In Vivo Expression of an SCA27A-linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.

Autosomal dominant mutations in FGF14 , which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 ( Fgf14 -/- ) exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that control the high frequency repetitive firing of Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the pathophysiological mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus ( Fgf14 F145S ), we determined the impact of in vivo expression of the mutant Fgf14 F145S allele on the motor performance of adult animals and on the firing properties of mature Purkinje neurons in acute cerebellar slices. Electrophysiological experiments revealed that repetitive firing rates are attenuated in adult Fgf14 F145S/+ cerebellar Purkinje neurons, attributed to a hyperpolarizing shift in the voltage-dependence of steady-state inactivation of Nav channels. More severe effects on firing properties and Nav channel inactivation were observed in homozygous Fgf14 F145S/F145S Purkinje neurons. Interestingly, the electrophysiological phenotypes identified in adult Fgf14 F145S/+ and Fgf14 F145S/F145S cerebellar Purkinje neurons mirror those observed in heterozygous Fgf14 +/- and homozygous Fgf14 -/- Purkinje neurons, respectively, suggesting that the mutation results in the loss of the iFGF14 protein. Western blot analysis of lysates from adult heterozygous Fgf14 F145S/+ and homozygous Fgf14 F145S/F145S animals revealed reduced or undetectable, respectively, iFGF14 expression, supporting the hypothesis that the mutant allele results in loss of the iFGF14 protein and that haploinsufficiency underlies SCA27A neurological phenotypes.

Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease.

Acute lower respiratory tract infection (ALRI) remains a major worldwide cause of childhood mortality, compelling innovation in prevention and treatment. Children in Papua New Guinea (PNG) experience profound morbidity from ALRI caused by Streptococcus pneumoniae. As a result of evolutionary divergence, the human PNG population exhibits profound genetic variation and diversity. To address unmet health needs of children in PNG, we tested whether genetic variants increased ALRI morbidity. Whole-exome sequencing of a pilot child cohort identified homozygosity for a novel single-nucleotide variant (SNV) in coenzyme Q6 (COQ6) in cases with ALRI. COQ6 encodes a mitochondrial enzyme essential for biosynthesis of ubiquinone, an electron acceptor in the electron transport chain. A significant association of SNV homozygosity with ALRI was replicated in an independent ALRI cohort (P = 0.036). Mice homozygous for homologous mouse variant Coq6 exhibited increased mortality after pneumococcal lung infection, confirming causality. Bone marrow chimeric mice further revealed that expression of variant Coq6 in recipient (that is, nonhematopoietic) tissues conferred increased mortality. Variant Coq6 maintained ubiquinone biosynthesis, while accelerating metabolic remodeling after pneumococcal challenge. Identification of this COQ6 variant provides a genetic basis for increased pneumonia susceptibility in PNG and establishes a previously unrecognized role for the enzyme COQ6 in regulating inflammatory-mediated metabolic remodeling.

Learning to direct one's care: barriers and facilitators reported by people with tetraplegia.

STUDY DESIGN: Qualitative analysis of focus group data. OBJECTIVE: Identifying barriers to and facilitators of learning to direct one's own care as a person with tetraplegia due to spinal cord injury (SCI). SETTING: Community, in New Jersey and Georgia, USA. METHODS: Three focus groups of veterans and civilians with SCI, involving 26 people with chronic (≥1 year) tetraplegia due to SCI who provided direction to caregivers on a daily basis. Content analysis was used to identify barriers and facilitators. RESULTS: Challenges to learning to direct one's care included: (1) lack of acceptance of lasting effects of SCI; (2) not yet understanding one's body post-SCI; (3) embarrassment; (4) being overwhelmed with information; (5) differences between the inpatient rehabilitation setting and the "real world"; (6) lack of capable and willing assistants; and (7) hesitance to criticize caregivers. Factors that helped participants become successful directors of care included: (1) experience living with SCI; (2) being observant; (3) communicating effectively; (4) developing confidence to advocate for one's own needs; (5) learning when to "let go" and when to speak up; and (6) learning from peers. CONCLUSIONS: Direction of care is a complex skill that is developed over time, and requires awareness of one's needs and preferences, self-confidence, and strong communication skills. Rehabilitation clinicians' efforts to prepare people with SCI to direct their own care effectively should cultivate awareness of one's body, identify strategies for communicating successfully with caregivers, and provide opportunities for practice of care direction skills and discussion with experienced peers.

Ovarian Cancer Retrospective European (O'CaRE) study: first-line outcomes by number of risk factors for progression.

Aim: The Ovarian Cancer Retrospective European (O'CaRE) study assessed the cumulative impact of high-risk factors on progression-free survival (PFS) and overall survival (OS) following first-line treatment in patients diagnosed with advanced ovarian cancer.Patients & methods: Medical records were collected from five European countries (2014 and 2015). Patients were grouped by number of high-risk factors: stage IV diagnosis, no known BRCA mutation, interval debulking surgery or no surgery, or visible residual disease.Results: Our analysis included 405 patients grouped based on having one (20.4%); two (32.3%); three (33.7%) or four (11.9%) high-risk factors. Increasing cumulative numbers of high-risk factors were associated with numerically shorter PFS and OS.Conclusion: Risk profiles should be carefully considered when planning clinical care.

Does the number of risk factors a person with advanced ovarian cancer have affect the likely success of their cancer treatment?What is already known on this topic? Studies have found that individual factors, such as disease stage, and whether any cancer cells remain after surgery are linked to earlier disease worsening and/or shorter survival after treatment in people with advanced ovarian cancer. These are known as 'risk factors'. However, few studies have looked at whether this link is stronger if a person has several of these risk factors.What does this study add? In this study, we looked at whether outcomes after treatment worsen as the number of risk factors increases. We found that patients with more high-risk factors saw a worsening of their cancer much sooner than those with a fewer number of risk factors. Also, patients with multiple risk factors did not live as long as patients with fewer risk factors.How might this study affect research, practice or policy? When selecting therapies, healthcare providers should consider the impact of patient risk factors on how effectively that treatment will treat their cancer. The number of high-risk factors may also make an important difference in clinical trials and, therefore, should be considered when comparing results from different clinical trials.

Concept Analysis: Challenge Coins as a Caring Support Tool to Prevent Farmer Suicide.

OBJECTIVES: Challenge coins have a history in the military as symbolic tokens of belonging and appreciation. Members of some agricultural communities have recently expressed interest in using a challenge coin as a caring support tool to improve mental health among farmers. The objective of this analysis is to clarify the meaning and use of a challenge coin as an upstream suicide prevention caring support tool in agricultural communities. METHODS: A systematic search was performed in Google Scholar, PsycInfo, Sociological Abstracts, Web of Science, and PubMed following PRISMA guidelines, identifying literature available through October 2023. Thirty-five articles were included and analyzed using Rodger's Evolutionary Method for Concept Analysis. RESULTS: The attributes of challenge coins include its material presence (i.e. a medallion with official insignia) and its presentation as a recognition for contributions to society and signifying belonging to a group. The antecedents of the challenge coin were achievement, rank, or proficiency related to a role in public duty and membership in an occupational group facing unique challenges. The consequences were identified as improved morale and pride and fostering belongingness, connectedness, and community. These consequences can lead to the challenge coin serving as a cue for behavior change. DISCUSSION: This concept analysis provides additional understanding of a challenge coin when used as a caring support tool, particularly in agricultural communities. The challenge coin has historically been used in a military or first responder context, but it could be expanded to other service-oriented occupations such as farming. CONCLUSION: Using a challenge coin for a mental health promotion intervention requires more community-based research to understand its efficacy in agricultural contexts. With the concept of a challenge coin clarified, a next step would be scientific efforts among mental health practitioners and industry leaders to support further development and testing of the challenge coin as a suicide prevention and caring support tool that fosters belongingness and appreciation within agriculture.

Intended And Unintended Outcomes After FDA Pediatric Antidepressant Warnings: A Systematic Review.

Since 2003, the Food and Drug Administration (FDA) has warned that antidepressants may be associated with suicidal thoughts and behaviors among youth. An FDA advisory in 2003 and a black-box warning in 2005 focused on children and adolescents younger than age eighteen. The FDA expanded the black-box warning in 2007 to include young adults. Both warnings were intended to increase physician monitoring of suicidal thoughts and behaviors. Our systematic review identified thirty-four studies of depression and suicide-related outcomes after these warnings; eleven of these studies met research design criteria established to reduce biases. The eleven studies examined monitoring for suicidal thoughts and behaviors, physician visits for depression, depression diagnoses, psychotherapy visits, antidepressant treatment and use, and psychotropic drug poisonings (a proxy for suicide attempts) and suicide deaths. We assessed possible spillover to adults not targeted by the warnings. The one study that measured intended physician monitoring of suicidal thoughts and behaviors did not find evidence of an increase. Multiple studies found significant unintended reductions in mental health care after the warnings. After these reductions, there were marked increases in psychotropic drug poisonings and suicide deaths. These findings support reevaluation of risks and benefits of the FDA's black-box antidepressant warnings.

The TELEhealth Shared decision-making COaching and navigation in Primary carE (TELESCOPE) intervention: a study protocol for delivering shared decision-making for lung cancer screening by patient navigators.

BACKGROUND: Lung cancer screening (LCS) can reduce lung cancer mortality but has potential harms for patients. A shared decision-making (SDM) conversation about LCS is required by the Centers for Medicare & Medicaid Services (CMS) for LCS reimbursement. To overcome barriers to SDM in primary care, this protocol describes a telehealth decision coaching and navigation intervention for LCS in primary care clinics delivered by patient navigators. The objective of the study is to evaluate the effectiveness of the intervention and its implementation potential, compared with an enhanced usual care (EUC) arm. METHODS: Patients (n = 420) of primary care clinicians (n = 120) are being recruited to a cluster randomized controlled trial. Clinicians are randomly assigned to 1) TELESCOPE intervention: prior to an upcoming non-acute clinic visit, patients participate in a telehealth decision coaching and navigation session about LCS delivered by trained patient navigators and nurse navigators place a low-dose CT scan (LDCT) order for each TELESCOPE patient wanting LCS, or 2) EUC: patients receive enhanced usual care from a clinician. Usual care is enhanced by providing clinicians in both arms with access to a Continuing Medical Education (CME) webinar about LCS and an LCS discussion guide. Patients complete surveys at baseline and 1-week after the scheduled clinic visit to assess quality of the SDM process. Re-navigation is attempted with TELESCOPE patients who have not completed the LDCT within 3 months. One month before being due for an annual screening, TELESCOPE patients whose initial LCS showed low-risk findings are randomly assigned to receive a telehealth decision coaching booster session with a navigator or no booster. Electronic health records are abstracted at 6, 12 and 18 months after the initial decision coaching session (TELESCOPE) or clinic visit (EUC) to assess initial and annual LCS uptake, imaging results, follow-up testing for abnormal findings, cancer diagnoses, treatment, and tobacco treatment referrals. This study will evaluate factors that facilitate or interfere with program implementation using mixed methods. DISCUSSION: We will assess whether a decision coaching and patient navigation intervention can feasibly and effectively support high-quality SDM for LCS and guideline-concordant LCS uptake for patients in busy primary care practices serving diverse patient populations. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov (NCT05491213) on August 4, 2022. PROTOCOL VERSION: Version 1, April 10, 2024.

The ivory lncRNA regulates seasonal color patterns in buckeye butterflies.

Long noncoding RNAs (lncRNAs) are transcribed elements increasingly recognized for their roles in regulating gene expression. Thus far, however, we have little understanding of how lncRNAs contribute to evolution and adaptation. Here, we show that a conserved lncRNA, ivory, is an important color patterning gene in the buckeye butterfly Junonia coenia. ivory overlaps with cortex, a locus linked to multiple cases of crypsis and mimicry in Lepidoptera. Along with a companion paper by Livraghi et al., we argue that ivory, not cortex, is the color pattern gene of interest at this locus. In J. coenia, a cluster of cis-regulatory elements (CREs) in the first intron of ivory are genetically associated with natural variation in seasonal color pattern plasticity, and targeted deletions of these CREs phenocopy seasonal phenotypes. Deletions of different ivory CREs produce other distinct phenotypes as well, including loss of melanic eyespot rings, and positive and negative changes in overall wing pigmentation. We show that the color pattern transcription factors Spineless, Bric-a-brac, and Ftz-f1 bind to the ivory promoter during wing pattern development, suggesting that they directly regulate ivory. This case study demonstrates how cis-regulation of a single noncoding RNA can exert diverse and nuanced effects on the evolution and development of color patterns, including modulating seasonally plastic color patterns.

Uterine Sarcoma or Degenerating Fibroid? Validating the New Consensus Magnetic Resonance Imaging Algorithm for Evaluating Atypical Uterine Masses.

OBJECTIVE: The aim of the study is to assess the validity of a recently published consensus magnetic resonance imaging (MRI) diagnostic algorithm for differentiating degenerating leiomyomas from uterine sarcomas and other atypical appearing uterine malignancies. METHODS: Atypical uterine masses on pelvic MRI were identified using a radiology report search engine and teaching files with the keywords "atypical leiomyoma," "atypical fibroid," and "sarcoma." All cases were pathology-proven. Two radiologists blinded to clinical, surgical, and pathologic reports retrospectively and independently reviewed 40 pelvic MRI examinations dated 1/2007-9/2022 to determine whether the masses appeared benign or malignant, using the 2022 consensus atypical uterine mass flow chart. Imaging features assessed included intermediate/high signal intensity (SI) at T2-weighted imaging, high diffusion weighted imaging SI (equal or higher SI than endometrium or lymph nodes on high b value imaging), apparent diffusion coefficient (ADC) value ≤0.905 × 10-3 mm2/s, peritoneal metastases, and abnormal lymph nodes. RESULTS: Among the 40 atypical uterine mass cases reviewed, 24 masses were benign (22 leiomyomas, 1 adenomyoma, and 1 borderline ovarian tumor) and 16 masses were malignant (6 leiomyosarcomas, 6 carcinosarcomas, 2 endometrial stromal sarcomas, 1 high-grade adenosarcoma, and 1 low-grade uterine sarcoma). Sensitivity, specificity, positive predictive value, and negative predictive value of whether a mass was benign or malignant were 75%, 95.8%, 92.3%, and 85% for reader 1, and 81.2%, 91.7%, 86.7%, and 88% for reader 2, respectively. Interrater agreement was strong, with a kappa statistic of 0.89. When excluding nonleiomyosarcoma uterine malignancies, sensitivity and negative predictive value improved to 100%. CONCLUSIONS: The new consensus pelvic MRI algorithm for evaluating atypical uterine masses has good specificity, sensitivity, positive predictive value, and negative predictive value for determining malignancy, particularly for uterine sarcomas that are leiomyosarcomas. However, if ADC value is near but not below 0.905 × 10-3 mm2/s, the mass may still be malignant, especially if a b value lower than 1000 is used. If the atypical uterine mass is predominantly endometrial, morphological features on T2 and postgadolinium sequences should guide suspicion, as some atypical appearing nonleiomyosarcoma uterine malignancies may have an ADC value greater than 0.905 × 10-3 mm2/s.

Collaborative Large Language Models for Automated Data Extraction in Living Systematic Reviews.

Objective: Data extraction from the published literature is the most laborious step in conducting living systematic reviews (LSRs). We aim to build a generalizable, automated data extraction workflow leveraging large language models (LLMs) that mimics the real-world two-reviewer process. Materials and Methods: A dataset of 10 clinical trials (22 publications) from a published LSR was used, focusing on 23 variables related to trial, population, and outcomes data. The dataset was split into prompt development (n=5) and held-out test sets (n=17). GPT-4-turbo and Claude-3-Opus were used for data extraction. Responses from the two LLMs were compared for concordance. In instances with discordance, original responses from each LLM were provided to the other LLM for cross-critique. Evaluation metrics, including accuracy, were used to assess performance against the manually curated gold standard. Results: In the prompt development set, 110 (96%) responses were concordant, achieving an accuracy of 0.99 against the gold standard. In the test set, 342 (87%) responses were concordant. The accuracy of the concordant responses was 0.94. The accuracy of the discordant responses was 0.41 for GPT-4-turbo and 0.50 for Claude-3-Opus. Of the 49 discordant responses, 25 (51%) became concordant after cross-critique, with an increase in accuracy to 0.76. Discussion: Concordant responses by the LLMs are likely to be accurate. In instances of discordant responses, cross-critique can further increase the accuracy. Conclusion: Large language models, when simulated in a collaborative, two-reviewer workflow, can extract data with reasonable performance, enabling truly 'living' systematic reviews.

Predictors of Psychiatric Hospitalization After Discharge From Inpatient Neurorehabilitation for Traumatic Brain Injury.

OBJECTIVE: To examine, among persons discharged from inpatient rehabilitation for traumatic brain injury (TBI), the degree to which pre-TBI factors were associated with post-TBI hospitalization for psychiatric reasons. The authors hypothesized that pre-TBI psychiatric hospitalization and other pre-TBI mental health treatment would predict post-TBI psychiatric hospitalization following rehabilitation discharge, up to 5 years post-TBI. SETTING: Five Veterans Affairs Polytrauma Rehabilitation Centers. PARTICIPANTS: Participants with nonmissing rehospitalization status and reason, who were followed at 1 year (N = 1006), 2 years (N = 985), and 5 years (N = 772) post-TBI. DESIGN: A secondary analysis of the Veterans Affairs TBI Model Systems, a multicenter, longitudinal study of veterans and active-duty service members with a history of mild, moderate, or severe TBI previously admitted to comprehensive inpatient medical rehabilitation. This study examined participants cross-sectionally at 3 follow-up timepoints. MAIN MEASURES: Psychiatric Rehospitalization was classified according to Healthcare Cost and Utilization Project multilevel Clinical Classifications diagnosis terminology (Category 5). RESULTS: Rates of post-TBI psychiatric hospitalization at years 1, 2, and 5 were 4.3%, 4.7%, and 4.1%, respectively. While bivariate comparisons identified pre-TBI psychiatric hospitalization and pre-TBI mental health treatment as factors associated with psychiatric rehospitalization after TBI across all postinjury timepoints, these factors were statistically nonsignificant when examined in a multivariate model across all timepoints. In the multivariable analysis, pre-TBI psychiatric hospitalization was significantly associated with increased odds of post-TBI psychiatric hospitalization only at 1-year post-TBI (adjusted odds ratio = 2.65; 95% confidence interval, 1.07-6.55, P = .04). Posttraumatic amnesia duration was unrelated to psychiatric rehospitalization. CONCLUSIONS: Study findings suggest the limited utility of age, education, and pre-TBI substance use and mental health utilization in predicting post-TBI psychiatric hospitalization. Temporally closer social and behavior factors, particularly those that are potentially modifiable, should be considered in future research.

Chronic pain after traumatic brain injury: a collaborative care approach.

Introduction: Chronic pain is common after traumatic brain injury (TBI), frequently limits daily activities, and is associated with negative outcomes such as decreased community participation. Despite the negative impact of chronic pain, few people with TBI receive effective treatment. This paper describes a collaborative care (CC) intervention, TBI Care, adapted specifically to treat chronic pain in people living with TBI, emphasizing expert clinician input, cognitive behavioral therapy (CBT) techniques, and other non-pharmacological approaches for decreasing pain interference. Methods: 79 participants engaged in the CC intervention from two academic medical rehabilitation clinics with weekly assessments of pain intensity, interference, and medication use. Participant feedback on the intervention was gathered by interview with the care manager (CM) at the last treatment session and/or booster session. Provider feedback was gathered by a confidential survey post intervention. Results: Ninety percent of participants received at least 11 of the target 12 sessions with a care manager (CM), the majority occurring over the phone. Participants endorsed an average of 7 pain locations. All participants received pain education, skills in self-monitoring, goal setting/behavioral activation and relaxation training. Pain interference scores (impact on activity and enjoyment), tracked weekly by the CM, significantly decreased across sessions. 89% of participants received recommendations for CBT skills, 65% received referrals for additional treatments targeting pain interference, and 43% received care coordination. 75% of participants reported 6 or more medications/supplements at both the first and last session, with changes recommended primarily for headache treatment. Feedback from participants and providers was positive. Discussion: TBI Care, a novel patient-centered CC approach, was flexibly delivered, tailored to the needs of those living with TBI and chronic pain, with a high level of participant engagement, and satisfaction among participants and providers. This approach, prioritizing pain self-management strategies and other non-pharmacological approaches, along with optimizing pharmacological treatment, led to significant reductions in self-reported pain interference and intensity during the intervention. Using a CC model in TBI is feasible and successfully improved access to evidence-based treatments for chronic pain as well as outcomes for pain interference and intensity. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03523923.

Vaginal Bacteria and Proinflammatory Host Immune Mediators as Biomarkers of Human Immunodeficiency Virus Acquisition Risk Among African Women.

BACKGROUND: Few investigations have assessed contributions of both vaginal bacteria and proinflammatory immune mediators to human immunodeficiency virus (HIV) acquisition risk in a prospective cohort. METHODS: We conducted a nested case-control study of African women who participated in a randomized placebo-controlled trial of daily oral versus vaginal tenofovir-based preexposure prophylaxis for HIV infection. Vaginal concentrations of 23 bacterial taxa and 16 immune mediators were measured. Relationships between individual bacterial concentrations or immune mediators and HIV risk were analyzed using generalized estimating equations in a multivariable model. Factor analysis assessed relationships between combinations of bacterial taxa, immune mediators, and HIV acquisition risk. RESULTS: We identified 177 HIV pre-seroconversion visits from 150 women who acquired HIV and 531 visits from 436 women who remained HIV uninfected. Fourteen bacterial taxa and 6 proinflammatory cytokines and chemokines were individually associated with greater HIV risk after adjusting for confounders. Women with all 14 taxa versus <14 taxa (adjusted odds ratio [aOR], 4.45 [95% confidence interval {CI}, 2.20-8.98]; P < .001) or all 6 immune mediators versus <6 mediators (aOR, 1.77 [95% CI, 1.24-2.52]; P < .001) had greater risk for HIV acquisition. Factor analysis demonstrated that a bacterial factor comprised of 14 high-risk bacterial taxa (aOR, 1.57 [95% CI, 1.27-1.93]; P < 0.001) and the interferon gamma-induced protein 10 (highest quartile: aOR, 3.19 [95% CI, 1.32-7.72]; P = 0.002) contributed to the highest HIV risk. CONCLUSIONS: Bacterial and host biomarkers for predicting HIV acquisition risk identify women at greatest risk for HIV infection and can focus prevention efforts.

Nyakaza-Move-for-Health: A Culturally Tailored Physical Activity Intervention for Adolescents in South Africa Using the Intervention Mapping Protocol.

BACKGROUND: The Nyakaza-Move-for-Health intervention program was developed in response to the alarming rise in non-communicable diseases (NCDs) globally, in sub-Saharan Africa and South Africa. The rise in NCDs is attributed to the low levels of participation in physical activity (PA) among adolescents. Therefore, this study aimed to design a culturally tailored PA intervention for adolescents, guided by the Intervention Mapping (IM) protocol. The intervention program aims to address the multifaceted determinants of physical activity behavior, promote healthy lifestyles and improve adolescent fitness levels. METHODS: The Intervention Mapping protocol was applied to design the intervention program. The IM has 6 steps: (1) Needs assessment, (2) developing a logic model of the problem (LMP), (3) Formulating program outcomes and objectives, (4) Program design and production, (5) Generating implementation plan, and (6) Generating intervention evaluation plan. Participants included (n = 48) adolescent learners recruited from 8 (n = 8) participating schools. Adolescent learners participated in focus group discussions (FGD) to identify personal, interpersonal and environmental determinants of physical inactivity. Twenty-six (n = 26) key informant stakeholders participated in a stakeholder engagement workshop (SEW) to determine the motivators and constraints in implementing physical activity interventions. RESULTS: The Nyakaza intervention program's process development involved extensive stakeholder engagement, capacity development training, and integration of community feedback into the design. The intervention included a social marketing campaign and structured after-school physical activity sessions based on the Health Belief Model (HBM) and Transtheoretical Model (TTM). Implementation and evaluation plans were created, emphasizing real-time monitoring and adaptations. Strategies to enhance parental and community support were developed to address participation barriers. Although not tested in this study, these plans laid a robust foundation for fostering sustainable behavior change and improving physical activity among adolescents in resource-constrained settings. CONCLUSION: The Nyakaza-Move-for-Health intervention demonstrates a promising framework for promoting adolescent physical activity and addressing Non-Communicable Diseases in a culturally relevant manner. The systematic approach, grounded in the intervention mapping protocol, ensured a robust and replicable intervention design. Future research should focus on long-term follow-up, integrating objective physical activity measures, and expanding the program to include nutrition education. Addressing identified barriers, such as parental involvement, is crucial for enhancing the intervention's effectiveness and sustainability.

Beyond modular enhancers: new questions in cis-regulatory evolution.

Our understanding of how cis-regulatory elements work has advanced rapidly, outpacing our evolutionary models. In this review, we consider the implications of new mechanistic findings for evolutionary developmental biology. We focus on three different debates: whether evolutionary innovation occurs more often via the modification of old cis-regulatory elements or the emergence of new ones; the extent to which individual elements are specific and autonomous or multifunctional and interdependent; and how the robustness of cis-regulatory architectures influences the rate of trait evolution. These discussions lead us to propose new questions for the evo-devo of cis-regulation.

Clinical cohort of nonalcoholic fatty liver disease in a primary care setting.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is increasingly common, and primary care physicians (PCPs) are often the first to diagnose NAFLD. While guidelines on NAFLD management in primary care exist, there are limited data on clinical practice patterns. Approach: We gathered data from over 370,000 patients with at least one PCP visit between July 2016 and September 2023. Using ICD-10 codes to identify patients with a diagnosis of NAFLD or Nonalcoholic Steatohepatitis (NASH), we extracted demographics, comorbidities, laboratory results, prescriptions, imaging orders, and referrals to describe their care. Results: We identified 10,334 patients with a diagnosis code of NAFLD (93.1%) and/or NASH (16.7%) during a PCP visit. Just over half (54.8%) were female, mean age was 52.8 years, and mean BMI was 33.2 kg/m2 with 90% having overweight or obese. More than 50% had hypertension and hyperlipidemia, and 38% had diabetes. At the diagnosis visit, 2.7% had ultrasound elastography ordered, 2.7% liver biopsy, and less than 1% magnetic resonance elastography. During follow-up ranging from 0 to 7 years, patients had a mean of 15 encounters, during which 4% were diagnosed with fibrosis or cirrhosis. Only 24.2% of patients were referred to a nutritionist and 18% had an appointment, and only 0.7% were referred to hepatology and 3.8% saw a hepatologist. Conclusion: PCPs have not widely implemented clinical practice guidelines for NAFLD, resulting in suboptimal care including for the substantial minority with fibrosis or cirrhosis. Patients might benefit from targeted NAFLD education for PCPs and improved decision and management support.

Uptake and Persistence of Safer Conception Strategies Among South African Women Planning for Pregnancy.

Safer conception strategies can minimize HIV acquisition during periconception periods among women living in HIV-endemic areas. We examined uptake and predictors of persistent use of the same safer conception strategy among a cohort of HIV-uninfected South African women ages 18-35 years planning for pregnancy with a partner living with HIV or of unknown HIV-serostatus. The safer conception strategies we evaluated included oral PrEP, condomless sex limited to peak fertility, and waiting for a better time to have a child (until, for example, the risks of HIV acquisition are reduced and/or the individual is prepared to care for a child); persistence was defined as using the same safer conception strategy from the first visit through 9 months follow-up. Modified Poisson regression models were used to examine predictors of persistent use of the same strategy. The average age of 227 women in our cohort was 24.6 (range: 18.0, 35.7) years. In this cohort, 121 (74.2%) women reported persisting in the same strategy through 9 months. Employment and HIV knowledge were associated with the persistent use of any strategy. Our results highlight the need to provide safer conception services to women exposed to HIV during periconception periods. Findings also offer some insights into factors that might influence persistent use. Further research is needed to better understand how to involve male partners and how their involvement might influence women's consistent use of safer conception strategies during periconception periods.

Characteristics and real-world outcomes of patients with epithelial ovarian cancer who received niraparib plus bevacizumab first-line maintenance therapy in the COMB1NE study.

OBJECTIVE: In the phase 2 OVARIO trial (NCT03326193) investigating niraparib-bevacizumab first-line maintenance, median progression-free survival was 14.2 months (95% confidence interval (CI) 8.6 to 16.8) for patients with homologous recombination (HR)-proficient (HRp) epithelial ovarian cancer, and 12.1 months (95% CI8.0-not evaluated) for patients with undefined HR status. However, real-world data are limited for patients who receive niraparib-bevacizumab first-line maintenance therapy. The COMB1NE study describes real-world clinical outcomes (time to treatment discontinuation; time to next treatment) in patients with epithelial ovarian cancer who received niraparib-bevacizumab first-line maintenance, regardless of first-line bevacizumab use. METHODS: This real-world, retrospective study used a US nationwide electronic health record-derived deidentified database. Eligible patients were 18 years or older at initial epithelial ovarian cancer diagnosis and initiated niraparib-bevacizumab first-line maintenance (January 1, 2017-September 2, 2022) following first-line treatment. The index date was the start of first-line maintenance. Patients were followed until death, last clinical activity, or end of study, whichever occurred first. Time to treatment discontinuation and time to next treatment, a proxy for real-world progression-free survival, were estimated using the Kaplan-Meier method. RESULTS: Among 59 included patients, the median age was 67 years (interquartile range (IQR) 61-76), and 81.4% had stage III/IV epithelial ovarian cancer at diagnosis. Overall, 83.1% of patients had BRCA wild-type with either HRp or HR status unknown disease. Median time to treatment discontinuation of first-line maintenance was 11.8 months (95% CI 8.7 to 13.5). Median time to next treatment was 14.1 months (95% CI 11.3 to 16.6). At 6 months after index, 77.9% of patients had not initiated second-line treatment; at 12 months, 61.3% had not. CONCLUSION: In this real-world study of patients receiving niraparib-bevacizumab first-line maintenance, the majority of whom had HRp/HR status unknown, the median time to next treatment was consistent with observed progression-free survival in patients with similar HR status in the OVARIO study.

α -catenin phosphorylation is elevated during mitosis to resist apical rounding and epithelial barrier leak.

Epithelial cell cohesion and barrier function critically depend on α -catenin, an actin-binding protein and essential constituent of cadherin-catenin-based adherens junctions. α -catenin undergoes actomyosin force-dependent unfolding of both actin-binding and middle domains to strongly engage actin filaments and its various effectors, where this mechanosensitivity is critical for adherens junction function. We previously showed that α -catenin is highly phosphorylated in an unstructured region that links mechanosensitive middle- and actin-binding domains (known as the P-linker region), but the cellular processes that promote α -catenin phosphorylation have remained elusive. Here, we leverage a previously published phosphor-proteomic data set to show that the α -catenin P-linker region is maximally phosphorylated during mitosis. By reconstituting α -catenin Crispr KO MDCK with wild-type, phospho- mutant and mimic forms of α -catenin, we show that full phosphorylation restrains mitotic cell rounding in the apical direction, strengthening interactions between dividing and non-dividing neighbors to limit epithelial barrier leak. Since major scaffold components of adherens junctions, tight junctions and desmosomes are also differentially phosphorylated during mitosis, we reason that epithelial cell division may be a tractable system to understand how junction complexes are coordinately regulated to sustain barrier function under tension-generating morphogenetic processes.

Genomic identification of Oryctes rhinoceros nudivirus isolates, a biocontrol agent for coconut rhinoceros beetle.

The coconut rhinoceros beetle (Oryctes rhinoceros, CRB) is a serious pest of coconut and oil palms. It is native to South and Southeast Asia and was inadvertently introduced to Samoa in 1909. It has invaded many other Pacific countries throughout the last century. Oryctes rhinoceros nudivirus (OrNV), a natural pathogen of CRB in its native range, was successfully introduced as a classical biocontrol agent and has effectively suppressed invasive CRB populations for decades. However, resurgence of CRB has been recorded, with new invasions detected in several Pacific Island Countries and Territories. Additionally, new populations of CRB are emerging in some invaded areas that have a degree of resistance to the virus isolates commonly released for CRB biocontrol. Here, we designed a fast and reliable tool for distinguishing between different OrNV isolates that can help with the selection process to identify effective isolates for management of new CRB invasions. A comparison of 13 gene/gene region sequences within the OrNV genome of 16 OrNV isolates from native and invaded ranges allowed us to identify unique Single Nucleotide Polymorphisms (SNPs). With these SNPs, we developed an assay using multiplex PCR-amplicon-based nanopore sequencing to distinguish between OrNV isolates. We found that as few as four gene fragments were sufficient to identify 15 out of 20 OrNV isolates. This method can be used as a tool to monitor the establishment and distribution of OrNV isolates selected for release as biocontrol agents in CRB-infected areas.