bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined effects of hypertension, hyperlipidemia, and diabetes mellitus on the presence and severity of carotid atherosclerosis in community-dwelling elders: A community-based study
Authors: Lu Shu-Xin , Wu Tzu-Wei , Chou Chao-Liang , Cheng Chun-Fang , Wang Li-Yu
Published: January 2023

Background:

Hypertension, hyperlipidemia, and diabetes mellitus (DM) are common cardiovascular disease (CVD) comorbidities and well-known major determinants of atherosclerosis. However, their combined effects and relative contributions have not been well explored. This study aimed to characterize the characteristics of carotid atherosclerosis and dissect the relative effects of these common CVD comorbidities on the presence and severity of carotid atherosclerosis in community-dwelling elderly individuals.

Methods:

We enrolled 817 elders from communities in northern Taiwan. We evaluated their cardiovascular risk profiles and scanned their extracranial carotid arteries using high-resolution ultrasonography systems.

Results:

The prevalence rates for hypertension, hyperlipidemia, and DM were 45.4%, 37.1%, and 16.8%, respectively. Sixty-two (7.6%) and 188 (23.0%) elderly had all three and two of these common CVD comorbidities, respectively. The prevalent rates of carotid plaque and moderate-to-severe atherosclerosis were 62.9% and 35.5%, respectively. The percentages of one or more common CVD comorbidities in elders with carotid plaque and moderate-to-severe atherosclerosis were 78.2% and 83.1%, respectively. Multivariate analyses showed that the number of common CVD comorbidities was the most predictive determinant. Multivariable-adjusted odds ratios (ORs) per comorbidity for the presence of carotid plaque and advanced carotid atherosclerosis were 1.52 (95% CI, 1.28-1.81) and 1.57 (95% CI, 1.28-1.93), respectively. Models containing hypertension and DM were the second most predictive. Combinatory analyses showed distinct relationship patterns between carotid atherosclerosis and hypertension, hyperlipidemia, and DM. Hypertension was significantly correlated with higher ORs for the presence of carotid plaque and advanced carotid atherosclerosis but not for hyperlipidemia.

Conclusion:

Carotid plaques are highly prevalent in community-dwelling elders. The number of common CVD comorbidities was the most predictive determinant of carotid plaques and advanced carotid atherosclerosis. Our results indicate that to reduce the impact of atherosclerotic diseases, blood pressure controls precede the control of blood lipids and glucose in the community-dwelling elders.
Investigation of preoperative asymptomatic bacteriuria as a risk factor for postvertebroplasty infection
Authors: Chen Kuan-Jung , Huang Yen-Chun , Yao Yu-Cheng , Yang Tzu-Cheng , Lin Hsi-Hsien , Wang Shih-Tien , Chang Ming-Chau , Chou Po-Hsin
Published: January 2023

Background:

Postvertebroplasty infection (PVI) is a catastrophic complication after vertebroplasty (VP). Although the urinary tract has been considered as a source of infectious pathogens, whether asymptomatic bacteriuria (ASB) is a risk factors for PVI remains unknown.

Methods:

This retrospective study included 716 patients (207 males; 509 females) treated with VP for osteoporotic vertebral fractures in a single medical center between May 2015 and December 2019. Clinical symptoms, urinalysis results, and culture data were collected preoperatively to identify patients with ASB. The primary outcome was PVI at the index level during follow-up. Demographic data and laboratory test results were compared between the PVI and non-PVI groups.

Results:

The mean age of the cohort was 78.6 ± 9.6 (range, 63–106). The prevalence of ASB was 14.1%, with female predominance (63.4%). The overall PVI rate was 1.26% (9/716). The PVI group had more patients with ASB (4/9, 44.4%) than did the non-PVI group (97/707, 13.7%) (p = 0.027). The rate of ASB treatment was similar between the PVI and non-PVI groups (25% vs. 23.7%, respectively). No case of PVI was caused by the urine culture pathogen. Multivariate analysis identified the following risk factors for PVI: ASB (odds ratio [OR], 5.61; 95% CI, 1.14–27.66; p = 0.034), smoking (OR, 16.26; 95% CI, 2.58–102.65; p = 0.003), and malignancy (OR 7.27; 95% CI, 1.31–40.31; p = 0.023).

Conclusion:

ASB was not uncommon among patients admitted for VP and should be considered a marker of relatively poor host immunity. Preoperative ASB, a history of malignancy, and smoking were identified as significant risk factors for PVI.
Transparency of Parental Leave Policies to Prospective Students in US Physician Assistant Programs: A Cross-Sectional Study
Authors: Neary Stephanie , Kamauf Renée , Ruggeri Mary
Published: January 2023

Introduction

Parental leave policies are not well established or always available for prospective graduate students. This study examined the availability and inclusivity of PA program parental leave policies to prospective students at accredited US programs.

Methods

The websites and available student handbooks of the 282 currently accredited PA programs were searched for the terms “pregnant,” “pregnancy,” “maternity,” “parent,” “family,” “child,” and/or “birth.” Descriptive statistics and Pearson’s chi-square test were used to analyze the data.

Results

In total, 13.5% (38/282) of PA program websites and available handbooks met search criteria. Of these 38 programs, 23 (60.5%) provide information with gendered language that discriminates based on sex, most commonly only mentioning the pregnant female.

Discussion

PA programs should create specific policies for pregnancy-related and parental leaves that are inclusive to heteronormative families as well as nontraditional and nonnuclear families, and these policies should be widely available to potential applicants and students.
From Protocol to Definitive Study—The State of Randomized Controlled Trial Evidence in Sports Medicine Research: A Systematic Review and Survey Study
Authors: Pellarin Mitchell , Youmbi Cheikh Tchouambou , Lotchuang Joyce , Tejpal Tushar , Thangathurai Gowtham , Khan Abdullah , Cohen Dan , Simunovic Nicole , Duong Andrew , Ayeni Olufemi R.
Published: January 2023

Objective:

To evaluate the progression, quality, and challenges associated with conducting and publishing randomized controlled trials (RCTs) in sports medicine.

Design:

Systematic review and survey.

Setting:

MEDLINE and Embase were searched for all publications before September 17, 2021. A targeted search of clinicaltrials.gov, BMC Musculoskeletal Disorders, PubMed, and Google Scholar were also conducted. The survey was administered to authors using REDCap.

Participants:

Where the systematic search revealed no corresponding published definitive trial, authors of the published pilots were surveyed.

Interventions:

Survey assessing limitations to definitive trials.

Main Outcome Measures:

Protocol/method articles, pilot articles, and relevant clinical trial registry records with corresponding definitive trials were pooled.

Results:

Our literature search yielded 27 006 studies; of which, we included 208 studies (60 (28.8%) pilot RCTs, 84 (40.4%) protocol/method articles, and 64 (30.8%) trial registry records). From these, 44 corresponding definitive RCTs were identified. Pilot study and definitive RCT methodological quality increased on average most significantly during the duration of this review (30.6% and 8.2%). Of the 176 authors surveyed, 59 (33.5%) responded; 24.6% (14/57) stated that they completed an unpublished definitive trial, while 52.6% (30/57) reported having one underway.

Conclusions:

The quality and number of RCT publications within the field of sports medicine has been increasing since 1999. The number of sports medicine–related protocol and pilot articles preceding a definitive trial publication showed a sharp increase over the past 10 years, although only 5 pilot studies have progressed to a definitive RCT.
Development and Evaluation of the Fuld Institute Evidence-based Implementation and Sustainability Toolkit for Health Care Settings
Authors: McNett Molly , Gorsuch Penelope F. , Gallagher-Ford Lynn , Thomas Bindu , Mazurek Melnyk Bernadette , Tucker Sharon
Published: January 2023

Routine implementation and sustainability of evidence-based practices (EBPs) into health care is often the most difficult stage in the change process. Despite major advances in implementation science and quality improvement, a persistent 13- to 15-year research-to-practice gap remains. Nurse leaders may benefit from tools to support implementation that are based on scientific evidence and can be readily integrated into complex health care settings. This article describes development and evaluation of an evidence-based implementation and sustainability toolkit used by health care clinicians seeking to implement EBPs. For this project, implementation science and EBP experts created initial iterations of the toolkit based on Rogers' change theory, the Advancing Research through Close Collaboration (ARCC) model, and phases and strategies from implementation science. Face validity and end-user feedback were obtained after piloting the tool with health care clinicians participating in immersive EBP sessions. The toolkit was then modified, with subsequent content validity and usability evaluations conducted among implementation science experts and health care clinicians. This article presents the newly updated Fuld Institute Evidence-based Implementation and Sustainability Toolkit for health care settings. Nurse leaders seeking to implement EBPs may benefit from an evidence-based toolkit to provide a science-informed approach to implementation and sustainability of practice changes.
Lanthony D15 for Occupational Testing: Short-term Repeatability
Authors: Lo Genna , Ng Jason S.
Published: January 2023

SIGNIFICANCE

The Lanthony D15 has been reported to have poorer repeatability than the Farnsworth D15. This study found that two trials of the test provide high short-term repeatability and can be administered this way for occupational testing.

PURPOSE

This study aimed to determine the short-term repeatability of the Lanthony D15 in patients with color vision deficiency. Repeated trials were used to examine if learning effects occur and to determine how many trials would be necessary to ensure the highest short-term repeatability for occupational testing.

METHODS

Twenty male subjects (mean [standard deviation] age, 27.2 [4.3] years) with congenital color vision deficiency, ranging from mild to severe, participated in this single-visit study. Visual acuity, color vision book screening, Farnsworth D15, and anomaloscope testing were performed for classification purposes. Ten trials of the Lanthony D15 were performed. Color confusion index scores from each trial were determined, and a repeated-measures analysis of variance was used to compare the scores across trials. Orthogonal polynomial analysis was performed to detect any trends across trials through the third order. The intraclass correlation coefficient was calculated.

RESULTS

No differences in color confusion index (mean [standard error of the mean], 3.57 [0.04]) were found across the 10 trials (P = .18). Legendre polynomials showed no statistical significance (all P > .39). The intraclass correlation coefficient was 0.81 (95% confidence interval, 0.70 to 0.90). Based on the method of Shrout and Fleiss, intraclass correlation coefficients of 0.7, 0.8, and 0.9 could be achieved with an average of one, two, and four trials of the test, respectively. However, empirically, 0.9 was not achievable.

CONCLUSIONS

The Lanthony D15 test has fairly high short-term repeatability. Thus, although more trials would likely improve clinical certainty, the mean result of two trials appears sufficient for occupational testing.
Afterword to “When the Supervisor Needs a Supervisor: A Case-based Guide for Developing Psychotherapy Supervisors”
Authors: Plakun Eric M.
Published: January 2023

Supervision of psychotherapy is recognized as fundamental for attaining competency in psychotherapy. However, there is a lack of training in “best practices” of supervisory skills, and some supervisors may lack contemporary knowledge to support supervisees adequately. Training program leadership challenged by limited time and resources to provide supervisors with the necessary education and support can benefit from additional resources for developing psychotherapy supervisors. The authors present 3 core elements of navigating supervisory challenges: training, open dialogue in supervision, and a formal program-level process. Common issues in psychotherapy supervision are then presented in a case-based format. Reflection questions are included to provide an opportunity to consider a personal approach to the case, while specific guidance based on the literature addresses critical aspects of the case examples. Complex supervisory conflicts can challenge programs, but they are normative to the learning process and promote growth in our supervisors.
Comparative Pharmacology of the 3 Marketed Dual Orexin Antagonists—Daridorexant, Lemborexant, and Suvorexant—Part 2. Principal Drug Metabolizing Enzyme, Drug-Drug Interactions, and Effects of Liver and Renal Impairment on Metabolism
Authors: Preskorn Sheldon H.
Published: January 2023

This column is the second in a 2-part series presenting the comparative pharmacology of the 3 Food and Drug Administration–approved dual orexin receptor antagonists, daridorexant, lemborexant, and suvorexant. Both of the columns in this series emphasize the pharmacokinetics of these drugs as they are relevant to their use as sleep medications. Although other classes of sleep medications are not discussed, the same pharmacokinetic principles also apply to them in terms of endeavoring to match the pharmacokinetics of an agent to the individual’s usual sleep cycle. This second column in the series focuses on the metabolism of each of the 3 drugs by the cytochrome P450 enzyme CYP3A, guidance for using these agents in combination with drugs that are CYP3A inhibitors or inducers, and how to adjust dosing in patients with comorbid conditions such as hepatic or renal impairment.
Multicompartmental trauma alters bone marrow erythroblastic islands
Authors: Kelly Lauren S. , Munley Jennifer A. , Pons Erick E. , Coldwell Preston S. , Kannan Kolenkode B. , Efron Philip A. , Mohr Alicia M.
Published: January 2023

BACKGROUND

Trauma is associated with widespread inflammation, neuroendocrine activation, and an inadequate bone marrow response to anemia. During late-stage erythropoiesis, erythroid progenitors/erythroblasts form clusters on the surface of specialized bone marrow macrophages where they are supported through terminal differentiation and enucleation. We hypothesized that these erythroblastic islands (EBIs) are adversely impacted by severe trauma.

METHODS

Male Sprague-Dawley rats (n = 8/group) were subjected to either multiple injuries (PT) (lung contusion, hemorrhagic shock, cecectomy, and bifemoral pseudofractures), PT plus 2 hours of daily chronic restraint stress (PT/CS), or naive controls. Bone marrow was harvested on days 2 and 7. Nuclear-stained, enriched bone marrow EBIs were fixed and stained for CD71, VCAM-1, and CD163, and confocal images were obtained at 20 times magnification. Numbers of erythroid cells/EBI and ratio of reticulocytes/EBI were counted by a blinded observer. Differences were compared using analysis of variance, with significance defined as p < 0.05.

RESULTS

PT and PT/CS had significantly reduced numbers of erythroid cells per EBI on day 2 when compared with naive (PT: 5.9 ± 1.0 cells [p < 0.05], PT/CS: 6.8 ± 0.8 cells [p < 0.05] vs. naive: 8.5 ± 0.8 cells). On day 7, the number of erythroid cells/EBI increased following PT (8.3 ± 0.4 cells) but remained reduced following PT/CS (5.9 ± 0.5 cells [p < 0.05]). This correlated with an increased proportion of reticulocytes/EBI on day 7 following PT, which was not present following PT/CS (PT: 54% [p < 0.05] vs. PT/CS: 28%).

CONCLUSION

Late-stage erythropoiesis was altered following multicompartmental PT early after injury, and these alterations persisted with the addition of daily chronic stress. Alterations in EBI structure and function after severe trauma and critical illness may serve as a promising new area of study to improve mechanistic understanding of persistent anemia after trauma.
Institutional outcomes of blunt liver and splenic injury in the Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium era
Authors: Stewart Shai , Fraser James A. , Rentea Rebecca M. , Aguayo Pablo , Juang David , Fraser Jason D. , Snyder Charles L. , Hendrickson Richard J. , St. Peter Shawn D. , Oyetunji Tolulope A.
Published: January 2023

BACKGROUND

The Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium practice management guideline was created to standardize management of blunt liver or spleen injury across pediatric trauma centers. We describe our outcomes since guideline adoption at our institution and hypothesize that blunt liver or spleen injury may be managed more expeditiously than currently reported without compromising safety.

METHODS

A retrospective cohort study was conducted on patients younger than 18 years presenting with blunt liver and/or splenic injuries from March 2016 to March 2021 at one participating center.

RESULTS

A total of 199 patients were included. There were no clinically relevant differences for age, body mass index, or sex among the cohort. Isolated splenic injuries (n = 91 [46%]) and motor vehicle collisions (n = 82 [41%]) were the most common injury and mechanism, respectively. The overall median length of stay (LOS) was 1.2 days (interquartile range, 0.45–3.3 days). Intensive care unit utilization was 23% (n = 46). There was no statistically significant difference in median LOS among patients with isolated solid organ injuries, regardless of injury grade. There were no readmissions associated with non-operative management.

CONCLUSION

The Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium guideline fosters high rates of nonoperative management with low intensive care unit utilization and LOS while demonstrating safety in implementation, irrespective of injury grade.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Primary Graft Dysfunction in Lung Transplantation: A Review of Mechanisms and Future Applications
Authors: Chacon-Alberty Lourdes , Fernandez Ramiro , Jindra Peter , King Madelyn , Rosas Ivan , Hochman-Mendez Camila , Loor Gabriel
Published: January 2023

Lung allograft recipients have worse survival than all other solid organ transplant recipients, largely because of primary graft dysfunction (PGD), a major form of acute lung injury affecting a third of lung recipients within the first 72 h after transplant. PGD is the clinical manifestation of ischemia–reperfusion injury and represents the predominate cause of early morbidity and mortality. Despite PGD’s impact on lung transplant outcomes, no targeted therapies are currently available; hence, care remains supportive and largely ineffective. This review focuses on molecular and innate immune mechanisms of ischemia–reperfusion injury leading to PGD. We also discuss novel research aimed at discovering biomarkers that could better predict PGD and potential targeted interventions that may improve outcomes in lung transplantation.
Directional hydrophone clusters reveal evasive responses of small cetaceans to disturbance during construction at offshore windfarms
Authors: Graham I. M. , Gillespie D. , Gkikopoulou K. C. , Hastie G. D. , Thompson P. M.
Published: January 2023

Mitigation measures to disperse marine mammals prior to pile-driving include acoustic deterrent devices and piling soft starts, but their efficacy remains uncertain. We developed a self-contained portable hydrophone cluster to detect small cetacean movements from the distributions of bearings to detections. Using an array of clusters within 10 km of foundation pile installations, we tested the hypothesis that harbour porpoises (
Phocoena phocoena
) respond to mitigation measures at offshore windfarm sites by moving away. During baseline periods, porpoise movements were evenly distributed in all directions. By contrast, animals showed significant directional movement away from sound sources during acoustic deterrent device use and piling soft starts. We demonstrate that porpoises respond to measures aimed to mitigate the most severe impacts of construction at offshore windfarms by swimming directly away from these sound sources. Portable directional hydrophone clusters now provide opportunities to characterize responses to disturbance sources across a broad suite of habitats and contexts.
Amending the literature through version control
Authors: Kane Adam , Amin Bawan
Published: January 2023

The ideal of self-correction in science is not well served by the current culture and system surrounding amendments to published literature. Here we describe our view of how amendments could and should work by drawing on the idea of an author-led version control system. We report a survey (
n
= 132) that highlights academics' dissatisfaction with the status quo and their support for such an alternative approach. Authors would include a link in their published manuscripts to an updatable website (e.g. a GitHub repository) that could be disseminated in the event of any amendment. Such a system is already in place for computer code and requires nothing but buy-in from the scientific community—a community that is already evolving towards open science frameworks. This would remove a number of frictions that discourage amendments leading to an improved scientific literature and a healthier academic climate.
Postural, pilo-erective and evaporative thermal windows of the short-beaked echidna (Tachyglossus aculeatus)
Authors: Cooper Christine Elizabeth , Withers Philip Carew
Published: January 2023

We identify for wild, free-living short-beaked echidnas (Tachyglossus aculeatus) a novel evaporative window, along with thermal windows, and demonstrate the insulating properties of the spines, using infrared thermography. The moist tip of their beak, with an underlying blood sinus, functions as a wet bulb globe thermometer, maximizing evaporative heat loss via an evaporative window. The ventral surface and insides of the legs are poorly insulated sites that act as postural thermal windows, while the spines provide flexible insulation (depending on piloerection). These avenues of heat exchange likely contribute to the higher-than-expected thermal tolerance of this species. Our study highlights how technological advances that allow for non-contact measurement of thermal variables allow us to better understand the physiological capacity of animals in their natural environment.
Strong host phylogenetic and ecological effects on host competency for avian influenza in Australian wild birds
Authors: Wille Michelle , Lisovski Simeon , Roshier David , Ferenczi Marta , Hoye Bethany J. , Leen Trent , Warner Simone , Fouchier Ron A. M. , Hurt Aeron C. , Holmes Edward C. , Klaassen Marcel
Published: January 2023

Host susceptibility to parasites is mediated by intrinsic and external factors such as genetics, ecology, age and season. While waterfowl are considered central to the reservoir community for low pathogenic avian influenza A viruses (LPAIV), the role of host phylogeny has received limited formal attention. Herein, we analysed 12 339 oropharyngeal and cloacal swabs and 10 826 serum samples collected over 11 years from wild birds in Australia. As well as describing age and species-level differences in prevalence and seroprevalence, we reveal that host phylogeny is a key driver in host range. Seasonality effects appear less pronounced than in the Northern Hemisphere, while annual variations are potentially linked to El Niño–Southern Oscillation. Our study provides a uniquely detailed insight into the evolutionary ecology of LPAIV in its avian reservoir community, defining distinctive processes on the continent of Australia and expanding our understanding of LPAIV globally.
Maritalea mediterranea sp. nov., isolated from marine plastic residues
Authors: Vidal-Verdú Àngela , Molina-Menor Esther , Satari Leila , Pascual Javier , Peretó Juli , Porcar Manuel
Published: January 2023

A novel Gram-reaction-negative, aerobic, motile, rod-shaped, grey bacterium, strain P4.10XT, was isolated from plastic debris sampled from shallow waters in the Mediterranean Sea (Valencia, Spain). P4.10XT was catalase- and oxidase-positive, and grew under mesophilic, neutrophilic and halophilic conditions. The 16S rRNA gene sequences revealed that P4.10XT was closely related to

Maritalea myrionectae

DSM 19524T and

Maritalea mobilis

E6T (98.25 and 98.03 % sequence similarity, respectively). The DNA G+C content of the genome sequence of P4.10XT was 53.66 %. The genomic indexes average nucleotide identity by blast (ANIb) and digital DNA–DNA hybridization (dDDH) confirmed its classification as representing a novel species of the genus

Maritalea

. The predominant fatty acids were summed feature 8 (C18 : 1ω7c/C18 : 1ω6c) and C18 : 1 ω7c 11-methyl. The results of this polyphasic study confirm that P4.10XT represents a novel species of the genus

Maritalea

, for which the name Maritalea mediterranea sp. nov. is proposed (type strain P4.10XT=CECT 30306T = DSM 112386T).
Targeting of Th17-related cytokines in patients with Darier Disease
Authors: Ettinger Monika , Burner Teresa , Sharma Anshu , Chang Yun-Tsan , Lackner Angelika , Prompsy Pacôme , Pospischil Isabella , Traxler Judith , Wahl Gerald , Altrichter Sabine , Tsai Yi-Chien , Varkhande Suraj R. , Schoeftner Leonie C. , Iselin Christoph , Gratz Iris K. , Kimeswenger Susanne , Guenova Emmanuella , Hoetzenecker Wolfram
Published: January 2023

Darier disease (DD) is a rare, inherited multi-organ disorder associated with mutations in the ATP2A2 gene. DD patients often have skin involvement characterized by malodorous, inflamed skin and recurrent, severe infections. Therapeutic options are limited and inadequate for the long-term management of this chronic disease. Using gene and protein expression profiling assays, we demonstrate enhanced expression of Th-17-related genes and cytokines and increased numbers of Th17 cells in six DD patients. We prove that targeting the IL-23/-17 axis in DD with monoclonal antibodies is an effective and safe therapy for DD patients, leading to significant clinical improvement. As DD is a chronic, relapsing disease, our findings provide new options for the long-term management of skin inflammation in patients with DD.
Microdiversity of the Vaginal Microbiome is Associated with Preterm Birth
Authors: Liao Jingqiu , Shenhav Liat , Urban Julia A. , Serrano Myrna , Zhu Bin , Buck Gregory A. , Korem Tal
Published: January 2023

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. The vaginal microbiome has been associated with PTB, yet the mechanisms underlying this association are not fully understood. Understanding microbial genetic adaptations to selective pressures, especially those related to the host, may yield new insights into these associations. To this end, we analyzed metagenomic data from 705 vaginal samples collected longitudinally during pregnancy from 40 women who delivered preterm spontaneously and 135 term controls from the Multi-Omic Microbiome Study-Pregnancy Initiative (MOMS-PI1). We find that the vaginal microbiome of pregnancies that ended preterm exhibits unique genetic profiles. It is more genetically diverse at the species level, a result which we validate in an additional cohort, and harbors a higher richness and diversity of antimicrobial resistance genes, likely promoted by transduction. Interestingly, we find thatGardnerellaspecies, a group of central vaginal pathobionts, are driving this higher genetic diversity, particularly during the first half of the pregnancy. We further present evidence thatGardnerellaspp. undergoes more frequent recombination and stronger purifying selection in genes involved in lipid metabolism. Overall, our results reveal novel associations between the vaginal microbiome and PTB using population genetics analyses, and suggest that evolutionary processes acting on the vaginal microbiome may play a vital role in adverse pregnancy outcomes such as preterm birth.
Learning fast and fine-grained detection of amyloid neuropathologies from coarse-grained expert labels
Authors: Wong Daniel R. , Magaki Shino D. , Vinters Harry V. , Yong William H. , Monuki Edwin S. , Williams Christopher K. , Martini Alessandra C. , DeCarli Charles , Khacherian Chris , Graff John P. , Dugger Brittany N. , Keiser Michael J.
Published: January 2023

Precise, scalable, and quantitative evaluation of whole slide images is crucial in neuropathology. We release a deep learning model for rapid object detection and precise information on the identification, locality, and counts of cored plaques and cerebral amyloid angiopathies (CAAs). We trained this object detector using a repurposed image-tile dataset without any human-drawn bounding boxes. We evaluated the detector on a new manually-annotated dataset of whole slide images (WSIs) from three institutions, four staining procedures, and four human experts. The detector matched the cohort of neuropathology experts, achieving 0.64 (model) vs. 0.64 (cohort) average precision (AP) for cored plaques and 0.75 vs. 0.51 AP for CAAs at a 0.5 IOU threshold. It provided count and locality predictions that correlated with gold-standard CERAD-like WSI scoring (p=0.07± 0.10). The openly-available model can quickly score WSIs in minutes without a GPU on a standard workstation.
Compensatory adaptation does not fully alleviate the costs associated with rifampicin resistance and occurs predominantly through off-target mutations
Authors: Cohen Yasmin , Rozen Gydeon A , Pennings Pleuni S , Katz Sophia , Hershberg Ruth
Published: January 2023

The manner in which costs associated with antibiotic resistance mutations are alleviated through the acquisition of compensatory mutations has bearing on the dynamics of resistance accumulation and spread as well as on our more general understanding of the persistence of adaptive genotypes. Here, we combine evolutionary experiments, fitness analyses, and whole genome sequencing to examine the way compensation to alleviate costs associated with rifampicin resistance is achieved, both when resistance is fixed and when initial majorities of resistant cells are grown alongside susceptible cells. We found compensatory mutations to occur across all examined populations. However, compensation never fully alleviates the initial costs of resistance. In contrast to prevalent assumptions, compensatory mutations mostly occurred outside of the RNA polymerase core enzyme, which serves as the target of rifampicin. The target size for compensatory mutations appears to be high, as great variation exists in compensatory mutations, even within a single population. At the same time, the pathways of compensation are quite convergent, meaning that, across independent populations, we often observe compensatory mutations in the same loci and sometimes even observe the precise same compensatory mutations across populations.
Effects ofMAPTrs17649553 on Structural Network Integrity and Verbal Memory in Parkinson’s Disease
Authors: Chen Zhichun , Wu Bin , Li Guanglu , Zhou Liche , Zhang Lina , Liu Jun
Published: January 2023

Background

Currently, over 90 genetic loci have been found to be associated with Parkinson’s disease (PD) in genome-wide association studies, nevertheless, the effects of these genetic variants on the clinical features and brain structure of PD patients are largely unknown.

Objective

This study investigated the effects of microtubule-associated protein tau (MAPT), rs17649553 (C>T), a genetic variant associated with reduced PD risk, on the functional and structural networks of PD patients.

Methods

Totally 83 PD subjects from Parkinson’s Progression Markers Initiative database were included for this study. They all received structural and functional magnetic resonance imaging and whole exome sequencing. The effects ofMAPTrs17649553 on brain structural and functional networks were systematically assessed.

Results

MAPTrs17649553 T allele was associated with better verbal memory in PD patients. In addition,MAPTrs17649553 significantly reshaped the topology of gray matter covariance network and white matter network but not that of functional network. Both the network metrics in gray matter covariance network and white matter network were correlated with verbal memory, however, the mediation analysis showed that it was the small-worldness topology in white matter network that mediated the effects ofMAPTrs17649553 on verbal memory.

Conclusion

In sum, we proposed thatMAPTrs17649553 T allele was associated with superior structural network topology and better verbal memory in PD. Future studies are needed to determine the role ofMAPTrs17649553 in PD initiation and progression.
Adverse childhood trauma and reoccurrence of illness impact the gut microbiome, which affects suicidal behaviors and the phenome of major depression: towards enterotypic-phenotypes
Authors: Maes Michael , Vasupanrajit Asara , Jirakran Ketsupar , Klomkliew Pavit , Chanchaem Prangwalai , Tunvirachaisakul Chavit , Plaimas Kitiporn , Suratanee Apichat , Payungporn Sunchai
Published: January 2023

The first publication demonstrating that major depressive disorder (MDD) is associated with alterations in the gut microbiota appeared in 2008 (Maes et al., 2008). The purpose of the present study is to delineate a) the microbiome signature of the phenome of depression, including suicidal behaviours and cognitive deficits; the effects of adverse childhood experiences (ACE) and recurrence of illness index (ROI) on the microbiome; and the microbiome signature of lowered high-density lipoprotein cholesterol (HDLc).

We determined isometric log-ratio abundances or prevalence of gut microbiome phyla, genera, and species by analyzing stool samples from 37 healthy Thai controls and 32 MDD patients using 16S rDNA sequencing.

Six microbiome taxa accounted for 36% of the variance in the depression phenome, namelyHungatellaandFusicatenibacter(positive associations) andButyricicoccus, Clostridium, Parabacteroides merdae, andDesulfovibrio piger(inverse association). This profile (labeled enterotype 1) indicates compositional dysbiosis, is strongly predicted by ACE and ROI, and is linked to suicidal behaviours. A second enterotype was developed that predicted a decrease in HDLc and an increase in the atherogenic index of plasma (Bifidobacterium, P. merdae, andRomboutsia were positively associated, whileProteobacteriaandClostridium sensu strictowere negatively associated). Together, enterotypes 1 and 2 explained 40.4% of the variance in the depression phenome, and enterotype 1 in conjunction with HDLc explained 39.9% of the variance in current suicidal behaviours.

In conclusion, the microimmuneoxysome is a potential new drug target for the treatment of severe depression and suicidal behaviours, and possibly for the prevention of future episodes.
The fitness consequences of wildlife conservation translocations: a meta-analysis
Authors: Gross Iwo P. , Wilson Alan E. , Wolak Matthew E.
Published: January 2023

Conservation translocation is a common strategy to offset mounting rates of population declines through the transfer of captive-or wild-origin organisms into areas where conspecific populations are imperiled or completely extirpated. Translocations that supplement existing populations are referred to as reinforcements, and can be conducted using captive-origin animals (ex situreinforcements [ESR]) or wild-origin animals without any captive ancestry (in situreinforcement [ISR]). These programs have been criticized for low success rates and husbandry practices that produce individuals with genetic and performance deficits, but the post-release performance of captive-origin or wild-origin translocated groups has not been systematically reviewed to quantify success relative to wild-resident control groups. To assess the disparity in post-release performance of translocated organisms relative to wild-resident conspecifics and examine the association of performance disparity with organismal and methodological factors across studies, we conducted a systematic review and meta-analysis of 821 performance comparisons from 171 studies representing nine animal classes (101 species). We found that translocated organisms have 64% decreased odds of out-performing their wild-resident counterparts, supporting claims of systemic issues hampering conservation translocations. To help identify translocation practices that could maximize program success in the future, we further quantified the impact of broad organismal and methodological factors on the disparity between translocated and wild-resident conspecific performance. Pre-release animal enrichment significantly reduced performance disparities, whereas our results suggest no overall effects of taxonomic group, sex, captive generation time, or the type of fitness surrogate measured. This work is the most comprehensive systematic review to date of animal conservation translocations in which wild conspecifics were used as comparators, thereby facilitating an evaluation of the overall impact of this conservation strategy and identifying specific actions to increase success. Our review highlights the need for conservation managers to include both sympatric and allopatric wild-reference groups to ensure the post-release performance of translocated animals can be evaluated. Further, our analyses identify pre-release animal enrichment as a particular strategy for improving the outcomes of animal conservation translocations, and demonstrate how meta-analysis can be used to identify implementation choices that maximize translocated animal contributions to recipient population growth and viability.
Temporal physiological, transcriptomic and metabolomic analyses revealed molecular mechanism ofCanna indica’s response to Cr stress
Authors: Wei Zhao , Zhongbing Chen , Xiuqing Yang , Luying Sheng , Huan Mao , Sixi Zhu
Published: January 2023

Chromium (Cr) can interfere with plant gene expression, change the content of metabolites and affect plant growth. However, the molecular response mechanism of wetland plants at different time sequences under Cr stress has yet to be fully understood.The results showed that Cr stress increased the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX) and peroxidase (POD), the contents of glutathione (GSH), malondialdehyde (MDA), and oxygen free radical (ROS), and inhibited the biosynthesis of photosynthetic pigments, thus leading to changes in plant growth and biomass. that Cr stress mainly affected 12 metabolic pathways, involving 38 differentially expressed metabolites, including amino acids, phenylpropane, and flavonoids. A total of 16247 differentially expressed genes were identified, among which, at the early stage of stress,C. indicaresponds to Cr toxicity mainly through galactose, starch and sucrose metabolism. With the extension of stress time, plant hormone signal transduction and MAPK signaling pathway inC. indicain the treatment group were significantly affected. Finally, in the late stage of stress,C. indicaco-defuses Cr toxicity by activating its Glutathione metabolism and Phenylpropanoid biosynthesis. In conclusion, this study revealed the molecular response mechanism ofC. indicato Cr stress at different times through multi-omics methods.

Graphical Abstract
Using a Topic Model to Map and Analyze a Large Curriculum
Authors: Takizawa Peter A
Published: January 2023

A qualitative and quantitative understanding of curriculum content is critical for knowing whether it’s meeting its learning objectives. Curricula for medical education present challenges due to amount of content, the diversity of topics and the large number of contributing faculty. To create a manageable representation of the content in the pre-clerkship curriculum at Yale School of Medicine, a topic model was generated from all educational documents given to students during the pre-clerkship period. The model was used to quantitatively map content to school-wide competencies. The model measured how much of the curriculum addressed each topic and identified a new content area of interest, gender identity, whose coverage could be tracked over four years. The model also allowed quantitative measurement of integration of content within and between courses in the curriculum. The methods described here should be applicable to curricula in which texts can be extracted from materials.
Stochastic Transmission in Epidemiological Models
Authors: Albani Vinicius V.L. , Zubelli Jorge P.
Published: January 2023

Recent empirical evidence suggests that the transmission coefficient in susceptible-exposed-infected-removed-like (SEIR-like) models evolves with time, presenting random patterns, and some stylized facts, such as mean-reversion and jumps. To address such observations we propose the use of jump-diffusion stochastic processes to parameterize the transmission coefficient in an SEIR-like model that accounts for death and time-dependent parameters. We provide a detailed theoretical analysis of the proposed model proving the existence and uniqueness of solutions as well as studying its asymptotic behavior. We also compare the proposed model with some variations possibly including jumps. The forecast performance of the considered models, using reported COVID-19 infections from New York City, is then tested in different scenarios, including major outbreaks. The proposed jump-diffusion model presented remarkably accurate out-of-sample predictions, even during larger forecasted periods.
Daily exposure to PM2.5and 1.5 million deaths: A time-stratified case-crossover analysis in the Mexico City Metropolitan Area
Authors: Gutiérrez-Avila Iván , Riojas-Rodríguez Horacio , Colicino Elena , Rush Johnathan , Tamayo-Ortiz Marcela , Borja-Aburto Víctor Hugo , Just Allan C.
Published: January 2023

Background

Satellite-based PM2.5predictions are being used to advance exposure science and air-pollution epidemiology in developed countries; including emerging evidence about the impacts of PM2.5on acute health outcomes beyond the cardiovascular and respiratory systems, and the potential modifying effects from individual-level factors in these associations. Research on these topics is lacking in Latin America.

Methods

We used a time-stratified case-crossover study design with 1,479,950 non-accidental deaths from Mexico City Metropolitan Area for the period of 2004-2019. Daily 1x1 km PM2.5(median=23.4 μg/m3; IQR=13.6 μg/m3) estimates from our satellite-based regional model were employed for exposure assessment at the sub-municipality level. Associations between PM2.5with broad-category (organ-system) and cause-specific mortality outcomes were estimated with distributed lag conditional logistic models. We also fit models stratifying by potential individual-level effect modifiers including; age, sex, and individual SES-related characteristics namely: education, health insurance coverage, and job categories.

Results

PM2.5exposure was associated with higher total non-accidental, cardiovascular, cerebrovascular, respiratory, and digestive mortality. A 10-μg/m3PM2.5higher cumulative exposure over one week (lag06) was associated with higher cause-specific mortality outcomes including hypertensive disease [2.28% (95%CI: 0.26%–4.33%)], acute ischemic heart disease [1.61% (95%CI: 0.59%–2.64%)], other forms of heart disease [2.39% (95%CI: -0.35%–5.20%)], hemorrhagic stroke [3.63% (95%CI: 0.79%–6.55%)], influenza and pneumonia [4.91% (95%CI: 2.84%–7.02%)], chronic respiratory disease [2.49% (95%CI: 0.71%–4.31%)], diseases of the liver [1.85% (95%CI: 0.31%–3.41%)], and renal failure [3.48% (95%CI: 0.79%–6.24%)]. No differences in effect size of associations were observed between SES strata.

Conclusions

Exposure to PM2.5was associated with mortality outcomes beyond the cardiovascular and respiratory systems, including specific death-causes from the digestive and genitourinary systems, with no indications of effect modification by individual SES-related characteristics.
Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies
Authors: Zou Peng
Published: January 2023

There has been an increasing trend towards subcutaneous (SC) delivery of fusion proteins and monoclonal antibodies (mAbs) in recent years versus intravenous (IV) administration. The prediction of bioavailability is one of the major barriers in clinical translation of SC administered therapeutic proteins due to a lack of reliable in vitro and preclinical in vivo predictive models. In this study, we explored the relationships between human SC bioavailability and physicochemical or pharmacokinetic properties of 20 Fc-or albumin-fusion proteins and 98 monoclonal antibodies. An inverse linear correlation was observed between human SC bioavailability and human intravenous clearance (CL) or isoelectric point (pI). The bioavailability of fusion proteins is more correlated with pI while the bioavailability of mAbs is more correlated with CL. A mAbs with intravenous CL < 4 mL/day/kg is likely to have SC bioavailability > 60%. Multivariate regression models were developed using intravenous CL and pI of a training set (N = 59) as independent variables. The predictive models were validated with an independent test set (N = 33). A linear regression model resulted in 27 among 33 (82%) predictions within 0.8-to 1.2-fold deviations. Overall, this study demonstrated that CL- and pI-based multivariate regression models could be used to predict human SC bioavailability of fusion proteins and mAbs.
Dynamics of Innate Immune Response Due to Bacteria-Induced Pulpitis
Authors: Erdogan Ozge , Xia Jingya , Chiu Isaac M. , Gibbs Jennifer L.
Published: January 2023

Introduction

Pulpitis is associated with dental carries and can lead to irreversible pulp damage. As bacteria penetrate deeper into dentin and pulp tissue, a pulpal innate immune response is initiated. However, an understanding of the types of immune cells in the pulp, how this relates to bacterial infiltration, and the dynamics of the immune response during pulpitis is limited. As conserving the vitality of the pulp tissue through conservative therapies becomes an important part of dental practice, there is a greater need to understand the kinetics and composition of the immune response during pulpitis.

Methods

Dental pulp exposure in molars of mice was used as an animal model of pulpitis. To investigate the kinetics of immune response, pulp tissue was collected from permanent molars at different time points after injury (baseline, day 1, and day 7). Flow cytometry analysis of CD45+ leukoctyes including macrophages, T cells, neutrophils and monocytes was performed. 16S in situ hybridization captured bacterial invasion of the pulp, and immunohistochemistry for F4/80 investigated spatial and morphological changes of macrophages during pulpitis. Data were analyzed using two-way ANOVA with Tukey’s multiple comparisons.

Results

Bacteria mostly remained close to the injury site, with some expansion towards non-injured pulp horns. We found that F4/80+macrophages were the main immune cell population in healthy pulp. Upon injury, CD11b+Ly6Ghighneutrophils and CD11b+Ly6GintLy6Cintmonocytes constituted 70-90% of all immune populations up to 7 days after injury. Even though there was a slight increase in T cells at day 7, myeloid cells remained the main drivers of the immune response.

Conclusions

As bacteria proliferate within the pulp chamber, innate immune cells including macrophages, neutrophils and monocytes predominate as the major immune populations, with minimal signs of transitioning to an adaptive immune response.