bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Levels of Calprotectin in Patients with Chronic Non-specific Colitis: A Brief Report
Authors: Rafiei Rahmatollah , Najjar Khodabakhsh Amin , Rafiei Fereshteh , Kamyab Amirhossein , Ebrahimi Alireza , Ashkani-Esfahani Soheil
Published: April 2023

Background

Patients with gastrointestinal symptoms of chronic diarrhea, chronic constipation, and abdominal pain might have unspecified signs and symptoms making them hardly characterized. These patients could be labeled as chronic nonspecific colitis patients. In this investigation, we aimed to compare the therapeutic effects of mesalamine in chronic nonspecific colitis patients with by measuring the levels of fecal calprotectin and assessing the reduction of their symptoms during the treatment.

Methods

Eighty-four outpatients (42 patients with normal, and 42 having high calprotectin levels) participated in this study. Participants were being treated by 2 grams of mesalamine for one month, and they were evaluated weekly. After one month, the participants’ signs and symptoms were reviewed, and the patients were labeled as treated or untreated.

Results

The result of this study demonstrated that there was no significant difference between the level of calprotectin among male or female participants, patients with different ages, or patients with different symptoms. Calprotectin levels were significantly different between patients who positively responded to mesalamine treatment compared to those who did not (p<0.001). On the other hand, patients with high calprotectin levels had a higher response rate to mesalamine (94.5%), compared to those with normal calprotectin levels (36.1%; p<0.001).

Conclusion

There was a significant correlation between the level of fecal calprotectin and the response rate of the patients to mesalamine; therefore, this parameter might be a good indicator to be used for treatment plans. Further studies are suggested to affirm this outcome.
Characterising personal, household, and community PM2.5 exposure in one urban and two rural communities in China
Authors: Chan Ka Hung , Xia Xi , Liu Cong , Kan Haidong , Doherty Aiden , Yim Steve Hung Lam , Wright Neil , Kartsonaki Christiana , Yang Xiaoming , Stevens Rebecca , Chang Xiaoyu , Sun Dianjianyi , Yu Canqing , Lv Jun , Li Liming , Ho Kin-Fai , Lam Kin Bong Hubert , Chen Zhengming
Published: April 2023

Background:

Cooking and heating in households contribute importantly to air pollution exposure worldwide. However, there is insufficient investigation of measured fine particulate matter (PM2.5) exposure levels, variability, seasonality, and inter-spatial dynamics associated with these behaviours.

Methods:

We undertook parallel measurements of personal, household (kitchen and living room), and community PM2.5in summer (May-September 2017) and winter (November 2017-Janauary 2018) in ∼480 participants from one urban and two rural communities in China. These recorded ∼61,000-81,000 person-hours of processed data per microenvironment. Age- and sex-adjusted geometric means of PM2.5were calculated by key participant characteristics, overall and by season. Spearman correlation coefficients between PM2.5levels across different microenvironments were computed.

Findings:

Overall, 25.1% reported use of solid fuel for both cooking and heating. Solid fuel users had ∼90% higher personal and kitchen 24-hour average PM2.5exposure than clean fuel users. Similarly, they also had a greater increase (∼75% vs ∼20%) in personal and household PM2.5from summer to winter, whereas community levels of PM2.5were 2-3 times higher in winter regardless of fuel use. Compared with clean fuel users, solid fuel users had markedly higher weighted annual average PM2.5exposure at personal (77.8 [95% CI 71.1-85.2] vs ∼40 µg/m3), kitchen (103.7 [91.5-117.6] vs ∼50 µg/m3) and living room (62.0 [57.1-67.4] vs ∼40 µg/m3) microenvironments. There was a remarkable diurnal variability in PM2.5exposure among the participants, with 5-minute moving average 700-1,200µg/m3in typical meal times. Personal PM2.5was moderately correlated with living room (Spearman r: 0.64-0.66) and kitchen (0.52-0.59) levels, but only weakly correlated with community levels, especially in summer (0.15-0.34) and among solid fuel users (0.11-0.31).

Conclusion:

Solid fuel use for cooking and heating was associated with substantially higher personal and household PM2.5exposure than clean fuel users. Household PM2.5appeared a better proxy of personal exposure than community PM2.5in this setting.
An end-to-end platform for digital pathology using hyperspectral autofluorescence microscopy and deep learning based virtual histology
Authors: McNeil Carson , Wong Pok Fai , Sridhar Niranjan , Wang Yang , Santori Charles , Wu Cheng-Hsun , Homyk Andrew , Gutierrez Michael , Behrooz Ali , Tiniakos Dina , Burt Alastair , Pai Rish K. , Tekiela Kamilla , Chen Po-Hsuan Cameron , Fischer Laurent , Martins Eduardo Bruno , Seyedkazemi Star , Freedman Daniel , Kim Charles C. , Cimermancic Peter
Published: April 2023

Conventional histopathology involves expensive and labor intensive processes that often consume tissue samples, rendering them unavailable for other analysis. We present a novel end-to-end workflow for pathology powered by hyperspectral microscopy and deep learning. First, we developed a custom hyperspectral microscope to non-destructively image the autofluorescence of unstained tissue sections. We then train a deep learning model to use the autofluorescence to generate virtual histological stains, which avoids the cost and variability of chemical staining procedures and conserves tissue samples. We showed that the virtual images reproduce the histological features present in the real stained images using a randomized nonalcoholic steatohepatitis (NASH) scoring comparison study where both real and virtual stains are scored by pathologists. The test showed moderate to good concordance between pathologists’ scoring on corresponding real and virtual stains. Finally, we developed deep learning-based models for automated NASH clinical research network (NASH CRN) score prediction. We showed that the end-to-end automated pathology platform is comparable to pathologists for NASH CRN scoring when evaluated against the expert pathologist consensus scores. This study provides proof of concept for this virtual staining strategy, which could improve cost, efficiency, and reliability in pathology, and enable novel approaches to spatial biology research.
PREVALENCE OF POST STROKE DEPRESSION AND ANXIETY AMONG PATIENTS ADMITTED IN KHYBER TEACHING HOSPITAL PESHAWAR
Authors: Hussain Sayed Sajid , Ullah Zaib , Bacha Mahmood , Khalil Sheikh Usman
Published: April 2023

INTRODUCTION

Stroke is a life-threatening medical condition that can result in lifelong brain damage, complications, and death. It is the second leading cause of death worldwide and could soon overtake as the biggest cause of death globally. This can be produced by ischemia from a thrombosis or embolism, or a hemorrhage. As a result, the brain’s damaged area is unable to operate, causing one or more limbs on one side of the body to become immobile, inability to recognize or produce speech, or seeing only one side of the visual field.

OBJECTIVE OF THE RESEARCH

To determine the prevalence of Post Stroke Depression and anxiety among stroke patients admitted in Khyber teaching hospital Peshawar

METHODOLOGY

A descriptive cross-sectional study was carried out to determine the prevalence of PSD and anxiety among stroke patients admitted at Khyber teaching hospital Peshawar. Data was collected through a questionnaire named HADs scale from participants. The sample size calculated for the research study was 109. The convenience sampling technique was used in the current study.

RESULTS

The findings of the study provide a baseline of information about the prevalence of Post Stroke Depression (PSD) and anxiety among stroke patients admitted in Khyber teaching hospital Peshawar. The prevalence of depression was 86(63.3%) and anxiety was 91(83.5%).

CONCLUSION

In current study we had concluded a high prevalence of post stroke depression and anxiety ranging from 65-74 years of age in Khyber teaching hospital Peshawar. So, we concluded that females suffering from stroke have more chances of post stroke depression.
An initial validation study of DigiBel, a web-application enabling self-assessment of air and bone-conduction audiometry in the community
Authors: Sienko Anna , Thirunavukarasu Arun J , Kuzmich Tanya , Allen Louise E
Published: April 2023

80% of primary school children suffer from glue ear which may impair hearing at a critical time for speech acquisition and social development. An online application, DigiBel, has been developed primarily to identify individuals with conductive hearing impairment who may benefit from temporary use of bone-conduction (BC) assistive technology in the community. This preliminary study aims to determine the screening accuracy and usability of DigiBel self-assessed air-conduction (AC) pure tone audiometry (PTA) in adult volunteers with simulated hearing impairment prior to formal clinical validation.

Healthy adults, each with one ear plugged, underwent standard automated AC PTA (reference test) and DigiBel audiometry in quiet community settings. Threshold measurements were compared across six tone frequencies and DigiBel test-retest reliability was calculated. The accuracy of DigiBel for detecting more than 20 decibels of hearing impairment was assessed.

30 adults (30 unplugged ears and 30 plugged ears) completed both audiometry tests. DigiBel had 100% sensitivity (95%CI 87.23-100) and 72.73% (95%CI 54.48-86.70) specificity in detecting hearing impairment. Threshold mean bias was insignificant except at 4000 and 8000Hz where a small but significant over-estimation of threshold measurement was identified. All 24 subjects completing feedback rated the DigiBel test good or excellent and 21(87.5%) agreed or strongly agreed that they would be able to do the test at home without help.

This study supports the potential use of DigiBel as a screening tool for hearing impairment. The findings will be used to improve the software further and undertake a formal clinical trial of AC and BC audiometry in individuals with suspected conductive hearing impairment.

Author Summary

Hearing loss is a major global health issue. It can affect many aspects of life such as education, employment, communication, and result in social isolation. Two thirds of people with severe hearing loss live in low and middle countries with poor access both to hearing testing (audiometry) or conventional hearing aids.

Several software applications (apps) like DigiBel, studied here, have been developed to enable individuals to test their own hearing in the community. Uniquely, DigiBel has the additional potential to identify individuals with hearing loss who could derive immediate hearing support from an affordable and rechargeable bone-conduction headphone / microphone kit while waiting specialist care.

This initial study of DigiBel provides confirmation that the app is easy to use and accurate at detecting simulated hearing impairment. It lays the groundwork for future clinical studies to assess DigiBel’s performance in children and adults with hearing impairment.
The Phenotypic Spectrum ofCOL4A3Heterozygotes
Authors: Solanki Kaushal V. , Hu Yirui , Moore Bryn S. , Abedi Vida , Avula Venkatesh , Mirshahi Tooraj ,   Regeneron Genetics Center, Strande Natasha T. , Bucaloiu Ion D. , Chang Alexander R.
Published: April 2023

Most data on Alport Syndrome (AS) due to COL4A3 are limited to families with autosomal recessive AS or severe manifestations such as focal segmental glomerulosclerosis (FSGS). Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants (0.2%) who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined autosomal dominant AS, we matched COL4A3 heterozygotes 1:5 to non-heterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis. COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and end-stage kidney disease (ESKD) (p<0.05 for all comparisons) but not bilateral sensorineural hearing loss (p=0.9). Phenotypic severity tended to be more severe among patients with glycine missense variants located within the collagenous domain. For example, patients with Gly695Arg (n=161) had markedly increased risk of dipstick hematuria (OR 9.47, 95% CI: 6.30, 14.22) and ESKD diagnosis (OR 7.01, 95% CI: 3.48, 14.12) whereas those with PTVs (n=119) had moderately increased risks of dipstick hematuria (OR 1.63, 95% CI: 1.03, 2.58) and ESKD diagnosis (OR 3.43, 95% CI: 1.28, 9.19). Less than a third of patients had albuminuria screening completed, and fewer than 1/3 were taking inhibitors of the renin-angiotensin-aldosterone system (RAASi). Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

Significance Statement

Alport Syndrome (AS) is the second most common genetic cause of end-stage kidney disease (ESKD), yet little is known about the penetrance and phenotypic spectrum of genetically-determined Autosomal Dominant AS. Using an unselected health system-based cohort, we compared individuals heterozygous for likely pathogenic or pathogenic variants in COL4A3 to a propensity score-matched control group and demonstrate increased risks of hematuria, albuminuria, and ESKD. Risks of kidney disease phenotypes were markedly elevated for missense glycine variants in the collagenous domain and moderately elevated for those with PTVs, compared to controls. The vast majority had not been diagnosed with AS and less than a third ever received albuminuria testing, suggesting opportunities to improve management by early genetic diagnosis.
Clinical, molecular, and immune correlates ofImmunotherapy Response Scorein advanced urothelial carcinoma patients under atezolizumab monotherapy: Analysis of the phase 2 IMvigor210 trial
Authors: Ferreiro-Pantín Miriam , Anido-Herranz Urbano , Betancor Yoel Z. , Cebey-López Víctor , León-Mateos Luis , García-González Jorge , García-Acuña Silvia Margarita , Fernández-Díaz Natalia , Tubio Jose M. C. , López-López Rafael , Ruiz-Bañobre Juan
Published: April 2023

Background

In the advanced urothelial carcinoma (aUC) scenario there are no consistent biomarkers to predict the benefit patients derived from immune checkpoint blockade. Recently a novel pan-tumor molecular tissue-based biomarker, the Immunotherapy Response Score (IRS), has been proposed. Herein we conducted a retrospective study to validate the prognostic and predictive utility of the IRS in aUC patients under atezolizumab monotherapy and to characterize its underline molecular and immune features in the context of the IMvigor210 phase 2 clinical trial.

Methods

This is a retrospective study of 261 patients with available clinical, molecular, and immune tumor data treated with atezolizumab monotherapy in the IMvigor210 phase 2 clinical trial. Efficacy endpoints were overall survival (OS), disease control rate (DCR), and overall response rate (ORR). Survival estimates were calculated by the Kaplan Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Factors associated with disease control (DC) and response were tested with logistic regression in univariable and multivariable analyses. Comparisons between patient and disease characteristics were carried out using Chi-squared or Fisher exact tests. All p values were 2-sided, and those less than 0.05 were considered statistically significant.

Results

High IRS was significantly associated with a better OS in univariable [hazard ratio (HR)=0.49, 95% CI 0.33–0.74, p<0.001] and multivariable (HR=0.57, 95% CI 0.37–0.86, p=0.007) analyses. DCR and ORR were significantly higher among high IRS patients (DCR for high IRS vs low IRS patients: 57% vs 32%, p<0.001; ORR for high IRS vs low IRS patients: 42% vs 10%, p<0.001). High IRS patients presented a higher probability of DC and response in univariable [DC: odds ratio (OR)=2.72, 95% CI 1.54–4.81, p<0.001; Response: OR=3.92, 95% CI 2.11–7.31; p<0.001] and multivariable (DC: OR=2.38, 95% CI 1.28–4.44, p=0.006; Response: OR=3.36, 95% CI 1.68–6.69, p<0.001) analyses.

Conclusions

This study validates IRS as a strong independent prognostic and predictive biomarker for OS and DC/response in aUC patients treated with atezolizumab monotherapy in the IMvigor210 phase 2 clinical trial.

Clinical Trial Registration

NCT02108652,NCT02951767.
Genetic and karyotype divergence between parents affect clonality and sterility in hybrids
Authors: Marta Anatolie , Tichopád Tomáš , Bartoš Oldřich , Klíma Jiří , Shah Mujahid Ali , Bohlen Vendula Šlechtová , Bohlen Joerg , Halačka Karel , Choleva Lukáš , Stöck Matthias , Dedukh Dmitrij , Janko Karel
Published: April 2023

Asexual reproduction can be triggered by interspecific hybridization, but its emergence is supposedly rare, relying on exceptional combinations of suitable genomes. To examine how genomic and karyotype divergence between parental lineages affect the incidence of asexual gametogenesis, we experimentally hybridized fishes (Cobitidae) across a broad phylogenetic spectrum, assessed by whole exome data. Gametogenic pathways generally followed a continuum from sexual reproduction in hybrids between closely related evolutionary lineages to sterile or inviable crosses between distant lineages. However, most crosses resulted in a combination of sterile males and asexually-reproducing females. Their gametes usually experienced problems in chromosome pairing, but females also produced a certain proportion of oocytes with premeiotically duplicated genomes, enabling their development into clonal eggs. Interspecific hybridization may thus commonly affect cell cycles in a specific way, allowing the formation of unreduced oocytes. The emergence of asexual gametogenesis appears tightly linked to hybrid sterility and constitutes an inherent part of the extended speciation continuum.
Associations between cardiorespiratory fitness and lifestyle-related factors with DNA methylation-based aging clocks in older men: WASEDA’S Health Study
Authors: Kawamura Takuji , Radak Zsolt , Tabata Hiroki , Akiyama Hiroshi , Nakamura Nobuhiro , Kawakami Ryoko , Ito Tomoko , Usui Chiyoko , Jokai Matyas , Torma Ferenc , Kim Hyeon-Ki , Miyachi Motohiko , Torii Suguru , Suzuki Katsuhiko , Ishii Kaori , Sakamoto Shizuo , Oka Koichiro , Higuchi Mitsuru , Muraoka Isao , McGreevy Kristen M. , Horvath Steve , Tanisawa Kumpei
Published: April 2023

DNA methylation-based age estimators (DNAm aging clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between objectively measured physical fitness, including cardiorespiratory fitness, and DNAm aging clocks are largely unknown. We investigated the relationships between physical fitness and the age-adjusted value from the residuals of the regression of DNAm aging clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of physical fitness variables to DNAmAgeAccel in the presence of other lifestyle factors. DNA samples from 144 Japanese men aged 65–72 years were used to calculate first- (i.e., DNAmHorvath and DNAmHannum) and second- (i.e., DNAmPhenoAge, DNAmGrimAge and DNAmFitAge) generation DNAm aging clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrients intake, smoking, alcohol consumption, disease status, sleep status, and chronotype. The peak oxygen uptake (VO2peak) per kg body weight had a significant negative correlation with GrimAgeAccel (r= -0.222,p= 0.008). A comparison of the tertile groups showed that the GrimAgeAccel of the highest VO2peakgroup was decelerated by 1.6 years compared to the lowest group (p= 0.035). Multiple regression analysis suggested that rather than physical fitness, serum triglycerides, carbohydrate intake, and smoking status, were significantly associated with DNAmAgeAccel. In conclusion, the contribution of cardiorespiratory fitness to DNAmAgeAccel was relatively low compared to lifestyle factors such as smoking. However, this study reveals a negative relationship between cardiorespiratory fitness and DNAmAgeAccel in older men.
Type 1 Diabetes Prevention: a systematic review of studies testing disease-modifying therapies and features linked to treatment response
Authors: Felton Jamie L. , Griffin Kurt J. , Oram Richard A. , Speake Cate , Long S. Alice , Onengut-Gumuscu Suna , Rich Stephen S. , Monaco Gabriela SF , Evans-Molina Carmella , DiMeglio Linda A. , Ismail Heba M. , Steck Andrea K. , Dabelea Dana , Johnson Randi K. , Urazbayeva Marzhan , Gitelman Stephen , Wentworth John M. , Redondo Maria J. , Sims Emily K.
Published: April 2023

Background

Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Efforts to prevent T1D have focused on modulating immune responses and supporting beta cell health; however, heterogeneity in disease progression and responses to therapies have made these efforts difficult to translate to clinical practice, highlighting the need for precision medicine approaches to T1D prevention.

Methods

To understand the current state of knowledge regarding precision approaches to T1D prevention, we performed a systematic review of randomized-controlled trials from the past 25 years testing disease-modifying therapies in T1D and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.

Results

We identified 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss in individuals at disease onset. Seventeen agents tested, mostly immunotherapies, showed benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employed precision analyses to assess features linked to treatment response. Age, measures of beta cell function and immune phenotypes were most frequently tested. However, analyses were typically not prespecified, with inconsistent methods reporting, and tended to report positive findings.

Conclusions

While the quality of prevention and intervention trials was overall high, low quality of precision analyses made it difficult to draw meaningful conclusions that inform clinical practice. Thus, prespecified precision analyses should be incorporated into the design of future studies and reported in full to facilitate precision medicine approaches to T1D prevention.

Plain Language Summary

Type 1 diabetes (T1D) results from the destruction of insulin-producing cells in the pancreas, necessitating lifelong insulin dependence. T1D prevention remains an elusive goal, largely due to immense variability in disease progression. Agents tested to date in clinical trials work in a subset of individuals, highlighting the need for precision medicine approaches to prevention. We systematically reviewed clinical trials of disease-modifying therapy in T1D. While age, measures of beta cell function, and immune phenotypes were most commonly identified as factors that influenced treatment response, the overall quality of these studies was low. This review reveals an important need to proactively design clinical trials with well-defined analyses to ensure that results can be interpreted and applied to clinical practice.
Long-term effects of extreme smoke exposure on COVID-19: A cohort study
Authors: Lane Tyler J. , Carroll Matthew , Borg Brigitte M. , McCaffrey Tracy A. , Smith Catherine L. , Gao Caroline , Brown David , Poland David , Allgood Shantelle , Ikin Jillian , Abramson Michael J.
Published: April 2023

In early 2014, the Hazelwood coalmine fire covered the regional Australian town of Morwell in smoke and ash for 45 days. One of the fire’s by-products, PM2.5, has been linked higher rates of COVID-19 infection to increased expression of the ACE2 receptor, which the COVID-19 virus uses to infect cells throughout the body. However, it is unclear whether the effect persists for years after exposure. In this study, we surveyed a cohort established prior to the pandemic to determine whether PM2.5from the coalmine fire increased long-term vulnerability to COVID-19 infection and severe disease.

In late 2022, 612 members of the Hazelwood Health Study’s adult cohort, established in 2016/17, participated in a follow-up survey including standardised items to capture COVID-19 infections, hospitalisations, and vaccinations. Associations were evaluated in crude and adjusted logistic regression models, applying statistical weighting for survey response and multiple imputation to account for missing data, with sensitivity analyses to test the robustness of results.

A total of 271 (44%) participants self-reported or met symptom criteria for at least one COVID-19 infection. All models found a positive association, with odds of infection increasing by between 4-21% for every standard deviation (12.3µg/m3) increase in mine fire-related PM2.5exposure. However, this was not statistically significant in any model. There were insufficient hospitalisations to examine severity (n=7; 1%).

The findings were inconclusive in ruling out an effect of PM2.5exposure from coalmine fire on long-term vulnerability to COVID-19 infection. Given the positive association that was robust to modelling variations as well as evidence for a causal mechanism, it would be prudent to treat PM2.5from fire events as a risk factor for long-term COVID-19 vulnerability until more evidence accumulates.
A Distinct Inflammatory Milieu in Patients with Right Heart Failure
Authors: Yang Bin Q , Park Arick C , Liu Jason , Byrnes Kathleen , Javaheri Ali , Mann Douglas L , Schilling Joel D
Published: April 2023

Background:

Right heart failure (RHF) is associated with worse clinical outcomes. In addition to hemodynamic perturbations, the syndrome of RHF involves liver congestion and dysfunction. The mechanisms that underlie heart-liver interactions are poorly understood and may involve secreted factors. As a first step to understand the cardiohepatic axis, we sought to elucidate the circulating inflammatory milieu in patients with RHF.

Methods:

Blood samples were collected from the IVC and hepatic veins during right heart catheterization from 3 groups of patients: 1) controls with normal cardiac function, 2) patients with heart failure (HF) who did not meet all criteria of RHF, and 3) patients who met prespecified criteria for RHF defined by hemodynamic and echocardiographic parameters. We performed multiplex protein assay to survey levels of several circulating markers and analyzed their association with mortality and need for left ventricular assist device or heart transplant. Finally, we leveraged publicly available single cell RNA sequencing (scRNAseq) data and performed tissue imaging to evaluate expression of these factors in the liver.

Results:

In this study of 43 patients, RHF was associated with elevated levels of a subset of cytokines/chemokines/growth factors compared to controls. In particular, soluble CD163 (sCD163) and CXCL12 were higher in RHF and predicted survival in an independent validation cohort. Furthermore, scRNAseq and immunohistochemistry of human liver biopsies suggest that these factors are expressed by Kupffer cells and may be liver derived.

Conclusions:

RHF is associated with a distinct circulating inflammatory profile. sCD163 and CXCL12 are novel biomarkers that can prognosticate patient outcomes. Future studies to define how these molecules influence HF phenotypes and disease progression may lead to new approaches to management of patients with RHF.
Mixed-method evaluation of an expedited partner therapy take-home medication program: a pilot ED intervention to improve sexual health equity
Authors: Ager Emily E. , Sturdavant William , Curry Zoe , Ahmed Fahmida , DeJonckheere Melissa , Gutting Andrew , Merchant Roland C. , Kocher Keith E. , Solnick Rachel E.
Published: April 2023

Background

Treatment for partners of patients diagnosed with sexually transmitted infections (STIs), referred to as expedited partner therapy (EPT), is infrequently used in emergency departments (EDs). This was a pilot program to initiate and evaluate EPT through medication-in-hand (“take-home”) kits or paper prescriptions. This study aimed to assess the frequency of EPT prescribing, the efficacy of a randomized best practice advisory (BPA) on the uptake of EPT, perceptions of ED clinicians regarding the EPT pilot, and factors associated with EPT prescribing.

Methods

This pilot study was conducted at an academic ED in the midwestern US between August and October 2021. The primary outcome was EPT prescription uptake and the BPA impact was measured via chart abstraction and analyzed through summary statistics and Fisher’s exact test. The secondary outcome of barriers and facilitators to program implementation was analyzed through ED staff interviews (physicians, physician assistants, and nurses). A rapid qualitative assessment method for the analysis of the interviews was employed.

Results

Fifty-two ED patients were treated for chlamydia/gonorrhea during the study period. EPT was offered to 25% (95% CI 15%-39%) of patients. EPT was prescribed twice as often (85% vs. 38%;p<0.01) when the interruptive pop-up alert BPA was shown. Barriers identified in the interviews included workflow constraints and knowledge of EPT availability. The BPA was viewed positively by the majority of participants.

Conclusions

In this pilot EPT program, EPT was provided to 25% of ED patients who appeared eligible to receive it. The interruptive pop-up alert BPA significantly increased EPT prescribing. Barriers identified to EPT prescribing can be the subject of future interventions to improve ED EPT provision.
Effect of Graft Fixation Angles in Double-Bundle Anterior Cruciate Ligament Reconstruction, a Systematic Review
Authors: Phadke Rohan , Song Bo
Published: April 2023

Context

Recent reviews have demonstrated a shift towards anatomical double bundle (DB) techniques for anterior cruciate ligament reconstruction (ACLR). However, to our knowledge, there are no reviews that have directly assessed the relationship between bone tunnel graft angle placement in DB ACLR and clinical outcomes.

Objective

To investigate the effect of bone tunnel graft angle on clinical outcomes in DB ACLR.

Data Sources

We performed a comprehensive search of the databases PubMed, Scopus, and Embase using the search terms (Fixation OR Angle) AND (ACL OR anterior cruciate ligament) AND (double-bundle OR DB OR double bundle) AND (Reconstruction OR surgery OR arthroscopy) across all time periods.

Study Selection

Two independent authors performed a systematic review of the literature. After removing duplicates and applying inclusion/exclusion criteria on a number of clinical outcomes and other factors, 5 eligible studies were recruited under PRISMA guidelines from the 1032 titles identified.

Study Design

Systematic Review

Level of Evidence

2a

Data Extraction

Systematic review of clinical trials and extraction of relevant surgical data.

Results

Our data did not support the original hypothesis and rather showed that increasing the PL bundle angle from 0° to 90° leads to better performance on the pivot-shift tests. Having a nonzero AM bundle graft fixation angle, more specifically at or above 20°, produces better performance on the ATT, Tegner, Lysholm and pivot-shift tests when compared to a 0° angle.

Conclusions

A PL bundle angle at or above 45° as well as a nonzero AM bundle angle both yielded better clinical outcome scores. However, with respect to a specific combination, there is no consensus on an optimal graft angle combination in DB ACLR currently. Future randomized controlled trials on this topic are recommended to better understand the effects of greater ranges of graft fixation angles on clinical outcome heterogeneity.
Exact confidence intervals for population growth rate, longevity and generation time
Authors: Hernandez-Suarez Carlos M , Rabinovich Jorge
Published: April 2023

By quantifying key life history parameters in populations, such as growth rate, longevity, and generation time, researchers and administrators can obtain valuable insights into its dynamics. Although point estimates of demographic parameters have been available since the inception of demography as a scientific discipline, the construction of confidence intervals has typically relied on approximations through series expansions or computationally intensive techniques. This study introduces the first mathematical expression for calculating confidence intervals for the aforementioned life history traits when individuals are unidentifiable and data are presented as a life table. The key finding is the accurate estimation of the confidence interval forr, the instantaneous growth rate, which is tested using Monte Carlo simulations with four arbitrary discrete distributions. In comparison to the bootstrap method, the proposed interval construction method proves more efficient, particularly for experiments with a total offspring size below 400. We discuss handling cases where data are organized in extended life tables or as a matrix of vital rates.
Suppressed vascular Rho-kinase activation is a protective cardiovascular mechanism in obese female mice
Authors: Barbosa Gabriela Souza , Costa Rafael M , Awata Wanessa MC , Singh Shubhnita , Alves Juliano V , Bruder-Nascimento Ariane , Corrêa Camila Renata , Bruder-Nascimento Thiago
Published: April 2023

Background

Obesity is the number one cardiovascular risk factor for both men and women and is a complex condition. Although a sex dimorphism on vascular function has already been noted, the underlying processes remain unclear. The Rho-kinase pathway has a unique role in controlling vascular tone, and in obese male mice, hyperactivation of this system results in worsened vascular constriction. We investigated whether female mice exhibit decreased Rho-kinase activation as a protective mechanism in obesity.

Methods

We exposed male and female mice to a high-fat diet (HFD) for 12 weeks. At the end, energy expenditure, glucose tolerance, adipose tissue inflammation, and vascular function were investigated.

Results

Male mice were more sensitive to HFD-induced body weight gain, glucose tolerance, and inflammation than female mice. After establishing obesity, female mice demonstrated increase in energy expenditure, characterized by an increase in heat, whereas male mice did not. Interestingly, obese female mice, but not male, displayed attenuated vascular contractility to different agonists, such difference was blunted by inhibition of Rho-kinase. Finally, aortae from obese female mice, but not male, responded prematurely to Rho-kinase inhibitor, which was accompanied by a suppressed Rho-kinase activation, measured by western blot.

Conclusion

In obesity, female mice demonstrate a vascular protective mechanism – suppression of vascular Rho-kinase – to minimize the cardiovascular risk associated with obesity, whereas male mice do not generate any adaptive response. Future investigations can help to understand how Rho-kinase becomes suppressed in female during obesity.
A tough nutlet to crack: resolving the phylogeny ofThesium(Thesiaceae), the largest genus in Santalales
Authors: García Miguel A. , Mucina Ladislav , Nickrent Daniel L.
Published: April 2023

With over 350 species,Thesiumis the largest genus in Santalales. It is found on all continents except Antarctica; however, its highest diversity is in the Cape Floristic Region of South Africa where approximately half the species occur.Thesiumsamples of ca. 590 collections from throughout its entire geographic range were obtained and nuclear ribosomal ITS sequenced from 396 accessions representing 196 named taxa and 30 currently unnamed taxa for a total of ca. 230 species. In addition, two chloroplast genome spacers (trnDTandtrnLF) were sequenced from 269 and 315 accessions, respectively. Maximum parsimony, maximum likelihood and Bayesian methods were employed to generate gene trees and infer phylogenies. The value of the morphological characters traditionally used in the taxonomy of the genus and previous infrageneric classifications are discussed. Broad scale relationships were generally congruent among the ITS and the chloroplast trees. For example, both the nuclear and chloroplast trees support the presence of Eurasian and African clades. In contrast, major incongruence was detected between nuclear and chloroplast trees for a number of taxa including the recently describedT. nautimontanumthat is sister to the entire African clade on the ITS tree. Although the causes of this incongruence are currently unknown, a novel form of chloroplast capture is hypothesized. A hypothesis of the biogeographical history of the genus based on our molecular phylogeny is presented.
A physiologically based pharmacokinetic model for CYP2E1 phenotyping via chlorzoxazone
Authors: Küttner Jonas , Grzegorzewski Jan , Tautenhahn Hans-Michael , König Matthias
Published: April 2023

The cytochrome P450 (CYP) superfamily of enzymes plays a critical role in the metabolism of drugs, toxins, and endogenous and exogenous compounds. The activity of CYP enzymes can be influenced by a variety of factors, including genetics, diet, age, environmental factors, and disease. Among the major isoforms, CYP2E1 is of particular interest due to its involvement in the metabolism of various low molecular weight chemicals, including alcohols, pharmaceuticals, industrial solvents, and halogenated anesthetics. Metabolic phenotyping of CYPs based on the elimination of test compounds is a useful method for assessing in vivo activity, with chlorzoxazone being the primary probe drug for phenotyping of CYP2E1. The aim of this work was to investigate the effect of changes in CYP2E1 level and activity, ethanol consumption, ethanol abstinence, and liver impairment on the results of metabolic phenotyping with chlorzoxazone. To accomplish this, an extensive pharmacokinetic dataset for chlorzoxazone was established and a physiologically based pharmacokinetic (PBPK) model of chlorzoxazone and its metabolites, 6-hydroxychlorzoxazone and chlorzoxazone-O-glucuronide, was developed and validated. The model incorporates the effect of ethanol consumption on CYP2E1 levels and activity by extending the model with a core ethanol pharmacokinetic model and a CYP2E1 turnover model. The model accurately predicts pharmacokinetic data from several clinical studies and is able to estimate the effect of changes in CYP2E1 levels and activity on chlorzoxazone pharmacokinetics. Regular ethanol consumption induces CYP2E1 over two to three weeks, resulting in increased conversion of chlorzoxazone to 6-hydroxychlorzoxazone and a higher 6-hydroxychlorzoxazone/chlorzoxazone metabolic ratio. After ethanol withdrawal, CYP2E1 levels return to baseline within one week. Importantly, liver impairment has an opposite effect, resulting in reduced liver function via CYP2E1. In alcoholics with liver impairment who also consume ethanol, these factors will have opposite confounding effects on metabolic phenotyping with chlorzoxazone.
Anisotropic Subcutaneous Response During Fingertip Normal and Tangential Loadings
Authors: Duprez Guillaume H.C. , Delhaye Benoit P. , Laurent Delannay
Published: April 2023

The subcutaneous mechanical response of the fingertip is highly anisotropic due to the presence of a network of collagen fibers linking the outer skin layer to the bone. Yet, the impact of this anisotropy on the fingerpad deformation had not been studied until now. This issue is here tackled using a two-dimensional finite element model of a transverse section of the finger. Different hypotheses about the orientation of the fibers are considered: radial (physiologic), circumferential, and random (isotropic behavior). The three variants of the model are assessed using experimental observations of a finger leaning on a flat surface. Predictions relying on the physiological orientation of fibers align best with reality. Moreover, the orientation of fibers plays a crucial role in determining the distribution of internal strain and stress. These factors, combined with the abrupt shift in contact pressure during the transition from sticking to slipping, represent important sensory cues for partial slip detection. This is valuable information for the development of haptic devices.
Evaluation of mRNA-LNP and adjuvanted protein SARS-CoV-2 vaccines in a maternal antibody mouse model
Authors: England Ross N. , Drapeau Elizabeth M. , Hosseinzadeh Reihaneh , Weissman Drew , Hensley Scott E.
Published: April 2023

Maternal antibodies (matAbs) protect against a myriad of pathogens early in life; however, these antibodies can also inhibitde novoimmune responses against some vaccine platforms. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) matAbs are efficiently transferred during pregnancy and protect infants against subsequent SARS-CoV-2 infections. It is unknown if matAbs inhibit immune responses elicited by different types of SARS-CoV-2 vaccines. Here, we established a mouse model to determine if SARS-CoV-2 spike-specific matAbs inhibit immune responses elicited by recombinant protein and nucleoside-modified mRNA-lipid nanoparticle (mRNA-LNP) vaccines. We found that SARS-CoV-2 mRNA-LNP vaccines elicited robustde novoantibody responses in mouse pups in the presence of matAbs. Recombinant protein vaccines were also able to circumvent the inhibitory effects of matAbs when adjuvants were co-administered. While additional studies need to be completed in humans, our studies raise the possibility that mRNA-LNP-based and adjuvanted protein-based SARS-CoV-2 vaccines have the potential to be effective when delivered very early in life.
Pleiotropic Influence of DNA Methylation QTLs on physiological and aging traits
Authors: Mozhui Khyobeni , Kim Hyeonju , Villani Flavia , Haghani Amin , Sen Saunak , Horvath Steve
Published: April 2023

DNA methylation is influenced by genetic and non-genetic factors. Here, we chart quantitative trait loci (QTLs) that modulate levels of methylation at highly conserved CpGs using liver methylome data from mouse strains belonging to the BXD Family. A regulatory hotspot on chromosome 5 had the highest density of trans-acting methylation QTLs (trans-meQTLs) associated with multiple distant CpGs. We refer to this locus as meQTL.5a. The trans-modulated CpGs showed age-dependent changes, and were enriched in developmental genes, including several members of the MODY pathway (maturity onset diabetes of the young). The joint modulation by genotype and aging resulted in a more “aged methylome” for BXD strains that inherited the DBA/2J parental allele at meQTL.5a. Further, several gene expression traits, body weight, and lipid levels mapped to meQTL.5a, and there was a modest linkage with lifespan. DNA binding motif and protein-protein interaction enrichment analysis identified the hepatic nuclear factor,Hnf1a(MODY3 gene in humans), as a strong candidate. The pleiotropic effects of meQTL.5a could contribute to variation in body size and metabolic traits, and influence CpG methylation and epigenetic aging that could have an impact on lifespan.
A calibration and uncertainty quantification analysis of classical, fractional and multiscale logistic models of tumour growth
Authors: Dimitriou Nikolaos M. , Demirag Ece , Strati Katerina , Mitsis Georgios D.
Published: April 2023

The validation of mathematical models of tumour growth is frequently hampered by the lack of sufficient experimental data, resulting in qualitative rather than quantitative studies. Recent approaches to this problem have attempted to extract information about tumour growth by integrating multiscale experimental measurements, such as longitudinal cell counts and gene expression data. In the present study, we investigated the performance of several mathematical models of tumour growth, including classical logistic, fractional and novel multiscale models, in terms of quantifyingin-vitrotumour growth in the presence and absence of therapy. We further examined the effect of genes associated with changes in chemosensitivity in cell death rates. State-of-the-art Bayesian inference, likelihood maximisation and uncertainty quantification techniques allowed a thorough evaluation of model performance. The results suggest that the classical single-cell population model (SCPM) was the best fit for the untreated and low-dose treatment conditions, while the multiscale model with a cell death rate symmetric with the expression profile of OCT4 (SymSCPM) yielded the best fit for the high-dose treatment data. Further identifiability analysis showed that the multiscale model was both structurally and practically identifiable under the condition of known OCT4 expression profiles. Overall, the present study demonstrates that model performance can be improved by incorporating multiscale measurements of tumour growth.
Combinatorial genetic strategy accelerates the discovery of cancer genotype-phenotype associations
Authors: Li Shan , Wong Alicia , Sun Huiyun , Bhatia Vipul , Javier Gerardo , Jana Sujata , Montgomery Robert B. , Wright Jonathan L. , Lam Hung-Ming , Hsieh Andrew C. , Faltas Bishoy M. , Haffner Michael C. , Lee John K.
Published: April 2023

Available genetically-defined cancer models are limited in genotypic and phenotypic complexity and underrepresent the heterogeneity of human cancer. Herein, we describe a combinatorial genetic strategy applied to an organoid transformation assay to rapidly generate diverse, clinically relevant bladder and prostate cancer models. Importantly, the clonal architecture of the resultant tumors can be resolved using single-cell or spatially resolved next-generation sequencing to uncover polygenic drivers of cancer phenotypes.
A mouse-specific model to detect genes under selection in tumors
Authors: Chen Hai , Shu Jingmin , Liu Li
Published: April 2023

Mouse is a widely used model organism in cancer research. However, no computational methods exist to identify cancer driver genes in mice due to a lack of labeled training data. To address this knowledge gap, we adapted the GUST (genes under selection in tumors) model, originally trained on human exomes, to mouse exomes using transfer learning. The resulting tool, called GUST-mouse, can estimate long-term and short-term evolutionary selection in mouse tumors, and distinguish between oncogenes, tumor suppressor genes, and passenger genes using high throughput sequencing data. We applied GUST-mouse to analyze 65 exomes of mouse primary breast cancer models, leading to the discovery of 24 driver genes. The GUST-mouse method is available as an open-source R package on github (https://github.com/liliulab/gust.mouse).