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How did general practitioners (GPs) (family physicians) manage infertility in females and males in primary care between 2000 and 2016? The number of GP infertility consultations for females increased 1.6 folds during the study period, with 42.9% of consultations resulting in a referral to a fertility clinic or specialist, compared to a 3-fold increase in the number of consultations for men, with 21.5% of consultations resulting in a referral. Infertility affects one in six couples and is expected to increase with the trend to later childbearing and reports of declining sperm counts. Despite GPs often being the first contact for infertile people, very limited information is available on the management of infertility in primary care. Data from the Bettering the Evaluation and Care of Health programme were used, which is a national study of Australian primary care (general practice) clinical activity based on 1000 ever-changing, randomly selected GPs involved in 100 000 GP-patient consultations per year between 2000 and 2016. Females and males aged 18-49 years attending GPs for the management of infertility were included in the study. Details recorded by GPs included patient characteristics, problems managed and management actions (including counselling/education, imaging, pathology, medications and referrals to specialists and fertility clinics). Analyses included trends in the rates of infertility consultations by sex of patient, descriptive and univariate analyses of patient characteristics and management actions and multivariate logistic regression to determine which patient and GP characteristics were independently associated with increased rates of infertility management and referrals. The rate of infertility consultations per capita increased 1.6 folds for women (17.7-28.3 per 1000 women aged 18-49 years) and 3 folds for men over the time period (3.4-10.2 per 1000 men aged 18-49 years). Referral to a fertility clinic or relevant specialist occurred in 42.9% of female infertility consultations and 21.5% of male infertility consultations. After controlling for age and other patient characteristics, being aged in their 30s, not having income assistance, attending primary care in later years of the study and coming from a non-English-speaking background, were associated with an increased likelihood of infertility being managed in primary care. In female patients, holding a Commonwealth concession card (indicating low income), living in a remote area and having a female GP all indicated a lower adjusted odds of referral to a fertility clinic or specialist. Data are lacking for the period of infertility and infertility diagnosis, which would provide a more complete picture of the epidemiology of treatment-seeking behaviour for infertility. Australia's universal insurance scheme provides residents with access to a GP, and therefore these findings may not be generalizable to other settings. This study informs public policy on how infertility is managed in primary care in different patient groups. Whether the management actions taken and rates of secondary referral to a fertility clinic or specialist are appropriate warrants further investigation. The development of clinical practice guidelines for the management of infertility would provide a standardized approach to advice, investigations, treatment and referral pathways in primary care. This paper is part of a study being funded by an Australian National Health and Medical Research Council project grant APP1104543. G.C. reports that she is an employee of The University of New South Wales (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The NPESU manages the Australian and New Zealand Assisted Reproductive Technology Database on behalf of the Fertility Society of Australia. W.L. reports being a part-time paid employee and minor shareholder of Virtus Health, a fertility company. R.N. reports being a small unitholder in a fertility company, receiving grants for research from Merck and Ferring and speaker travel grants from Merck. NA.

Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. Gates Foundation.

What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature? The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI. UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation. The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated. Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee. This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided. Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised. The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI. The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose. This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).

Can a video clip detailing the patient journey decrease women's anxiety on the day of their first oocyte retrieval? The video clip does not affect women's anxiety on the day of their first oocyte retrieval. IVF triggers anxious reactions in women and men, with peaks of anxiety on the day of (especially the first) oocyte retrieval as shown by reliable questionnaires and biomarkers of distress. Several trials showed that videos with preparatory information reduce women's and men's anxiety for out-patient procedures. This monocentric open-label randomized controlled trial (RCT) randomized (computerized 1:1 allocation) 190 heterosexual couples about to start their first IVF cycle during a 24 months' recruitment period (2018-2020). In addition to the standard of care offered to both the intervention group and the control group, the intervention group received a video clip, the day prior to their first oocyte retrieval, detailing the patient journey on the day of oocyte retrieval. After completion of the RCT, 35 additional couples were recruited as part of a qualitative process evaluation (QPE). Upon arrival at a private secondary care fertility centre in Belgium for their first oocyte retrieval, women and men independently filled out the State module of the 'State-Trait Anxiety Inventory' (STAI) and the 'Infertility-Specific Distress Scale' (IDS) and evaluated the novel intervention, if applicable. In addition, clinical and discontinuation outcomes were extracted from couples' electronic medical records 24 months later. The data of 155 couples (76-79/group) were subjected to an intention-to-treat analysis. The 35 couples taking part in the QPE filled out two questionnaires assessing knowledge and, if applicable, took part in an in-depth interview on their experience watching the video clip, immediately before their first oocyte retrieval. The video clip did not affect women's anxiety on the day of oocyte retrieval (mean STAI-State score intervention group = 42.7 ± 8.1 vs control group = 42.1 ± 8.5, P = 0.68). Men who watched the video clip were, however, significantly less anxious than men who did not watch it (35.8 (±6.4) vs 38.2 (±7.6), P = 0.034). Surprisingly, infertility-specific distress was higher among women and men who watched the video clip, as compared to women and men who did not watch the video clip (mean Infertility-specific Distress (IDS) scale score for women, 25.8 (±4.9) vs 24.3 (±4.6), P = 0.051; men, 22.6 (±5.0) vs 20.8 (±4.7), P = 0.023). The QPE clarified that watching the video clip did not increase knowledge about what would happen but that some women and men found the visualization of invasive procedural steps more confrontational than the earlier received, abstract, written, and verbal information. All but one woman and all men in the intervention group would recommend the video clip to friends and family going through IVF. The intervention and control groups did not differ regarding secondary clinical and discontinuation outcomes. Due to the nature of the intervention it was not possible to blind the participants. Furthermore, we did not have an attention control group, which could have separated plausible benefits of the intervention from attentional effects, although limiting performance bias in educational intervention studies is difficult as study personnel cannot be blinded. Of note, this RCT was partially conducted during the COVID-19 pandemic; thus, postponement of the oocyte retrieval and plausible side effects of the pandemic itself might have impacted our results, but group differences are corrected by the randomized controlled design of our trial. Providing additional procedural information is interesting for clinics as patients recommended the video clip and as it decreased men's anxiety on the day of couples' first oocyte retrieval. The effect of the intervention was observed in a Dutch-speaking population, and investigating beneficial effects of the video clip in non-native speakers and patients with a lower education or literacy level may be of interest, as they are more prone to health information overload and often benefit from visual rather than verbal or written information. This research was supported by the Research Council of the KU Leuven (C14/18/106; project of J.V., K.P., and E.A.F.D.) and it is an Investigator Sponsored Study for Merck N.V./S.A., an affiliate of Merck KGaA, Darmstadt, Germany. Merck N.V./S.A. had no ultimate authority nor any other role in the design, data collection, data management, data analysis, data processing, data interpretation, and on the decision to submit this study for publication. T.M.D. is vice president and Head of Global Medicine Affairs Fertility, Research and Development, Merck Healthcare KGaA, Darmstadt, Germany. He is also a visiting professor in Reproductive Medicine and Biology at KU Leuven, Belgium and an adjunct professor at the Department of Obstetrics and Gynecology at the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. The other co-authors have no conflict of interest. This trial is registered at clinicaltrials.gov as NCT03717805. 10 October 2018. 29 October 2018.

Is there a difference in live birth rate and/or cost-effectiveness between antral follicle count (AFC)-based individualized FSH dosing or standard FSH dosing in women starting IVF or ICSI treatment? In women initiating IVF/ICSI, AFC-based individualized FSH dosing does not improve live birth rates or reduce costs as compared to a standard FSH dose. In IVF or ICSI, ovarian reserve testing is often used to adjust the FSH dose in order to normalize ovarian response and optimize live birth rates. However, no robust evidence for the (cost-)effectiveness of this practice exists. Between May 2011 and May 2014 we performed a multicentre prospective cohort study with two embedded RCTs in women scheduled for IVF/ICSI. Based on the AFC, women entered into one of the two RCTs (RCT1: AFC < 11; RCT2: AFC > 15) or the cohort (AFC 11-15). The primary outcome was ongoing pregnancy achieved within 18 months after randomization resulting in a live birth (delivery of at least one live foetus after 24 weeks of gestation). Data from the cohort with weight 0.5 were combined with both RCTs in order to conduct a strategy analysis. Potential half-integer numbers were rounded up. Differences in costs and effects between the two treatment strategies were compared by bootstrapping. In both RCTs women were randomized to an individualized (RCT1:450/225 IU, RCT2:100 IU) or standard FSH dose (150 IU). Women in the cohort all received the standard dose (150 IU). Anti-M&#xfc;llerian hormone (AMH) was measured to assess AMH post-hoc as a biomarker to individualize treatment. For RCT1 dose adjustment was allowed in subsequent cycles based on pre-specified criteria in the standard group only. For RCT2 dose adjustment was allowed in subsequent cycles in both groups. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. We included 1515 women, of whom 483 (31.9%) entered the cohort, 511 (33.7%) RCT1 and 521 (34.4%) RCT2. Live births occurred in 420/747 (56.3%) women in the individualized strategy and 447/769 (58.2%) women in the standard strategy (risk difference -0.019 (95% CI, -0.06 to 0.02), P = 0.39; a total of 1516 women due to rounding up the half integer numbers). The individualized strategy was more expensive (delta costs/woman = &#x20ac;275 (95% CI, 40 to 499)). Individualized dosing reduced the occurrence of mild and moderate ovarian hyperstimulation syndrome (OHSS) and subsequently the costs for management of these OHSS categories (costs saved/woman were &#x20ac;35). The analysis based on AMH as a tool for dose individualization suggested comparable results. Despite a training programme, the AFC might have suffered from inter-observer variation. In addition, although strict cancel criteria were provided, selective cancelling in the individualized dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as both first cycle live birth rates and cumulative live birth rates show no difference between strategies, the open design probably did not mask a potential benefit for the individualized group. Despite increasing consensus on using GnRH antagonist co-treatment in women predicted for a hyper response in particular, GnRH agonists were used in almost 80% of the women in this study. Hence, in those women, the AFC and bloodsampling for the post-hoc AMH analysis were performed during pituitary suppression. As the correlation between AFC and ovarian response is not compromised during GnRH agonist use, this will probably not have influenced classification of response. Individualized FSH dosing for the IVF/ICSI population as a whole should not be pursued as it does not improve live birth rates and it increases costs. Women scheduled for IVF/ICSI with a regular menstrual cycle are therefore recommended a standard FSH starting dose of 150 IU per day. Still, safety management by individualized dosing in predicted hyper responders is open for further research. This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). AMH measurements were performed free of charge by Roche Diagnostics. TCT, HLT and SCO received an unrestricted personal grant from Merck BV. AH declares that the department of Obstetrics and Gynecology, University Medical Centre Groningen receives an unrestricted research grant from Ferring pharmaceutics BV, The Netherlands. CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other autors have nothing to declare. Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.

Endometrial intraepithelial neoplasia (EIN), also known as atypical endometrial hyperplasia (AEH), is a precursor lesion of endometrial carcinoma (EC). In endometrial cancer patients, lymph node assessment with biopsy during hysterectomy is part of surgical staging. However, routine lymph node assessment for EIN is inconsistently utilized. This study aims to investigate the surgical management of EIN in the military to inform best-practice guidelines tailored for the Military Health System to avoid delays in care, manage cost, ensure military readiness and optimize clinical outcome. We performed a retrospective chart review of patients with EIN treated at 2 military treatment facilities over a 10-year period between July 1, 2013 and July 1, 2023. Pathology reports were queried to identify patients with a preoperative diagnosis of EIN. Patients not surgically managed were excluded. Statistical analysis was performed using chi-squared test and Wilcoxon rank-sum test. Independent associations were investigated using logistic regression modeling. There were 95 evaluable patients with an EIN diagnosis, including 43 (45.3%) patients upstaged to EC based on final pathology (95% CI: 35.0-55.8). Older patients diagnosed with EIN &#x2265;65&#x2009;years old and those with endometrial thickness &#x2265;15&#x2009;mm exhibited the highest risk for upstaging EIN to an EC diagnosis. Of the 50 patients who underwent lymph node assessment, none had positive lymph nodes. Patients diagnosed with EIN via hysteroscopy vs. an endometrial biopsy had the lowest risk of being upstaged to EC. Upstaging from EIN to EC occurred in 45.3% of the 95 patients emphasizing the value of performing surgicopathologic staging in this setting. In contrast, none of the 50 EIN patients who underwent lymph node resection had positive lymph nodes indicating morbidity risk with low likelihood of clinical benefit. We identified risk factors for upstaging to EC, including age &#x2265;65 years and endometrial thickness &#x2265;15&#x2009;mm, and confirmed the diagnostic superiority of hysteroscopy. These findings have informed clinical practice guideline recommendations for the surgical management of EIN in the Military Health System.

Management of diabetes in pregnancy requires input from multiple health professionals throughout the course of an individual's pregnancy. Implementing healthcare delivery that suits the local context of a metropolitan or rural region may contribute to improvements in care delivery and pregnancy and birthing outcomes. To compare healthcare delivery for people with diabetes in pregnancy in metropolitan and rural areas of Australia. A cross-sectional survey was conducted, with questions focused on healthcare delivery for women with diabetes in pregnancy, including the multidisciplinary care provided. Data were collected via a nationwide survey of health professionals currently involved in the healthcare management of people with diabetes in pregnancy in Australia. Survey data were analysed using descriptive and inferential statistics. The main aspects of healthcare delivery were similar between metropolitan and rural respondents. The proportion of health professionals offering face-to-face services was greater in rural areas (n&#x2009;=&#x2009;38, 100%) compared to metropolitan (n&#x2009;=&#x2009;34, 71%). Rural respondents (21%) reported they were collocated with an endocrinologist and 48% with an obstetrician. This was compared to 71% of metropolitan respondents reporting being collocated with an endocrinologist, and 63% with an obstetrician. This research offers direction as to potential considerations when planning and implementing models of care in rural areas. Additional research confirming the priorities within the rural context is needed to support the development of optimal care delivery for pregnant people with diabetes living in rural regions.

What is the effectiveness of a multifaceted implementation strategy compared to usual care on improving the adherence to guideline recommendations on expectant management for couples with unexplained infertility? The multifaceted implementation strategy did not significantly increase adherence to guideline recommendations on expectant management compared to care as usual. Intrauterine insemination (IUI) with or without ovarian hyperstimulation has no beneficial effect compared to no treatment for 6 months after the fertility work-up for couples with unexplained infertility and a good prognosis of natural conception. Therefore, various professionals and policy makers have advocated the use of prognostic profiles and expectant management in guideline recommendations. A cluster randomized controlled trial in 25 clinics in the Netherlands was conducted between March 2013 and May 2014. Clinics were randomized between the implementation strategy (intervention, n = 13) and care as usual (control, n = 12). The effect of the implementation strategy was evaluated by comparing baseline and effect measurement data. Data collection was retrospective and obtained from medical record research and a patient questionnaire. A total of 544 couples were included at baseline and 485 at the effect measurement (247 intervention group/238 control group). Guideline adherence increased from 49 to 69% (OR 2.66; 95% CI 1.45-4.89) in the intervention group, and from 49 to 61% (OR 2.03; 95% CI 1.38-3.00) in the control group. Multilevel analysis with case-mix adjustment showed that the difference of 8% was not statistically significant (OR 1.31; 95% CI 0.67-2.59). The ongoing pregnancy rate within six months after fertility work-up did not significantly differ between intervention and control group (25% versus 27%: OR 0.72; 95% CI 0.40-1.27). There is a possible selection bias, couples included in the study had a higher socio-economic status than non-responders. How this affects guideline adherence is unclear. Furthermore, when powering for this study we did not take into account the unexpected improvement of adherence in the control group. Generalization of our results to other countries with recommendations on expectant management might be questionable because barriers for expectant management can be very different in other countries. Furthermore, due to a large variation in improved adherence rate in the intervention group it will be interesting to further analyse the process of implementation in each clinic with a process evaluation on professionals and couples' exposure to and experiences with the strategy. Supported by Netherlands Organisation for Health Research and Development (ZonMW, project number 171203005). No competing interests. Dutch trial Register, www.trialregister.nl NTR3405. 19 April 2012. 10 July 2012.

The Netherlands reformed its long-term care policy to encourage older adults to age in place with the support of informal caregivers. It remains unclear whether the available care and support options align with the needs and preferences of older adults and caregivers. Discrete choice experiments (DCE) are increasingly used to identify individual preferences. This study describes the development of attributes (e.g., emotional support) and attribute levels (e.g., psychologist and case manager) for a DCE on aging-in-place preferences among older adults and informal caregivers in The Netherlands. Semi-structured interviews were conducted with older adults and informal caregivers to identify key components for successful aging in place. Interviews were transcribed, and reflexive thematic analysis identified patterns that led to a list of attributes. Visuals of these attributes were created and presented to a new sample of informal caregivers and older adults in focus groups to rank attributes and define attribute levels. Attributes identified through the interviews (N = 28) included housing, personal care, household tasks, transportation, social activities, digital skills, and help navigating the healthcare system. Focus groups (N = 35) found that older adults prioritized housing, while informal caregivers prioritized navigating the healthcare system. Transportation and digital skills were ranked as the least important and were excluded from the final list of attributes. Our findings provide a detailed understanding of aging-in-place preferences of older adults and informal caregivers. These insights will inform a DCE to quantify preferences and provide evidence for policymakers. This study increases transparency about the process of attribute development and level selection, contributing to the quality of the final DCE study.

Up to 50% of those diagnosed with HIV in the U.S. are not retained in medical care. Care retention provides opportunity to monitor benefits of HIV therapy and enable viral suppression. To increase retention, there is a need to prioritize best practices appropriate for translation and dissemination for real-world implementation. Eighteen interventions from CDC's Compendium of Evidence-Based Interventions were scored using the RE-AIM framework to determine those most suitable for dissemination. A CDC Division of HIV Prevention workgroup developed a RE-AIM scale with emphasis on the Implementation and Maintenance dimensions and less emphasis on the Efficacy dimension since all 18 interventions were already identified as evidence-based or evidence-informed. Raters referenced primary efficacy publications and scores were averaged for a ranked RE-AIM score for interventions. Of 18 interventions, four included care linkage and 7 included viral suppression outcomes. Interventions received between 20.6 and 35.3 points (45 maximum). Scores were converted into a percentage of the total possible with ranges between 45.8 and 78.4%. Top four interventions were ARTAS (78.4%); Routine Screening for HIV (RUSH) (73.2%); Optn4Life (67.4%) and Virology Fast Track (65.9%). All four scored high on Implementation and Maintenance dimensions. Select items within the scale were applicable to health equity, covering topics such as reaching under-served focus populations and acceptability to that population. Navigation-enhanced Case Management (NAV) scored highest on the health equity subscale. RE-AIM prioritization scores will inform dissemination and translation efforts, help clinical staff select feasible interventions for implementation, and support sustainability for those interventions. Hasta el 50% de las personas diagnosticadas con VIH en USA no son retenidos en cuidados m&#xe9;dicos impactando su monitoreo y supresi&#xf3;n viral. Dieciocho intervenciones de retenci&#xf3;n fueron evaluadas utilizando el marco RE-AIM para determinar su adecuaci&#xf3;n para la difusi&#xf3;n. Evaluadores promediaron las intervenciones. Cuatro intervenciones incluyeron enlace de atenci&#xf3;n y 7 supresi&#xf3;n viral. Las cuatro intervenciones principales fueron ARTAS, detecci&#xf3;n de rutina para el VIH, Optn4Life y V&#xed;a r&#xe1;pida de virolog&#xed;a. Elementos del marco fueron usados para evaluar equidad en salud y cubrieron temas de c&#xf3;mo llegar a las poblaciones desatendidas y la aceptabilidad de esa poblaci&#xf3;n. La intervenci&#xf3;n gesti&#xf3;n de casos para mejorar con navegaci&#xf3;n (NAV) obtuvo la puntuaci&#xf3;n m&#xe1;s alta en la subescala de equidad. RE-AIM y los puntajes de priorizaci&#xf3;n de equidad informar&#xe1;n los esfuerzos de difusi&#xf3;n y traducci&#xf3;n, ayudar&#xe1;n al personal cl&#xed;nico a seleccionar las intervenciones para la implementaci&#xf3;n y apoyar&#xe1;n la sostenibilidad.

Pain assessment and management in children remain challenging, particularly in those with neurodevelopmental disorders. Attention-deficit/hyperactivity disorder (ADHD) is characterized by alterations in attention, executive function, emotional regulation, and reward processing. These domains are also critically involved in pain perception and expression. Emerging evidence suggests that children with ADHD may experience pain differently, display atypical pain behaviors, and face substantial challenges in pain assessment and treatment. However, the literature on pediatric ADHD and pain is fragmented across experimental, clinical, and behavioral studies. This narrative review critically examines the neurobiological, psychological, and clinical interactions between ADHD and pain in children. We discuss proposed mechanisms linking ADHD to altered pain processing, summarize evidence on pain perception and expression, explore common pain conditions where this interaction is clinically relevant, and analyze challenges in pain assessment and management. Finally, we identify knowledge gaps and propose future directions toward function- and child-centered pain care. By considering ADHD as a modifier of pain experience and a potential contributor to pain chronification rather than a mere comorbidity, this review highlights the importance of adapting pain assessment and management strategies to the specific neurodevelopmental profile of pediatric patients.

Pharmacotherapy is vital in medicine, but inappropriate and inadequate use of medications significantly impacts global mortality and morbidity. Increased prescribing may indicate irrational use or prolonged illness, while decreased prescribing could suggest undertreatment, supply shortages, or the availability of safer and, more effective treatments. The COVID-19 pandemic disrupted health systems, potentially altering prescribing patterns. This study examined its impact on the prescribing patterns of common therapeutic categories and high-risk medicines in general practice in England. Common therapeutic categories were identified from English General Practice prescription data, and high-risk medicines were identified by mapping the UK pharmacovigilance data onto the English prescribing data. A retrospective analysis compared monthly prescription data pre-pandemic, during the pandemic, and post-pandemic. Significant changes in the prescribing volumes of therapeutic categories and high-risk medicines were tracked to determine persistence, intensification, or diminution post-pandemic. Linear regression models analysed prescribing trends. Among 220 therapeutic categories, 16 experienced significant changes: 14 increased and two decreased during the pandemic. Of 78 high-risk medicines, six showed significant changes: two increased and three decreased. Only three therapeutic categories and two high-risk medicines returned to pre-pandemic levels. Despite a reduction in general practice appointments during the pandemic, prescribing for several therapeutic categories and certain high-risk medicines surged, indicating increased treatment, prolonged illness or stockpiling. Post-pandemic downward trends suggest long-term under-treatment or reduced stockpiling. Continuous monitoring, strategic healthcare planning, and regulatory interventions are needed to optimise prescribing. Future research is needed to assess the long-term effects on disease management.

Does a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety? Although in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed. Excessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response. Between May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders. Women with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost-effectiveness were evaluated from an intention-to-treat perspective. We randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85-1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28-0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38-4.07], P = 0.728). As dose reduction was not less expensive (&#x20ac;4.622 versus &#x20ac;4.714, delta costs/woman &#x20ac;92 [95%CI, -479-325]), there was no dominant strategy in the economic analysis. Despite our training programme, the AFC might have suffered from inter-observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings. In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates. This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020). SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657. 20 December 2010. 12 May 2011.

How does the cost-effectiveness (CE) of immediate IVF compared with postponing IVF for 1 year, depend on prognostic characteristics of the couple? The CE ratio, i.e. the incremental costs of immediate versus delayed IVF per extra live birth, is the highest (range of &#x20ac;15 000 to >&#x20ac;60 000) for couples with unexplained infertility and for them depends strongly on female age and the duration of infertility, whilst being lowest for endometriosis (range 8000-23 000) and, for such patients, only slightly dependent on female age and duration of infertility. A few countries have guidelines for indications of IVF, using the diagnostic category, female age and duration of infertility. The CE of these guidelines is unknown and the evidence base exists only for bilateral tubal occlusion, not for the other diagnostic categories. A modelling approach was applied, based on the literature and data from a prospective cohort study among couples eligible for IVF or ICSI treatment, registered in a national waiting list in The Netherlands between January 2002 and December 2003. A total of 5962 couples was included. Chances of natural ongoing pregnancy were estimated from the waiting list observations and chances of ongoing pregnancy after IVF from follow-up data of couples with primary infertility that began treatment. Prognostic characteristics considered were female age, duration of infertility and diagnostic category. Costs of IVF were assessed from a societal perspective and determined on a representative sample of patients. A cost-effectiveness comparison was made between two scenarios: (I) wait one more year and then undergo IVF for 1 year and (II) immediate IVF during 1 year, and try to conceive naturally in the following year. Comparisons were made for strata determined by the prognostic factors. The final outcome was a live birth. The gain in live birth rate of the immediate IVF scenario versus postponed IVF increased with female age, and was independent from diagnostic category or duration of infertility. By contrast, the corresponding increase in costs primarily depended on diagnostic category and duration of infertility. The lowest CE ratio was just below &#x20ac;10 000 per live birth for endometriosis from age 34 onwards at 1 year duration. The highest CE ratio reached &#x20ac;56 000 per live birth for unexplained infertility at age 30 and 3 years duration, dropping to values below &#x20ac; 30 000 per live birth from age 32 onwards. It reached values below &#x20ac;20 000 per live birth with 3 years duration at age 34 and older. The CE ratio was in between for the three other diagnostic categories (i.e. Male infertility, Hormonal and Immunological/Cervical). We applied estimates of chances with IVF, excluding frozen embryos, for which we had no data. Therefore, we do not know the effect of frozen embryo transfers on the CE. The duration of infertility at which IVF becomes cost-effective depends, firstly, on the level of society's willingness to pay for one extra live birth, and secondly, given a certain level of willingness to pay, on the woman's age and the diagnostic category. In current guidelines, the chances of a natural conception should always be taken into account before deciding whether to start IVF treatment and at which time. Supported by Netherlands Organisation for Health Research and Development (ZonMW, grant 945-12-013). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none.

This study was conducted to determine the effects of the methods used in the management of maternal obesity on pregnancy and birth outcomes. This study was conducted following the PRISMA Statement. The articles to be used in the meta-analysis were searched in PubMed, National Thesis Center, DergiPark, MEDLINE, Cochrane Library and EBSCO search engines in October 2021 and updated in September 2023. The methodological qualities of the studies were evaluated using ROB2. The data were synthesized using meta-analysis, and the GRADE approach was used to rate the certainty of the evidence and the strength of the recommendations. Twenty-one studies published between 2013 and 2021 were included in the study. The total sample size of the studies was 7695. Weight management interventions significantly reduced weight gain during pregnancy (p&#x2009;<&#x2009;0.001) and birth weight (p&#x2009;<&#x2009;0.01). Did not affect other adverse pregnancy outcomes included in the synthesis (p&#x2009;>&#x2009;0.05). The subgroup analyses showed that the method of handing out brochures resulted in lower levels of birth weight (p&#x2009;<&#x2009;0.01) and weight gained during pregnancy (p&#x2009;<&#x2009;0.001); the use of metformin was associated with a significant drop in admissions to the neonatal intensive care unit (p&#x2009;<&#x2009;0.01); the method of exercise was associated with lower in gestational diabetes (p&#x2009;<&#x2009;0.001), weight gained during pregnancy (p&#x2009;<&#x2009;0.001), birth weight (p&#x2009;=&#x2009;0.01) and large-for-gestational-age baby birth (p&#x2009;<&#x2009;0.05), while and the combination of diet and exercise significantly reduced weight gained during pregnancy (p&#x2009;=&#x2009;0.001). The certainty of evidence assessed using GRADE for all 15 critical outcomes was high 15 outcomes. The study revealed that methods used in the treatment of maternal obesity may reduce some negative maternal and newborn outcomes, but it is more important to start pregnancy with an ideal weight.

To evaluate fertility clinic management of male factor infertility, including website educational content as well as factors associated with referral for urologic evaluation and care. Using 2015-2018 Centers for Disease Control and Prevention Fertility Clinic Success Rates Reports, 480 operative fertility clinics in the United States were identified. Clinic websites were systematically reviewed for content regarding male infertility. Structured telephone interviews of clinic representatives were performed to determine clinic-specific practices for management of male factor infertility. Multivariable logistic regression models were used to predict how clinic characteristics (geographic region, practice size, practice setting, proximity to urologist, in-state andrology fellowship, state-mandated fertility coverage, annual in vitro fertilization cycles, and percentage of in vitro fertilization cycles for male factor infertility) were associated with patient referral to a urologist for male infertility care. We interviewed 477 fertility clinics and analyzed available websites (n&#x202f;=&#x202f;474). The majority of websites (77%) discussed male infertility evaluation while 46% discussed treatment. Fifty clinics (11%) had an on-site urologist. Clinics with on-site urologists were more likely to be larger practices, academically affiliated, and discuss male infertility treatment on their website (all P &#x2264; .05). For clinics without an on-site urologist, practice size and presence of an in-state andrology fellowship program were the strongest predictors of urologic referral (P <.02). Variability in patient-facing education and infertility practice setting and size influence access to urologic care for couples with male factor infertility.

Insulin resistance increases after the first trimester of pregnancy, leading to glycaemic challenges for women with pregestational type 1 diabetes or type 2 diabetes. Additionally, insulin resistance can promote hyperglycaemia in pregnant women without type 1 diabetes or type 2 diabetes, who develop gestational diabetes. Although most (>95%) women with diabetes deliver healthy babies, maternal dysglycaemia can have consequences for the mother and child, including prenatal, perinatal, immediate, and long-term postnatal complications. Diabetes technologies, such as continuous glucose monitoring (CGM) and automated insulin delivery (AID) systems can aid in optimising glycaemia outside of pregnancy. These novel technologies have not been extensively tested in large randomised controlled trials before and during pregnancy. However, compelling data report the benefits of CGM in type 1 diabetes, and increasing data report on AID systems in pregnancies complicated by type 1 diabetes. Appropriate CGM glucose thresholds for the diagnosis of gestational diabetes and the recommended time in range treatment targets for the routine management of gestational diabetes and type 2 diabetes still need to be determined. The recommendations in this Consensus Statement emphasise the value of CGM during preconception and pregnancy for women with pregestational type 1 diabetes in reducing pregnancy complications. Recommendations also include the use of AID systems in women with pregestational type 1 diabetes to improve glycaemic management during preconception, during pregnancy and delivery, and in the postpartum period. This Consensus Statement has been endorsed by 24 societies and groups.

Agitation is a frequently occurring and challenging neuropsychiatric symptom of Alzheimer's disease (AD) that substantially affects quality of life, caregiver burden, and healthcare utilization. Nonpharmacological interventions, especially trigger identification, environmental adjustments, and supportive activities, remain the first-line approach for treating agitation. Pharmacological treatment should be considered only when nondrug measures are insufficient or when agitation causes severe distress or safety risks. This consensus integrates evidence up to June 2025, the Taiwan Ministry of Health and Welfare approval status, and expert opinion from Taipei Veterans General Hospital. Among the approved agents, brexpiprazole demonstrated the strongest evidence and most favorable safety profile. Risperidone and aripiprazole are effective, but require careful monitoring for cerebrovascular and extrapyramidal risks. Selected antidepressants, particularly citalopram and agomelatine, should be considered when safety is prioritized. Anticonvulsants, acetylcholinesterase inhibitors, and memantine have limited efficacy and should be reserved for refractory cases. Long-term or routine pharmacological use is not supported by current evidence. Future research should focus on identifying responsive patient subgroups, optimizing dosing strategies, and integrating medications into individualized, multidisciplinary care plans.

Which recommendations can be provided by the European Society of Human Reproduction and Embryology Special Interest Group (ESHRE SIG) Embryology to support laboratory specialists in the organization and management of IVF laboratories and the optimization of IVF patient care? Structured in 13 sections, the guideline development group formulated recommendations for good practice in the organization and management of IVF laboratories, and for good practice of the specific procedures performed within the IVF laboratory. NA. The guideline was produced by a group of 10 embryologists representing different European countries, settings and levels of expertise. The group evaluated the document of 2008, and based on this assessment, each group member rewrote one or more sections. Two 2-day meetings were organized during which each of the recommendations was discussed and rewritten until consensus within the guideline group was reached. After finalizing the draft, the members of the ESHRE SIG embryology were invited to review the guideline. NA. The guideline provides recommendations on the general organization of an IVF laboratory (staffing and direction, quality management, laboratory safety), and on the specific aspects of the procedures performed in IVF laboratories (Identification of patients and traceability of their reproductive cells, consumables, handling of biological material, oocyte retrieval, sperm preparation, insemination of oocytes, scoring for fertilization, embryo culture and transfer, and cryopreservation). A last section provides recommendations regarding an Emergency plan for IVF laboratories. Evidence on most of the issues described is scarce, and therefore it was decided not to perform a formal search for and assessment of scientific evidence. However, recommendations published in the EUTCD and relevant and recent documents, manuals and consensus papers were taken into account when formulating the recommendations. Despite the limitations, the guideline group is confident that this document will be helpful to directors and managers involved in the management and organization of IVF laboratories, but also to embryologists and laboratory technicians performing daily tasks. The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings. The guideline group members did not receive payment. Dr Coticchio reports speaker's fees from IBSA and Cook, outside the submitted work; Dr Lundin reports grants from Vitrolife, personal fees from Merck Serono, non-financial support from Unisense, outside the submitted work; Dr. Rienzi reports personal fees from Merck Serono, personal fees from MSD, grants from GFI, outside the submitted work; the other authors had nothing to disclose. NA.