Nurturing Societal Values in and Through Health Innovations; Comment on “What Health System Challenges Should Responsible Innovation in Health Address?”

Aligning innovation processes in healthcare with health system demands is a societal objective, not always achieved. In line with earlier contributions, Lehoux et al outline priorities for research, public communication, and policy action to achieve this objective. We endorse setting these priorities, while also highlighting a ‘commitment gap’ in collectively addressing system-level challenges. To acknowledge that stakeholders engaged in dialogue with one another are addressing the commitment gap is not a small step but a giant leap towards realising a socially responsible innovation agenda. Translating system-level demand signals into innovation opportunities is, therefore, the task-cum-art of all stakeholders, one that often prompts them to innovate how they deal with innovations

Intrachromosomal homologous recombination between inverted amplicons on opposing Y-chromosome arms

Amplicons – large, nearly identical repeats in direct or inverted orientation – are abundant in the male-specific region of the human Y chromosome (MSY) and provide targets for intrachromosomal non-allelic homologous recombination (NAHR). Thus far, NAHR events resulting in deletions, duplications, inversions, or isodicentric chromosomes have been reported only for amplicon pairs located exclusively on the short arm (Yp) or the long arm (Yq). Here we report our finding of four men with Y chromosomes that evidently formed by intrachromosomal NAHR between inverted repeat pairs comprising one amplicon on Yp and one amplicon on Yq. In two men with spermatogenic failure, sister-chromatid crossing-over resulted in pseudoisoYp chromosome formation and loss of distal Yq. In two men with normal spermatogenesis, intrachromatid crossing-over generated pericentric inversions. These findings highlight the recombinogenic nature of the MSY, as intrachromosomal NAHR occurs for nearly all Y-chromosome amplicon pairs, even those located on opposing chromosome arms.National Institutes of Health (U.S.)Netherlands Organization for Scientific ResearchAcademic Medical Center (University of Amsterdam

Female subfertility

The WHO defines female subfertility as failure to achieve a clinical pregnancy after 12 months of regular intercourse or due to impairment of a woman’s capacity to reproduce. This PrimeView highlights some of the mechanisms that may contribute to this condition

Isodicentric Y Chromosomes and Sex Disorders as Byproducts of Homologous Recombination that Maintains Palindromes

Massive palindromes in the human Y chromosome harbor mirror-image gene pairs essential for spermatogenesis. During evolution, these gene pairs have been maintained by intrapalindrome, arm-to-arm recombination. The mechanism of intrapalindrome recombination and risk of harmful effects are unknown. We report 51 patients with isodicentric Y (idicY) chromosomes formed by homologous crossing over between opposing arms of palindromes on sister chromatids. These ectopic recombination events occur at nearly all Y-linked palindromes. Based on our findings, we propose that intrapalindrome sequence identity is maintained via noncrossover pathways of homologous recombination. DNA double-strand breaks that initiate these pathways can be alternatively resolved by crossing over between sister chromatids to form idicY chromosomes, with clinical consequences ranging from spermatogenic failure to sex reversal and Turner syndrome. Our observations imply that crossover and noncrossover pathways are active in nearly all Y-linked palindromes, exposing an Achilles' heel in the mechanism that preserves palindrome-borne genes.National Institutes of Health (U.S.)Howard Hughes Medical InstituteNetherlands Organization for Scientific ResearchUniversity of Amsterdam. Academic Medical CenterBoehringer Ingelheim (Fellowship

Childhood cancer and hematological disorders negatively affect spermatogonial quantity at diagnosis : a retrospective study of a male fertility preservation cohort

Peer reviewe

Health Care Professionals’ Experiences With a Mobile Self-Care Solution for Low Complex Orthopedic Injuries: Mixed Methods Study

Background: To cope with the rising number of patients with trauma in an already constrained Dutch health care system, Direct Discharge (DD) has been introduced in over 25 hospitals in the Netherlands since 2019. With DD, no routine follow-up appointments are scheduled after the emergency department (ED) visit, and patients are supported through information leaflets, a smartphone app, and a telephone helpline. DD reduces secondary health care use, with comparable patient satisfaction and primary health care use. Currently, little is known about the experiences of in-hospital health care professionals with DD. Objective: The aim of this study was to explore the experiences of health care professionals with the DD protocol to enhance durable adoption and improve the protocol. Methods: We conducted a mixed methods study parallel to the implementation of DD in 3 hospitals. Data were collected through a preimplementation survey, a postimplementation survey, and semistructured interviews. Quantitative data were reported descriptively, and qualitative data were reported using thematic analysis. Outcomes included the Bowen feasibility parameters: implementation, acceptability, preliminary efficacy, demand, and applicability. Preimplementation expectations were compared with postimplementation experiences. Health care professionals involved in the daily clinical care of patients with low-complex, stable injuries were eligible for this study. Results: Of the 217 eligible health care professionals, 128 started the primary survey, 37 completed both surveys (response rate of 17%), and 15 participated in semistructured interviews. Health care professionals expressed satisfaction with the DD protocol (median 7.8, IQR 6.8-8.9) on a 10-point scale, with 82% (30/37) of participants noting improved information quality and uniformity and 73% (27/37) of patients perceiving reduced outpatient follow-up and imaging. DD was perceived as safe by 79% (28/37) of participants in its current form, but a feedback system to reassure health care professionals that patients had recovered adequately was suggested to improve DD. The introduction of DD had varying effects on workload and job satisfaction among different occupations. Health care professionals expressed intentions to continue using DD due to increased efficiency, patient empowerment, and self-management. Conclusions: Health care professionals perceive DD as an acceptable, applicable, safe, and efficacious alternative to traditional treatment. A numerical in-app feedback system (eg, in-app communication tools or recovery scores) could alleviate health care professionals’ concerns about adequate recovery and further improve DD protocols. DD can reduce health care use, which is important in times of constrained resources. Nonetheless, both advantages and disadvantages should be considered while evaluating this type of treatment. In the future, clinicians and policy makers can use these insights to further optimize and implement DD in clinical practice and guidelines

Comparing genome-scale DNA methylation and CNV marks between adult human cultured ITGA6+ testicular cells and seminomas to assess in vitro genomic stability

Autologous transplantation of spermatogonial stem cells is a promising new avenue to restore fertility in infertile recipients. Expansion of the initial spermatogonial stem cell pool through cell culturing is a necessary step to obtain enough cells for effective repopulation of the testis after transplantation. Since in vitro propagation can lead to (epi-)genetic mutations and possibly malignant transformation of the starting cell population, we set out to investigate genome-wide DNA methylation status in uncultured and cultured primary testicular ITGA6+ sorted cells and compare them with germ cell tumor samples of the seminoma subtype. Seminomas displayed a severely global hypomethylated profile, including loss of genomic imprinting, which we did not detect in cultured primary testicular ITGA6+ cells. Differential methylation analysis revealed altered regulation of gamete formation and meiotic processes in cultured primary testicular ITGA6+ cells but not in seminomas. The pivotal POU5F1 marker was hypomethylated in seminomas but not in uncultured or cultured primary testicular ITGA6+ cells, which is reflected in the POU5F1 mRNA expression levels. Lastly, seminomas displayed a number of characteristic copy number variations that were not detectable in primary testicular ITGA6+ cells, either before or after culture. Together, the data show a distinct DNA methylation patterns in cultured primary testicular ITGA6+ cells that does not resemble the pattern found in seminomas, but also highlight the need for more sensitive methods to fully exclude the presence of malignant cells after culture and to further study the epigenetic events that take place during in vitro culture

Does Centralization of Radical Prostatectomy Reduce the Incidence of Postoperative Urinary Incontinence?

Background: On the basis of previous analyses of the incidence of urinary incontinence (UI) after radical prostatectomy (RP), the hospital RP volume threshold in the Netherlands was gradually increased from 20 per year in 2017, to 50 in 2018 and 100 from 2019 onwards. Objective: To evaluate the impact of hospital RP volumes on the incidence and risk of UI after RP (RP-UI). Design, setting, and participants: Patients who underwent RP during 2016–2020 were identified in the claims database of the largest health insurance company in the Netherlands. Incontinence was defined as an insurance claim for ≥1 pads/d. Outcome measurements and statistical analysis: The relationship between hospital RP volume (HV) and RP-UI was assessed via multivariable analysis adjusted for age, comorbidity, postoperative radiotherapy, and lymph node dissection. Results and limitations: RP-UI incidence nationwide and by RP volume category did not decrease significantly during the study period, and 5-yr RP-UI rates varied greatly among hospitals (19–85%). However, low-volume hospitals (≤120 RPs/yr) had a higher percentage of patients with RP-UI and higher variation in comparison to high-volume hospitals (&gt;120 RPs/yr). In comparison to hospitals with low RP volumes throughout the study period, the risk of RP-UI was 29% lower in hospitals shifting from the low-volume to the high-volume category (&gt;120 RPs/yr) and 52% lower in hospitals with a high RP volume throughout the study period (&gt;120 RPs/yr for 5 yr). Conclusions: A focus on increasing hospital RP volumes alone does not seem to be sufficient to reduce the incidence of RP-UI, at least in the short term. Measurement of outcomes, preferably per surgeon, and the introduction of quality assurance programs are recommended. Patient summary: In the Netherlands, centralization of surgery to remove the prostate (RP) because of cancer has not yet improved the occurrence of urinary incontinence (UI) after surgery. Hospitals performing more than 120 RP operations per year had better UI outcomes. However, there was a big difference in UI outcomes between hospitals.</p

Establishing reference values for age-related spermatogonial quantity in prepubertal human testes : a systematic review and meta-analysis

Objective: To collect published data on spermatogonial quantity in the testes of healthy children and calculate the reference values of spermatogonial quantities throughout prepuberty. Design: Systematic literature search in PubMed and EMBASE focusing on the number of spermatogonia per transverse tubular cross section (S/T) and spermatogonial density per cubic centimeter (cm(3)) of testicular volume (S/V) throughout prepuberty. Setting: None. Patient(s): None. Intervention(s): None. Main Outcome Measure(s): Polynomial meta-regression analyses of S/T and S/V of healthy boys from the ages of 0 to 14 years. Result(s): We found six papers describing original quantitative data on S/T and S/V of healthy boys (total n = 334 and 62, respectively) that were suitable formeta-analysis. Polynomialmeta-regression analyses of S/T and S/V demonstrated a clear pattern of spermatogonial quantity throughout prepubertal life. This consisted of a decline during the first 3 years of life, a gradual increase until the ages of 6 to 7 years, a plateau until the age of 11 years, and a sharp incline reaching pubertal numbers at 13 to 14 years of age. The association between S/T and S/V allowed us to perform S/T to S/V extrapolation, creating reference S/V (rS/V) values throughout prepubertal life from a cohort of 372 boys. Conclusion(s): Spermatogonial quantity varies during testicular development toward puberty. The values found in this study may serve as a baseline clinical reference to study the impact of diseases and adverse effects of gonadotoxic treatments on spermatogonial quantity in prepubertal testes. Spermatogonial quantity reference values may also help to evaluate the quality of testicular biopsy samples acquired for fertility preservation of prepubertal boys. Copyright (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American Society for Reproductive Medicine.Peer reviewe

Chimpanzee and Human Y Chromosomes Are Remarkably Divergent in Structure and Gene Content

LetterThe human Y chromosome began to evolve from an autosome hundreds of millions of years ago, acquiring a sex-determining function and undergoing a series of inversions that suppressed crossing over with the X chromosome[1, 2]. Little is known about the recent evolution of the Y chromosome because only the human Y chromosome has been fully sequenced. Prevailing theories hold that Y chromosomes evolve by gene loss, the pace of which slows over time, eventually leading to a paucity of genes, and stasis [3, 4]. These theories have been buttressed by partial sequence data from newly emergent plant and animal Y chromosomes [5, 6, 7, 8], but they have not been tested in older, highly evolved Y chromosomes such as that of humans. Here we finished sequencing of the male-specific region of the Y chromosome (MSY) in our closest living relative, the chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. By comparing the MSYs of the two species we show that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. We suggest that the extraordinary divergence of the chimpanzee and human MSYs was driven by four synergistic factors: the prominent role of the MSY in sperm production, ‘genetic hitchhiking’ effects in the absence of meiotic crossing over, frequent ectopic recombination within the MSY, and species differences in mating behaviour. Although genetic decay may be the principal dynamic in the evolution of newly emergent Y chromosomes, wholesale renovation is the paramount theme in the continuing evolution of chimpanzee, human and perhaps other older MSYs.National Institutes of Health (U.S.)Howard Hughes Medical Institut