.

Conclusion

Both recovered and vaccinated HCWs presented a predominantly good humoral immune response with decreasing antibody levels over the temporal course. Smoking and higher age limited the humoral SARS-CoV-2 immunity. This reduced immune response is an important aspect as people with these risk factors are recognized as people with an increased risk for a severe course of disease.
Performance of Existing and Novel Symptom- and Antigen Testing-Based COVID-19 Case Definitions in a Community Setting
Authors: Lee Scott , Almendares Olivia , Prince-Guerra Jessica L. , Heilig Charles M. , Tate Jacqueline E. , Kirking Hannah L.
Published: May 2022

Point-of-care antigen tests are an important tool for SARS-CoV-2 detection, but they are less clinically sensitive than real-time reverse-transcription PCR (RT-PCR), impacting their efficacy as screening procedures. Our goal in this study was to see whether we could improve this sensitivity by considering antigen test results in combination with other relevant information, namely exposure status and reported symptoms. In November of 2020, we collected 3,419 paired upper respiratory specimens tested by RT-PCR and the Abbott BinaxNOW antigen test at two community testing sites in Pima County, Arizona. We used symptom, exposure, and antigen testing data to evaluate the sensitivity and specificity of various symptom definitions in predicting RT-PCR positivity. Our analysis yielded 6 novel multi-symptom case definitions with and without antigen test results, the best of which overall achieved a Youden’s J index of 0.66, as compared with 0.52 for antigen testing alone. Using a random forest as a guide, we show that this definition, along with our others, does not lose the ability to generalize well to new data despite achieving optimal performance in our sample. Our methodology is broadly applicable, and we have made our code publicly available to aid public health practitioners in developing or fine- tuning their own screening rules.
Associations between recreational cannabis legalization and cannabis-related emergency department visits by age, gender, and geographic status in Ontario, Canada: an interrupted time series study
Authors: Kim Chungah , Chum Antony , Nielsen Andrew , Allin Sara , Penny Tara , Rittenbach Katherine , MacMaster Frank P. , O’Campo Patricia
Published: May 2022

Legalization of recreational cannabis in Ontario included the legalization of flower and herbs (Phase 1, October 2018), and was followed by the deregulation of cannabis retailers and sales of edibles (Phase 2, February 2020). Research on the impact of cannabis legalization on acute care utilization is nascet; no research has investigated potential age, gender, and geographically vulnerable subgroup effects. Residents living in Northern Ontario not only have higher levels of substance use problems, but also have inadequate access to primary healthcare. Our study investigated the impact of Ontario’s recreational cannabis policy (including Phase 1 and 2) on cannabis-attributable emergency department (ED) visits, and estimated the impact separately for different age and gender groups, with additional analyses focused on Northern Ontarians. We created a cohort of adults (18 and over) eligible for provincial universal health insurance with continuous coverage from 2015-2021 (n=14,900,820). An interrupted time-series was used to examine the immediate impact and month-to-month changes in cannabis-related ED visits associated with Phase 1 & 2 for each subgroup. While Northern Ontario has higher rates of cannabis-related ED visits, both Northern and Southern Ontario show similar patterns of changes. Phase 1 was associated with significant increases in adults 25-64, with the strongest increases seen in women 45-64. Month-to-month trends were flattened in most groups compared to pre-legalisation. Phase 2 was associated with significant immediate increases for adults aged 18-44 in both genders, but the increases were larger in women than men. No significant month-to-month changes were detected in this period. While current preventive efforts are largely focused on reducing cannabis-related harms in youths and younger adults, our results show that adults 25-64, particularly women, have been significantly impacted by cannabis policies. Further research on gender-specific cannabis dosage and targeted interventions for adult women should be investigated. Legalization did not appear to have a differential impact on Northern versus Southern Ontario, but higher rates of ED visits in the North should be addressed.
A Phase1 Results of a Non-Stabilized Spike-Encoding mRNA Vaccine in Adults
Authors: Gatechompol Sivaporn , Kittanamongkolchai Wonngarm , Ketloy Chutitorn , Prompetchara Eakachai , Thitithanyanont Arunee , Jongkaewwattana Anan , Buranapraditkun Supranee , Alameh Mohamad-Gabriel , Ubolyam Sasiwimol , Sophonphan Jiratchaya , Apornpong Tanakorn , Kerr Stephen , Kamarulzaman Adeeba , Siwamogsatham Sarawut , Kroon Eugène , Puthanakit Thanyawee , Patarakul Kanitha , Palaga Tanapat , Wijagkanalan Wassana , Weissman Drew , Ruxrungtham Kiat ,   ChulaVAC-001 study team
Published: May 2022

Background

Effective COVID-19 mRNA vaccines are mainly available in high-income countries. ChulaCov19, a prefusion non-stabilized Spike protein-encoding, nucleoside-modified mRNA, lipid nanoparticle encapsulated vaccine development, aims to enhance accessibility of mRNA vaccine and future pandemic preparedness for low- to middle-income countries.

Methods

Seventy-two eligible volunteers, 36 aged 18-55 (adults) followed by 36 aged 56-75 (elderly) enrolled in a dose escalation study of ChulaCov19 mRNA vaccine. Two doses of vaccine were given 21 days apart at 10, 25, or 50 µg/dose (12/group). Safety was the primary and immunogenicity the secondary outcome. Human convalescents’ (HCS) and Pfizer/BioNTech vaccinees’ sera provided comparison panels.

Results

All three doses of ChulaCov19 were well tolerated and elicited robust dose-dependent and age- dependent B- and T-cell responses. Transient mild/moderate injection site pain, fever, chills, fatigue, and headache were more common after the second dose. Four weeks after the second ChulaCov19: dose at 10, 25, and 50 µg dose, MicroVNT-50 Geometric mean titer (GMT) against wild-type was 848, 736 and 1,140 IU/mL, respectively, versus 267 IU/mL for HCS. All dose levels elicited 100% seroconversion, with GMT ratio 4-8-fold higher than for HCS (p<0.01), and high IFNγ spot-forming cells/million peripheral blood mononuclear cells. The 50 µg dose induced better cross-neutralization against Alpha, Beta, Gamma, and Delta variants than lower doses.

Conclusions

ChulaCov19 at 50 µg/dose is well tolerated and elicited higher neutralizing antibodies than HCS with strong T-cell responses. These antibodies cross neutralized four variants of concern and ChulaCov19 has therefore proceeded to phase 2 and 3 clinical trials.

Trial registration number

ClinicalTrials.gov Identifier NCT04566276

Graphical Abstract
Latent class analysis identifies distinctive behavioral subtypes in children with fragile X syndrome
Authors: Kaufmann Walter E. , Raspa Melissa , Bann Carla M. , Gable Julia M. , Harris Holly K. , Budimirovic Dejan B. , Lozano Reymundo ,   FORWARD Consortium
Published: May 2022

Fragile X syndrome (FXS) is associated with a characteristic profile of physical and neurobehavioral abnormalities. These phenotypical features are highly variable among affected individuals, which leads to difficulties in developing and evaluating treatments as well as in determining accurate prognosis. The current investigation employed data from FORWARD, a clinic-based natural history study of FXS, to identify subtypes by applying latent class analysis (LCA).

A pediatric cross-sectional sample of 1,072 males and 338 females was subjected to LCA to identify neurobehavioral classes (groups). Input consisted of multiple categorical and continuous cognitive and behavioral variables, including co-occurring behavioral conditions, sleep and sensory problems, measures of autistic behavior (SCQ, SRS-2), and scores on the Aberrant Behavior Checklist revised for FXS (ABCFX). Clinically relevant class solutions were further delineated by identifying predictors using stepwise logistic regressions and pairwise comparisons. Following this, classes were characterized in terms of key demographic, genetic, and clinical parameters.

LCA fit parameters supported 2- to 6-class models, which showed good correspondence between patterns of co-occurring conditions and scores on standardized measures. The 5-class solution yielded the most clinically meaningful characterization of groups with unique cognitive and behavioral profiles. The “Mild” class (31%) included patients with attention problems and anxiety but few other major behavioral challenges as reflected by scale scores. Most individuals in the “Severe” class (9%) exhibited multiple co-occurring conditions and high mean scale scores on behavioral measures. Three “Moderate” classes were identified: a “Moderate Behavior” class (32%), a “Social Impairment” class (7%), and a “Disruptive Behavior” class (20%). All classes displayed distinctive SRS-2, SCQ, and ABCFX profiles, which reflected their degree of non-overlap as estimated by pairwise effect sizes. Groups differed with regard to sex, intellectual disability, autism spectrum disorder diagnosis, and medication use.

These findings support the notion that, it is possible to identify behavioral subtypes in children with FXS, reflecting both overall level of severity and specific areas of impairment. These subtypes have implications for clinical management and therapeutic development and assessment. Future studies are needed to determine the stability of these group profiles and their relationship with other aspects of the FXS phenotype.
Optimality of Maximal-Effort Vaccination
Authors: Penn Matthew J. , Donnelly Christl A.
Published: May 2022

It is widely acknowledged that vaccinating at maximal effort in the face of an ongoing epidemic is the best strategy to minimise infections and deaths from the disease. Despite this, no one has proved that this is guaranteed to be true if the disease follows multi-group SIR (Susceptible-Infected-Recovered) dynamics. This paper provides a novel proof of this principle for the existing SIR framework, showing that the total number of deaths or infections from an epidemic is decreasing in vaccination effort. Furthermore, it presents a novel model for vaccination which assumes that vaccines assigned to a subgroup are distributed randomly to the unvaccinated population of that subgroup. It suggests, using COVID-19 data, that this more accurately captures vaccination dynamics than the model commonly found in the literature. However, as the novel model provides a strictly larger set of possible vaccination policies, the results presented in this paper hold for both models.
Evaluation of a clinical decision support system for detection of patients at risk after kidney transplantation
Authors: Roller Roland , Mayrdorfer Manuel , Duettmann Wiebke , Naik Marcel G. , Schmidt Danilo , Halleck Fabian , Hummel Patrik , Burchardt Aljoscha , Möller Sebastian , Dabrock Peter , Osmanodja Bilgin , Budde Klemens
Published: May 2022

Patient care after kidney transplantation requires integration of complex information to make informed decisions on risk constellations. Many machine learning models have been developed for detecting patient outcomes in the past years. However, performance metrics alone do not determine practical utility. Often, the actual performance of medical professionals on the given task is not known. We present a newly developed clinical decision support system (CDSS) for detection of patients at risk for rejection and death-censored graft failure. The CDSS is based on clinical routine data including 1516 kidney transplant recipients and more than 100 000 data points. Additionally, we conduct a reader study to compare the performance of the system to estimations of physicians at a nephrology department with and without the CDSS. Internal validation shows AUC-ROC scores of 0.83 for rejection, and 0.95 for graft failure. The reader study shows that although the predictions by physicians converge towards the suggestions made by the CDSS, performance in terms of AUC-ROC does not improve (0.6413 vs. 0.6314 for rejection; 0.8072 vs. 0.7778 for graft failure). Finally, the study shows that the CDSS detects partially different patients at risk compared to physicians without CDSS. This indicates that the combination of both, medical professionals and a CDSS might help detect more patients at risk for graft failure. However, the question of how to integrate such a system efficiently into clinical practice remains open.
The Proportion of Randomized Controlled Trials That Inform Clinical Practice: A Longitudinal Cohort Study of Trials Registered on ClinicalTrials.gov
Authors: Hutchinson Nora , Moyer Hannah , Zarin Deborah A. , Kimmelman Jonathan
Published: May 2022

Background

Prior studies suggest that clinical trials are often hampered by problems in design, conduct and reporting that limit their uptake in clinical practice. We have described “informativeness” as the ability of a trial to guide clinical, policy or research decisions. Little is known about the proportion of initiated trials that inform clinical practice.

Methods

We created a cohort of randomized interventional clinical trials in three disease areas (ischemic heart disease, diabetes mellitus and lung cancer), that were initiated between 1 January 2009 and 31 December 2010 using ClinicalTrials.gov. We restricted inclusion to trials aimed at answering a clinical question related to the treatment or prevention of disease. Our primary outcome was the proportion of clinical trials fulfilling four conditions of informativeness: importance of the clinical question, trial design, feasibility, and reporting of results.

Results

Our study included 125 clinical trials. The proportion meeting four conditions for informativeness was 26.4% (95% CI 18.9 – 35.0). Sixty-seven percent of participants were enrolled in informative trials. The proportion of informative trials did not differ significantly between our three disease areas.

Conclusions

Our results suggest that the majority of clinical trials designed to guide clinical practice possess features that may compromise their ability to do so. This highlights opportunities to improve the scientific vetting of clinical research.

Funding

This study was funded by the Fonds de recherche Santé Québec postdoctoral research grant (NH). This funding body was not involved in study design, conduct or reporting.
The impact of sampling bias on viral phylogeographic reconstruction
Authors: Liu Pengyu , Song Yexuan , Colijn Caroline , MacPherson Ailene
Published: May 2022

Genomic epidemiology plays an ever-increasing role in our understanding of and response to the spread of infectious pathogens. Phylogeography, the reconstruction of the historical location and movement of pathogens from the evolutionary relationships among sampled pathogen sequences, can inform policy decisions related to viral movement among jurisdictions. However, phylogeographic reconstruction is impacted by the fact that the sampling and virus sequencing policies differ among jurisdictions, and these differences can cause bias in phylogeographic reconstructions. Here we assess the potential impacts of geographic-based sampling bias on estimated viral locations in the past, and on whether key viral movements can be detected. We quantify the effect of bias using simulated phylogenies with known geographic histories, and determine the impact of the biased sampling and of the underlying migration rate on the accuracy of estimated past viral locations. We then apply these insights to the geographic spread of Ebolavirus in the 2014-2016 West Africa epidemic. This work highlights how sampling policy can both impact geographic inference and be optimized to best ensure the accuracy of specific features of geographic spread.
Outcomes of open transverse abdominis release for ventral hernias- A systematic review, meta-analysis and meta-regression of factors affecting them
Authors: Vasavada Bhavin B , Patel Hardik
Published: May 2022

Objectives

The primary objectives were to evaluate Surgical Site Occurrences (SSO) and Surgical Site Occurrences requiring procedural Intervention (SSOPI) after open transversus abdominis release and to study various factors affecting it. Secondary objectives were to evaluate Surgical Site Infections (SSI), recurrence rates and overall complications after transversus abdominis release (TAR) and the factors responsible for those.

Methods

We searched PUBMED, SCOPUS and Cochrane databases with keywords “transversus abdominis release” or “TAR” OR “Surgical Site Occurrences” OR “posterior component separation AND “outcomes” as per PRISMA 2020 and MOOSE guidelines. Full texts and English literature studies were included, studies mentioning outcomes for open transversus abdominis release for ventral hernia were included and studies with robotic transversus abdominis release were excluded. Percentage occurrences of SSO, SSOPI, SSI, recurrence and overall complications after TAR were evaluated. Random effect meta-analysis with restricted maximum likehood methods was used for meta-analysis. Heterogeneity was analysed using I2 statistics. Publication bias with eager’s test and funnel plots. Meta0regression analysis was done to evaluate factors affecting the heterogeneity. JASP 0.16.2 software was used for meta-analysis.

Results

Twenty two studies including 5284 patients who underwent TAR for ventral hernia were included in systematic review and meta-analysis. Overall pooled SSO, SSOPI, Overall Complications, SSI and recurrence rates were 21.72% [95% C.I 17.18-26.27%], 9.82% [95% C.I 7.64 −12%], 33.34% [95% C.I. 27.43-39.26%], 9.13% [95% 6.41-11.84] and 1.6% [0.78-2.44] respectively. Heterogeneity was significant in all the analysis. Age (p<0.001),sex (p<0.001), BMI (p<0.001),presence of comorbidities (p<0.001), prior recurrence, defect size (p<0.001) and current or past history of tobacco exposure were associated with SSO in multivariate meta-regression analysis. Defect size (p=0.04) was associated with SSOPI. Age (p=0.011), BMI (p=0.013), comorbidities (p<0.01), tobacco exposure (p=0.018),prior recurrence (p <0.01) and sex (p < 0.01) were associated with overall complications.

Conclusion

Open transversus abdominis release is associated with high rates of SSO, SSOPI, SSI and overall complications but recurrence rates are low. Various preoperative factors mentioned may be responsible for heterogeneity across studies.
Laboratory diagnostic of acute kidney injury and its progression: risk of underdiagnosis in female and elderly patients
Authors: Kister Thea Sophie , Schmidt Maria , Heuft Lara , Federbusch Martin , Haase Michael , Kaiser Thorsten
Published: May 2022

Objective

Acute kidney injury (AKI) is a common disease, with high morbidity and mortality rates. In this study, we investigate the potential influence of sex and age on laboratory diagnostic and outcome. It is known that serum creatinine (SCr) has limitations as a laboratory diagnostic parameter for AKI due to its dependence on muscle mass, which may lead to incorrect or delayed diagnosis for certain patient groups, such as women and the elderly.

Methods

Overall, 7592 cases with AKI, hospitalized at the University of Leipzig Medical Center (ULMC) between 1st January 2017 and 31st December 2019, were retrospectively analyzed. Diagnosis and staging of AKI was performed according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, based on the level and dynamics of SCr. The impact of sex and age was analyzed by the recalculation of a female to male and an old to young SCr using the CKD-EPI equation.

Results

The incidence proportion of AKI in our study cohort was 12.0%, with progressive AKI occurring in 19.2% of these cases (n = 1458). Male cases with AKI were overrepresented (59.6%), with a significantly higher first (+3.5 ml/min) and last eGFR (+2.7 ml/min) (p < 0.001). The highest incidence proportion of AKI was found in the [61–81) age group in female (49.5%) and male (52.7%) cases. Males with progressive AKI were overrepresented (p = 0.04). By defining and staging AKI on the basis of relative and absolute changes in SCr level, it is more difficult for patients with low muscle mass and thus a lower baseline SCr to be diagnosed by an absolute SCr increase. AKIN1 and AKIN3 can be diagnosed by a relative or absolute change in SCr. In females, both stages were less frequently detected by an absolute criterion alone (AKIN1 ♀ 20.2%, ♂ 29.5%, p < 0.001; AKIN3 ♀ 13.4%, ♂ 15.2%, p < 0.001). A recalculated SCr for females (to males) and males (to young males) displayed the expected increase in AKI occurrence and severity with age and in general in females.

Conclusion

Our study illustrates how SCr as the sole parameter for diagnosis and staging of AKI bears the risk of underdiagnosis of patient groups with low muscle mass, such as women and the elderly. A sex- and age-adapted approach might offer advantages.