bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACT

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

ABSTRACTRegulated 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 statementIntegrated 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

ABSTRACTIntroductionSexual 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.MethodsA 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).ResultsThe 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.ConclusionsSexual 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

AbstractReplication 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.SignificanceDespite 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

ABSTRACTThe 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

ABSTRACTIn 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.
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

AbstractChemosensory 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.