bluuebunny/crossref_metadata_2025 huggingface dataset:
The testis, eunuchs, and testosterone: a historical review over the ages and around the world
Authors: Morgentaler Abraham , Hanafy Han M
Published: December 2023

Introduction

Testosterone therapy for men with testosterone deficiency is widely used, yet remains controversial. The rich and fascinating history of the testicles, including human castration, provides a valuable perspective on this important topic.

Objectives

This study reviewed the history of testosterone from antiquity to the modern day.

Methods

Primary sources consisted of books and relevant articles, augmented by a MEDLINE search using the key words “testis,” “testicles,” “castration,” “eunuchs,” “testosterone,” and “testicular function.”

Results

An early scientific observation was that castration reduced sexual development and activity, originating with domestication of animals approximately 10 000 years ago. Human castration appears in ancient Egyptian mythology more than 4000 years ago, in Greek mythology from 8th century BCE, and in the Bible. The history of eunuchs in China spanned 2000 years, beginning with the Hsia dynasty (2205-1766 BCE). The concept that the testicles produced some factor responsible for male sexual development and behavior was thus known throughout the world since the beginning of recorded history. Testosterone was isolated and synthesized in 1935 and was soon available as a treatment. Multiple benefits of testosterone therapy were apparent by 1940. Recent large, controlled testosterone studies have conclusively demonstrated sexual and general health benefits, with a strong safety profile.

Conclusion

Testosterone has been a known substance for <1% of the historical timeline, yet knowledge that the testes were responsible for male sexual development and behavior has been known since the beginning of recorded history. Today, modern evidence has demonstrated the importance of normal levels of testosterone for general health as well as sexual function and desire. Yet, testosterone therapy remains controversial. We believe this historical review provides a helpful perspective on this age-old issue.
Nurse Faculty Perceptions of External Factors Affecting Psychological Capital and Leadership Development
Authors: Singh Ashley
Published: December 2023

BACKGROUND

Psychological capital (PsyCap) is a higher order construct that includes four psychological capacities: hope, efficacy, resiliency, and optimism (known as HERO). PsyCap can be instrumental in navigating workplace challenges; it can be impeded by factors within the environment that may also impact intention to seek leadership development.

METHOD

A descriptive, qualitative study guided by Husserl’s descriptive phenomenology sought to explore faculty perceptions of the external factors of workload, organizational support, organizational resources, and incentive on PsyCap and intent to seek leadership development.

RESULTS

Analysis uncovered three themes: reset button, driving factors for seeking leadership development, and faculty as leaders.

CONCLUSION

External factors can either hinder or promote PsyCap and intent to seek leadership development. Constructs within PsyCap are critical for nursing faculty to achieve a “reset.” Organizations should offer resources or support to further foster PsyCap.
Potassium Leak Channels and Mitochondrial Complex I Interact in Glutamatergic Interneurons of the Mouse Spinal Cord
Authors: Woods Christian B. , Predoi Beatrice , Howe Miranda , Reczek Colleen R. , Kayser Ernst-Bernhard , Ramirez Jan-Marino , Morgan Philip G. , Sedensky Margaret M.
Published: December 2023

Background

Volatile anesthetics induce hyperpolarizing potassium currents in spinal cord neurons that may contribute to their mechanism of action. They are induced at lower concentrations of isoflurane in noncholinergic neurons from mice carrying a loss-of-function mutation of the Ndufs4 gene, required for mitochondrial complex I function. The yeast NADH dehydrogenase enzyme, NDi1, can restore mitochondrial function in the absence of normal complex I activity, and gain-of-function Ndi1 transgenic mice are resistant to volatile anesthetics. The authors tested whether NDi1 would reduce the hyperpolarization caused by isoflurane in neurons from Ndufs4 and wild-type mice. Since volatile anesthetic behavioral hypersensitivity in Ndufs4 is transduced uniquely by glutamatergic neurons, it was also tested whether these currents were also unique to glutamatergic neurons in the Ndufs4 spinal cord.

Methods

Spinal cord neurons from wild-type, NDi1, and Ndufs4 mice were patch clamped to characterize isoflurane sensitive currents. Neuron types were marked using fluorescent markers for cholinergic, glutamatergic, and γ-aminobutyric acid–mediated (GABAergic) neurons. Norfluoxetine was used to identify potassium channel type. Neuron type–specific Ndufs4 knockout animals were generated using type-specific Cre-recombinase with floxed Ndufs4.

Results

Resting membrane potentials (RMPs) of neurons from NDi1;Ndufs4, unlike those from Ndufs4, were not hyperpolarized by 0.6% isoflurane (Ndufs4, ΔRMP –8.2 mV [–10 to –6.6]; P = 1.3e-07; Ndi1;Ndufs4, ΔRMP –2.1 mV [–7.6 to +1.4]; P = 1). Neurons from NDi1 animals in a wild-type background were not hyperpolarized by 1.8% isoflurane (wild-type, ΔRMP, –5.2 mV [–7.3 to –3.2]; P = 0.00057; Ndi1, ΔRMP, 0.6 mV [–1.7 to 3.2]; P = 0.68). In spinal cord slices from global Ndufs4 animals, holding currents (HC) were induced by 0.6% isoflurane in both GABAergic (ΔHC, 81.3 pA [61.7 to 101.4]; P = 2.6e-05) and glutamatergic (ΔHC, 101.2 pA [63.0 to 146.2]; P = 0.0076) neurons. In neuron type–specific Ndufs4 knockouts, HCs were increased in cholinergic (ΔHC, 119.5 pA [82.3 to 156.7]; P = 0.00019) and trended toward increase in glutamatergic (ΔHC, 85.5 pA [49 to 126.9]; P = 0.064) neurons but not in GABAergic neurons.

Conclusions

Bypassing complex I by overexpression of NDi1 eliminates increases in potassium currents induced by isoflurane in the spinal cord. The isoflurane-induced potassium currents in glutamatergic neurons represent a potential downstream mechanism of complex I inhibition in determining minimum alveolar concentration.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Oral anti-coagulants use in Chinese hospitalized patients with atrial fibrillation
Authors: Lin Jing , Long Deyong , Jiang Chenxi , Sang Caihua , Tang Ribo , Li Songnan , Wang Wei , Guo Xueyuan , Ning Man , Sun Zhaoqing , Yang Na , Hao Yongchen , Liu Jun , Liu Jing , Du Xin , Morgan Louise , Fonarow Gregg C. , Smith Sidney C. , Lip Gregory Y.H. , Zhao Dong , Dong Jianzeng , Ma Changsheng ,   On behalf of CCC-AF investigators
Published: December 2023

Background:

Oral anti-coagulants (OAC) are the intervention for the prevention of stroke, which consistently improve clinical outcomes and survival among patients with atrial fibrillation (AF). The main purpose of this study is to identify problems in OAC utilization among hospitalized patients with AF in China.

Methods:

Using data from the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation (CCC-AF) registry, guideline-recommended OAC use in eligible patients was assessed.

Results:

A total of 52,530 patients with non-valvular AF were enrolled from February 2015 to December 2019, of whom 38,203 were at a high risk of stroke, 9717 were at a moderate risk, and 4610 were at a low risk. On admission, only 20.0% (6075/30,420) of patients with a diagnosed AF and a high risk of stroke were taking OAC. The use of pre-hospital OAC on admission was associated with a lower risk of new-onset ischemic stroke/transient ischemic attack among the diagnosed AF population (adjusted odds ratio: 0.54, 95% confidence interval: 0.43–0.68; P <0.001). At discharge, the prescription rate of OAC was 45.2% (16,757/37,087) in eligible patients with high stroke risk and 60.7% (2778/4578) in eligible patients with low stroke risk. OAC utilization in patients with high stroke risk on admission or at discharge both increased largely over time (all P <0.001). Multivariate analysis showed that OAC utilization at discharge was positively associated with in-hospital rhythm control strategies, including catheter ablation (adjusted odds ratio [OR] 11.63, 95% confidence interval [CI] 10.04–13.47; P <0.001), electronic cardioversion (adjusted OR 2.41, 95% CI 1.65–3.51; P <0.001), and anti-arrhythmic drug use (adjusted OR 1.45, 95% CI 1.38–1.53; P <0.001).

Conclusions:

In hospitals participated in the CCC-AF project, >70% of AF patients were at a high risk of stroke. Although poor performance on guideline-recommended OAC use was found in this study, over time the CCC-AF project has made progress in stroke prevention in the Chinese AF population.Registration:ClinicalTrials.gov, NCT02309398.
Family Planning Experiences and Challenges of Mohs Fellowship Trainees
Authors: Kuo Alyce M. , Dusza Stephen W. , Minkis Kira , Pugliano-Mauro Melissa , Stevenson Mary , Yu Siegrid , Lee Erica H.
Published: December 2023

BACKGROUND

There is a paucity of literature describing family planning challenges faced by Mohs fellows.

OBJECTIVE

To characterize perceptions about and experiences with family planning, fertility, lactation, and parental leave and identify ways to support parental health and family planning for Mohs fellows.

MATERIALS AND METHODS

A voluntary, anonymous survey was distributed to Mohs surgeons who recently completed fellowship.

RESULTS

In total, 116 Mohs surgeons completed the survey. Their mean age was 34.5 years old, and more were female (n = 81, 69.8%) than male (n = 35, 30.2%). Most had children before completion of their Mohs training (n = 73, 62.9%). The most significant barrier to having children during fellowship was “loss of education or training time.” Over 20% (n = 23) of respondents or their partner had experienced infertility. Half of the 20 respondents (n = 10) who breastfed or pumped did not have a convenient place to do so.

CONCLUSION

This study elucidates trainee perceptions and gaps in parental support for Mohs fellowship trainees. In addition, barriers to implementing a universal family planning policy in Mohs surgery are discussed.
The Mas-related G protein–coupled receptor d (Mrgprd) mediates pain hypersensitivity in painful diabetic neuropathy
Authors: George Dale S. , Jayaraj Nirupa D. , Pacifico Paola , Ren Dongjun , Sriram Nikhil , Miller Rachel E. , Malfait Anne-Marie , Miller Richard J. , Menichella Daniela Maria
Published: December 2023

Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. Painful diabetic neuropathy is characterized by neuropathic pain accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability, axonal degeneration, and changes in cutaneous innervation. However, the complete molecular profile underlying the hyperexcitable cellular phenotype of DRG nociceptors in PDN has not been elucidated. This gap in our knowledge is a critical barrier to developing effective, mechanism-based, and disease-modifying therapeutic approaches that are urgently needed to relieve the symptoms of PDN. Using single-cell RNA sequencing of DRGs, we demonstrated an increased expression of the Mas-related G protein–coupled receptor d (Mrgprd) in a subpopulation of DRG neurons in the well-established high-fat diet (HFD) mouse model of PDN. Importantly, limiting Mrgprd signaling reversed mechanical allodynia in the HFD mouse model of PDN. Furthermore, in vivo calcium imaging allowed us to demonstrate that activation of Mrgprd-positive cutaneous afferents that persist in diabetic mice skin resulted in an increased intracellular calcium influx into DRG nociceptors that we assess in vivo as a readout of nociceptors hyperexcitability. Taken together, our data highlight a key role of Mrgprd-mediated DRG neuron excitability in the generation and maintenance of neuropathic pain in a mouse model of PDN. Hence, we propose Mrgprd as a promising and accessible target for developing effective therapeutics currently unavailable for treating neuropathic pain in PDN.
Increased risk of persistent neuropathic pain after traumatic nerve injury and surgery for carriers of a human leukocyte antigen haplotype
Authors: Miclescu Adriana , Rönngren Clara , Bengtsson Mats , Gordh Torsten , Hedin Anders
Published: December 2023

It is not known why some patients develop persistent pain after nerve trauma while others do not. Among multiple risk factors for the development of persistent posttrauma and postsurgical pain, a neuropathic mechanism due to iatrogenic nerve lesion has been proposed as the major cause of these conditions. Because there is some evidence that the human leukocyte antigen (HLA) system plays a role in persistent postsurgical pain, this study aimed to identify the genetic risk factors, specifically among HLA loci, associated with chronic neuropathic pain after traumatic nerve injuries and surgery in the upper extremities. Blood samples were taken to investigate the contribution of HLA alleles (ie, HLA-A, HLA-B, HLA-DRB1, HLA-DQB1, and HLA-DPB1) in a group of patients with persistent neuropathic pain (n = 70) and a group of patients with neuropathy without pain (n = 61). All subjects had intraoperatively verified nerve damage in the upper extremity. They underwent bedside clinical neurological examination to identify the neuropathic pain component according to the present grading system of neuropathic pain. Statistical analyses on the allele and haplotype were conducted using the BIGDAWG package. We found that the HLA haplotype A*02:01-B*15:01-C*03:04-DRB1*04:01-DQB1*03:02 was associated with an increased risk of developing persistent neuropathic pain in the upper extremity (OR = 9.31 [95% CI 1.28-406.45], P < 0.05). No significant associations were found on an allele level when correcting for multiple testing. Further studies are needed to investigate whether this association is on a haplotypic level or if certain alleles may be causing the association.
Identifying Barriers and Facilitators to Veterans Affairs Whole Health Integration Using the Updated Consolidated Framework for Implementation Research
Authors: Kimpel Christine C. , Myer Elizabeth Allen , Cupples Anagha , Roman Jones Joanne , Seidler Katie J. , Rick Chelsea K. , Brown Rebecca , Rawlins Caitlin , Hadler Rachel , Tsivitse Emily , Lawlor Mary Ann C. , Ratcliff Amy , Holt Natalie R. , Callaway-Lane Carol , Godwin Kyler , Ecker Anthony H.
Published: December 2023

Background:

Veterans Affairs (VA) implemented the Veteran-centered Whole Health System initiative across VA sites with approaches to implementation varying by site.

Purpose:

Using the Consolidated Framework for Implementation Research (CFIR), we aimed to synthesize systemic barriers and facilitators to Veteran use with the initiative. Relevance to healthcare quality, systematic comparison of implementation procedures across a national healthcare system provides a comprehensive portrait of strengths and opportunities for improvement.

Methods:

Advanced fellows from 11 VA Quality Scholars sites performed the initial data collection, and the final report includes CFIR-organized results from six sites.

Results:

Key innovation findings included cost, complexity, offerings, and accessibility. Inner setting barriers and facilitators included relational connections and communication, compatibility, structure and resources, learning centeredness, and information and knowledge access. Finally, results regarding individuals included innovation deliverers, implementation leaders and team, and individual capability, opportunity, and motivation to implement and deliver whole health care.

Discussion and implications:

Examination of barriers and facilitators suggest that Whole Health coaches are key components of implementation and help to facilitate communication, relationship building, and knowledge access for Veterans and VA employees. Continuous evaluation and improvement of implementation procedures at each site is also recommended.
Procedural Insights and Clinical Outcomes of a Novel Superior Vena Cava Occlusion Device for Acute Heart Failure: A Single-Center Experience
Authors: Yousefzai Rayan , Patel Kelsey , Barr Deborah , Kapur Navin K. , Bhimaraj Arvind
Published: December 2023

The preCARDIA system is a device combining a balloon-mounted catheter and an extracorporeal system designed for intermittent occlusion of the superior vena cava. Studies have established safety and efficacy in acute decompensated heart failure. We present a single-center experience detailing 90 days outcomes and procedural insights. A 24 hours therapy session demonstrated reduced pulmonary wedge pressures and increased urine output, with cardiac output remaining unchanged. There was one readmission and no heart failure-related readmissions at 90 days. The preCARDIA device appears to be a safe mechanical diuretic strategy to manage patients with acute decompensated heart failure beyond current therapeutic strategies.
The Influence of Preoperative Waiting Time on Anxiety and Pain Levels in Outpatient Surgery for Breast Diseases
Authors: Wu Bei , Wang Han-Jin , Yang Xiu-Pin , Zhong Zhen-Hua
Published: December 2023

Objective

This study aims to examine the effects of different preoperative waiting times on anxiety and pain levels in patients undergoing outpatient surgery for breast diseases, providing insights for clinical interventions during the perioperative phase.

Methods

Patients who underwent outpatient surgery at a hospital breast center in Ningbo between January 2021 and December 2021 were selected. Their anxiety levels at the time when they entered the preoperative preparation room and when they ended the postoperative waiting period for the rapid frozen section procedure were assessed using the State Anxiety Inventory (S-AI) questionnaire, and their pain levels at the end of the postoperative waiting period were assessed using the short-form McGill Pain Questionnaire. The patients enrolled were divided into 3 groups according to the preoperative waiting time: <2 hours (T1 group), 2 to 4 hours (T2 group), and >4 hours (T3 group); there were 150 patients in each group, and the anxiety and pain levels were compared between the groups.

Results

At the time of entering the preoperative preparation room, patients’ S-AI score T1 = T2 (P > 0.05), both T1 and T2 < T3 (P < 0.05); however, at the time of the postoperative waiting period, patients’ S-AI score was T1 < T2 < T3 (P < 0.05), and the postoperative waiting period patients’ short-form McGill Pain Questionnaire scores were T1 = T2 < T3 (P < 0.05).

Conclusions

The perioperative anxiety and pain levels of patients undergoing outpatient breast surgery increased with the prolongation of preoperative waiting time; 4 hours was the critical time point for change, after which the anxiety and pain levels of patients increased significantly.
Enhancing Pressure Injury Surveillance Using Natural Language Processing
Authors: Milliren Carly E. , Ozonoff Al , Fournier Kerri A. , Welcher Jennifer , Landschaft Assaf , Kimia Amir A.
Published: December 2023

Objective

This study assessed the feasibility of nursing handoff notes to identify underreported hospital-acquired pressure injury (HAPI) events.

Methods

We have established a natural language processing–assisted manual review process and workflow for data extraction from a corpus of nursing notes across all medical inpatient and intensive care units in a tertiary care pediatric center. This system is trained by 2 domain experts. Our workflow started with keywords around HAPI and treatments, then regular expressions, distributive semantics, and finally a document classifier. We generated 3 models: a tri-gram classifier, binary logistic regression model using the regular expressions as predictors, and a random forest model using both models together. Our final output presented to the event screener was generated using a random forest model validated using derivation and validation sets.

Results

Our initial corpus involved 70,981 notes during a 1-year period from 5484 unique admissions for 4220 patients. Our interrater human reviewer agreement on identifying HAPI was high (κ= 0.67; 95% confidence interval [CI], 0.58–0.75). Our random forest model had 95% sensitivity (95% CI, 90.6%–99.3%), 71.2% specificity (95% CI, 65.1%–77.2%), and 78.7% accuracy (95% CI, 74.1%–83.2%). A total of 264 notes from 148 unique admissions (2.7% of all admissions) were identified describing likely HAPI. Sixty-one described new injuries, and 64 describe known yet possibly evolving injuries. Relative to the total patient population during our study period, HAPI incidence was 11.9 per 1000 discharges, and incidence rate was 1.2 per 1000 bed-days.

Conclusions

Natural language processing–based surveillance is proven to be feasible and high yield using nursing handoff notes.
Longitudinal Magnetic Resonance Imaging–Based Superficial Femoral Artery Velocity Measurements in Diabetic and Nondiabetic Patients With Peripheral Artery Disease
Authors: Sinharoy Ankita , Reddy Neeti , Lin John Kent , Nambi Vijay , Yang Eric Y. , Kougias Panagiotis , Taylor Addison A. , Lumsden Alan B. , Ballantyne Christie M. , Brunner Gerd
Published: December 2023

Background:

Longitudinal associations of noninvasive 2-dimensional phase-contrast magnetic resonance imaging (2D-PC-MRI) velocity markers of the superficial femoral artery (SFA) were analyzed along with the characteristics of peripheral artery disease (PAD). We hypothesized that the 2-year differences in MRI-based measures of SFA velocity were associated with longitudinal changes in markers of PAD.

Methods:

A total of 33 (11 diabetic, 22 nondiabetic) patients with PAD with baseline and 2-year follow-up MRI scans were included in this secondary analysis of the Effect of Lipid Modification on Peripheral Artery Disease after Endovascular Intervention Trial (ELIMIT). Electrocardiographically gated 2D-PC-MRI was performed at a proximal and a distal location of the distal SFA territory. SFA lumen, wall, and total vessel volumes and the normalized wall index (NWI) were analyzed.

Results:

Baseline characteristics did not differ between diabetic and nondiabetic PAD patients. Maximum proximal and distal SFA velocity measures did not differ between baseline and 2 years (41.98 interquartile range (IQR) (23.58–72.6) cm/s vs. 40.31 IQR (26.69–61.29) cm/s; P = 0.30). Pooled analysis (N = 33) showed that the 24-month change in the NWI was inversely associated with the 24-month change in the proximal maximal SFA velocity (beta = −168.36, R2 = 0.150, P value = 0.03). The 24-month change of the maximum velocity differences between the proximal and distal SFA locations was inversely associated with the 24-month changes in peak walking distance (beta = −0.003, R2 = 0.360, P value = 0.011).

Conclusion:

The 2-year change of SFA plaque burden is inversely associated with the 2-year change of proximal peak SFA blood flow velocity. 2D-PC-MRI measured SFA velocity may be of interest in assessing PAD longitudinally.
What Medical-Legal Partnerships can do for Trauma Patients and Trauma Care
Authors: Alur Rucha , Hall Erin , Smith MJ , Zakrison Tanya , Loughran Carly , Cosey-Gay Franklin , Kaufman Elinore
Published: December 2023

Trauma patients are particularly vulnerable to the impact of pre-existing social and legal determinants of health post-injury. Trauma patients have a wide range of legal needs, including housing, employment, debt, insurance coverage, and access to federal and state benefits. Legal support could provide vital assistance to address the social determinants of health for injured patients. Medical Legal Partnerships (MLPs) embed legal professionals within healthcare teams to improve health by addressing legal needs that affect health. MLPs have a successful track record in oncology, HIV/AIDS, and pediatrics, but have been little used in trauma. We conducted a scoping review to describe the role of MLPs and their potential to improve health outcomes for patients with traumatic injuries. We found that MLPs use legal remedies to address a variety of social and structural conditions that could affect patient health across several patient populations, such as children with asthma and patients with cancer. Legal intervention can assist patients in obtaining stable and healthy housing, employment opportunities, debt relief, access to public benefits, and immigration assistance. MLP structure varies across institutions. In some, MLP lawyers are employed directly by a healthcare institution. In others, MLPs function as partnerships between a health system and an external legal organization. MLPs have been found to reduce hospital readmissions, increase treatment utilization by patients, decrease patient stress levels, and benefit health systems financially. This scoping review outlines the potential of MLPs to improve outcomes for injured patients. Establishing trauma-focused MLPs could be a feasible intervention for trauma centers around the country seeking to improve health outcomes and reduce disparities for injured patients.
Empiric Cryoprecipitate Transfusion in Patients with Severe Hemorrhage: Results from the US Experience in the International CRYOSTAT-2 Trial
Authors: Van Gent Jan-Michael , Kaminski Carter W , Praestholm Caroline , Pivalizza Evan G , Clements Thomas W , Kao Lillian S , Stanworth Simon , Brohi Karim , Cotton Bryan A
Published: December 2023

BACKGROUND:

Hypofibrinogenemia has been shown to predict massive transfusion and is associated with higher mortality in severely injured patients. However, the role of empiric fibrinogen replacement in bleeding trauma patients remains controversial. We sought to determine the effect of empiric cryoprecipitate as an adjunct to a balanced transfusion strategy (1:1:1).

STUDY DESIGN:

This study is a subanalysis of patients treated at the single US trauma center in a multicenter randomized controlled trial. Trauma patients (more than 15 years) were eligible if they had evidence of active hemorrhage requiring emergent surgery or interventional radiology, massive transfusion protocol (MTP) activation, and received at least 1 unit of blood. Transfer patients, those with injuries incompatible with life, or those injured more than 3 hours earlier were excluded. Patients were randomized to standard MTP (STANDARD) or MTP plus 3 pools of cryoprecipitate (CRYO). Primary outcomes included all-cause mortality at 28 days. Secondary outcomes were transfusion requirements, intraoperative and postoperative coagulation laboratory values, and quality-of-life measures (Glasgow outcome score-extended).

RESULTS:

Forty-nine patients (23 in the CRYO group and 26 in the STANDARD group) were enrolled between May 2021 and October 2021. Time to randomization was similar between groups (14 vs 24 minutes, p = 0.676). Median time to cryoprecipitate was 41 minutes (interquartile range 37 to 48). There were no differences in demographics, arrival physiology, laboratory values, or injury severity. Intraoperative and ICU thrombelastography values, including functional fibrinogen, were similar between groups. There was no benefit to CRYO with respect to post-emergency department transfusions (intraoperative and ICU through 24 hours), complications, Glasgow outcome score, or mortality.

CONCLUSIONS:

In this study of severely injured, bleeding trauma patients, empiric cryoprecipitate did not improve survival or reduce transfusion requirements. Cryoprecipitate should continue as an “on-demand” addition to a balanced transfusion strategy, guided by laboratory values and should not be given empirically.
Cell-type specific molecular signatures of aging revealed in a brain-wide transcriptomic cell-type atlas
Authors: Jin Kelly , Yao Zizhen , van Velthoven Cindy T. J. , Kaplan Eitan S. , Glattfelder Katie , Barlow Samuel T. , Boyer Gabriella , Carey Daniel , Casper Tamara , Chakka Anish Bhaswanth , Chakrabarty Rushil , Clark Michael , Departee Max , Desierto Marie , Gary Amanda , Gloe Jessica , Goldy Jeff , Guilford Nathan , Guzman Junitta , Hirschstein Daniel , Lee Changkyu , Liang Elizabeth , Pham Trangthanh , Reding Melissa , Ronellenfitch Kara , Ruiz Augustin , Sevigny Josh , Shapovalova Nadiya , Shulga Lyudmila , Sulc Josef , Torkelson Amy , Tung Herman , Levi Boaz , Sunkin Susan M. , Dee Nick , Esposito Luke , Smith Kimberly , Tasic Bosiljka , Zeng Hongkui
Published: December 2023

Biological aging can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Aging is a complex and dynamic process which influences distinct cell types in a myriad of ways. The cellular architecture of the mammalian brain is heterogeneous and diverse, making it challenging to identify precise areas and cell types of the brain that are more susceptible to aging than others. Here, we present a high-resolution single-cell RNA sequencing dataset containing ∼1.2 million high-quality single-cell transcriptomic profiles of brain cells from young adult and aged mice across both sexes, including areas spanning the forebrain, midbrain, and hindbrain. We find age-associated gene expression signatures across nearly all 130+ neuronal and non-neuronal cell subclasses we identified. We detect the greatest gene expression changes in non-neuronal cell types, suggesting that different cell types in the brain vary in their susceptibility to aging. We identify specific, age-enriched clusters within specific glial, vascular, and immune cell types from both cortical and subcortical regions of the brain, and specific gene expression changes associated with cell senescence, inflammation, decrease in new myelination, and decreased vasculature integrity. We also identify genes with expression changes across multiple cell subclasses, pointing to certain mechanisms of aging that may occur across wide regions or broad cell types of the brain. Finally, we discover the greatest gene expression changes in cell types localized to the third ventricle of the hypothalamus, including tanycytes, ependymal cells, andTbx3+ neurons found in the arcuate nucleus that are part of the neuronal circuits regulating food intake and energy homeostasis. These findings suggest that the area surrounding the third ventricle in the hypothalamus may be a hub for aging in the mouse brain. Overall, we reveal a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal aging that will serve as a foundation for the investigation of functional changes in the aging process and the interaction of aging and diseases.
Using computational approaches to enhance the interpretation of missense variants in thePAX6gene
Authors: Andhika Nadya S. , Biswas Susmito , Hardcastle Claire , Green David , Ramsden Simon C. , Birney Ewan , Black Graeme C. , Sergouniotis Panagiotis I.
Published: December 2023

Purpose

ThePAX6gene encodes a highly-conserved transcription factor involved in eye development. Heterozygous loss-of-function variants inPAX6can cause a range of ophthalmic disorders including aniridia. A key molecular diagnostic challenge is that manyPAX6missense changes are presently classified as variants of uncertain significance. While computational tools can be used to assess the effect of genetic alterations, the accuracy of their predictions varies. Here, we evaluated and optimised the performance of computational prediction tools in relation toPAX6missense variants.

Methods

Through inspection of publicly available resources (including HGMD, ClinVar, LOVD and gnomAD), we identified 241PAX6missense variants that were used for model training and evaluation. The performance of ten commonly-used computational tools was assessed and a threshold optimization approach was utilized to determine optimal cut-off values. Validation studies were subsequently undertaken usingPAX6variants from a local database.

Results

AlphaMissense, SIFT4G and REVEL emerged as the best-performing predictors; the optimized thresholds of these tools were 0.967, 0.025, and 0.772, respectively. Combining the prediction from these top-three tools resulted in lower performance compared to using AlphaMissense alone.

Conclusion

Tailoring the use of computational tools by employing optimized thresholds specific toPAX6can enhance algorithmic performance. Our findings have implications forPAX6variant interpretation in clinical settings.
A community-based participatory research approach to the development, refinement, and distribution of Test-to-PrEP: A peer-to-peer distributed at-home HIV self-test and prevention information kit in Miami-Dade, Florida
Authors: Butts Stefani , Rodriguez Edda , Craker Lacey , Johnson Ariana L. , Whiteside Patrick , Blackmon Jakisha , Kenya Sonjia , Kanamori Mariano , Doblecki-Lewis Susanne
Published: December 2023

In the US, there is a need for interventions that address gaps in awareness, interest, and uptake of HIV testing and biomedical HIV prevention strategies, such as pre-exposure prophylaxis and non-occupational post-exposure prophylaxis. The Test-to-PrEP intervention; an HIV self-test bundled with prevention information that was distributed via a social network strategy, was found to be effective at bridging said gaps. This manuscript presents the development and design of Test-to-PrEP, in which a community-based participatory research approach was used.

The intervention combines peer-to-peer distribution of HIV self-testing kits with tailored HIV prevention education. Key features include culturally sensitive educational materials, a strategic emphasis on the connection between intervention distributors and recipients, and rigorous training protocols.

Our process led to the creation of materials that were neutral to sexual identity, highlighting the importance of inclusivity and cultural relevance. It also led to a mechanism that allows enhanced network member selection. Stakeholder guidance ensured the initiative was well-aligned with community needs, enhancing its potential acceptability and effectiveness.

By centering community needs and cultural nuances, interventions like Test-to-PrEP can potentially increase their reach and efficacy. Our development process underscores the importance of community engagement, cultural relevance, and well-defined reporting.
Projecting trends in the disease burden of adult edentulism in China between 2020 and 2030: a systematic study based on the global burden of disease
Authors: Qin Xiaofeng , Chen Li , Yuan Xihua , Lin Dan , Liu Qiulin , Zeng Xiaojuan , Ma Fei
Published: December 2023

PURPOSE

This study was based on the Global Burden of Disease (GBD) database and aimed to analyze the trend of disease burden for edentulism in Chinese adults between 1990 and 2030, and to provide valuable information for the development of more effective management and preventive measures.

METHODS

Data on Chinese adults with edentulism from 1990 to 2019 was analyzed using GHDx data. Descriptive analyses were used to analyze changes in the prevalence and burden of edentulism, gender and age distribution between 1990 and 2019. In addition, we used an autoregressive integrated moving average (ARIMA) model to predict the trend of disease burden for Chinese adults with edentulism between 2020 and 2030.

RESULTS

The incidence, prevalence, and rate of YLDs in adults with edentulism in China showed an increasing trend from 1990 to 2019. In 2019, the incidence was 251.20 per 100,000, the prevalence was 4512.78 per 100,000, and the YLDs were 123.44 per 100,000, marking increases of 20.58%, 94.18%, and 93.12% from 1990. Males experienced a higher increase than females. However, the standardized rates decreased over the same period. The ARIMA model predicts a subsequent upward and then downward trend for all indicators between 2019 and 2030, except for the standardized incidence rate which remained essentially unchanged. Specifically, the incidence is predicted to decrease from 388.93 to 314.40 per 100,000, prevalence from 4512.78 to 3049.70 per 100,000, and YLDs from 123.44 to 103.44 per 100,000. The standardized prevalence and YLDs rates are also expected to decrease.

CONCLUSION

The burden of edentulism in China is projected to show an increasing trend from 2020 to 2022 and a decreasing trend from 2023 to 2030. Despite the decline in the burden of disease associated with edentulism in China, many problems remain to be solved.
Evaluation of imputation performance of multiple reference panels in a Pakistani population
Authors: Xu Jiayi , Liu Dongjing , Hassan Arsalan , Genovese Giulio , Cote Alanna C. , Fennessy Brian , Cheng Esther , Charney Alexander W. , Knowles James A. , Ayub Muhammad , Peterson Roseann E. , Bigdeli Tim B. , Huckins Laura M.
Published: December 2023

Genotype imputation is crucial for GWAS, but reference panels and existing benchmarking studies prioritize European individuals. Consequently, it is unclear which publicly available reference panel should be used for Pakistani individuals, and whether ancestry composition or sample size of the panel matters more for imputation accuracy. Our study compared different reference panels to impute genotype data in 1814 Pakistani individuals, finding the best performance balancing accuracy and coverage with meta-imputation with TOPMed and the expanded 1000 Genomes (ex1KG) reference. Imputation accuracy of ex1KG outperformed TOPMed despite its 30-fold smaller sample size, supporting efforts to create future panels with diverse populations.
Automated self-service cohort selection for large-scale population sciences and observational research: The California Teachers Study Researcher Platform
Authors: Lacey James V. , Spielfogel Emma S. , Benbow Jennifer L. , Savage Kristen E. , Lin Kai , Anderson Cheryl A.M. , Clague-DeHart Jessica , Duffy Christine N. , Martinez Maria Elena , Park Hannah Lui , Thompson Caroline A. , Wang Sophia S. , Chandra Sandeep
Published: December 2023

Objective

Cohort selection is ubiquitous and essential, but manual and ad hoc approaches are time-consuming, labor-intense, and difficult to scale. We sought to automate the task of cohort selection by building self-service tools that enable researchers to independently generate datasets for population sciences research.

Materials and Methods

The California Teachers Study (CTS) is a prospective observational study of 133,477 women who have been followed continuously since 1995. The CTS includes extensive survey-based and real-world data from cancer, hospitalization, and mortality linkages. We curated data from our data warehouse into a column-oriented database and developed a researcher-facing web application that guides researchers through the project lifecycle; captures researchers’ inputs; and automatically generates custom and analysis-ready data, code, dictionaries, and documentation.

Results

Researchers can register, access data, and propose projects on the CTS Researcher Platform via our CTS website. The Platform supports cohort and cross-sectional study designs for cancer, mortality, and any other ICD-based phenotypes or endpoints. User-friendly prompts and menus capture analytic design, inclusion/exclusion criteria, endpoint definitions, censoring rules, and covariate selection. Our platform empowers researchers everywhere to query, choose, review, and automatically and quickly receive custom data, analytic scripts, and documentation for their research projects. Research teams can review, revise, and update their choices anytime.

Discussion

We replaced inefficient traditional cohort-selection processes with an integrated self-service approach that simplifies and improves cohort selection for all stakeholders. Compared with manual methods, our solution is faster and more scalable, user-friendly, and collaborative. Other studies could re-configure our individual database, project-tracking, website, and data-delivery components for their own specific needs, or they could utilize other widely available solutions (e.g., alternative database or project-tracking tools) to enable similarly automated cohort-selection in their own settings. Our comprehensive and flexible framework could be adopted to improve cohort selection in other population sciences and observational research settings.
Progress Update for the Multisite Optical Genome Mapping Evaluation and Validation Study: Prenatal Applications
Authors: Levy Brynn , Liu Jie , Iqbal M Anwar , DuPont Barbara , Sahajpal Nikhil , Ho Monique , Yu Jingwei , Brody Sam J. , Mason-Suares Heather , Ganapathi Mythily , Rajkovic Aleksandar , Smolarek Teresa A. , Toydemir Reha M. , Bui Peter , Kolhe Ravindra , Stevenson Roger E.
Published: December 2023

Optical genome mapping (OGM) is an emerging technology with great potential for prenatal diagnosis. OGM can identify and resolve all types of balanced and unbalanced cytogenomic abnormalities in a single test, which are typically assessed by multiple standard of care (SOC) methods including karyotyping, fluorescence in situ hybridization and chromosomal microarray.

To assess OGM’s viability as an alternative to conventional SOC testing, a comprehensive clinical research study was conducted across multiple sites, operators, and instruments to evaluate its accuracy and clinical utility. This report provides an update for the phase 2 results of the ongoing multisite evaluation and validation study evaluating OGM for prenatal applications. In phase 1, 123 prenatal cases were assessed by OGM, and in phase 2, 219 retrospective and prospective prenatal cases have been evaluated. For 71% of cases, at least two SOC tests were performed. The study found that OGM had an overall accuracy of 99.6% and positive predictive value of 100% when compared to all cytogenetic SOC results.

With its standardized workflow, cost-effectiveness, and high-resolution cytogenomic analysis, OGM shows great promise as an alternative technology that uses a single assay to consolidate the multiple SOC tests usually used for prenatal cytogenetic diagnosis.
Using Generative Artificial Intelligence to Classify Primary Progressive Aphasia from Connected Speech
Authors: Rezaii Neguine , Quimby Megan , Wong Bonnie , Hochberg Daisy , Brickhouse Michael , Touroutoglou Alexandra , Dickerson Bradford C. , Wolff Phillip
Published: December 2023

Neurodegenerative dementia syndromes, such as Primary Progressive Aphasias (PPA), have traditionally been diagnosed based in part on verbal and nonverbal cognitive profiles. Debate continues about whether PPA is best subdivided into three variants and also regarding the most distinctive linguistic features for classifying PPA variants. In this study, we harnessed the capabilities of artificial intelligence (AI) and natural language processing (NLP) to first perform unsupervised classification of concise, connected speech samples from 78 PPA patients. Large Language Models discerned three distinct PPA clusters, with 88.5% agreement with independent clinical diagnoses. Patterns of cortical atrophy of three data-driven clusters corresponded to the localization in the clinical diagnostic criteria. We then used NLP to identify linguistic features that best dissociate the three PPA variants. Seventeen features emerged as most valuable for this purpose, including the observation that separating verbs into high and low-frequency types significantly improves classification accuracy. Using these linguistic features derived from the analysis of brief connected speech samples, we developed a classifier that achieved 97.9% accuracy in predicting PPA subtypes and healthy controls. Our findings provide pivotal insights for refining early-stage dementia diagnosis, deepening our understanding of the characteristics of these neurodegenerative phenotypes and the neurobiology of language processing, and enhancing diagnostic evaluation accuracy.

One sentence summary

Computational linguistic analyses of naturalistic speech samples can classify the aphasic variant of patients similarly to expert clinicians and identify well-established and novel linguistic features crucial for classification.
WITHDRAWN: Visual information is broadcast among cortical areas in discrete channels
Authors: Yu Yiyi , Stirman Jeffery N. , Dorsett Christopher R. , Smith Spencer LaVere
Published: December 2023

Withdrawal Statement

The authors have withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2018/469114. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The correct preprint can be found at doi: 10.1101/469114
Dual-specificity phosphatases 13 and 27 as key switches in muscle stem cell transition from proliferation to differentiation
Authors: Hayashi Takuto , Sadaki Shunya , Tsuji Ryosuke , Okada Risa , Fuseya Sayaka , Kanai Maho , Nakamura Ayano , Okamura Yui , Muratani Masafumi , Wenchao Gu , Sugasawa Takehito , Mizuno Seiya , Warabi Eiji , Kudo Takashi , Takahashi Satoru , Fujita Ryo
Published: December 2023

Muscle regeneration depends on muscle stem cell (MuSC) activity. Myogenic regulatory factors, including myoblast determination protein 1 (MyoD), regulate the fate transition of MuSCs. However, the direct target of MYOD in the process is not completely clear. Using previously established MyoD knock-in (MyoD-KI) mice, we revealed that MyoD targets dual-specificity phosphatase (Dusp) 13 and Dusp27. InDusp13:Dusp27double knock-out (DKO) mice, the ability for muscle regeneration after injury was reduced. Moreover, single-cell RNA sequencing of MyoD-high expressing MuSCs from MyoD-KI mice revealed thatDusp13andDusp27are expressed only in specific populations within MyoD-high MuSCs, which also expressMyogenin. OverexpressingDusp13in MuSCs causes premature muscle differentiation. Thus, we propose a model where DUSP13 and DUSP27 contribute to the fate transition of MuSCs from proliferation to differentiation during myogenesis.

Significance Statement

MYOD protein is not expressed in quiescent muscle stem cells but accumulates rapidly following muscle injury, leading to the proliferation of myogenic progenitors for differentiation. However, the direct targets of MYOD, aside from myogenin, which play roles in myogenic differentiation remain incompletely understood. Using previously established MyoD knock-in mice and single-cell RNA sequencing, we discovered that Dusp13 and Dusp27 are potential target genes of MYOD that promote myogenesis during muscle regeneration in adult mice.
Transcriptional analysis of neuronal ensembles of alcohol memories within the nucleus accumbens
Authors: Aronovici Coral , Prilutski Yael , Urshansky Nataly , Nathanzon Lubov , Rubio F. Javier , Savell Katherine. E. , Hope Bruce T. , Barak Segev
Published: December 2023

Alcohol-associated memories play an important role in relapse in alcohol use disorder. Disrupting these memories, which become labile upon retrieval, through interference with their reconsolidation process, could reduce relapse. Memories are thought to be encoded within specific patterns of sparsely distributed neurons, called neuronal ensembles. Here, we explored the role of neuronal ensembles in alcohol-memory reconsolidation and relapse and characterized their transcriptional signature. Upon retrieving alcohol-related memories, we observed increased neuronal activation in the nucleus accumbens (NAc). We established the causal role of these NAc ensembles in alcohol-memory reconsolidation using the Daun02 method with the Fos-LacZ transgenic rat, which expresses β-galactosidase (β-gal) under the Fos promoter, allowing the selective ablation of activated neurons. Selective inactivation of the active NAc neuronal ensemble produced a long-lasting attenuation of relapse. Through fluorescence-activated cell sorting (FACS) and RNA sequencing, we found a unique transcriptional fingerprint in activated Fos-positive neuronal ensembles in NAc following alcohol memory retrieval (vs. no retrieval controls) that was not present in the Fos-negative neurons. Our findings underscore the critical role of NAc neuronal ensembles in alcohol-associated memory reconsolidation. These neurons have a unique transcriptional profile that can provide novel targets for reducing alcohol relapse.