bluuebunny/crossref_metadata_2025 huggingface dataset:
Secretome from myoblasts statically loaded at low intensity promotes tenocyte proliferation via the IGF‐1 receptor pathway
Authors: Li Junhong , Zhou Xin , Chen Jialin , Eliasson Pernilla , Kingham Paul J. , Backman Ludvig J.
Published: September 2023

Exercise is widely recognized as beneficial for tendon healing. Recently, it has been described that muscle‐derived molecules secreted in response to static exercise influence tendon healing. In this study, the optimal static loading intensity for tendon healing and the composition of secretome released by myoblasts in response to different intensities of static strain were investigated. In an in vitro coculture model, myoblasts were mechanically loaded using a Flexcell Tension System. Tenocytes were seeded on transwell inserts that allowed communication between the tenocytes and myoblasts without direct contact. Proliferation and migration assays, together with RNA sequencing, were used to determine potential cellular signaling pathways. The secretome from myoblasts exposed to 2% static loading increased the proliferation and migration of the cocultured tenocytes. RNA‐seq analysis revealed that this loading condition upregulated the expression of numerous genes encoding secretory proteins, including insulin‐like growth factor‐1 (IGF‐1). Confirmation of IGF‐1 expression and secretion was carried out using qPCR and enzyme‐linked immunosorbt assay (ELISA), revealing a statistically significant upregulation in response to 2% static loading in comparison to both control conditions and higher loading intensities of 5% and 10%. Addition of an inhibitor of the IGF‐1 receptor (PQ401) to the tenocytes significantly reduced myoblast secretome‐induced tenocyte proliferation. In conclusion, IGF‐1 may be an important molecule in the statically loaded myoblast secretome, which is responsible for influencing tenocytes during exercise‐induced healing.
ICN Congress 2023
Authors: McSpedon Corinne
Published: September 2023

The world's nurses meet in person for the first time in four years.
Surgical Team Dynamics Affect Operative Efficiency
Authors: Rosenberg Karen
Published: September 2023

According to this study:
Pearls for surviving unprecedented healthcare challenges
Authors: Bosek Marcia Sue Dewolf , Ware Catherine , Laramee Ann , Hoffman Sarah
Published: September 2023

Purpose:

Before the COVID-19 pandemic, nurses had little experience providing care during a pandemic. This project aimed to identify Pearls (suggestions) to survive a pandemic as a nurse.

Methods:

A phenomenologic design was implemented. Narrative comments were analyzed using Braun & Clarke's Six Phases of Summative Concept Analysis. This paper focuses on responses to a secondary question of this design.

Results:

One hundred thirty-four professional nurses provided 150 Pearls; of these, 123 Pearls reflected a positive sentiment. The Pearls fit into four themes: take care of yourself and find a balance, work as a team, practice safety, and appreciate that this is a hard time.

Conclusion:

The COVID-19 pandemic provides a valuable lesson for how nurses can survive future pandemics. Further research is warranted to investigate how useful the Pearls are for nurses in future pandemics and other crises threatening healthcare.
Using Theory-Informed Group Processes to Make TIMELESS Promotion Decisions
Authors: Kinnear Benjamin , Santen Sally A. , Schumacher Daniel J. , Kelleher Matthew , Awosika Bi , Edje Louito , Warm Eric J.
Published: September 2023

Competency-based medical education (CBME) depends on effective programs of assessment to achieve the desired outcomes and goals of training. Residency programs must be able to defend clinical competency committee (CCC) group decisions about learner readiness for practice, including decisions about time-variable resident promotion and graduation. In this article, the authors describe why CCC group decision-making processes should be supported by theory and review 3 theories they used in designing their group processes: social decision scheme theory, functional theory, and wisdom of crowds. They describe how these theories were applied in a competency-based, time-variable training pilot—Transitioning in Internal Medicine Education Leveraging Entrustment Scores Synthesis (TIMELESS) at the University of Cincinnati internal medicine residency program in 2020–2022—to increase the defensibility of their CCC group decision-making. This work serves as an example of how use of theory can bolster validity arguments supporting group decisions about resident readiness for practice.
Scaffolding the Transition to Residency: A Qualitative Study of Coach and Resident Perspectives
Authors: Park Agnes , Gillespie Colleen , Triola Marc , Buckvar-Keltz Lynn , Greene Richard E. , Winkel Abigail F.
Published: September 2023

Purpose

This study explores coaching during transition from medical school to residency through the perspectives of residents and faculty coaches participating in a coaching program from residency match through the first year of residency.

Method

From January to September 2020, 15 faculty coaches in internal medicine, obstetrics and gynecology, emergency medicine, orthopedics, and pathology participated in a synchronous, in-person coaching training course. All 94 postgraduate year 1 residents in these 5 training programs participated. Between November 2021 and March 2022, focus groups were held with interns from all residency programs participating in the program. Interviews were conducted with faculty coaches in February 2022. Faculty and residents discussed their experiences with and perceptions of coaching. Deidentified transcripts were coded, and researchers organized these codes into broader categories, generated cross-cutting themes from the concepts described in both cohorts, and proposed a model for the potential of coaching to support the transition to residency. Descriptive themes were constructed and analytic themes developed by identifying concepts that crossed the data sets.

Results

Seven focus groups were held with 39 residents (42%). Residents discussed the goals of a coaching program, coach attributes, program factors, resident attributes, and the role of the coach. Coaches focused on productivity of coaching, coaching skills and approach, professional development, and scaffolding the coaching experience. Three analytic themes were created: (1) coaching as creating an explicit curriculum for growth through the transition to residency, (2) factors contributing to successful coaching, and (3) ways in which these factors confront graduate medical education norms.

Conclusions

Learner and faculty perspectives on coaching through the transition to residency reveal the potential for coaching to make an explicit and modifiable curriculum for professional growth and development. Creating structures for coaching in graduate medical education may allow for individualized professional development, improved mindset, self-awareness, and self-directed learning.
Preliminary Workforce Outcomes of an Urban Longitudinal Integrated Clerkship
Authors: Adams Jennifer E. , Ard Catherine , Cunningham John M. , Jiménez Sheilah , Lockspeiser Tai , Hirsh David A. , Kulasekaran Vishnu
Published: September 2023

Purpose

The authors examined whether students participating in an urban longitudinal integrated clerkship (LIC) with a curriculum focused on care for underserved populations have a sustained commitment to urban underserved care through residency training and into practice.

Method

This mixed-methods study collected data from medical student application essays to the Denver Health LIC (DH-LIC), end-of-course surveys, residency match outcomes, and postgraduation surveys annually for academic years 2014 to 2022. The authors analyzed students' responses to the surveys on interest in working with underserved patients, understanding the rewards and challenges of working in safety net institutions, working in the community to improve health, and working at DH. The authors qualitatively coded the 70 application essays of all selected students using summative content analysis.

Results

Seventy DH-LIC students were compared with 1,450 medical students between 2014 and 2022. Qualitative analysis of LIC application essays revealed 3 themes: interest in working with underserved populations, work experience with underserved populations, and personal experience with medical vulnerability. Fifty-seven DH-LIC participants (81.4%) expressed high levels of career interest in working with underserved populations, 45 (64.3%) had high levels of work experience with underserved populations, and 18 (25.7%) expressed high levels of personal experience. Graduates of the DH-LIC program demonstrated a high degree of continuing interest in practicing in urban underserved settings throughout medical school and postgraduate training. Ten graduates (71.4%) in practice work in urban underserved settings. Participants reported a high or very high level of interest and commitment to working with underserved populations (96.7%–100%), understanding the safety net health care system (91.7%–98.6%), and working in communities (95.0%–100%) at all time points studied.

Conclusions

Early data indicate high rates of graduates working in urban underserved settings. These preliminary outcomes suggest the LIC may support the development of a committed workforce for urban underserved communities.
Development of a Maternal Equity Safety Bundle to Eliminate Racial Inequities in Massachusetts
Authors: Kheyfets Anna , Vitek Kali , Conklin Claire , Tu Christianna , Larson Elysia , Zera Chloe , Iverson Ronald , Reiff Emily , Healy Andrew , Lauring Julianne , Schoen Corina , Manganaro Karen , Pomerleau Mary , Glass Bonnell , Amutah-Onukagha Ndidiamaka , Diop Hafsatou , Meadows Audra R.
Published: September 2023

OBJECTIVE:

The PNQIN (Perinatal-Neonatal Quality Improvement Network of Massachusetts) sought to adapt the Reduction of Peripartum Racial and Ethnic Disparities Conceptual Framework and Maternal Safety Consensus Bundle by selecting and defining measures to create a bundle to address maternal health inequities in Massachusetts. This study describes the process of developing consensus-based measures to implement the PNQIN Maternal Equity Bundle across Massachusetts hospitals participating in the Alliance for Innovation on Maternal Health Initiative.

METHODS:

Our team used a mixed-methods approach to create the PNQIN Maternal Equity Bundle through consensus including a literature review, expert interviews, and a modified Delphi process to compile, define, and select measures to drive maternal equity-focused action. Stakeholders were identified by purposive and snowball sampling and included obstetrician–gynecologists, midwives, nurses, epidemiologists, and racial equity scholars. Dedoose 9.0 was used to complete an inductive analysis of interview transcripts. A modified Delphi method was used to reach consensus on recommendations and measures for the PNQIN Maternal Equity Bundle.

RESULTS:

Twenty-five interviews were completed. Seven themes emerged, including the need for 1) data stratification by race, ethnicity and language; 2) performance of a readiness assessment; 3) culture shift toward equity; 4) inclusion of antiracism and bias training; 5) addressing challenges of nonacademic hospitals; 6) a life-course approach; and 7) selection of timing of implementation. Twenty initial quality measures (structure, process, and outcome) were identified through expert interviews. Group consensus supported 10 measures to be incorporated into the bundle.

CONCLUSION:

Structure, process, and outcome quality measures were selected and defined for a maternal equity safety bundle that seeks to create an equity-focused infrastructure and equity-specific actions at birthing facilities. Implementation of an equity-focused safety bundle at birthing facilities may close racial gaps in maternal outcomes.
Basic Concepts in Nail Pathology
Authors: Fernandez-Flores Angel
Published: September 2023

Understanding nail pathology is complex for general pathologists and even for those dermatopathologists who do not receive many nail samples in their laboratories. In this article, we attempt to review some of the primary entities in nail pathology with the aid of modern interpretations of nail histology and embryology. We also provide diagrams that can aid in comprehending this field of pathology.
The Era of Progress on Gun Mortality: State Gun Regulations and Gun Deaths from 1991 to 2016
Authors: Sharkey Patrick , Kang Megan
Published: September 2023

Background:

The recent rise of gun violence may lead to the perception that the problem of gun mortality in the United States is intractable. This article provides evidence to counter this perception by bringing attention to the period spanning from 1991 to 2016 when most US states implemented more restrictive gun laws. Over this period, the United States experienced a decline in household gun ownership, and gun-related deaths fell sharply.

Methods:

The main analysis examines the conditional association between the change in gun regulations at the state level and the change in gun mortality from 1991 to 2016. We include a range of robustness checks and two instrumental variable analyses to allow for stronger causal inferences.

Results:

We find strong, consistent evidence supporting the hypothesis that restrictive state gun policies reduce overall gun deaths, homicides committed with a gun, and suicides committed with a gun. Each additional restrictive gun regulation a given state passed from 1991 to 2016 was associated with −0.21 (95% confidence interval = −0.33, −0.08) gun deaths per 100,000 residents. Further, we find that specific policies, such as background checks and waiting periods for gun purchases, were associated with lower overall gun death rates, gun homicide rates, and gun suicide rates.

Conclusion:

State regulations passed from 1991 to 2016 were associated with substantial reductions in gun mortality. We estimate that restrictive state gun policies passed in 40 states from 1991 to 2016 averted 4297 gun deaths in 2016 alone, or roughly 11% of the total gun deaths that year.
A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis
Authors: Rinella Mary E. , Lieu Hsiao D. , Kowdley Kris V. , Goodman Zachary D. , Alkhouri Naim , Lawitz Eric , Ratziu Vlad , Abdelmalek Manal F. , Wong Vincent Wai-Sun , Younes Ziad H. , Sheikh Aasim M. , Brannan Donald , Freilich Bradley , Membreno Fernando , Sinclair Marie , Melchor-Khan Liza , Sanyal Arun J. , Ling Lei , Harrison Stephen A.
Published: September 2023

Background and Aims:

Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population.

Approach and Results:

In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n = 7), 1 mg (n = 42), 3 mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was −0.5 (95% CI, −0.7 to −0.2; p = 0.0003) between the 3 mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1 mg, and 3 mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1 mg, and 3 mg group, respectively, discontinued due to treatment-related adverse events.

Conclusions:

Aldafermin 3 mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.
Stress and Work Performance Responses to a Multicomponent Intervention for Reducing and Breaking up Sitting in Office Workers
Authors: Maylor Benjamin D. , Hough John , Edwardson Charlotte L. , Zakrzewski-Fruer Julia K. , Bailey Daniel P.
Published: September 2023

Objective

The aim of the study is to explore the potential of a sitting reduction workplace intervention for improving stress and work performance.

Methods

A cluster randomized controlled trial evaluated an intervention to reduce and break up occupational sitting in 12 clusters (n = 89 office workers) over 8 weeks. Outcomes were physiological stress (cortisol concentrations), perceived stress, and work performance.

Results

Linear mixed model group × time interaction effects were nonsignificant. Exploratory analyses showed a trend, with a large effect, for lower cortisol concentrations over the day in the intervention group relative to controls at 8 weeks (−0.85; 95% confidence interval, −1.70 to 0.03 nmol·L−1; P = 0.06, d = 0.79). The intervention group had higher vigor and cognitive liveliness at 8 weeks relative to controls (P ≤ 0.05).

Conclusions

This exploratory study suggests that there could be meaningful changes in physiological stress and work-related outcomes that should be investigated in future studies.
Safety of longer-term doxycycline use: A systematic review and meta-analysis with implications for bacterial STI chemoprophylaxis
Authors: Chan Philip A. , Le Brazidec Danielle L. , Becasen Jeffrey S. , Martin Harrison , Kapadia Jhanavi , Reno Hilary , Bachmann Laura , Barbee Lindley A.
Published: September 2023

Background

Sexually transmitted infections (STIs) such as syphilis, gonorrhea, and chlamydia have significantly increased over the past decade in the United States. Doxycycline as chemoprophylaxis (i.e., post-exposure prophylaxis [PEP]) offers promise for addressing bacterial STIs. The goal of the current study was to evaluate the safety of longer-term doxycycline use (defined as eight or more weeks) in the context of potential use as STI chemoprophylaxis through a systematic literature review and meta-analysis.

Methods

This review used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to search MEDLINE/PubMed for clinical studies published from August 2003 through January 2023 that reported on adverse events with doxycycline use with a focus on side-effects and metabolic effects of long-term use.

Results

A total of 67 studies were included in the systematic review. Overall, studies on longer-term doxycycline use reported 0% to over 50% adverse events ranging from mild to severe. Most common adverse events included gastrointestinal symptoms (i.e., nausea, vomiting, and abdominal pain), dermatologic (i.e., rash), and neurological (i.e., headache and dizziness) symptoms. Discontinuation of doxycycline due to adverse events was relatively uncommon in most studies. A meta-analysis of placebo controlled clinical trials (N = 18) revealed gastrointestinal and dermatological adverse events were more likely to occur in the doxycycline group.

Conclusion

Longer-term (8+ weeks) doxycycline use is generally safe and may be associated with minor side-effects. Further research is needed on the potential metabolic impact of longer-term doxycycline use.
COVID-19, Vaccine Hesitancy, and HIV Pre-exposure Prophylaxis Among Black Sexual Minority Men
Authors: Turpin Rodman E. , Mandell CJ , Camp Aaron D. , Davidson Mhonde Rochelle R. , Dyer Typhanye V. , Mayer Kenneth H. , Liu Hongjie , Coates Thomas , Boekeloo Bradley O.
Published: September 2023

Background:

The COVID-19 pandemic has created substantial and profound barriers to several forms of health care engagement. For Black sexual minority men, this may include engagement with pre-exposure prophylaxis (PrEP) to prevent HIV infection, with significant implications for HIV disparities. Our study explored how the COVID-19 pandemic affected Black sexual minority men, with a focus on relationships between COVID-19 and PrEP engagement.

Setting:

We sampled 24 Black sexual minority men attending HIV prevention-related events in the greater D.C. Metropolitan area (D.C., Maryland, Virginia).

Methods:

We conducted qualitative phone interviews among our sample. Questions were primarily focused on the COVID-19 pandemic and how it affected engagement and considerations of PrEP use. Interviews were transcribed and qualitatively analyzed using the 6 stages of thematic analysis.

Results:

We identified 3 major themes from our thematic analysis: Changes in the health care system, changes in sexual and relationship contexts, and COVID-19 vaccine hesitancy and misinformation. Relationships between COVID-19 vaccine hesitancy and PrEP hesitancy were especially prevalent, with participants describing that COVID-19 hesitancy can directly deter PrEP use through eroding medical trust further.

Conclusions:

We identified changes in the health care system, sexual and relationship contexts, and COVID-19 vaccine hesitancy as important issues driven by COVID-19 with significant implications for PrEP use. The COVID-19 pandemic has changed the health care and social landscape in profound ways that affect PrEP access, sexual networks, and associated HIV vulnerability. Future research further exploring relationships between specific pandemic stressors and HIV prevention among Black sexual minority men is recommended.
Nonhome Discharge in Patients Undergoing Pelvic Reconstructive Surgery: A National Analysis
Authors: Ross James H. , Wood Nicole , Simmons Adrienne , Lua-Mailland Lannah L. , Wallace Shannon L. , Chapman Graham C.
Published: September 2023

Importance

Discharge to home after surgery has been recognized as a determinant of long-term survival and is a common concern in the elderly population.

Objective

The aim of the study was to determine the incidence and risk factors for nonhome discharge in patients undergoing major surgery for pelvic organ prolapse.

Study Design

We performed a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program Database from 2010 to 2018. We included patients who underwent sacrocolpopexy, vaginal colpopexy, and colpocleisis. We compared perioperative characteristics in patients who were discharged home versus those who were discharged to a nonhome location. Stepwise backward multivariate logistic regression was then used to control for confounding variables and identify independent predictors of nonhome discharge.

Results

A total of 38,012 patients were included in this study, 209 of whom experienced nonhome discharge (0.5%). Independent predictors of nonhome discharge included preoperative weight loss (adjusted odds ratio [aOR], 5.9; 95% confidence interval [CI], 1.3–27.5), dependent health care status (aOR, 5.0; 95% CI, 2.6–9.5), abdominal hysterectomy (aOR, 2.3; 95% CI, 1.4–3.7), American Society of Anesthesiologists class 3 or greater (aOR, 2.0; 95% CI, 1.5–2.7), age (aOR, 1.1; 95% CI, 1.05–1.09), operative time (aOR, 1.005; 95% CI, 1.003–1.006), laparoscopic hysterectomy (aOR, 0.6; 95% CI, 0.4–1.0), and laparoscopic sacrocolpopexy (aOR, 0.5; 95% CI, 0.3–0.8).

Conclusions

In patients undergoing surgery for pelvic organ prolapse, nonhome discharge is associated with various indicators of frailty, including age, health care dependence, and certain comorbidities. An open surgical approach increases the risk of nonhome discharge, while a laparoscopic approach is associated with lower risk.
Factors Associated With Stress Urinary Incontinence and Diastasis of Rectus Abdominis in Women at 6–8 Weeks Postpartum
Authors: Liu Xiaohong , Wang Qin , Chen Yanling , Luo Jiamao , Wan Yifeng
Published: September 2023

Importance

In recent years, pelvic-abdominal dynamics has become a research topic in the field of pelvic floor dysfunction (PFD), and the relationship between diastasis of the rectus abdominis (DRA) and stress urinary incontinence (SUI) has been controversial. The study is helpful to further strengthen perinatal education, accurately identify the risk factors of SUI and DRA, and improve the quality of life of puerperae.

Objective

This study aimed to investigate the association of SUI and DRA in women with PFD as measured by vaginal palpation or pelvic floor biofeedback machine testing.

Study Design

A total of 301 patients diagnosed with female PFD who were 6–8 weeks postpartum at The Fifth People's Hospital of Zhuhai between May 2018 and April 2021 were enrolled. The prevalence rates and potential influencing factors of SUI and DRA were analyzed.

Results

A total of 29.5% (89 of 301) of the patients were diagnosed with SUI, and 31.9% (96 of 301) were diagnosed with DRA. Binary logistic regression showed that a history of delivery (P = 0.012; odds ratio [OR], 1.982) and vaginal delivery with perineal lacerations or episiotomy (P = 0.016; OR, 2.187) were risk factors for SUI. High birth weight (weight>4.0 kg, P < 0.001; OR, 14.507) was a risk factor for DRA.

Conclusions

A history of delivery and vaginal delivery with perineal lacerations or episiotomy increased the risk of SUI, and high birth weight was an independent risk factor for DRA. Early intervention, including exercise therapy, manual therapy, and neuromuscular electrical stimulation, may be important for patients with PFD having these risk factors.
Twelve Month Outcomes of Pelvic Organ Prolapse Surgery in Patients With Uterovaginal or Posthysterectomy Vaginal Prolapse Enrolled in the Multicenter Pelvic Floor Disorders Registry
Authors: Ferrando Cecile A. , Bradley Catherine S. , Meyn Leslie A. , Brown Heidi W. , Moalli Pamela A. , Heisler Christine A. , Murarka Shivani M. , Foster Raymond T. , Chung Doreen E. , Whitcomb Emily L. , Gutman Robert E. , Andy Uduak U. , Shippey Stuart H. , Anger Jennifer , Yurteri-Kaplan Ladin A.
Published: September 2023

Objective

The aim of the study was to compare 12-month subjective and objective outcomes between 3 approaches to apical pelvic organ prolapse (POP) surgery in patients presenting with uterovaginal or posthysterectomy vaginal prolapse enrolled in the Pelvic Floor Disorders Registry for Research.

Study Design

This was an analysis of a multicenter, prospective registry that collected both patient- and physician-reported data for up to 3 years after conservative (pessary) and surgical treatment for POP. Twelve-month subjective and anatomic outcomes for patients who underwent surgical treatment were extracted from the registry for analysis. Pelvic organ prolapse recurrence was defined as a composite outcome and compared between the 3 apical surgery groups (native tissue repair, sacrocolpopexy, colpocleisis) as well as the 2 reconstructive surgery groups (native tissue repair and sacrocolpopexy).

Results

A total of 1,153 women were enrolled in the registry and 777 (67%) opted for surgical treatment, of whom 641 underwent apical repair and were included in this analysis (404 native tissue repair, 187 sacrocolpopexy, and 50 colpocleisis). The overall incidence of recurrence was as follows: subjective 6.5%, anatomic 4.7%, retreatment 7.2%, and composite 13.6%. The incidence of recurrence was not different between the 3 surgical groups. When baseline patient characteristics were controlled for, composite POP recurrence between the native tissue and sacrocolpopexy groups remained statistically nonsignificant. Concurrent perineorrhaphy with any type of apical POP surgery was associated with a lower risk of recurrence (adjusted odds ratio, 0.43; 95% confidence interval, 0.25–0.74; P = 0.002) and prior hysterectomy was associated with a higher risk (adjusted odds ratio, 1.77, 95% confidence interval, 1.04–3.03; P = 0.036).

Conclusion

Pelvic Floor Disorders Registry for Research participants undergoing native tissue apical POP repair, sacrocolpopexy, and colpocleisis surgery had similar rates of POP recurrence 12 months after surgery.
A novel bivalent interaction mode underlies a non-catalytic mechanism for Pin1-mediated Protein Kinase C regulation
Authors: Chen Xiao-Ru , Dixit Karuna , Yang Yuan , McDermott Mark I. , Imam Hasan T. , Bankaitis Vytas A. , Igumenova Tatyana I.
Published: September 2023

Regulated hydrolysis of the phosphoinositide phosphatidylinositol(4,5)-bis-phosphate to diacylglycerol and inositol-1,4,5-P3defines a major eukaryotic pathway for translation of extracellular cues to intracellular signaling circuits. Members of the lipid-activated protein kinase C isoenzyme family (PKCs) play central roles in this signaling circuit. One of the regulatory mechanisms employed to downregulate stimulated PKC activity is via a proteasome-dependent degradation pathway that is potentiated by peptidyl-prolyl isomerase Pin1. Here, we show that contrary to prevailing models, Pin1 does not regulate conventional PKC isoforms α and βII via a canonicalcis-transisomerization of the peptidyl-prolyl bond. Rather, Pin1 acts as a PKC binding partner that controls PKC activity via sequestration of the C-terminal tail of the kinase. The high-resolution structure of Pin1 complexed to the C-terminal tail of PKCβII reveals that a novel bivalent interaction mode underlies the non-catalytic mode of Pin1 action.

Specifically, Pin1 adopts a compact conformation in which it engages two conserved phosphorylated PKC motifs, the turn motif and hydrophobic motif, the latter being a non-canonical Pin1-interacting element. The structural information, combined with the results of extensive binding studies andin vivoexperiments suggest that non-catalytic mechanisms represent unappreciated modes of Pin1-mediated regulation of AGC kinases and other key enzymes/substrates.

Impact statement

Integrated biophysical, structural, andin vivoapproaches demonstrate a non-canonical and non-isomerizable binding motif-dependent mode of protein kinase C regulation by the peptidyl-prolyl isomerase Pin1 in mammalian cells.
Sexual dysfunction among Nigerian women living with HIV infection
Authors: Ezechi Oliver , Akinsolu Folahanmi , Gbajabiamila Tititola , Idigbe Ifeoma , Ezeobi Paschal , Musa Adesola , Wapmuk Agatha
Published: September 2023

Introduction

Sexual dysfunction in women with HIV is a necessary but understudied aspect of HIV complications in women living with HIV. This study reports the prevalence, pattern, and risk factors for sexual dysfunction in women living with HIV in southwest Nigeria.

Methods

A validated Female Sexual Function Index was used to determine sexual dysfunction in a cross-sectional study design involving 2926 adult women living with HIV in a large, publicly funded tertiary HIV treatment centre in Lagos, Nigeria. A score of less than 26.5 indicated sexual dysfunction. Multivariate logistic regression analysis was performed to identify risk factors for sexual dysfunction. P<0.05 was considered statistically significant at a 95% confidence interval (CI).

Results

The prevalence of sexual dysfunction was 71.4%. The types of dysfunctions detected included disorder of desire (76.8%), sexual arousal (66.0%), orgasm (50.0%), pain (47.2%), lubrication (47.2%), and satisfaction (38.8%). Multivariate analysis showed that menopause (aOR: 2.0; 1.4 – 4.1), PHQ score of 10 and above (aOR: 2.3; 1.7 – 3.2), co-morbid medical conditions (aOR: 1.8; 1.4 – 2.7), use of protease inhibitor-based antiretroviral therapy (aOR: 1.3; 1.2 - 2.1) and non-disclosure of HIV status (aOR: 0.7; 0.6-0.8) were factors associated with sexual dysfunction.

Conclusions

Sexual dysfunction is common among Nigerian women living with HIV. Menopause, use of protease inhibitor-based regimens, PHQ score of at least 10, co-morbid medical condition, and non-disclosure of HIV status were associated with sexual dysfunction. National HIV programmes, in addition to incorporating screening and management of sexual dysfunction in the guidelines, should sensitise and train health workers on the detection and treatment of sexual dysfunction.
Structure of RADX and mechanism for regulation of RAD51 nucleofilaments
Authors: Balakrishnan Swati , Adolph Madison , Tsai Miaw-Sheue , Gallagher Kaitlyn , Cortez David , Chazin Walter J.
Published: September 2023

Replication fork reversal is a fundamental process required for resolution of encounters with DNA damage. A key step in the stabilization and eventual resolution of reversed forks is formation of RAD51 nucleoprotein filaments on exposed ssDNA. To avoid genome instability, RAD51 filaments are tightly controlled by a variety of positive and negative regulators. RADX is a recently discovered negative regulator that binds tightly to ssDNA, directly interacts with RAD51, and regulates replication fork reversal and stabilization in a context-dependent manner. Here we present a structure-based investigation of RADX’s mechanism of action. Mass photometry experiments showed that RADX forms multiple oligomeric states in a concentration dependent manner, with a predominance of trimers in the presence of ssDNA. The structure of RADX, which has no structurally characterized orthologs, was determinedab initioby cryo-electron microscopy (EM) from maps in the 2-3 Å range. The structure reveals the molecular basis for RADX oligomerization and binding of ssDNA binding. The binding of RADX to RAD51 filaments was imaged by negative stain EM, which showed a RADX oligomer at the end of filaments. Based on these results, we propose a model in which RADX functions by capping and restricting the growing end of RAD51 filaments.

Significance

Despite the central role of RAD51 in DNA replication and repair processes, the mechanisms of action of its many modulators are poorly understood. Here we combine structural and biophysical data to determine how the negative regulator RADX functions. We show that RADX oligomerizes upon binding DNA, and caps RAD51 filaments at the ends to prevent extension. This work advances knowledge of how RAD51 filaments can be modulated to regulate replication fork reversal and maintain genomic stability.
Mesoscale molecular assembly is favored by the active, crowded cytoplasm
Authors: Shu Tong , Mitra Gaurav , Alberts Jonathan , Viana Matheus P. , Levy Emmanuel D. , Hocky Glen M. , Holt Liam J.
Published: September 2023

The mesoscale organization of molecules into membraneless biomolecular condensates is emerging as a key mechanism of rapid spatiotemporal control in cells1. Principles of biomolecular condensation have been revealed throughin vitroreconstitution2. However, intracellular environments are much more complex than test-tube environments: They are viscoelastic, highly crowded at the mesoscale, and are far from thermodynamic equilibrium due to the constant action of energy-consuming processes3. We developed synDrops, a synthetic phase separation system, to study how the cellular environment affects condensate formation. Three key features enable physical analysis: synDrops are inducible, bioorthogonal, and have well-defined geometry. This design allows kinetic analysis of synDrop assembly and facilitates computational simulation of the process. We compared experiments and simulations to determine that macromolecular crowding promotes condensate nucleation but inhibits droplet growth through coalescence. ATP-dependent cellular activities help overcome the frustration of growth. In particular, actomyosin dynamics potentiate droplet growth by reducing confinement and elasticity in the mammalian cytoplasm, thereby enabling synDrop coarsening. Our results demonstrate that mesoscale molecular assembly is favored by the combined effects of crowding and active matter in the cytoplasm. These results move toward a better predictive understanding of condensate formationin vivo.
Monkeypox virus spreads from cell-to-cell and leads to neuronal death in human neural organoids
Authors: Schultz-Pernice Isabel , Fahmi Amal , Brito Francisco , Liniger Matthias , Chiu Yen-Chi , David Teodora , Oliveira Esteves Blandina I. , Golomingi Antoinette , Zumkehr Beatrice , Gerber Markus , Jandrasits Damian , Züst Roland , Steiner Selina , Wotzkow Carlos , Blank Fabian , Engler Olivier B. , Summerfield Artur , Ruggli Nicolas , Baud David , Alves Marco P.
Published: September 2023

In 2022-23, the world experienced the largest recorded monkeypox virus (MPXV) outbreak outside of endemic regions. Remarkably, cases of neurological manifestations were reported, some of which fatal. MPXV DNA and MPXV-specific antibodies were detected in the cerebrospinal fluid of encephalitis-affected patients, suggesting neuroinvasive potential of MPXV. We explored the susceptibility of neural tissue to MPXV infection using human neural organoids (hNOs) exposed to a primary isolate belonging to clade IIb lineage. The virus efficiently replicates in hNOs as indicated by the exponential increase of infectious viral loads and the elevated frequency of MPXV-positive cells over time. Electron microscopy imaging revealed the presence of viral particles as well as perinuclear viral factories. We observed susceptibility of several cell types to the virus, including neural progenitor cells and neurons. Furthermore, we detected the presence of viral antigen in neurites and in foci of grouped cells distributed throughout the tissue. In line with this, we documented significantly more cell-associated than released infectious virus, suggesting viral spread by cell-to-cell contact. Using an mNeonGreen-expressing recombinant MPXV, we confirmed cell-associated virus transmission through live-cell imaging. While hNOs displayed no evident outer morphological changes upon infection, we detected the formation of beads in neurites, a phenomenon commonly associated with neurodegenerative disorders. Live-cell imaging further confirmed the recurrent formation of neuritic beads in neurons in the days following MPXV infection, with bead formation preceding neurite-initiated cell death. Notably, treatment of MPXV infected hNOs with the antiviral drug tecovirimat resulted in a significant reduction of infectious viral loads by several orders of magnitude. Taken together, our findings suggest viral manipulation of axonal transport driving neuronal degeneration and identify a mechanism potentially contributing to MPXV-mediated neuropathology that may have therapeutic implications.
Pattern formation by bacteria-phage interactions
Authors: Martínez-Calvo Alejandro , Wingreen Ned S. , Datta Sujit S.
Published: September 2023

The interactions between bacteria and phages—viruses that infect bacteria—play critical roles in agriculture, ecology, and medicine; however, how these interactions influence the spatial organization of both bacteria and phages remain largely unexplored. Here, we address this gap in knowledge by developing a theoretical model of motile, proliferating bacteria that aggregate via motility-induced phase separation (MIPS) and encounter phage that infect and lyse the cells. We find that the non-reciprocal predator-prey interactions between phage and bacteria strongly alter spatial organization, in some cases giving rise to a rich array of finite-scale stationary and dynamic patterns in which bacteria and phage coexist. We establish principles describing the onset and characteristics of these diverse behaviors, thereby helping to provide a biophysical basis for understanding pattern formation in bacteria-phage systems, as well as in a broader range of active and living systems with similar predator-prey or other non-reciprocal interactions.
Diverse domain architectures of CheA histidine kinase, a central component of bacterial and archaeal chemosensory systems
Authors: Berry Marissa A. , Andrianova Ekaterina P. , Zhulin Igor B.
Published: September 2023

Chemosensory systems in bacteria and archaea are complex, multi-protein pathways that enable rapid cellular responses to environmental changes. The CheA histidine kinase is a central component of chemosensory systems. In contrast to other histidine kinases, it lacks a sensor (input) domain and utilizes dedicated chemoreceptors for sensing. CheA is a multi-domain protein; in model organisms as diverse asEscherichia coliandBacillus subtilis, it contains five single-copy domains. Deviations from this canonical domain architecture have been reported, however, a broad genome-wide analysis of CheA diversity is lacking. Here, we present results of a genomic survey of CheA domain composition carried out using an unbiased set of thousands of CheA sequences from bacteria and archaea. We found that four out of five canonical CheA domains comprise a minimal functional unit (core domains), as they are present in all surveyed CheA homologs. The most common deviations from a classical five-domain CheA architecture are the lack of a P2/CheY-binding domain, which is missing from more than a half of CheA homologs and the acquisition of a response regulator receiver (CheY-like) domain, which is present in ∼35% of CheA homologs. We also document other deviations from classical CheA architecture, including bipartite CheA proteins, domain duplications and fusions, and reveal that phylogenetically defined CheA classes have pre-dominant domain architectures. This study lays a foundation for a better classification of CheA homologs and identifies targets for experimental investigations.
Diversity and ecological functions of viruses inhabiting the oil reservoirs
Authors: An Liyun , Liu Xinwu , Wang Jianwei , Xu Jingbo , Chen Xiaoli , Liu Xiaonan , Hu Bingxin , Nie Yong , Wu Xiao-Lei
Published: September 2023

Oil reservoirs, being one of the most significant subsurface repositories of energy and carbon, have long hosted diverse microorganisms affecting energy production and carbon emissions. Viruses play crucial roles in the ecology of microbiomes, however, their distribution and ecological significance in oil reservoirs remain undetermined. Here, we assembled an extensive catalogue encompassing viral and prokaryotic genomes sourced from oil reservoirs. The catalogue comprises 7,229 prokaryotic genomes and 6,218 viral genomes from 182 oil reservoir metagenomes, respectively. Based on sequence clustering we identified 3,886 Operational Taxonomic Units (vOTUs) approximately at species level, 94.80% of which were not found in any other environments. The results showed that viruses were widely distributed in oil reservoirs, and oil reservoirs contain a significant number of unique and unexplored viruses. We also constructed a catalogue of 322,060 viral gene clusters including 105 virus-encoded putative auxiliary metabolic genes (AMGs) that participate in host metabolism and adaptation to the environment. Furthermore, our investigation has yielded a total of 7,197 putative virus-host pairs based on CRISPR and tRNA profiles. Viruses within oil reservoirs profoundly infected bacterial Actinobacteriota, Desulfobacterota, as well as archaeal Halobacteriota and Methanobacteriota. Combined microcosm enrichment experiments and bioinformatics analysis, we validated the ecological roles of viruses in regulating the community structure of sulfate reduction microorganisms, primarily through the predation of virulent viruses. Collectively, these findings have unveiled a rich diversity of novel viruses and their ecological functions within oil reservoirs. This study provides a comprehensive understanding of the role of viral communities in the biogeochemical cycle of the deep biosphere. It also facilitates microbial applications aimed at addressing challenges related to fossil-fuel production and carbon emissions in the petroleum industry.
Bacterial Efflux Pump Modulators Prevent Bacterial Growth in Macrophages and Under Broth Conditions that Mimic the Host Environment
Authors: Allgood Samual C. , Su Chih-Chia , Crooks Amy L. , Meyer Christian T. , Zhou Bojun , Betterton Meredith D. , Barbachyn Michael R. , Yu Edward W. , Detweiler Corrella S.
Published: September 2023

New approaches for combatting microbial infections are needed. One strategy for disrupting pathogenesis involves developing compounds that interfere with bacterial virulence. A critical molecular determinant of virulence for Gram-negative bacteria are efflux pumps of the resistance-nodulation-division (RND) family, which includes AcrAB-TolC. We previously identified small molecules that bind AcrB, inhibit AcrAB-TolC, and do not appear to damage membranes. These efflux pump modulators (EPMs) were discovered in an in-cell screening platform called SAFIRE (Screen for Anti-infectives using Fluorescence microscopy of IntracellulaR Enterobacteriaceae). SAFIRE identifies compounds that disrupt the growth of a Gram-negative human pathogen,Salmonella entericaserotype Typhimurium (S.Typhimurium) in macrophages. We used medicinal chemistry to iteratively design ∼200 EPM35 analogs and test them for activity in SAFIRE, generating compounds with nanomolar potency. Analogs were demonstrated to bind AcrB in a substrate binding pocket by cryo-electron microscopy (cryo-EM). Despite having amphipathic structures, the EPM analogs do not disrupt membrane voltage, as monitored by FtsZ localization to the cell septum. The EPM analogs had little effect on bacterial growth in standard Mueller Hinton Broth. However, under broth conditions that mimic the micro-environment of the macrophage phagosome,acrABis required for growth, the EPM analogs are bacteriostatic, and increase the potency of antibiotics. These data suggest that under macrophage-like conditions the EPM analogs prevent the export of a toxic bacterial metabolite(s) through AcrAB-TolC. Thus, compounds that bind AcrB could disrupt infection by specifically interfering with the export of bacterial toxic metabolites, host defense factors, and/or antibiotics.

IMPORTANCE

Bacterial efflux pumps are critical for resistance to antibiotics and for virulence. We previously identified small molecules that inhibit efflux pumps (efflux pump modulators, EPMs) and prevent pathogen replication in host cells. Here we used medicinal chemistry to increase the activity of the EPMs against pathogens in cells into the nanomolar range. We show by cryo-electron microscopy that these EPMs bind an efflux pump subunit. In broth culture, the EPMs increase the potency (activity), but not the efficacy (maximum effect), of antibiotics. We also found that bacterial exposure to the EPMs appear to enable the accumulation of a toxic metabolite that would otherwise be exported by efflux pumps. Thus, inhibitors of bacterial efflux pumps could interfere with infection not only by potentiating antibiotics, but also by allowing toxic waste products to accumulate within bacteria, providing an explanation for why efflux pumps are needed for virulence in the absence of antibiotics.
Incomplete immunity in a natural animal-microbiota interaction boosts pathogen virulence
Authors: Hoang Kim L. , Read Timothy D. , King Kayla C.
Published: September 2023

Strong partial immunity in recovered hosts is predicted to favour more virulent pathogens upon re-infection in the population. We present empirical evidence that the incomplete immunity generated by commensal host microbiota can similarly select for higher pathogen virulence. We tracked the evolutionary trajectories of a widespread pathogen (Pseudomonas aeruginosa) experimentally passaged through populations of nematode hosts which had been immune-primed by a natural commensal. Immune protection selected for pathogens more than twice as likely to kill the nematode as those evolved in non-primed or immune-compromised animals. Despite the higher virulence that emerged, pathogen molecular evolution in immune-primed hosts was slower and more constrained compared to evolution in immune-compromised hosts, where substantial genetic differentiation was exhibited. These findings directly attribute the partial protective immunity provided by host-microbiome interactions as a significant selective force shaping the virulence and evolutionary dynamics of novel infectious diseases.