Sperm selection with hyaluronic acid improved live birth outcomes among older couples and was connected to sperm DNA quality, potentially affecting all treatment outcomes.

STUDY QUESTION: What effects did treatment using hyaluronic acid (HA) binding/selection prior to ICSI have on clinical outcomes in the Hyaluronic Acid Binding sperm Selection (HABSelect) clinical trial? SUMMARY ANSWER: Older women randomized to the trial's experimental arm (selection of sperm bound to immobilized (solid-state) HA) had the same live birth rates as younger women, most likely a result of better avoidance of sperm with damaged DNA. WHAT IS KNOWN ALREADY: Recent randomized controlled trials (RCTs) investigating the efficacy of HA-based sperm selection prior to ICSI, including HABSelect, have consistently reported reductions in the numbers of miscarriages among couples randomized to the intervention, suggesting a pathological sperm-mediated factor mitigated by prior HA-binding/selection. The mechanism of that protection is unknown. STUDY DESIGN, SIZE, DURATION: The original HABSelect Phase 3 RCT ran from 2014 to 2017 and included 2752 couples from whom sperm samples used in control (ICSI) and intervention (Physiological IntraCytoplasmic Sperm Injection; PICSI) arms of the trial were stored frozen for later assessment of DNA quality (DNAq). The trial overlapped with its mechanistic arm, running from 2016 to 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: As miscarriage reduction was a significant secondary outcome of the trial, samples (n = 1247) selected for the mechanistic analysis were deliberately enriched for miscarriage outcomes (n = 92 or 7.4%) from a total of 154 miscarriages (5.6%) among all (n = 2752) couples randomized by stratified random sampling. Values from fresh semen samples for sperm concentration (mml), percentage forward progressive motility and percentage HA-binding score (HBS) were obtained before being processed by differential density gradient centrifugation or (rarely) by swim-up on the day of treatment. Surplus sperm pellets were recovered, aliquoted and cryopreserved for later analysis of DNAq using slide-based Comet, TUNEL, acridine orange (AO) and the sperm chromatin dispersion (SCD) assays. Following their classification into normal and abnormal sample subcategories based on reference values for sperm concentration and motility, relationships with HBS and DNAq were examined by Spearman correlation, Student's t-tests, Mann Whitney U tests, and logistic regression (univariable and multivariable). Parsimonious selection enabled the development of models for exploring and explaining data trends. Potential differences in future cumulative pregnancy rates relating to embryo quality were also explored. MAIN RESULTS AND THE ROLE OF CHANCE: Results from the 1247 sperm samples assayed for HBS and/or DNAq, generated data that were considered in relation to standard physiological measures of (sperm) vitality and to treatment outcomes. All measures of HBS and DNAq discriminated normal from abnormal sperm samples (P < 0.001). SCD correlated negatively with the Comet (r = -0.165; P < 0.001) and TUNEL assays (r = -0.200; P < 0.001). HBS correlated negatively with AO (r = -0.211; P < 0.001), Comet (r = -0.127; P < 0.001) and TUNEL (r = -0.214; P < 0.001) and positively with SCD (r = 0.255; P < 0.001). A model for predicting live birth (and miscarriage) rates included treatment allocation (odds ratio: OR 2.167, 95% CI 1.084-4.464, P = 0.031), female age (OR 0.301, 95% CI 0.133-0.761, P = 0.013, per decade) and the AO assay (OR 0.79, 95% CI 0.60-1. 02.761, P = 0.073, per 10 points rise). A model predicting the expected rate of biochemical pregnancy included male age (OR 0.464, 95% CI 0.314-0.674, P < 0.001, per decade) and the SCD assay (OR 1.04, 95% CI 1.007-1.075, P = 0.018, per 10 point rise). A model for conversion from biochemical to clinical pregnancy did not retain any significant patient or assay variables. A model for post-injection fertilization rates included treatment allocation (OR 0.83, 95% CI 0.75-0.91, P < 0.001) and the Comet assay (OR 0.950, 95% CI 0.91-1.00, P = 0.041). LIMITATIONS, REASONS FOR CAUTION: HABSelect was a prospective RCT and the mechanistic study group was drawn from its recruitment cohort for retrospective analysis, without the full benefit of randomization. The clinical and mechanistic aspects of the study were mutually exclusive in that measures of DNAq were obtained from residual samples and not from HA-selected versus unselected sperm. Models for fitting mechanistic with baseline and other clinical data were developed to compensate for variable DNAq data quality. HABSelect used a solid-state version of PICSI and we did not assess the efficacy of any liquid-state alternatives. PICSI reduced fertilization rates and did not improve the outlook for cumulative pregnancy rates. WIDER IMPLICATIONS OF THE FINDINGS: Notwithstanding the interventional effect on fertilization rates and possibly blastocyst formation (neither of which influenced pregnancy rates), poor sperm DNAq, reflected by lower HBS, probably contributed to the depression of all gestational outcomes including live births, in the HABSelect trial. The interventional avoidance of defective sperm is the best explanation for the equalization in live birth rates among older couples randomized to the trial's PICSI arm. As patients going forward for assisted conception cycles globally in future are likely to be dominated by an older demographic, HA-based selection of sperm for ICSI could be considered as part of their treatment plan. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the National Institute for Health Research (NIHR) EME (Efficacy and Mechanism Evaluation)-11-14-34. National Research Ethics Service approval 11/06/2013: 13/YH/0162. S.L. is CEO of ExamenLab Ltd (company number NI605309). TRIAL REGISTRATION NUMBER: ISRCTN99214271.

State of Mind Ireland-Higher Education: A Mixed-Methods Longitudinal Evaluation of a Positive Mental Health Intervention.

OBJECTIVE: This study evaluates the impact of the State of Mind Ireland-Higher Education (SOMI-HE) Mental Fitness intervention on student wellbeing, resilience, and physical activity (PA) participation. DESIGN: A mixed-methods research design, comprising of a self-report questionnaire, and semi-structured focus group interviews at pre, post and follow-up phases were employed. Participants were a sample of 134 higher education students (29% male: 71% female; mean age range 18 to 25 years old). The quantitative outcome measures of wellbeing, resilience and PA data were analysed using SPSS version 26.0, (IBM, Armonk, NY, USA) with appropriate statistical analysis. Qualitative data were analysed using thematic analysis to capture the long-term outcomes and impact of the intervention. RESULTS: The results indicate a significant intervention effect on participants' wellbeing (t (120) = -4.27, p < 0.001), PA levels (t (126) = 3.91, p < 0.001) and motivational readiness for exercise change (χ2 (1, n = 131) = 6.9, p < 0.009 (2-sided). Qualitative findings suggest a sustained long-term increase in PA and resilience skills for positive mental health, and reduced stigma and barriers to positive mental health. CONCLUSION: The findings demonstrate the effectiveness of the SOMI-HE evidence-based intervention, and beneficial outcomes of a salutary approach to higher education student mental health.

The repetition of suicidal behavior: a multicenter cohort study.

OBJECTIVES: To determine the proportion of individuals who repeated nonfatal suicidal behavior within 12 months of an index episode, to investigate the timing of repetition, and to investigate risk factors associated with repetition and their population impact. METHOD: We carried out a prospective cohort study (1997-2002) in 4 large hospitals in North West England. We included subjects aged 15 years and over who attended with "self-harm" (an act of intentional self-poisoning or injury irrespective of the apparent purpose of the act). Following the episode, a standard assessment form, which included detailed demographic and clinical data, was completed by a clinician. RESULTS: 9213 individuals presented during the study period. The incidence of repetition within 12 months of the index episode was 13.6% (95% CI: 12.9% to 14.4%). The median time to first repetition was 73.5 days (interquartile range, 20 to 187 days). One in 10 subjects repeated within 5 days of the index episode. Independent risk factors for repetition included previous suicidal behavior, psychiatric treatment, being unemployed or registered sick, self-injury, alcohol misuse, and reporting suicidal plans or hallucinations at the time of the index episode. The combined population attributable fraction (an indicator of the potential population impact) for these variables was 65%. CONCLUSION: The repetition of suicidal behavior is common and occurs quickly. On a population level, our study suggests that the most important strategies to reduce repetition might include primary prevention of suicidal behavior, targeting psychiatric illness, and tackling social factors such as unemployment. Specific interventions may be required for individual subgroups.

Suicide after deliberate self-harm: a 4-year cohort study.

OBJECTIVE: The purposes of this study were to estimate suicide rates up to 4 years after a deliberate self-harm episode, to investigate time-period effects on the suicide rate over the follow-up period, and to examine potential sociodemographic and clinical predictors of suicide within this cohort. METHOD: This prospective cohort study included 7,968 deliberate self-harm attendees at the emergency departments of four hospital trusts in the neighboring cities of Manchester and Salford, in northwest England, between September 1, 1997, and August 31, 2001. Suicide rates and standardized mortality ratios (SMRs) for the cohort were calculated. Potential risk factors were investigated by using Cox's proportional hazards models. RESULTS: Sixty suicides occurred in the cohort during the follow-up period. An approximately 30-fold increase in risk of suicide, compared with the general population, was observed for the whole cohort. The SMR was substantially higher for female patients than for male patients. Suicide rates were highest within the first 6 months after the index self-harm episode. The independent predictors of subsequent suicide were avoiding discovery at the time of self-harm, not living with a close relative, previous psychiatric treatment, self-mutilation, alcohol misuse, and physical health problems. CONCLUSIONS: The results highlight the importance in a suicide prevention strategy of early intervention after an episode of self-harm. Treatment should include attention to physical illness, alcohol problems, and living circumstances. Self-harm appears to confer a particularly high risk of suicide in female patients.

Factors that influence emergency department doctors' assessment of suicide risk in deliberate self-harm patients.

OBJECTIVES: To determine the patient factors influencing UK Emergency Department doctors' assessment of suicide risk. To establish whether immediate clinical management is consistent with perceived risk. METHODS: The Manchester and Salford Self-Harm project is a multi-centre deliberate self-harm monitoring study. Data collected were used to analyse risk assessments made by Emergency Department doctors between September 1997 and August 1999. We used univariate and logistic regression analyses to determine the factors Emergency Department doctors used to make suicide risk assessments. RESULTS: A total of 3220 deliberate self-harm assessment forms were completed in two years by Emergency Department doctors; 2922 (91%) included a clinical assessment of risk; 28 out of 48 variables were associated with perceived suicide risk. Multiple logistic regression analyses showed that current mental state, high suicidal intent (including medical seriousness of attempt), and male sex were the most important independent predictors of suicide risk. Being referred to psychiatric services directly from the Emergency Department or to surgical/medical services was also strongly associated with a perceived high risk. CONCLUSION: In contrast to the negative findings of previous research, we found that Emergency Department doctors were influenced by key risk factors for suicide in their assessment of deliberate self-harm patients. Emergency Department doctors' assessments reflected the immediate risk of suicide, indicated by factors such as current mental state and strong suicidal intent. Background risk factors such as social adversity and psychiatric history were less influential. We would recommend that training for emergency doctors should emphasize the importance of both immediate and background risk factors.