Current global status of male reproductive health

BACKGROUND: The widespread interest in male reproductive health (MRH), fueled by emerging evidence, such as the global decline in sperm counts, has intensified concerns about the status of MRH. Consequently, there is a pressing requirement for a strategic, systematic approach to identifying critical questions, collecting pertinent information, and utilizing these data to develop evidence-based strategies. The methods for addressing these questions and the pathways toward their answers will inevitably vary based on the variations in cultural, geopolitical, and health-related contexts. To address these issues, a conjoint ESHRE and Male Reproductive Health Initiative (MRHI) Campus workshop was convened.OBJECTIVE AND RATIONALE: The three objectives were: first, to assess the current state of MRH around the world; second, to identify some of the key gaps in knowledge; and, third, to examine how MRH stakeholders can collaboratively generate intelligent and effective paths forward.SEARCH METHODS: Each expert reviewed and summarized the current literature that was subsequently used to provide a comprehensive overview of challenges related to MRH.OUTCOMES: This narrative report is an overview of the data, opinions, and arguments presented during the workshop. A number of outcomes are presented and can be summarized by the following overarching themes: MRH is a serious global issue and there is a plethora of gaps in our understanding; there is a need for widespread international collaborative networks to undertake multidisciplinary research into fundamental issues, such as lifestyle/environmental exposure studies, and high-quality clinical trials; and there is an urgent requirement for effective strategies to educate young people and the general public to safeguard and improve MRH across diverse population demographics and resources.LIMITATIONS REASONS FOR CAUTION: This was a workshop where worldwide leading experts from a wide range of disciplines presented and discussed the evidence regarding challenges related to MRH. While each expert summarized the current literature and placed it in context, the data in a number of areas are limited and/or sparse. Equally, important areas for consideration may have been missed. Moreover, there are clear gaps in our knowledge base, which makes some conclusions necessarily speculative and warranting of further study.WIDER IMPLICATIONS: Poor MRH is a global issue that suffers from low awareness among the public, patients, and heathcare professionals. Addressing this will require a coordinated multidisciplinary approach. Addressing the significant number of knowledge gaps will require policy makers prioritizing MRH and its funding.STUDY FUNDING/COMPETING INTERESTS: The authors would like to extend their gratitude to ESHRE for providing financial support for the Budapest Campus Workshop, as well as to Microptic S.L. (Barcelona) for kindly sponsoring the workshop. P.B. is the Director of the not-for-profit organization Global Action on Men's Health and receives fees and expenses for his work, (which includes the preparation of this manuscript). Conflicts of interest: C.J.D.J., C.L.R.B., R.A.A., P.B., M.P.C., M.L.E., N.G., N.J., C.K., AAP, M.K.O., S.R.-H., M.H.V.-L.: ESHRE Campus Workshop 2022 (Travel support-personal). C.J.D.J.: Cambridge University Press (book royalties-personal). ESHRE Annual Meeting 2022 and Yale University Panel Meeting 2023 (Travel support-personal). C.L.R.B.: Ferring and IBSA (Lecture), RBMO editor (Honorarium to support travel, etc.), ExSeed and ExScentia (University of Dundee), Bill &amp; Melinda Gates Foundation (for research on contraception). M.P.C.: Previously received funding from pharmaceutical companies for health economic research. The funding was not in relation to this work and had no bearing on the contents of this work. No funding from other sources has been provided in relation to this work (funding was provided to his company Global Market Access Solutions). M.L.E.: Advisor to Ro, Doveras, Next, Hannah, Sandstone. C.K.: European Academy of Andrology (Past president UNPAID), S.K.: CEO of His Turn, a male fertility Diagnostic and Therapeutic company (No payments or profits to date). R.I.M.: www.healthymale.org.au (Australian Government funded not for profit in men's health sector (Employed as Medical Director 0.2 FET), Monash IVF Pty Ltd (Equity holder)). N.J.: Merck (consulting fees), Gedeon Richter (honoraria). S.R.-H.: ESHRE (Travel reimbursements). C.N.: LLC (Nursing educator); COMMIT (Core Outcomes Measures for Infertility Trials) Advisor, meeting attendee, and co-author; COMMA (Core Outcomes in Menopause) Meeting attendee, and co-author; International Federation of Gynecology and Obstetrics (FIGO) Delegate Letters and Sciences; ReproNovo, Advisory board; American Board of Urology Examiner; American Urological Association Journal subsection editor, committee member, guidelines co-author Ferring Scientific trial NexHand Chief Technology Officer, stock ownership Posterity Health Board member, stock ownership. A.P.: Economic and Social Research Council (A collaborator on research grant number ES/W001381/1). Member of an advisory committee for Merck Serono (November 2022), Member of an advisory board for Exceed Health, Speaker fees for educational events organized by Mealis Group; Chairman of the Cryos External Scientific Advisory Committee: All fees associated with this are paid to his former employer The University of Sheffield. Trustee of the Progress Educational Trust (Unpaid). M.K.O.: National Health and Medical Research Council and Australian Research Council (Funding for research of the topic of male fertility), Bill and Melinda Gates Foundation (Funding aimed at the development of male gamete-based contraception), Medical Research Future Fund (Funding aimed at defining the long-term consequences of male infertility). M.H.V.-L.: Department of Sexual and Reproductive Health and Research (SRH)/Human Reproduction Programme (HRP) Research Project Panel RP2/WHO Review Member; MRHI (Core Group Member), COMMIT (member), EGOI (Member); Human Reproduction (Associate Editor), Fertility and Sterility (Editor), AndroLATAM (Founder and Coordinator).</p

Effect of VX-770 in Persons with Cystic Fibrosis and the G551D- CFTR Mutation

A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Clinical Trial Participants Compared with Nonparticipants in Cystic Fibrosis

Rationale: The randomized clinical trial has been an important tool for expanding our knowledge of disease. This study is the first to compare trial participants to the entire eligible population

Cystic fibrosis physicians’ perspectives on the timing of referral for lung transplant evaluation: a survey of physicians in the United States

Abstract Background Prior studies reveal that a significant proportion of patients with cystic fibrosis (CF) and advanced lung disease are not referred for lung transplant (LTx) evaluation. We sought to assess expert CF physician perspectives on the timing of LTx referral and investigate their LTx knowledge. Methods We developed an online anonymous survey that was distributed by the Cystic Fibrosis Foundation (CFF) to the medical directors of all CFF-accredited care centers in the United States in 2015. The survey addressed only adult patients (≥18 years old) and was sent to 119 adult CF physicians, 86 CFF-affiliated CF physicians (who see adults and children, but have smaller program sizes than adult or pediatric centers), and 127 pediatric CF physicians (who see some adults, but mostly children). The focus of the questions was on CFF-care center characteristics, physician experience and indications/contraindications to referral for LTx evaluation. Results There were 114/332 (34%) total responses to the survey. The response rates were: 57/119 (48%) adult physicians, 12/86 (14%) affiliate physicians and 43/127 (34%) pediatric physicians; 2 physicians did not include their CFF center type. Despite the poor ability of FEV1 < 30% to predict death within 2 years, 94% of responding CF physicians said they would refer an adult patient for LTx evaluation if the patient’s lung function fell to FEV1 < 30% predicted. Only 54% of respondents report that pulmonary hypertension would trigger referral. Pulmonary hypertension is an internationally recommended indication to list a patient for LTx (not just for referral for evaluation). Very few physicians (N = 17, 15%) employed components of the lung allocation score (LAS) to determine the timing of referral for LTx evaluation. Interestingly, patient preference not to undergo LTx was “often” or “always” the primary patient-related reason to defer referral for LTx evaluation for 41% (47/114) of respondents. Conclusions Some potential barriers to timely LTx referral for patients with CF include physician knowledge regarding non-lung function-based recommendations related to timing of referral and listing for LTx, and patient preference not to undergo LTx. Further exploration of physician-level and CF patient-level barriers to timely LTx referral is warranted

A survey identifying nutritional needs in a contemporary adult cystic fibrosis cohort

Abstract Background Cystic fibrosis (CF) is a disease in which nutritional barriers are diverse and common, with malnutrition greatly influencing pulmonary trajectory and overall outcomes. Despite this, the most effective methods to optimize CF nutrition are unknown, and literature describing patients’ perspectives on their specific nutritional needs is lacking, particularly in the modern era of CF care. This study aimed to identify the most important nutritional needs and desired health-improvement resources in a contemporary adult CF cohort. Methods A 14-question investigator-designed survey addressing nutrition concerns, preferred health-improvement resources, and dietary/exercise routines was administered to CF adults. Clinical characteristics and survey responses are presented with descriptive statistics, and responses compared by body mass index (BMI) category (< 18.5 kg/m2; 18.5–24.99 kg/m2; 25–29.99 kg/m2; ≥30 kg/m2), gender, and socioeconomic status using Chi square or Fisher’s Exact testing. Results Of 66 total patients, nine (13.6%) were underweight (BMI < 18.5 kg/m2), while 19 (28.8%) were overweight or obese (BMI ≥ 25 kg/m2). In the overall cohort, the most common primary concern was preventing weight loss [in 20/66 patients (30.3%)], but there were significant differences by BMI (p < 0.001), with the most common concern in the overweight subgroup being preventing weight gain. Fifteen (46.9%) men (BMI mean 20.7, range 16.4–29.2 kg/m2) listed preventing weight loss as the primary concern, compared to only 5 (14.7%) women (BMI mean 18.4, range 16.2–19.9 kg/m2), representing a trend toward a difference in primary concerns by gender (p = 0.066). The most commonly desired health-improvement resource was online CF nutrition and fitness information, found in 26 patients (39.4%) in the overall cohort, without significant differences by BMI (p = 0.814) or gender (p = 0.199). Financial assistance was the preferred resource in 17 (26.2%), without differences by socioeconomic status (p = 0.367). Conclusions We identified a wide variety of nutritional needs in CF adults, including a high prevalence of overweight status, many patients desiring weight loss, and many seeking financial resources. Our findings support the individualization of modern-day CF nutrition programs and development of online resources, in an effort to address the heterogeneous barriers that exist in the contemporary CF population and improve outcomes in patients with the disease

Investigation of the mechanisms by which the molecular chaperone HSPA2 regulates the expression of sperm surface receptors involved in human spermoocyte recognition

A unique characteristic of mammalian spermatozoa is that, upon ejaculation, they are unable to recognize and bind to an ovulated oocyte. These functional attributes are only realized following the cells' ascent of the female reproductive tract whereupon they undergo a myriad of biochemical and biophysical changes collectively referred to as ‘capacitation’. We have previously shown that this functional transformation is, in part, engineered by the modification of the sperm surface architecture leading to the assembly and/or presentation of multimeric sperm–oocyte receptor complexes. In this study, we have extended our findings through the characterization of one such complex containing arylsulfatase A (ARSA), sperm adhesion molecule 1 (SPAM1) and the molecular chaperone, heat shock 70kDa protein 2 (HSPA2). Through the application of flow cytometry we revealed that this complex undergoes a capacitation-associated translocation to facilitate the repositioning of ARSA to the apical region of the human sperm head, a location compatible with a role in the mediation of sperm–zona pellucida (ZP) interactions. Conversely, SPAM1 appears to reorient away from the sperm surface, possibly reflecting its primary role in cumulus matrix dispersal preceding sperm–ZP recognition. The dramatic relocation of the complex was completely abolished by incubation of capacitating spermatozoa in exogenous cholesterol or broad spectrum protein kinase A (PKA) and tyrosine kinase inhibitors suggesting that it may be driven by alterations in membrane fluidity characteristics and concurrently by the activation of a capacitation-associated signal transduction pathway. Collectively these data afford novel insights into the sub-cellular localization and potential functions of multimeric protein complexes in human spermatozoa