Clinical Evaluation of a Custom Gene Panel as a Tool for Precision Male Infertility Diagnosis by Next-Generation Sequencing

Background: Up to 15% of couples are infertile and male factor infertility accounts for approximately 50% of these cases. Male infertility is a multifactorial pathological condition. The genetic of male infertility is very complex and at least 2000 genes are involved in its etiology. Genetic testing by next-generation sequencing (NGS) technologies can be relevant for its diagnostic value in male infertile patients. Therefore, the aim of this study was to implement the diagnostic offer with the use of an NGS panel for the identification of genetic variants. Methods: We developed an NGS gene panel that we used in 22 male infertile patients. The panel consisted of 110 genes exploring the genetic causes of male infertility; namely spermatogenesis failure due to single-gene mutations, central hypogonadism, androgen insensitivity syndrome, congenital hypopituitarism, and primary ciliary dyskinesia. Results: NGS and a subsequent sequencing of the positive pathogenic or likely pathogenic variants, 5 patients (23%) were found to have a molecular defect. In particular, pathogenic variants were identified in TEX11, CCDC39, CHD7, and NR5A1 genes. Moreover, 14 variants of unknown significance and 7 novel variants were found that require further functional studies and family segregation. Conclusion: This extended NGS-based diagnostic approach may represent a useful tool for the diagnosis of male infertility. The development of a custom-made gene panel by NGS seems capable of reducing the proportion of male idiopathic infertility

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Male fertility in relapsing-remitting multiple sclerosis patients treated with natalizumab and ocrelizumab: A prospective case-control study

Scarce data are available about the impact of natalizumab (NTZ) and ocrelizumab (OCR) on male fertility in relapsing-remitting multiple sclerosis (RRMS). In this case-control prospective study, the gonadal steroids and the sperm parameters have been analysed at the time of the RRMS diagnosis and after 12months from the beginning of the investigated therapies. Sixteen men with RRMS and sixteen matched healthy controls were included. At enrolment and after 12months on therapy, the gonadal steroids and the sperm parameters of men with RRMS did not differ from the healthy controls. In conclusion, therapy with NTZ and OCR had no impact on fertility status in our cohort of men with RRMS. Further randomized and prospective studies are needed

Globozoospermia: A Case Report and Systematic Review of Literature

Purpose: Globozoospermia is a genetic syndrome characterized by the presence of round-headed spermatozoa and infertility due to the inability of these spermatozoa to fertilize the oocyte. In this article, we present the clinical case of a young globozoospermic patient with a new, not yet described mutation of the DPY19L2 gene. We also performed a systematic review of the literature on gene mutations, the outcome of assisted reproductive techniques, and the risk of transmission of abnormalities to the offspring in patients with globozoospermia and made recommendations to offer a more appropriate clinical management of these patients. Materials and Methods: We performed a systematic search in the PubMed, Google Scholar, and Scopus databases from their inception to December 2021. The search strategy included the combination of the following Medical Subjects Headings (MeSH) terms and keywords: “globozoospermia”, “round-headed spermatozoa”, “round head spermatozoa”, “intracytoplasmic sperm injection”, “ICSI”, “offspring”, “child health”, “assisted reproductive technique outcome”. All the eligible studies were selected following the PECOS (Population, Exposure, Comparison/Comparator, Outcomes, Study design) model. The quality of included studies was assessed by applying the “Cambridge Quality Checklists”. Results: The main genes involved in the pathogenesis of globozoospermia are DPY19L2, SPATA16, PICK1, GGN, SPACA1, ZPBP, CCDC62, and CCNB3 genes. Other genes could also play a role. These include C2CD6, C7orf61, CCIN, DNH17, DNH6, PIWIL4, and CHPT1. Globozoospermic patients should undergo ART to achieve fertility. In particular, intracytoplasmic sperm injection with assisted oocyte activation or intracytoplasmic morphologically-selected sperm injection appears to be associated with a higher success rate. Patients with globozoospermia should also be evaluated for the high rate of sperm aneuploidy which appears to influence the success rate of ART but does not appear to be associated with an increased risk of transmission of genetic abnormalities to offspring. Conclusions: This systematic review summarizes the evidence on the gene panel to be evaluated, ICSI outcomes, and the\ud health of the offspring in patients with globozoospermia. Evidence-based recommendations on the management of patients with globozoospermia are provided

Substance Abuse and Male Hypogonadism

Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a recognized cause of possible alterations of steroidogenesis and spermatogenesis. Alcohol, opioids and anabolic-androgenic steroids are capable to reduce testosterone production in male interfering with testicular and/or hypothalamic-pituitary function. Other substances such as nicotine, cannabis, and amphetamines alter spermatogenesis inducing oxidative stress and subsequent apoptosis in testicular tissue. Substance and drug abuse is a potentially reversible cause of hypogonadism, defined as the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa. The identification of the abuse is important because the withdrawal of substance intake can reverse the clinical syndrome. This review summarizes the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production

Erectile Dysfunction after Kidney Transplantation

Patients with kidney transplantation often have a worse quality of life than the general population. One of the reasons for this, in male patients, is the high prevalence of erectile dysfunction. This is mainly due to the presence of comorbidities, surgery for kidney transplantation, adverse drug effects, psychological changes related to chronic disease, as well as hyperprolactinemia and hypogonadism. Whenever these endocrine dysfunctions occur after kidney transplantation, they must be corrected with appropriate treatment, i.e., testosterone replacement therapy. Administration of the phosphodiesterase-5 inhibitor (PDE5i) sildenafil at the recommended posology does not significantly alter the pharmacokinetics of the calcineurin inhibitors cyclosporin A or tacrolimus and does not impair kidney allograft function. Tacrolimus increases the peak concentration and prolongs the half-life of PDE5i in kidney transplant patients and, therefore, daily administration cannot be recommended due to the significant drop in blood pressure. Intracavernous injection or topical application of alprostadil can be a second-line option for the treatment of erectile dysfunction after kidney transplantation, which does not alter cyclosporine concentrations and does not deteriorate kidney function. Finally, penile prostheses can be successfully implanted following pelvic organ transplantation after eliminating the risk of infection associated with surgery

Gonadal Steroids and Sperm Quality in a Cohort of Relapsing Remitting Multiple Sclerosis: A Case-Control Study

Introduction: Evaluation of the hypothalamic-pituitary-testicular axis and sperm analyses are not a standard examination of patients with Relapsing-Remitting Multiple Sclerosis (RRMS). Methods: This is a prospective-case-controlled study. Patients, aged 18–55, with a confirmed diagnosis of RRMS, naïve to any DMT were enrolled. Controls were men with normal evaluation who acceded to the Andrology Center of Catania in a contemporary matched randomized fashion to the group of RRMS patients. The aim of the study is to evaluate gonadal steroids and sperm quality in men at the time of RRMS diagnosis and 12 months following the first disease modifying treatment (DMT). Results: Out of 41 patients with RRMS, 38 were included in the study (age 40.3 ± 12.3) to be compared with matched controls. Patients with RRMS showed no differences in gonadal steroids or sperm parameters, except for free testosterone (fT) plasma levels, which were lower in RRMS patients than controls (median 0.09 vs. 1.4, p < 0.0001). The correlation analyses, corrected for age and Body Mass Index, did not reveal any correlation between hormonal/sperm parameters and level of disability or disease activity at onset. Additionally, 12 months following the start of DMT, there were no differences in gonadal steroids and sperm quality compared to baseline. Conclusions: Results suggest that RRMS may not have an impact on fertility status but prospective long-term studies are needed

Prevalence of intratubular germ cell neoplasia and multifocality in testicular germ cell tumors ≤ 2 cm: relationship with other pathological features

Introduction: The aim of this study was to determine the prevalence of TIN and multifocality in men undergoing radical orchiectomy for testicular germ cell tumor (TGCT), and among those with a main tumor size ≤ 2 cm, potentially eligible for testis-sparing surgery. Patients and Methods: Orchiectomy specimens from 126 consecutive patients treated for TGCT tumor between 2003 and 2012 were included. Multifocality was defined as a distinct tumor focus with a diameter ≥ 1 mm separable from the main tumor mass. Uni- and multivariate logistic regression was performed to identify the association between pathological variables and multifocality and to identify variables for predicting clinical stage II to III and pathological stage ≥ pT2. Results: Of the 126 patients, 103 (82.0%) had clinical stage I cancer at presentation and 23 (18.0%) had clinical stage II to III. The median size of the primary tumor mass was 3.7 cm (range, 0.5-12 cm) in multifocality and 3.0 cm (range, 0.6-8.0 cm) in monofocality, respectively (P < .05). The prevalence of multifocality and TIN was lower in the presence of a smaller main tumor mass (≤ 1 cm) compared with tumors 1.1 to 2.0 cm (P < .05), and increased when the index mass tumor diameter was ≥ 2 cm (P trend < .05). No association was found between tumor histology and multifocality (P = .95) or TIN (P = .54) using the χ2 test. Conclusion: The prevalence of multifocality and TIN was decreased in smaller tumors (≤ 1 cm) and increased when the index mass tumor diameter was ≥ 1.1 cm

Prediction equation for estimating cognitive function using physical fitness parameters in older adults.

Ageing is associated with declines in cognitive functions and physical fitness (PF). Physical exercise training and physical activity (PA) have been shown to have positive effects on cognitive functions and brain plasticity. This study aims to establish a practical equation for evaluating cognitive functions using PF parameters in healthy older adults. One-hundred and two older subjects were physically and clinically evaluated. Participants performed the Short Physical Performance Battery (SPPB) and handgrip test (HG); general cognitive functions were examined using the Mini Mental State Examination (MMSE). For all of them, a multiple regression analysis was used to predict MMSE from age, SPPB and HG variables. The new equation was cross validated to determine its prediction accuracy. Considering that SPPB and MMSE reference score are not different between genders, only one equation was developed for females and males. Age, SPPB and HG correlated significantly (p<0.01) with the MMSE score. The developed equation was MMSE = 19.479 + (1.548 x SPPB)-(0.130 x age) (R2 = 0.72 and root mean square errors of 3.6). The results of PF are useful for exercise specialists to achieve the best physical exercise training and PA in older adults. In conclusion, this study showed for the first time that our new equation can be used to predict subjects' cognitive functions based on SPPB results and subject age. We suggest its use when patients' cognitive functions or more appropriate clinical tests cannot be pursued

Use of Biosimilar Follicle-Stimulating Hormone in Asthenozoospermic Infertile Patients: A Multicentric Study

There is increasing data in favour of follicle-stimulating hormone (FSH) therapy in patients with oligo-asthenozoospermia and normal-range gonadotropins in order to increase sperm count and above all sperm motility. Some studies showed an improvement in DNA fragmentation and spontaneous pregnancy. Recently, biosimilar FSH has been marketed with the same indications. We performed a retrospective multicentric case-control study involving 147 asthenozoospermic patients between 18 and 45 years of age. A total of 97 patients were treated with biosimilar FSH 150 UI three times a week for 3 months, while 50 control subjects received no treatment. Patients were evaluated at baseline and after 3 months with semen analysis including DNA fragmentation, testicular colour Doppler ultrasound, and blood tests. Spontaneous pregnancies were recorded during a further follow-up period of 6 months. Treated patients showed after treatment a statistically significant increase in sperm concentration, total sperm count, and total motile sperm, as well as improved progressive motility and non-progressive motility. DNA fragmentation showed a significant reduction. Conversely, in the control group, no significant change was found. Pregnancy rate was significantly higher in treated patients. These data suggest comparable efficacy of biosimilar FSH in the treatment of male infertility; however, larger studies are needed to confirm our results