bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative phenotype of circulating versus tissue immune cells in human lung and blood compartments during health and disease
Authors: Colombo Stefano A P , Brown Sheila L , Hepworth Matthew R , Hankinson Jenny , Granato Felice , Kitchen Semra J , Hussell Tracy , Simpson Angela , Cook Peter C , MacDonald Andrew S
Published: July 2023

The lung is a dynamic mucosal surface constantly exposed to a variety of immunological challenges including harmless environmental antigens, pollutants, and potentially invasive microorganisms. Dysregulation of the immune system at this crucial site is associated with a range of chronic inflammatory conditions including asthma and Chronic Pulmonary Obstructive Disease (COPD). However, due to its relative inaccessibility, our fundamental understanding of the human lung immune compartment is limited. To address this, we performed flow cytometric immune phenotyping of human lung tissue and matched blood samples that were isolated from 115 donors undergoing lung tissue resection. We provide detailed characterization of the lung mononuclear phagocyte and T cell compartments, demonstrating clear phenotypic differences between lung tissue cells and those in peripheral circulation. Additionally, we show that CD103 expression demarcates pulmonary T cells that have undergone recent TCR and IL-7R signalling. Unexpectedly, we discovered that the immune landscape from asthmatic or COPD donors was broadly comparable to controls. Our data provide a much-needed expansion of our understanding of the pulmonary immune compartment in both health and disease.
Spontaneously disappearing right atrial mass in a preterm infant: a case report
Authors: Klimek Jan , Culcer Mihaela , Veerappan Sundar
Published: July 2023

Background

There is currently a lack of evidence-based guidelines regarding ideal management of a neonate, specifically a preterm, with thrombo-embolus. There are no clear guidelines as to the time-frame of spontaneous resolution of a thrombo-embolus.

Case summary

A large pedunculated right atrial mass was identified on a clinician-performed cardiac ultrasound in a preterm neonate. The mass was smaller than half of the atrial size and was not causing obstruction. The mass disappeared spontaneously within 6 days and was retrospectively presumed to have been a thrombus. The neonate remained asymptomatic with no signs suggesting that the mass may have embolized.

Discussion

In this case of an incidentally identified asymptomatic intracardiac mass in a preterm infant, presumed to be a thrombus, our conservative ‘wait and watch’ approach was not associated with any adverse pulmonary or systemic effects.
The causal effects of education on adult health, mortality and income: evidence from Mendelian randomization and the raising of the school leaving age
Authors: Davies Neil M , Dickson Matt , Davey Smith George , Windmeijer Frank , van den Berg Gerard J
Published: July 2023

Background

On average, educated people are healthier, wealthier and have higher life expectancy than those with less education. Numerous studies have attempted to determine whether education causes differences in later health outcomes or whether another factor ultimately causes differences in education and subsequent outcomes. Previous studies have used a range of natural experiments to provide causal evidence. Here we compare two natural experiments: a policy reform, raising the school leaving age in the UK in 1972; and Mendelian randomization.

Methods

We used data from 334 974 participants of the UK Biobank, sampled between 2006 and 2010. We estimated the effect of an additional year of education on 25 outcomes, including mortality, measures of morbidity and health, ageing and income, using multivariable adjustment, the policy reform and Mendelian randomization. We used a range of sensitivity analyses and specification tests to assess the plausibility of each method’s assumptions.

Results

The three different estimates of the effects of educational attainment were largely consistent in direction for diabetes, stroke and heart attack, mortality, smoking, income, grip strength, height, body mass index (BMI), intelligence, alcohol consumption and sedentary behaviour. However, there was evidence that education reduced rates of moderate exercise and increased alcohol consumption. Our sensitivity analyses suggest that confounding by genotypic or phenotypic confounders or specific forms of pleiotropy are unlikely to explain our results.

Conclusions

Previous studies have suggested that the differences in outcomes associated with education may be due to confounding. However, the two independent sources of exogenous variation we exploit largely imply consistent causal effects of education on outcomes later in life.
Low-dose perinatal supplementation with Enterococcus faecalis increases concentrations of short-chain fatty acids in the offspring but does not protect against allergic asthma
Authors: Arntz Jeanne L , Alhasan Moumen M , Datye Swarali , Kahhaleh Fariz G , Almousa Yahia , Barrientos Gabriela , Schwiertz Andreas , Conrad Melanie L
Published: July 2023

Childhood allergic asthma is associated with a dysbiotic gut microbiome in early life, and maternal perinatal treatment with probiotics is a potential way alter the infant microbiome, which may improve asthma outcomes. This study used a mouse model to examine the effect of maternal supplementation with the probiotic Enterococcus faecalis on faecal short-chain fatty acid (SCFA) concentrations and asthma risk in the offspring. Pregnant/lactating mice were treated daily, from gestation day 6 to postnatal day 21, with an oral suspension of 106, 107 or 108 colony-forming units of a live preparation of the probiotic E. faecalis (Symbioflor®1). At weaning, offspring were subjected to an ovalbumin-induced experimental asthma protocol. Faeces were collected from the mothers and offspring at several different time points to determine SCFA concentrations. It was found that maternal supplementation with E. faecalis did not alter litter size, sex ratio or offspring weight, and was associated with an increase in SCFAs in offspring faeces at weaning and after allergy induction. However, allergic offspring from E. faecalis supplemented mothers showed no difference in asthma severity when compared with allergic offspring from control mothers. In conclusion, although maternal perinatal supplementation with low-dose E. faecalis was associated with increased faecal SCFAs in the offspring, it did not protect against offspring asthma. This is may be because SCFA concentrations were not increased to an immunoprotective level. We recommend that future studies concentrate on probiotic supplementation in high-risk cases, for instance, to repair gut dysbiosis resulting from antibiotic use in pregnant mothers or their infants.
Semi-parametric estimation of treatment effects in randomised experiments
Authors: Athey Susan , Bickel Peter J , Chen Aiyou , Imbens Guido W , Pollmann Michael
Published: July 2023

We develop new semi-parametric methods for estimating treatment effects. We focus on settings where the outcome distributions may be thick tailed, where treatment effects may be small, where sample sizes are large, and where assignment is completely random. This setting is of particular interest in recent online experimentation. We propose using parametric models for the treatment effects, leading to semi-parametric models for the outcome distributions. We derive the semi-parametric efficiency bound for the treatment effects for this setting, and propose efficient estimators. In the leading case with constant quantile treatment effects, one of the proposed efficient estimators has an interesting interpretation as a weighted average of quantile treatment effects, with the weights proportional to minus the second derivative of the log of the density of the potential outcomes. Our analysis also suggests an extension of Huber’s model and trimmed mean to include asymmetry.
Large-scale structures in the stellar wind of fast-rotating stars spawned by the presence of Earth-like planets
Authors: Canet Ada , Gómez de Castro Ana I
Published: July 2023

Forming planets around young, fast-rotating solar-like stars are exposed to an intense X-ray/extreme ultraviolet radiation field and strongly magnetized stellar winds, as a consequence of the high magnetic activity of these stars. Under these conditions, Earth-like exoplanets may experience a rapid loss of their primordial hydrogen atmospheres, resulting in atmosphereless rocky obstacles for the stellar winds. The interaction of stellar winds with those planets leads to the formation of potentially observable structures due to the formation of large-scale magnetic field and density disturbances in the vicinity of these planets, such as bow shocks, induced magnetospheres, and comet-like tails. In this work, we study the interaction between the stellar winds of active, fast-rotating solar-like stars in the superfast-magnetosonic regime with Earth-like, unmagnetized, tenuous atmosphere, planetary obstacles through numerical three-dimensional simulations using the pluto magnetohydrodynamical code. The properties of AB Doradus, a nearby young star with a small rotation period (0.51 d) and a strong flaring activity, have been used to parametrize this early wind state. Bow shock and induced magnetosphere formation are characterized through the Alfvénic Mach number MA of the wind, for different stellar wind configurations. Large bow shocks, up to an extension of ∼7.0 planetary radii, are found for low-MA winds. The general increase of density, temperature, and magnetic field in these large-scale structures formed around planets may result in potentially detectable spectral signatures.
Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas
Authors: Holdhoff Matthias , Nicholas M Kelly , Peterson Richard A , Maraka Stefania , Liu Li C , Fischer James H , Wefel Jeffrey S , Fan Timothy M , Vannorsdall Tracy , Russell Meredith , Iacoboni Michaella , Tarasow Theodore M , Hergenrother Paul J , Dudek Arkadiusz Z , Danciu Oana C
Published: July 2023

Background

Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas.

Methods

A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 mg) on days 1–21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study.

Results

Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF.

Conclusions

Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.
Surgery versus radiosurgery for vestibular schwannoma: Shared decision making in a multidisciplinary clinic
Authors: Colombo Francesca , Maye Helen , Rutherford Scott , King Andrew , Hammerbeck-Ward Charlotte , Whitfield Gillian A , McBain Catherine , Colaco Rovel , Entwistle Helen , Wadeson Andrea , Lloyd Simon , Freeman Simon , Pathmanaban Omar N
Published: July 2023

Background

Our neurosurgical unit adopted a model of shared decision-making (SDM) based on multidisciplinary clinics for vestibular schwannoma (VS). A unique feature of this clinic is the interdisciplinary counseling process with a surgeon presenting the option of surgery, an oncologist radiosurgery or radiotherapy, and a specialist nurse advocating for the patient.

Methods

This is a retrospective cohort study. All new patients seen in the combined VS clinic and referred from the skull base multidisciplinary team (MDT) from beginning of June 2013 to end of January 2019 were included. Descriptive statistics and frequency analysis were carried out for the full cohort.

Results

Three hundred and fifty-four patients presenting with new or previously untreated VS were included in the analysis. In our cohort, roughly one-third of patients fall into each of the treatment strategies with slightly smaller numbers of patients undergoing surgery than watch, wait and rescan (WWR) ,and SRS (26.6% vs. 32.8% and 37.9%, respectively).

Conclusion

In our experience, the combined surgery/oncology/specialist nurse clinic streamlines the patient experience for those with a VS suitable for either microsurgical or SRS/radiotherapy treatment. Decision-making in this population of patients is complex and when presented with all treatment options patients do not necessarily choose the least invasive option as a treatment. The unique feature of our clinic is the multidisciplinary counseling process with a specialist nurse advocating and guiding the patient. Treatment options are likely to become more rather than less complex in future years making combined clinics more valuable than ever in the SDM process.
Changes in E-cigarette Use, Cigarette Smoking, and Dual-Use Among the Youth (13–15 Years) in 10 Countries (2013–2019)—Analyses of Global Youth Tobacco Surveys
Authors: Sreeramareddy Chandrashekhar T , Acharya Kiran , Manoharan Anusha , Oo Phyu Synn
Published: July 2023

Introduction

The increasing use of e-cigarettes among the youth is a public health problem that needs surveillance. We report changes in e-cigarette use, cigarette smoking, and “dual use” among youth in 10 countries.

Aims and Methods

Global Youth Tobacco Survey (GYTS)s from Georgia, Iraq, Italy, Latvia, Montenegro, Paraguay, Peru, Qatar, Romania, and San Marino were analyzed. Changes in prevalence of “awareness of e-cigarettes,” “ever use” (even tried a few puffs) and “current use” (during last 30 days) of e-cigarettes and cigarette smoking, and “dual use” (both e-cigarette and cigarette smoking) between baseline (2013 and 2014) and most recent (2017–2019) surveys were estimated.

Results

“Awareness of e-cigarettes” and “ever e-cigarette use” significantly increased (p < .001). “Ever e-cigarette use” was highest in Italy, 93% (95% CI 90.9, 94.4). “Current e-cigarette use” significantly (p < .05) increased by > 50% in most countries. During the most recent surveys, “current e-cigarette” use was > 10% in five countries Italy (18.3%) and Latvia (18.5%) being the highest. Cigarette smoking significantly declined in Italy, Latvia, Peru, and San Marino (p < .05) but remains unchanged in other countries. “Dual use” (both electronic and conventional cigarettes) significantly increased in all countries (p < .001). During the most recent surveys “dual use” was highest in Italy (10%, 95% CI 8.1, 12.2) and Latvia (8.6%, 95% CI 7.2, 10.2). Youth aged 14 and ≥15 years the smokers, were more likely to be e-cigarette users.

Conclusions

Awareness and use of e-cigarettes and “dual use” among youth have increased. Closer monitoring of tobacco use among youths and comprehensive tobacco control policies inclusive of e-cigarettes are needed.

Implications

Secondary data analyses of serial GYTSs in 10 countries showed that both awareness of e-cigarette and e-cigarette use has increased among school-going youth aged 13–15 years. A concurrent increase in “dual use” of e-cigarettes and cigarette smoking during the last 30 days in all 10 countries indicates continued cigarette smoking in the absence of e-cigarettes because of the common risk construct of tobacco product use. Results call for continued surveillance of both e-cigarettes and cigarette smoking among school-going youth. Comprehensive tobacco control measures inclusive of e-cigarettes should be implemented to reduce tobacco use among the youth.
Out-of-pocket expenses reported by families of children with medical complexity
Authors: Belza Christina , Cohen Eyal , Orkin Julia , Fayed Nora , Major Nathalie , Quartarone Samantha , Moretti Myla
Published: July 2023

Objectives

Due to their medical and technology dependence, families of children with medical complexity (CMC) have significant costs associated with care. Financial impact on families in general have been described, but detailed exploration of expenses in specific categories has not been systematically explored. Our objective was to describe out-of-pocket (OOP) expenses incurred by caregivers of CMC and to determine factors associated with increased expenditures.

Methods

This is a secondary observational analysis of data primary caregiver-reported OOP expenses as part of a randomized control trial conducted in Ontario, Canada. Caregivers completed questionnaires reporting OOP costs. Descriptive statistics were utilized to report OOP expenses and a linear regression model was conducted.

Results

107 primary caregivers of CMC were included. The median (IQR) age of participants was 34.5 years (30.5 to 40.5) and 83.2% identified as the mother. The majority were married or common-law (86.9%) and 50.5% were employed. The participant’s children [median (IQR) age 4.5 (2.2 to 9.7); 57.9% male] most commonly had a neurological/neuromuscular primary diagnosis (46.1%) and 88% utilized medical technology. Total OOP expenses were $8,639 CDN annually (IQR = $4,661 to $31,326) with substantial expenses related to childcare/homemaking, travel to appointments, hospitalizations, and device costs. No factors associated with greater likelihood of OOP expenses were identified. A P-value of <0.05 was considered significant.

Conclusion

Caregivers of CMC incur significant OOP expenses related to the care of their children resulting in financial burden. Future exploration of the financial impact on caregiver productivity, employment, and identification of resources to mitigate OOP expenses will be important for this patient population.
Radiation injury and gut microbiota-based treatment
Authors: Wang Weihong , Cui Bota , Nie Yongzhan , Sun Lijuan , Zhang Faming
Published: July 2023

The exposure to either medical sources or accidental radiation can cause varying degrees of radiation injury (RI). RI is a common disease involving multiple human body parts and organs, yet effective treatments are currently limited. Accumulating evidence suggests gut microbiota are closely associated with the development and prevention of various RI. This article summarizes 10 common types of RI and their possible mechanisms. It also highlights the changes and potential microbiota-based treatments for RI, including probiotics, metabolites, and microbiota transplantation. Additionally, a 5P-Framework is proposed to provide a comprehensive strategy for managing RI.
Microvascular arterial disease of the brain and the heart: a shared pathogenesis
Authors: Bradley C P , Berry C
Published: July 2023

Microvascular arterial disease in the heart manifest as coronary microvascular dysfunction. This condition causes microvascular angina and is associated increased morbidity and mortality. Microvascular arterial disease in the brain is referred to as cerebrovascular small vessel disease. This is responsible for 45% of dementias and 25% of ischaemic strokes. The heart and brain share similar vascular anatomy and common pathogenic risk factors are associated with the development of both coronary microvascular dysfunction and cerebrovascular small vessel disease. Microvascular disease in the heart and brain also appear to share common multisystem pathophysiological mechanisms. Further studies on diagnostic approaches, epidemiology and development of disease-modifying therapy seem warranted.
Frailty in younger adults in hospital
Authors: Gordon E H , Peel N M , Hubbard R E , Reid N
Published: July 2023

Background

Even though frailty has been extensively measured in the acute care setting, relatively little is known about the frailty of younger adult inpatients.

Aim

This study aimed to measure frailty in a sample of hospitalized adults aged 18 years and over and to examine how frailty in younger adult inpatients differs from middle-aged and older adult inpatients.

Design

Secondary analyses of prospectively collected cohort data.

Methods

Research nurses assessed 910 patients at admission to four Australian hospitals using the interRAI Acute Care instrument. Comparison of frailty index (FI) scores and domains was conducted across three age groups: younger (18–49 years), middle-aged (50–69 years) and older adults (≥70 years). Multivariable logistic regression examined risk of prolonged length of stay and unfavourable discharge destination.

Results

Younger adults (n = 214; 23.5%) had a mean (SD) FI of 0.19 (0.10). Approximately 27% (n = 57) of younger adults were frail (FI > 0.25). Mood and behaviour, health symptoms and syndromes, nutrition and pain were the most frequently affected domains in younger adults and 50% had ≥3 comorbidities. Frailty increased the risk of long length of stay (odds ratio (OR) = 1.77, P < 0.001) but not the risk of an unfavourable discharge (OR = 1.40, P = 0.20) in younger adults.

Conclusions

This study showed that frailty is prevalent in younger patients admitted to acute care and is associated with adverse outcomes. This study was a critical first step towards establishing an understanding of frailty in younger hospitalized adults.
The Non-Dereliction in Evolution: Trophic Specialisation Drives Convergence in the Radiation of Red Devil Spiders (Araneae: Dysderidae) in the Canary Islands
Authors: Bellvert Adrià , Adrián-Serrano Silvia , Macías-Hernández Nuria , Toft Søren , Kaliontzopoulou Antigoni , Arnedo Miquel A
Published: July 2023

Natural selection plays a key role in deterministic evolution, as clearly illustrated by the multiple cases of repeated evolution of ecomorphological characters observed in adaptive radiations. Unlike most spiders, Dysdera species display a high variability of cheliceral morphologies, which has been suggested to reflect different levels of specialization to feed on isopods. In this study, we integrate geometric morphometrics and experimental trials with a fully resolved phylogeny of the highly diverse endemic species from the Canary Islands to 1) quantitatively delimit the different cheliceral morphotypes present in the archipelago, 2) test their association with trophic specialization, as reported for continental species, 3) reconstruct the evolution of these ecomorphs throughout the diversification of the group, 4) test the hypothesis of convergent evolution of the different morphotypes, and 5) examine whether specialization constitutes a case of evolutionary irreversibility in this group. We show the existence of 9 cheliceral morphotypes and uncovered their significance for trophic ecology. Further, we demonstrate that similar ecomorphs evolved multiple times in the archipelago, providing a novel study system to explain how convergent evolution and irreversibility due to specialization may be combined to shape phenotypic diversification in adaptive radiations.
Effect of progesterone infused controlled internal drug releasing (CIDR) device and timing of gonadotropin stimulation using P.G. 600 on reproductive success in ewes bred out of season
Authors: Redden Reid R , Neville Tammi L , Black Danielle N , Crosswhite Mellissa R , Dahlen Crosswhite Carl R
Published: July 2023

Objectives of this study were to determine effects of exogenous progesterone (via controlled internal drug releasing devices; CIDR) in combination with exogenous gonadotropins (PMSG/hCG) use either at CIDR removal or 1 d before CIDR removal to induce estrus and cyclicity and subsequently enhance the proportion of ewes lambing, lambing rate, prolificacy, and days to lambing in ewes bred out of season. Multiparous ewes (n = 414) were randomly assigned to one of four treatments: untreated (U, n = 122), 7 d CIDR (C, n = 97), 7 d CIDR plus P.G. 600 (240 IU pregnant mare serum gonadotropin [PMSG] and 120 IU human chorionic gonadotropin [hCG]) at CIDR removal (CPG0, n = 97), and 7 d CIDR plus P.G. 600 (240 IU PMSG and 120 IU hCG) 1 d before CIDR removal (CPG-1, n = 98). Rams (n = 15) were joined with ewes immediately after CIDR removal and remained with ewes for a 21 d breeding period. Lambing data were summarized for the first 10 days of the lambing season and overall. Categorical data were analyzed using the GLIMMIX procedure of SAS whereas non-categorical data were analyzed using the mixed procedure. Proportion of ewes lambing in the first 10 d was greater (P < 0.05) for CPG0 and CPG-1 ewes compared with C ewes, which was greater (P < 0.0001) compared with U ewes. Overall proportion of ewes lambing was greater (P ≤ 0.0001) in all treatments utilizing CIDR compared with U ewes, but no differences (P ≥ 0.84) due to P.G. 600 were detected compared with C. Lambing rate in the first 10 d was greater (P < 0.05) for CPG-1 than C, with CPGO being intermediate, and all CIDR-treated ewes being greater than U (P < 0.0001). Overall lambing rate increased (P ≤ 0.0001) in all treatments utilizing CIDR compared with U ewes, but no differences (P ≥ 0.76) due to P.G. 600 were detected compared with C. Prolificacy was similar among all treatments both for the first 10 d of the lambing season (P = 0.86) and overall (P = 0.80). Day of lambing in the lambing season was reduced (P ≤ 0.03) for CPG0 and CPG-1 compared with CIDR-treated ewes, which was reduced (P < 0.0001) compared with U ewes (days 10.6, 9.0, 13.4, and 24.4 ± 0.9 for CPG0, CPG-1, CON, and U, respectively). Though timing of P.G. 600 did not influence results, the combination of CIDR and P.G. 600 enhanced the proportion of lambs born earlier in the lambing season, and incorporating a CIDR with or without P.G. 600 enhanced the overall proportion of ewes lambing and lambing rate in out-of-season breeding scenarios.
Tardigrade proteins: molecular tools in the phenomenon of anhydrobiosis
Authors: Krakowiak Michalina , Bartylak Tomasz , Kmita Hanna , Kaczmarek Łukasz , Nawrot Robert
Published: July 2023

Tardigrada (water bears) are a group of small invertebrates known for their ability to survive extreme desiccation by entering an anhydrobiotic state. This state is characterized by the loss of ≤ 98% of body water, resulting in body shrinkage and almost complete cessation of metabolism. In anhydrobiosis, multiple mechanical and biochemical stress effects, such as protein denaturation and aggregation, DNA damage, formation of reactive oxygen species, membrane disintegration and degeneration of cellular compartments, are counteracted by various proteins. Although multiple studies of individual proteins and tardigrade proteomes have been conducted, our knowledge of tardigrade anhydrobiosis-related proteins has not yet been reviewed. To fill this gap, based on available papers, we present a review of all tardigrade proteins known to contribute to desiccation survival, including intrinsically disordered proteins, heat shock proteins and reactive oxygen species-scavenging enzymes. Although proteins are the major anhydrobiosis-related factors in tardigrades, many questions regarding the role of the tardigrade proteome in anhydrobiosis remain unanswered.
Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes
Authors: Chen Xueying , Yang Xiaoyan , Ren Yanhong , Xie Bingbing , Xie Sheng , Zhao Ling , Wang Shiyao , Geng Jing , Jiang Dingyuan , Luo Sa , He Jiarui , Shu Shi , Hu Yinan , Zhu Lili , Li Zhen , Zhang Xinran , Liu Min , Dai Huaping
Published: July 2023

Background:

The presence of fibrosis is a criterion for subtype classification in the newly updated hypersensitivity pneumonitis (HP) guidelines. The present study aimed to summarize differences in clinical characteristics and prognosis of non-fibrotic hypersensitivity pneumonitis (NFHP) and fibrotic hypersensitivity pneumonitis (FHP) and explore factors associated with the presence of fibrosis.

Methods:

In this prospective cohort study, patients diagnosed with HP through a multidisciplinary discussion were enrolled. Collected data included demographic and clinical characteristics, laboratory findings, and radiologic and histopathological features. Logistic regression analyses were performed to explore factors related to the presence of fibrosis.

Results:

A total of 202 patients with HP were enrolled, including 87 (43.1%) NFHP patients and 115 (56.9%) FHP patients. Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP. Serum levels of carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 153, gastrin-releasing peptide precursor, squamous cell carcinoma antigen, and antigen cytokeratin 21-1, and count of bronchoalveolar lavage (BAL) eosinophils were higher in the FHP group than in the NFHP group. BAL lymphocytosis was present in both groups, but less pronounced in the FHP group. Multivariate regression analyses revealed that older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors for the development of FHP. Twelve patients developed adverse outcomes, with a median survival time of 12.5 months, all of whom had FHP.

Conclusions:

Older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors associated with the development of FHP. Prognosis of patients with NFHP was better than that of patients with FHP. These results may provide insights into the mechanisms of fibrosis in HP.
Professionalism in Physician Assistant Education as a Predictor of Future Licensing Board Disciplinary Actions
Authors: Barry Carey L. , Coombs Jennifer , Buchs Shalon , Kim Sooji , Grant Travis , Henry Trenton , Parente Jason , Spackman Jared
Published: July 2023

Purpose

The purpose of this study was to evaluate associations between postgraduate disciplinary actions (PGDA) by state licensing boards and physician assistant (PA) school documented professionalism violations (DPV) and academic probation.

Methods

This was a retrospective cohort study comprising PA graduates from 2001 to 2011 at 3 institutions (n = 1364) who were evaluated for the main outcome of PGDA and independent variable of DPV and academic probation. Random-effects multiple logistic regression and accelerated failure time parametric survival analysis were used to investigate the association of PGDA with DPV and academic probation.

Results

Postgraduate disciplinary action was statistically significant and positively associated with DPV when unadjusted (odds ratio [OR] = 5.15; 95% CI: 1.62–16.31; P = .01) and when adjusting for age, sex, overall PA program GPA (GPA), and Physician Assistant National Certifying Exam Score (OR = 5.39; 95% CI: 1.54–18.85; P = .01) (fully adjusted). Academic probation increased odds to 8.43 times (95% CI: 2.85–24.92; P < .001) and 9.52 times (95% CI: 2.38–38.01; P < .001) when fully adjusted.

Conclusion

Students with professionalism violation or academic probation while in the PA school had significant higher odds of receiving licensing board disciplinary action compared with those who did not. Academic probation had a greater magnitude of effect and could represent an intersection of professionalism and academic performance.
Implicit Association Test Alone Is Not Sufficient to Increase Underrepresented Minority Representation in Physician Assistant Programs
Authors: Ryujin Darin , Dalton Doris , Yole-Lobe Menerva , DiBiase Michelle , Phelps Paula , Madden Ann , Clark Jon , Barry Carey L. , Rodriguez José E. , Honda Trenton
Published: July 2023

Purpose

Physician assistant (PA) program matriculants are consistently less diverse than the US population. This study evaluates whether administration of an Implicit Association Test (IAT) to PA program admission committees is associated with changes in the likelihood of (1) receiving an admission interview, (2) receiving an offer of admission, and (3) matriculation of individuals underrepresented in medicine (URiM).

Methods

Admission committees from 4 PA programs participated in an IAT before the 2019/2020 admissions cycle. Applicant outcome data (n = 5796) were compared with 2018/2019 cycle (n = 6346). Likelihood of URiM students receiving offers to interview, offers of admission, and matriculation were evaluated using random effects multiple logistic regression models. Fully adjusted random effects models included URiM status, year (control vs. intervention), multiplicative interaction terms between URiM and year, applicant age, and undergraduate grade point average (GPA) Secondary analyses examined associations of each race/ethnicity individually.

Results

Underrepresented in medicine status, age, and GPA were significantly associated with all admission outcomes (P < .05). The intervention effect was not statistically significant. In sensitivity analyses examining each individual race rather than URiM status, our results did not importantly differ.

Conclusion

Findings suggest admission committee member participation in IAT before admissions had no significant impact on the likelihood of admission of URiM students. This may suggest that making individuals aware of their implicit biases is not, in and of itself, sufficient to meaningfully affect the diversity of PA program admission metrics.
Young-onset Rectal Cancer
Authors: White Michael G. , Damania Ashish , Alshenaifi Jumanah , Sahasrabhojane Pranoti , Peacock Oliver , Losh Jillian , Wong Matthew C. , Lutter-Berkova Zuzana , Chang George J. , Futreal Andrew , Wargo Jennifer A. , Ajami Nadim J. , Kopetz Scott , You Y. Nancy
Published: July 2023

Objective:

External exposures, the host, and the microbiome interact in oncology. We aimed to investigate tumoral microbiomes in young-onset rectal cancers (YORCs) for profiles potentially correlative with disease etiology and biology.

Background:

YORC is rapidly increasing, with 1 in 4 new rectal cancer cases occurring under the age of 50 years. Its etiology is unknown.

Methods:

YORC (<50 y old) or later-onset rectal cancer (LORC, ≥50 y old) patients underwent pretreatment biopsied of tumor and tumor-adjacent normal (TAN) tissue. After whole genome sequencing, metagenomic analysis quantified microbial communities comparing tumors versus TANs and YORCs versus LORCs, controlling for multiple testing. Response to neoadjuvant therapy (NT) was categorized as major pathological response (MPR, ≤10% residual viable tumor) versus non-MPR.

Results:

Our 107 tumors, 75 TANs from 37 (35%) YORCs, and 70 (65%) LORCs recapitulated bacterial species were previously associated with colorectal cancers (all P<0.0001). YORC and LORC tumoral microbiome signatures were distinct. After NT, 13 patients (12.4%) achieved complete pathologic response, whereas MPR occurred in 47 patients (44%). Among YORCs, MPR was associated with Fusobacterium nucleaum, Bacteroides dorei, and Ruminococcus bromii (all P<0.001), but MPR in LORC was associated with R. bromii (P<0.001). Network analysis of non-MPR tumors demonstrated a preponderance of oral bacteria not observed in MPR tumors.

Conclusions:

Microbial signatures were distinct between YORC and LORC. Failure to achieve an MPR was associated with oral bacteria in tumors. These findings urge further studies to decipher correlative versus mechanistic associations but suggest a potential for microbial modulation to augment current treatments.
Paraburkholderiasymbionts isolated fromDictyostelium discoideuminduce bacterial carriage in otherDictyosteliumspecies
Authors: Mather Rory Vu , Larsen Tyler J. , Brock Debra A. , Queller David C. , Strassmann Joan E.
Published: July 2023

The social amoebaDictyostelium discoideumengages in a complex relationship with bacterial endosymbionts in the genusParaburkholderia, which can benefit their host by imbuing it with the ability to carry prey bacteria throughout its life cycle. The relationship betweenD. discoideumandParaburkholderiahas been shown to take place across many strains and a large geographical area, but little is known aboutParaburkholderia's potential interaction with other dictyostelid species. We explore the ability of threeParaburkholderiaspecies to stably infect and induce bacterial carriage in other dictyostelid hosts. We found that all threeParaburkholderiaspecies successfully infected and induced carriage in seven species ofDictyosteliumhosts. While the overall behaviour was qualitatively similar to that previously observed in infections ofD. discoideum, differences in the outcomes of different host/symbiont combinations suggest a degree of specialization between partners.Paraburkholderiawas unable to maintain a stable association with the more distantly related hostPolysphondylium violaceum. Our results suggest that the mechanisms and evolutionary history ofParaburkholderia's symbiotic relationships may be general withinDictyosteliumhosts, but not so general that it can associate with hosts of other genera. Our work further develops an emerging model system for the study of symbiosis in microbes.
Reproductive phenology is a repeatable, heritable trait linked to the timing of other life-history events in a migratory marine predator
Authors: Oosthuizen W. C. , Pistorius P. A. , Bester M. N. , Altwegg R. , de Bruyn P. J. N.
Published: July 2023

Population-level shifts in reproductive phenology in response to environmental change are common, but whether individual-level responses are modified by demographic and genetic factors remains less well understood. We used mixed models to quantify how reproductive timing varied across 1772 female southern elephant seals (
Mirounga leonina
) breeding at Marion Island in the Southern Ocean (1989–2019), and to identify the factors that correlate with phenological shifts within and between individuals. We found strong support for covariation in the timing of breeding arrival dates and the timing of the preceding moult. Breeding arrival dates were more repeatable at the individual level, as compared with the population level, even after accounting for individual traits (wean date as a pup, age and breeding experience) associated with phenological variability. Mother–daughter similarities in breeding phenology were also evident, indicating that additive genetic effects may contribute to between-individual variation in breeding phenology. Over 30 years, elephant seal phenology did not change towards earlier or later dates, and we found no correlation between annual fluctuations in phenology and indices of environmental variation. Our results show how maternal genetic (or non-genetic) effects, individual traits and linkages between cyclical life-history events can drive within- and between-individual variation in reproductive phenology.
A Combination of Machine Learning and PBPK Modeling Approach for Pharmacokinetics Prediction of Small Molecules in Humans
Authors: Li Yuelin , Wang Zonghu , Li Yuru , Du Jiewen , Gao Xiangrui , Li Yuanpeng , Lai Lipeng
Published: July 2023

Recently, there has been rapid development in model-induced drug development, which has the potential to reduce animal experiments and accelerate drug discovery. Physiologically based pharmacokinetic (PBPK) and machine learning (ML) models are commonly used in early drug discovery to predict drug properties. However, basic PBPK models require a large number of molecule-specific inputs from in vitro experiments, which hinders the efficiency and accuracy of these models. To address this issue, this paper introduces a new computational platform that combines ML and PBPK models. The platform predicts molecule PK profiles with high accuracy and without the need for experimental data.

This study developed a whole-body PBPK model and ML models of plasma protein unbinding (fup), Caco-2 cell permeability, and total plasma clearance to predict the PK of small molecules. Pharmacokinetic profiles were simulated using a “bottom-up” PBPK modeling approach with ML inputs. Additionally, 40 compounds were used to evaluate the platform’s accuracy. Results showed that the ML-PBPK model predicted the area under the concentration-time curve (AUC) with 62.5% accuracy within a 2-fold range, which was higher than using in vitro inputs with 47.5% accuracy.

The ML-PBPK model platform provides high accuracy in prediction and reduces the number of experiments and time required compared to traditional PBPK approaches. The platform successfully predicts human PK parameters without in vitro and in vivo experiments and can potentially guide early drug discovery and development.
A host AAA-ATPase exhibits bacteriolytic activity for clearance of microbial infection
Authors: Ghosh Sourav , Roy Suvapriya , Baid Navin , Das Udit Kumar , Rakshit Sumit , Sanghavi Paulomi , Hajra Dipasree , Menon Sneha , Sahil Mohammad , Shaw Sudipti , Rajmani Raju S , Adicherla Harikrishna , Mondal Jagannath , Chakravortty Dipshikha , Mallik Roop , Banerjee Anirban
Published: July 2023

An array of host cytosol guarding factors impede bacterial proliferation and preserve cellular sterility. Amongst them, proteasomal degradation of ubiquitinated pathogens has emerged as a critical mechanism for ensuring cytosolic sanctity. We wondered how proteasomes, with their small size and inability to extract membrane-bound proteins, can eradicate pathogens. Here, we unveil a unique strategy, wherein VCP/p97, a host AAA-ATPase, eliminates pathogens by exerting mechanical force that physically unfolds and pulls out ubiquitinated proteins from bacterial membrane. Combining a single-molecule approach along with molecular dynamic simulation andin-vitroreconstitution, we demonstrate that protein extraction by p97 causes extensive membrane lysis and release of cytosolic contents from phylogenetically diverse microbes. Additionally, in anin-vivomouse sepsis model, this segregase-dependent bactericidal effect of p97 abrogated microbial proliferation in host tissues. Overall, we discovered a distinct innate antimicrobial function of p97, that protects the host against lethal bacterial infections.

One Sentence Summary

A host AAA-ATPase exhibits bacteriolytic activity.
COVID-19: a catalyst for change in remote and rural advanced clinical practice – A qualitative study
Authors: King Rachel , Carolan Clare , Robertson Steve
Published: July 2023

Purpose

The purpose of this study is to explore the sustainability of innovations introduced during the coronavirus disease 2019 (Covid-19) pandemic in remote and rural primary care advanced clinical practice.

Design/methodology/approach

The methodology includes an exploratory qualitative study of eight key stakeholders from Scottish remote and rural primary care advanced practice (three policymakers and five advanced practitioners). Data were collected using semi-structured interviews during 2022 and analysed thematically.

Findings

Advanced practice in remote and rural primary care is characterised by a shortage of doctors, close-knit communities and a broad scope of practice. Covid-19 catalysed changes in the delivery of healthcare. Innovations which participants wanted to sustain include hybrid working, triage, online training and development, and increased inter-professional support networks.

Practical implications

Findings provide valuable insights into how best to support remote and rural advanced practice which may have implications for retaining healthcare professionals. They also identified useful innovations which could benefit from further investment.

Originality/value

Given current healthcare workforce pressures, identifying and sustaining innovations which will support and retain staff are imperative. Hybrid consultations and online access to training, development and support should be sustained to support the remote and rural advanced practice workforce. Further research should explore the sustainability of innovations introduced during the Covid-19 pandemic in other care contexts.
The dark side of online transition of exams in higher education: a perspective of an emerging nation
Authors: Koswatte Isuru , Fernando Chandrika , Jayawardena Nirma Sadamali
Published: July 2023

Purpose

Higher educational institutes (HEIs) are experiencing a significant shift towards online education, which has been fast-forwarded with the global pandemic of COVID-19. The forced shift has also exposed many vulnerabilities in online education, especially assessments. The purpose of this study is to investigate the potential dark side of the digital transformation of examinations through the lens of university students.

Design/methodology/approach

This study involves a sample of 127 university students from the fields of business and science, technology, education and management (STEM) and the key factors affecting student perception were assessed quantitatively to explore the interrelationships.

Findings

Results revealed that both business and STEM students have a similar impression of the use of online examinations, and the majority still have mixed feelings about them as a replacement for physical examinations. The regrouping of the factors revealed two key dimensions, trustworthiness and apprehensible education, as key areas of student perception in the context of online examinations.

Research limitations/implications

This study aims to strengthen the understanding of Kolb’s experiential learning mechanism through a discussion on the importance of abstract conceptualization as opposed to concrete experience in the establishment of the online assessment and learning space. Practically speaking, increasing investment in internet infrastructure and forming strategic alliances with important parties, like internet providers, to create uninterrupted network coverage, are an effective place to start if one wants to make sure that the process of moving to online learning is becoming more and more accepted by educators, students, and the general public.

Originality/value

The online transition to higher education has seen expedited growth since the pandemic and has not given much room for many HEIs globally to adjust. The procedures and techniques implemented take a Western lens, and less attention is given to the emerging context and its context-specific characteristics in such implementation. This study takes the theoretical lens of Kolb and proposes the key learnings for a successful online transition to assessment in emerging contexts.
Happier on the outside? Discourses of exclusion, disempowerment and belonging from former autistic school staff
Authors: Wood Rebecca
Published: July 2023

Autistic individuals can have poor outcomes from school, including high rates of unemployment. Despite a growing focus on the work experiences of autistic people, and various approaches to remediate the difficulties they undergo, the school sector remains largely unexplored, as are the insights available from former autistic employees. In a discourse analysis of 12 former autistic school staff previously in a range of roles in the UK, the multiple and intersecting issues they experienced are analysed. These reveal different forms of marginalisation, disempowerment, invisibility and exclusion at play, including in relation to being autistic, before the final departure. However, participant discourses also demonstrate important autistic aptitudes of particular benefit to pupils at risk of marginalisation themselves, and provide insights into how autistic staff—including visiting professionals—can be better supported in the school sector in the future. Such steps could provide significant benefits for the education field generally, especially in relation to the inclusion of autistic and otherwise neurodivergent pupils.