The use of actigraphy to objectively define motion and function before and after shoulder arthroplasty.

Introduction: Actigraphy is a quantitative means of measuring activity data that has proven viable in post-surgery recovery analysis for arthroplasties in lower extremities, but scant literature has been published on the utilization actigraphy to evaluate shoulder motion and function before and after shoulder arthroplasty. The purpose of this prospective cohort study is to identify if actigraphy can serve as a valid means for objective evaluation of shoulder function and motion before and after shoulder arthroplasty. Secondarily, the data collected by the actigraphy can be analyzed with standard patient-reported outcomes to report correlations between the subjective and objective methods used in this study. Materials and methods: Sixty-four subjects wore an actigraphy device for one day at pre-op, six, twelve and twenty-four weeks. In addition, subjects completed three patient-reported outcome surveys at each time-point. Student t-tests were used to compare percent activity preoperatively with 24-weeks and to compare PROs preoperatively with 24-week results; categorical variables were compared with one-way ANOVAs. Results: All Patient reported outcome scores significantly improved following arthroplasty (p-value<0.001). The percent of physical activity was highly correlated with vector magnitude (p-value<0.001), but neither percent activity or the vector magnitude were correlated with any of the PROs: UCLA Pain p-value = 0.656, SANE p-value = 0.328, UCLA Function p-value = 0.532. Conclusions: Actigraphy results from this study mirror findings in previous literature utilizing the technology in similar manners and demonstrate its potential for motion and function analysis before and after total shoulder arthroplasties. Despite both being suitable methods independently for the evaluation of shoulder function, there was no significant correlation between standard actigraphy measurements and PROs at 24-weeks. Future research to determine clinical utility and an overall broader scope for actigraphy monitoring could benefit from improved technology, such as increased battery life for prolonged durations of data collection during observation periods.

Quantifying differences in iron deficiency-attributable anemia during pregnancy and postpartum.

Pregnant women in resource-limited settings are highly susceptible to anemia and iron deficiency, but the etiology of postpartum anemia remains poorly defined. To inform the optimal timing for anemia interventions, changes in iron deficiency-attributable anemia through pregnancy and postpartum need to be understood. In 699 pregnant Papua New Guinean women attending their first antenatal care appointment and following up at birth and 6 and 12 months postpartum, we undertake logistic mixed-effects modeling to determine the effect of iron deficiency on anemia and population attributable fractions, calculated from odds ratios, to quantify the contribution of iron deficiency to anemia. Anemia is highly prevalent during pregnancy and 12 months postpartum, with iron deficiency increasing the odds of anemia during pregnancy and, to a lesser extent, postpartum. Iron deficiency accounts for ≥72% of anemia during pregnancy and 20%-37% postpartum. Early iron supplementation during and between pregnancies could break the cycle of chronic anemia in women of reproductive age.

Planning, implementation, and sustaining high coverage of human papillomavirus (HPV) vaccination programs: What works in the context of low-resource countries?

Cervical cancer due to human papillomavirus (HPV) infection is a leading cause of mortality among women in low-resource settings. Many Sub-Saharan African countries have introduced HPV vaccination programs at the national level in the last few years. However, countries are struggling to maintain sustainable coverage. This study focuses on the introduction and sustainability challenges, context-specific key lessons learned, and mechanisms of action to achieve high sustainable coverage from low and lower-middle-income countries (LLMICs) that have introduced HPV vaccination programs by collating evidence from a literature review and key informant interviews. Local data availability was a challenge across countries, with the lack or absence of registries, data collection and reporting mechanisms. Multi-sectoral coordination and early involvement of key stakeholders were cited as an integral part of HPV programs and facilitators for sustainable coverage. Key informants identified periodic sensitization and training as critical due to high staff turnover. Health workforce mobilization was fundamental to ensure that the health workforce is aware of the disease etiology, eligibility requirements, and can dispel misinformation. Schools were reported to be an ideal sustainable platform for vaccination. However, this required teachers to be trained, which was often not considered in the programs. District-level staff were often poorly informed and lacked the technical and logistic capacity to support vaccination rounds and data collection. To improve the sustainability of HPV vaccination programs, there is a need for timely microplanning, efficient preparedness assessment, assessing training approaches, periodic training, finding innovative ways to achieve equity and adoption of a bottom-up approach to ensure that processes between districts and central level are well-connected and resources are distributed efficiently.

Acceptability of an integrated school-based HPV vaccination program within two districts of Tanzania: A qualitative descriptive study.

Tanzania has one of the highest cervical cancer incidence and mortality rates in sub-Saharan Africa. The Tanzanian Ministry of Health developed an integrated adolescent health program, HPV-Plus, that combines HPV vaccination with additional health services: nutritional assessments, vision screening, and vaccination for adolescent girls, and education for all genders. This qualitative descriptive study evaluated the acceptability of the HPV-Plus program in two districts in Tanzania. Key informants comprising of adolescent girls, parents, program planners, and program implementers in Njombe and Dar es Salaam Tanzania were interviewed to assess the program acceptability. Transcripts were analyzed using a team-based iterative thematic analysis approach, consisting of both inductive and deductive coding. The Theoretical Framework of Acceptability was used to guide analysis, with themes categorized according to theoretical constructs of intervention coherence, affective attitudes and perceptions, and perceived effectiveness. Overall acceptability of the HPV-Plus program was high among stakeholders. The most salient finding regarding factors that influenced HPV vaccine acceptability was largely related to education and knowledge levels surrounding the HPV, cervical cancer, and HPV vaccines. The educational component of the HPV-Plus program was key in increasing acceptability. Parents reported the lowest acceptability towards the program. This was found to be primarily due to perceptions of not being sufficiently engaged throughout program implementation. Increasing acceptability of HPV vaccination programs among key stakeholders is critical to facilitating vaccine uptake and meeting vaccination coverage targets. Our results demonstrate that the inclusion of a comprehensive education component within the HPV-Plus program was key in facilitating HPV vaccine acceptability amongst stakeholders.

Feasibility and sustainability of a school-based platform for integrated delivery of HPV vaccination with adolescent health services in Tanzania: qualitative insights from stakeholders.

To meet lofty human papillomavirus (HPV) immunization goals in Tanzania, the Ministry of Health integrated HPV vaccination with adolescent health services using a school-based approach. A qualitative study was conducted in June-July 2021, examining the feasibility and sustainability of an integrated service package, HPV Plus. In-depth interviews with 46 programme implementers (i.e. health-care workers and teachers) and planning stakeholders (i.e. government officials and school administrators) in Dar es Salaam and Njombe Regions explored enablers and constraints to HPV Plus programme implementation, including resource and staffing requirements. Two facilitators and three barriers to HPV Plus feasibility and sustainability were identified from thematic analysis of interviews. Interviewed stakeholders emphasized the programme's feasibility, especially if the efficiencies offered by a school-based platform were optimized. Implementation facilitators included (1) optimized service delivery efficiency through a school-based platform and (2) resources saved by combining adolescent health services and HPV immunization into a single programme package. Key barriers to HPV Plus feasibility and sustainability were (1) time, space and resource constraints (e.g. commodity stockouts and challenges delivering the complete service package to large cohorts of students within allotted times); (2) human resource gaps and increased workloads within the health workforce and (3) insufficient referral mechanisms linking schools to health facilities. Scaling up HPV Plus will require proactive commodity procurement and security; resource mobilization to reach ambitious service delivery targets and close co-ordination of programme implementation with school administrators.

Point-of-care HPV DNA testing of self-collected specimens and same-day thermal ablation for the early detection and treatment of cervical pre-cancer in women in Papua New Guinea: a prospective, single-arm intervention trial (HPV-STAT).

BACKGROUND: WHO recommends human papillomavirus (HPV) testing and same-day treatment for cervical screening in low-income and middle-income countries (LMICs); however, few published data exist on the validity of the strategy. We aimed to evaluate the clinical performance, treatment completion rates, adverse events profile, and acceptability of a fully integrated strategy, comprising point-of-care HPV DNA testing of self-collected specimens and same-day thermal ablation, for screening of cervical cancer in women in Papua New Guinea. METHODS: HPV-STAT was a large-scale, prospective, single-arm intervention trial conducted at two clinical sites in Papua New Guinea. Cervical screening clinics with an on-site consultant gynaecologist were selected in consultation with national and provincial health authorities, church health services, and local stakeholders. Eligible participants were women aged 30-59 years attending cervical screening services at the two clinics, who were willing to comply with study procedures and able to provide written informed consent. Women self-collected vaginal specimens for point-of-care GeneXpert testing (Cepheid, Sunnyvale, CA, USA) for oncogenic HPV types. Women testing positive for HPV underwent pelvic examination followed by same-day thermal ablation or referral for gynaecology review. All HPV-positive women and a 15% random sample of HPV-negative women provided a clinician-collected cervical specimen for liquid-based cytology. The primary outcome was clinical performance (ie, sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) of the strategy for the detection of high-grade squamous intraepithelial lesion (HSIL) or worse. This trial is registered with ISRCTN, ISRCTN13476702. FINDINGS: Between June 5, 2018, and Jan 6, 2020, we recruited 4285 women, 3638 (84·9%) of whom tested negative for HPV and 647 (15·1%) tested positive for one or more oncogenic HPV type. Sensitivity of the algorithm to detect HSIL or worse was 85·4% (95% CI 81·0-89·6), with specificity 89·6% (88·6-90·6), PPV 35·2% (31·6-39·0), and NPV 98·9% (98·6-99·2). Among HPV-positive women, 602 (93·0%) received same-day thermal ablation and 42 (6·5%) were referred for gynaecology review, 37 (88·1%) of whom attended. Acceptability was high among both HPV-positive and HPV-negative women. Among the 329 HPV-positive women who attended a 3-month follow-up visit, 51 (15·5%) reported mild adverse symptoms that resolved in all cases by the follow-up visit. There were no serious adverse events. INTERPRETATION: We conducted the first real-world evaluation of a fully integrated point-of-care HPV self-collect, test, and treat strategy for same-day cervical screening in a LMIC and found it to be effective, acceptable, and safe when implemented at scale in primary health-care facilities in Papua New Guinea. Our findings support the introduction and scale-up of HPV screening and treatment for the control and elimination of cervical cancer in LMICs, as recommended by WHO. FUNDING: Australian National Health and Medical Research Council.

Integration of other services with human papillomavirus vaccination; lessons from earlier in the life course highlight the need for new policy and implementation evidence.

Integration of vaccination against human papillomavirus (HPV) with other essential health services for adolescents has been proposed in global strategies and tested in demonstration projects in low- and middle-income countries (LMIC). Published experiences, global guidance, and one key example, the implementation of "HPV Plus" in Tanzania, all demonstrate the need for greater operational evidence to guide future implementation and policy. Review of experiences earlier in the life course, integrating post-partum family planning with infant immunization, show lessons from 13 LMICs that can apply to provision of adolescent health information and services alongside HPV vaccination. Three distinct models of integration emerge from this review comprising: 1) multiple tasks and functions by health staff providing vaccination and other care, or 2) secondary tasks added to the main function of vaccination, or 3) co-location of matched services provided by different staff. These models, with strengths and weaknesses demonstrated in family planning and immunization experiences, apply in different ways to the three main platforms used for HPV vaccination: school, facility or community. For HPV vaccination policy and programming, an initial need is to combine the existing evidence on vaccine service delivery - including coverage, efficiency, cost, and cost-effectiveness information - with what is known on how integration works in practice; the operational detail and models employed. This synthesis may enable assessment which models best suit the different service delivery platforms. An additional need is to link this with more tailored local assessments of the adolescent burden of disease and other determinants of their well-being to develop new thinking on what can and cannot be done to integrate other services alongside HPV vaccination. New approaches placing adolescents at the center are needed to design services tailored to their preferences and needs. The potential synergies with cervical cancer screening and treatment for older generations of women, also require further exploration. Coordinated action aligning HPV vaccination with broader adolescent health and wellbeing will generate social, economic and demographic benefits, which in themselves are sufficient justification to devote more attention to integrated approaches.

Integrating HPV vaccination programs with enhanced cervical cancer screening and treatment, a systematic review.

A WHO global strategy launched in November 2020 sets out an ambitious pathway towards the worldwide elimination of cervical cancer as a public health problem within the next 100 years. Achieving this goal will require investment in innovative approaches. This review aims to describe integrated approaches that combine human papillomavirus (HPV) vaccination and cervical cancer screening in low- and middle-income countries (LMIC), and their efficacy in increasing uptake of services. A systematic review was conducted analyzing relevant papers from Embase, Medline, CINAHL and CAB Global Health databases, as well as grey literature. Narrative synthesis was performed on the included studies. Meta-analysis was not appropriate due to the heterogeneity and nature of included studies. From 5,278 titles screened, 11 uncontrolled intervention studies from four countries (from Africa and east Asia) were included, all from the past 12 years. Four distinct typologies of integration emerged that either increased awareness of HPV and/or cervical cancer screening, and/or coupled the delivery of HPV vaccination and cervical cancer screening programs. The synthesis of findings suggests that existing HPV vaccination programs can be a useful pathway for educating mothers and other female caregivers about cervical cancer screening; through in person conversations with care providers (preferred) or take-home communications products. Integrated service delivery through outreach and mobile clinics may overcome geographic and economic barriers to access for both HPV vaccination and cervical cancer screening, however these require significant program and system resources. One study promoted HPV vaccination as part of integrated service delivery, but there were no other examples found that examined use of cervical cancer screening platforms to promote or educate on HPV vaccination. This review has demonstrated gaps in published literature on attempts to integrate HPV vaccination and cervical cancer screening. The most promising practices to date seem to relate to integrated health communications for cervical cancer prevention. Future research should further explore the opportunities for integrated health communications to support the efforts towards the new global cervical cancer elimination agenda, and costs and feasibility of integrated service delivery for underserved populations.

Promoting adolescent health through integrated human papillomavirus vaccination programs: The experience of Togo.

The introduction of the Human papillomavirus (HPV) vaccine has shown potential to not only prevent cervical cancer but also drive adolescents' access to other health care services, even in low-income countries. Few studies have been conducted to date to identify best practices and estimate the acceptance, operational challenges and benefits of including broader adolescent health interventions into immunization efforts, knowledge which is essential to supporting widespread integration. In this paper we review the efforts undertaken by the government of Togo to integrate adolescent health programming with the HPV vaccination roll out. With the support of partners (GAVI, WHO, UNFPA and UNICEF), the country successfully completed, in 2017, two years of an HPV vaccine demonstration project, which entailed vaccinating 10-year-old girls against HPV in two selected districts of the country and integrating a health education component focused on puberty education / menstrual hygiene and hand washing practice. Our study is a post-implementation program evaluation, using mixed methods to assess key questions of feasibility and acceptability of an integrated adolescent package of care. It showed that the HPV vaccination in conjunction with the health education sessions was well received by the majority of health care providers, teachers and parents. Our study confirmed that in Togo it proved feasible to combine education and HPV vaccination in school-based service delivery. However, more operational research is neded to understand how to increase the impact and sustainability of the co-delivery of interventions. We did not analyze the health impact and cost implications of the intervention, which will be an important consideration for scaling up such integration efforts alongside routine immunization.

Designing a Pro-Equity HPV Vaccine Delivery Program for Girls Who Have Dropped Out of School: Community Perspectives From Uttar Pradesh, India.

India experiences a substantial burden of cervical cancer and accounts for nearly one third of cervical cancer deaths worldwide. While human papillomavirus (HPV) vaccines have been introduced subnationally in some states, HPV has not yet been rolled out nationally. Given the target age group, schools are the most common delivery channel for HPV vaccines, but this fails to account for local girls who never attended or no longer attend school. We conducted a qualitative, design-informed, community-based study conducted in Uttar Pradesh, India. We assessed facilitators and barriers among out-of-school girls and proposed program characteristics to inform the design of pro-equity HPV vaccine delivery programs for out-of-school girls. Programs should improve parental knowledge of the risk of cervical cancer, engage vaccinated girls as vaccine champions, utilize varied media options for low-literacy populations, and ensure that HPV vaccine services are accessible and flexible to accommodate out-of-school girls. In areas with poor or irregular school attendance among adolescent girls, HPV vaccine coverage will remain suboptimal until programs can effectively address their needs and reach this priority population. Our findings present a meaningful opportunity for program planners to purposefully design HPV vaccination programs according to these parameters, rather than modifying existing programs to include HPV vaccine. Adolescent girls, their parents, and other community members should be involved in program design to ensure that the program can effectively meet the needs of adolescent girls who are not in school.

Women With Polycystic Ovary Syndrome Have an Increased Risk of Major Cardiovascular Events: a Population Study.

CONTEXT: The effects of polycystic ovary syndrome (PCOS) on cardiovascular morbidity and mortality are unclear. OBJECTIVE: This work aims to establish the relative risk of myocardial infarction (MI), stroke, angina, revascularization, and cardiovascular mortality for women with PCOS. METHODS: Data were extracted from the Clinical Practice Research Datalink Aurum database. Patients with PCOS were matched to controls (1:1) by age, body mass index (BMI) category, and primary care practice. The primary outcome was the time to major adverse cardiovascular event (MACE); a composite end point incorporating MI, stroke, angina, revascularization and cardiovascular mortality. Secondary outcomes were the individual MACE end points. RESULTS: Of 219 034 individuals with a diagnosis of PCOS, 174 660 (79.7%) met the eligibility criteria and were matched. Crude rates of the composite end point, MI, stroke, angina, revascularization, and cardiovascular mortality were respectively 82.7, 22.7, 27.4, 32.8, 10.5, and 6.97 per 100 000 patient-years for cases, and 64.3, 15.9, 25.7, 19.8, 7.13, and 7.75 per 100 000 patient-years for controls. In adjusted Cox proportional hazard models (CPHMs), the hazard ratios (HRs) were 1.26 (95% CI, 1.13-1.41), 1.38 (95% CI, 1.11-1.72), 1.60 (95% CI, 1.32-1.94), and 1.50 (95% CI, 1.08-2.07) for the composite outcome, MI, angina, and revascularization, respectively. In a time-dependent CPHM, weight gain (HR 1.01; 1.00-1.01), prior type 2 diabetes mellitus (T2DM) (HR 2.40; 1.76-3.30), and social deprivation (HR 1.53; 1.11-2.11) increased risk of progression to the composite end point. CONCLUSION: The risk of incident MI, angina, and revascularization is increased in young women with PCOS. Weight and T2DM are potentially modifiable risk factors amenable to intervention.

Acting on the call: A framework for action for rapid acceleration of access to the HPV vaccination in low- and lower-middle-income countries.

Cervical cancer, caused by HPV infection, is responsible for more than 311  000 preventable deaths every year. A global call to accelerate efforts to eliminate this disease has generated a new global strategy proposing ambitious, but achievable, targets for HPV vaccination of girls, and screening and treatment of women. The present paper addresses the suboptimal access to HPV vaccination in low-income and lower-middle-income countries (LICs/LMICs), where the burden of disease weighs most heavily, in part through co-infection with HIV. A proposed framework for action was formulated by first reviewing the reasons underlying gaps in HPV vaccine coverage. Good practices from recent introductions of HPV vaccine at scale in LICs/LMICs were then assessed based on targeted literature reviews and the experience and views of the authors. Difficulties in uptake and coverage of the HPV vaccine relate to the costs of the vaccine and service delivery, lack of prioritization, the challenges of vaccinating adolescents, and shortage of vaccines as the supply failed to keep pace with the rapid expansion in global demand, including from LICs/LMICs. The framework for action calls for new strategic thinking to consolidate global learning and invigorate operationalization at a country level.

Health outcomes of iron supplementation and/or food fortification in iron-replete children aged 4-24 months: protocol for a systematic review and meta-analysis.

BACKGROUND: Direct supplementation or food fortification with iron are two public health initiatives intended to reduce the prevalence of iron deficiency (ID) and iron deficiency anaemia (IDA) in 4-24-month-old infants. In most high-income countries where IDA prevalence is < 15%, the recommended daily intake levels of iron from supplements and/or consumption of fortified food products are at odds with World Health Organisation (WHO) guidelines that recommend shorter-term (3 months/year) supplementation only in populations with IDA prevalence > 40%. Emerging concerns about delayed neurological effects of early-life iron overexposure have raised questions as to whether recommended guidelines in high-income countries are unnecessarily excessive. This systematic review will gather evidence from supplementation/fortification trials, comparing health outcomes in studies where iron-replete children did or did not receive additional dietary iron; and determine if replete children at study outset were not receiving additional iron show changes in haematological indices of ID/IDA over the trial duration. METHODS: We will perform a systematic review of the literature, including all studies of iron supplementation and/or fortification, including study arms with confirmed iron-replete infants at the commencement of the trial. This includes both dietary iron intervention or placebo/average dietary intakes. One reviewer will conduct searches in electronic databases of published and ongoing trials (Medline, Web of Science, Scopus, CENTRAL, EBSCO [e.g. CINAHL Complete, Food Science and Technology Abstracts], Embase, ClinicalTrials.gov, ClinicalTrialsRegister.eu and who.it/trialsearch), digital theses and dissertations (WorldCat, Networked Digital Library of Theses and Dissertations, DART-Europe E-theses Portal, Australasian Digital Theses Program, Theses Canada Portal and ProQuest). For eligible studies, one reviewer will use a data extraction form, and a second reviewing entered data for accuracy. Both reviewers will independently perform quality assessments before qualitative and, if appropriate, quantitative synthesis as a meta-analysis. We will resolve any discrepancies through discussion or consult a third author to resolve discrepancies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement will be used as the basis for reporting. DISCUSSION: Recommended iron supplementation and food fortification practices in high-income countries have been criticised for being both excessive and based on outdated or underpowered studies. This systematic review will build a case for revisiting iron intake guidelines for infants through the design of new trials where health effects of additional iron intake in iron-replete infants are the primary outcome. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018093744.

Barriers to cervical cancer screening among rural women in eastern China: a qualitative study.

OBJECTIVES: To explore barriers to free cervical cancer screening among rural women in China from the perspective of women, healthcare providers and women's husbands to inform intervention planning. DESIGN: A qualitative study framed around potential policy and practice options, drawing on the concepts of descriptive phenomenology and implementation research. SETTING: This study was carried out at township level within two counties in Jining Prefecture of eastern China. PARTICIPANTS AND DATA COLLECTION: Semi-structured in-depth interviews with 21 women and five healthcare providers, focus group discussions with nine healthcare providers and key informant interviews with four husbands of women eligible for screening. RESULTS: Thematic analysis generated five major themes: (1) gaps in knowledge of cervical cancer and health awareness, (2) fear of cancer and screening outcomes, (3) cultural barriers including reticence for intimate examinations, (4) influence of close contacts on screening decisions and (5) inconvenience. These demonstrate key knowledge gaps challenging current community health education. Important barriers, including fear of treatment cost and the time needed for screening, were also raised. CONCLUSION: Our study details important barriers to cervical cancer screening relating to knowledge gaps, attitudes of fear or embarrassment and the role of contacts and service models. These provide data for policy and planning to improve the screening that will decrease the incidence and mortality rates of cervical cancer in China.

Polycystic Ovary Syndrome Is Associated With Adverse Mental Health and Neurodevelopmental Outcomes.

Context: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and subfertility, but the effects on mental health and child neurodevelopment are unclear. Objectives: To determine if (1) there is an association between PCOS and psychiatric outcomes and (2) whether rates of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are higher in children of mothers with PCOS. Design: Data were extracted from the Clinical Practice Research Datalink. Patients with PCOS were matched to two control sets (1:1) by age, body mass index, and primary care practice. Control set 2 was additionally matched on prior mental health status. Primary outcomes were the incidence of depression, anxiety, and bipolar disorder. Secondary outcomes were the prevalence of ADHD or ASD in the children. Results: Eligible patients (16,986) were identified; 16,938 and 16,355 were matched to control sets 1 and 2, respectively. Compared with control set 1, baseline prevalence was 23.1% vs 19.3% for depression, 11.5% vs 9.3% for anxiety, and 3.2% vs 1.5% for bipolar disorder (P < 0.001). The hazard ratio for time to each endpoint was 1.26 (95% confidence interval 1.19 to 1.32), 1.20 (1.11 to 1.29), and 1.21 (1.03 to 1.42) for set 1 and 1.38 (1.30 to 1.45), 1.39 (1.29 to 1.51), and 1.44 (1.21 to 1.71) for set 2. The odds ratios for ASD and ADHD in children were 1.54 (1.12 to 2.11) and 1.64 (1.16 to 2.33) for set 1 and 1.76 (1.27 to 2.46) and 1.34 (0.96 to 1.89) for set 2. Conclusions: PCOS is associated with psychiatric morbidity and increased risk of ADHD and ASD in their children. Screening for mental health disorders should be considered during assessment.

Sex differences in microRNA-mRNA networks: examination of novel epigenetic programming mechanisms in the sexually dimorphic neonatal hypothalamus.

BACKGROUND: Sexual differentiation of the male brain, and specifically the stress circuitry in the hypothalamus, is primarily driven by estrogen exposure during the perinatal period. Surprisingly, this single hormone promotes diverse programs of sex-specific development that vary widely between different cell types and across the developing male brain. The complexity of this phenomenon suggests that additional layers of gene regulation, including microRNAs (miRNAs), must act downstream of estrogen to mediate this specificity. METHODS: To identify noncanonical mediators of estrogen-dependent sex-specific neural development, we assayed the miRNA complement of the mouse PN2 hypothalamus by microarray following an injection of vehicle or the aromatase inhibitor, formestane. Initially, multivariate analyses were used to test the influence of sex and experimental group on the miRNA environment as a whole. Then, we utilized traditional hypothesis testing to identify individual miRNA with significantly sex-biased expression. Finally, we performed a transcriptome-wide mapping of Argonaute footprints by high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (Ago HITS-CLIP) to empirically characterize targeting relationship between estrogen-responsive miRNAs and their messenger RNA (mRNA) targets. RESULTS: In this study, we demonstrated that the neonatal hypothalamic miRNA environment has robust sex differences and is dynamically responsive to estrogen. Analyses identified 162 individual miRNAs with sex-biased expression, 92 of which were estrogen-responsive. Examining the genomic distribution of these miRNAs, we found three miRNA clusters encoded within a 175-kb region of chromosome 12 that appears to be co-regulated by estrogen, likely acting broadly to alter the epigenetic programming of this locus. Ago HITS-CLIP analysis uncovered novel miRNA-target interactions within prototypical mediators of estrogen-driven sexual differentiation of the brain, including Esr1 and Cyp19a1. Finally, using Gene Ontology annotations and empirically identified miRNA-mRNA connections, we identified a gene network regulated by estrogen-responsive miRNAs that converge on biological processes relevant to sexual differentiation of the brain. CONCLUSIONS: Sexual differentiation of the perinatal brain, and that of stress circuitry in the hypothalamus specifically, seems to be particularly susceptible to environmental programming effects. Integrating miRNA into our conceptualization of factors, directing differentiation of this circuitry could be an informative next step in efforts to understand the complexities behind these processes.

Rules of RNA specificity of hnRNP A1 revealed by global and quantitative analysis of its affinity distribution.

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a multipurpose RNA-binding protein (RBP) involved in normal and pathological RNA metabolism. Transcriptome-wide mapping and in vitro evolution identify consensus hnRNP A1 binding motifs; however, such data do not reveal how surrounding RNA sequence and structural context modulate affinity. We determined the affinity of hnRNP A1 for all possible sequence variants (n = 16,384) of the HIV exon splicing silencer 3 (ESS3) 7-nt apical loop. Analysis of the affinity distribution identifies the optimal motif 5'-YAG-3' and shows how its copy number, position in the loop, and loop structure modulate affinity. For a subset of ESS3 variants, we show that specificity is determined by association rate constants and that variants lacking the minimal sequence motif bind competitively with consensus RNA. Thus, the results reveal general rules of specificity of hnRNP A1 and provide a quantitative framework for understanding how it discriminates between alternative competing RNA ligands in vivo.

Healthcare resource utilization and related financial costs associated with glucose lowering with either exenatide or basal insulin: A retrospective cohort study.

AIMS: Type 2 diabetes is a major health problem placing increasing demands on healthcare systems. Our objective was to estimate healthcare resource use and related financial costs following treatment with exenatide-based regimens prescribed as once-weekly (EQW) or twice-daily (EBID) formulations, compared with regimens based on basal insulin (BI). MATERIALS AND METHODS: This retrospective cohort study used data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES). Patients with type 2 diabetes who received exenatide or BI between 2009 and 2014 as their first recorded exposure to injectable therapy were selected. Costs were attributed to primary care contacts, diabetes-related prescriptions and inpatient admissions using standard UK healthcare costing methods (2014 prices). Frequency and costs were compared between cohorts before and after matching by propensity score using Poisson regression. RESULTS: Groups of 8723, 218 and 2180 patients receiving BI, EQW and EBID, respectively, were identified; 188 and 1486 patients receiving EQW and EBID, respectively, were matched 1:1 to patients receiving BI by propensity score. Among unmatched cohorts, total crude mean costs per patient-year were £2765 for EQW, £2549 for EBID and £4080 for BI. Compared with BI, the adjusted annual cost ratio (aACR) was 0.92 (95% CI, 0.91-0.92) for EQW and 0.82 (95% CI, 0.82-0.82) for EBID. Corresponding costs for the propensity-matched subgroups were £2646 vs £3283 (aACR, 0.80, 0.80-0.81) for EQW vs BI and £2532 vs £3070 (aACR, 0.84, 0.84-0.84) for EBID vs BI. CONCLUSION: Overall, exenatide once-weekly and twice-daily-based regimens were associated with reduced healthcare resource use and costs compared with basal-insulin-based regimens.

Hydrogen Exchange Mass Spectrometry of Related Proteins with Divergent Sequences: A Comparative Study of HIV-1 Nef Allelic Variants.

Hydrogen exchange mass spectrometry can be used to compare the conformation and dynamics of proteins that are similar in tertiary structure. If relative deuterium levels are measured, differences in sequence, deuterium forward- and back-exchange, peptide retention time, and protease digestion patterns all complicate the data analysis. We illustrate what can be learned from such data sets by analyzing five variants (Consensus G2E, SF2, NL4-3, ELI, and LTNP4) of the HIV-1 Nef protein, both alone and when bound to the human Hck SH3 domain. Regions with similar sequence could be compared between variants. Although much of the hydrogen exchange features were preserved across the five proteins, the kinetics of Nef binding to Hck SH3 were not the same. These observations may be related to biological function, particularly for ELI Nef where we also observed an impaired ability to downregulate CD4 surface presentation. The data illustrate some of the caveats that must be considered for comparison experiments and provide a framework for investigations of other protein relatives, families, and superfamilies with HX MS. Graphical Abstract ᅟ.

Contemporary Reproductive Outcomes for Patients With Polycystic Ovary Syndrome: A Retrospective Observational Study.

CONTEXT: Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility and may be associated with adverse pregnancy and neonatal outcomes. However, it is difficult to establish how much of this risk is due to PCOS and how much to obesity. OBJECTIVE: This study aimed to determine the effect of PCOS upon fertility, pregnancy, and neonatal outcomes. DESIGN AND SETTING: Data were extracted from the Clinical Practice Research Datalink (CPRD), a longitudinal anonymized primary care research database in the United Kingdom. Patients with a diagnosis of PCOS were matched to controls (1:2) by age (±1 y), body mass index (± 3 U), and CPRD practice. Standardized fertility ratios before and after diagnosis (index date) were calculated. Rates of miscarriage, pre-eclampsia, gestational diabetes, premature delivery, delivery method, and neonatal outcomes were compared. RESULTS: Nine thousand sixty-eight women with PCOS matched study criteria. Prior to index date the standardized fertility ratio for patients with PCOS was 0.80 (95% confidence interval, 0.77­0.83); following index date it was 1.16 (1.12­1.20). The adjusted odds ratios (95% CI) for miscarriage (1.70; 1.56­1.84), pre-eclampsia (1.32; 1.16­1.49), gestational diabetes (1.41; 1.2­1.66), and premature delivery (1.25; 1.1­1.43) were all increased compared with controls. Of PCOS births, 27.7% were by Caesarean section compared with 23.7% of controls (1.13; 1.05­1.21). Infants born to mothers with PCOS had an increased risk of neonatal jaundice (1.20; 1.03­1.39) and respiratory complications (1.20; 1.06­1.37). CONCLUSIONS: PCOS is associated with subfertility but fertility rates are restored to those of the background population following diagnosis. Pregnancy complications and adverse neonatal outcomes are more prevalent for women with PCOS independently of obesity.