Pharmacists' roles in assisted reproductive technology

Background: The global issue of infertility has prompted an increased reliance on Assisted Reproductive Technology (ART) for conception. In Australia, patients have previously accessed ART medications through specialist clinics, however recently due to modifications in ART medication subsidisation, community pharmacists now dispense and counsel patients on ART medications. Patients residing in rural and remote locations face challenges in accessing fertility clinics, which are primarily located in metropolitan and large regional cities. Objective: To investigate the perceived role, experience, confidence, and training requirements that pharmacists have in relation to providing ART medications and counselling to patients. Methods: Purposive sampling related to location of practice, pharmacist experience with ART and self-classification as an ART specialist was used to recruit 19 Australian pharmacists from rural, remote, large regional, and metropolitan areas, who participated in semi-structured interviews based on the Consolidated Framework for Implementation Research (CFIR). Interview transcriptions were transcribed, imported into NVivo, analysed using thematic analysis and mapped to CFIR domains and constructs. Results: Of the nineteen pharmacists interviewed, six were from rural and remote areas and thirteen were from metropolitan or large regional areas. Eight participants perceived themselves as specialist pharmacists in ART, all of which were in metropolitan or large regional locations. Three CFIR domains were identified as relevant for this study, which were further developed, with data mapped to eleven constructs under those domains. Emergent themes were identified that contributed to the pharmacist role including patient needs, external policies, fertility clinics, pharmacist experience and training, procuring ART, and the personal attributes of participants. Some constructs and themes differed between participants dependent on self-reported specialisation status and geographical location (e.g., self-efficacy), whereas others were consistent (e.g., knowledge and belief about the intervention). Pharmacists considered their role not to be limited to the supply and counselling of medication, but to also involve a support role for patients undergoing an emotionally difficult and sensitive journey, without guaranteed success. Conclusion: This study reveals the diverse role of Australian pharmacists in ART, influenced by location, experience, and confidence. Pharmacists have an important role to play in reducing barriers to ART access by offering fertility education, addressing concerns, providing medications and counselling, and monitoring patient well-being, improving outcomes for this cohort of patients particularly in rural and remote areas

The rural pharmacy practice landscape: challenges and motivators

Background: Health outcome delivery for rural and remote Australian communities is challenged by the maldistribution of the pharmacy workforce. High staff turnover rates, reduced pharmacist numbers, and reliance on temporary staff have placed great strain on both state health services and rural community pharmacies. However, recent changes to the demographic profile of the rural pharmacist including a lower average age and increased time spent in rural practice highlights a more positive future for the delivery of better health outcomes for rural communities. The aim of this study was to investigate the factors that motivate and challenge pharmacists' choice to practice rurally. Methods: Rural pharmacists were invited to participate in semi-structured interviews using purposive non-probability sampling. Twelve pharmacists were interviewed with early-, middle- and late-career pharmacists represented. Participants described their experiences of working and living in rural and remote locations. Three themes emerged: workforce, practice environment and social factors, which were examined to determine the underlying challenges and motivators impacting rural and remote pharmacy practice. Results: Lack of staff presented a workforce challenge, while motivators included potential for expanded scope of practice and working as part of a multidisciplinary team. While social isolation has often been presented as a challenge, an emerging theme highlighted that this may no longer be true, and that notions of "rural and remote communities as socially isolated was a stigma that needed to be stopped". Conclusion: This study highlights that despite the challenges rural pharmacists face, there is a shift happening that could deliver better health outcomes for isolated communities. However, for this to gain momentum, it is important to examine both the challenges and motivators of rural pharmacy practice to provide a platform for the development and implementation of appropriate frameworks and programs to better support the rural pharmacy workforce

Exercise-based cardiac rehabilitation for adult patients with an implantable cardioverter defibrillator

Review question: We reviewed the benefits and harms of exercise-based cardiac rehabilitation programmes in adults who have been treated with an implantable cardioverter defibrillator from any cause. Background: An implantable cardioverter defibrillator is a very effective device that prevents sudden cardiac death. This is done by the use of either antitachycardia pacing, high-voltage shock therapy, or both. In spite of the potential mortality benefits, patients may also experience a negative impact on their health-related quality of life, increased readmission to hospital and healthcare facilities, loss of productivity and employment earnings, and increased morbidity and mortality. Exercise-based cardiac rehabilitation may benefit patients with an implantable cardioverter defibrillator. Study characteristics: We searched for randomised controlled trials (experiments in which participants are randomly allocated to an experimental intervention compared with a control intervention) that investigated exercise-based interventions compared with no exercise intervention control. We found eight trials published from 2004 to 2017 with a total of 1730 participants. Two trials did not report on funding and one trial reported funding from industry. The evidence is current to 30 August 2018. Key results: The review showed no evidence of an impact on the risk of death, harmful side effects or having antitachycardia pacing or shock therapy when comparing the exercise intervention to the control. There was also little or no evidence of a difference on health-related quality of life. However, there was an improvement in exercise capacity in favour of the exercise group. Quality of the evidence: The quality of the evidence ranged from moderate to very low for all outcomes. The number of events was low, it was possible for people in the trials to know to which intervention group they were randomised, the reporting of the results was not complete in some trials, and for some outcomes, the results varied across trials. These considerations limited our confidence in the overall results of the review. Conclusion: Further adequately powered and well-conducted randomised trials are needed to assess the impact of exercise-based cardiac rehabilitation in adults with an implantable cardioverter defibrillator

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction.

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function.The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss

Perinatal mental health services in pregnancy and the year after birth: the ESMI research programme including RCT

Background It is unclear how best to identify and treat women with mental disorders in pregnancy and the year after birth (i.e. the perinatal period). Objectives (1) To investigate how best to identify depression at antenatal booking [work package (WP) 1]. (2) To estimate the prevalence of mental disorders in early pregnancy (WP1). (3) To develop and examine the efficacy of a guided self-help intervention for mild to moderate antenatal depression delivered by psychological well-being practitioners (WP1). (4) To examine the psychometric properties of the perinatal VOICE (Views On Inpatient CarE) measure of service satisfaction (WP3). (5) To examine the clinical effectiveness and cost-effectiveness of services for women with acute severe postnatal mental disorders (WPs 1–3). (6) To investigate women’s and partners’/significant others’ experiences of different types of care (WP2). Design Objectives 1 and 2 – a cross-sectional survey stratified by response to Whooley depression screening questions. Objective 3 – an exploratory randomised controlled trial. Objective 4 – an exploratory factor analysis, including test–retest reliability and validity assessed by association with the Client Satisfaction Questionnaire contemporaneous satisfaction scores. Objective 5 – an observational cohort study using propensity scores for the main analysis and instrumental variable analysis using geographical distance to mother and baby unit. Objective 6 – a qualitative study. Setting English maternity services and generic and specialist mental health services for pregnant and postnatal women. Participants Staff and users of mental health and maternity services. Interventions Guided self-help, mother and baby units and generic care. Main outcome measures The following measures were evaluated in WP1(i) – specificity, sensitivity, positive predictive value, likelihood ratio, acceptability and population prevalence estimates. The following measures were evaluated in WP1(ii) – participant recruitment rate, attrition and adverse events. The following measure was evaluated in WP2 – experiences of care. The following measures were evaluated in WP3 – psychometric indices for perinatal VOICE and the proportion of participants readmitted to acute care in the year after discharge. Results WP1(i) – the population prevalence estimate was 11% (95% confidence interval 8% to 14%) for depression and 27% (95% confidence interval 22% to 32%) for any mental disorder in early pregnancy. The diagnostic accuracy of two depression screening questions was as follows: a weighted sensitivity of 0.41, a specificity of 0.95, a positive predictive value of 0.45, a negative predictive value of 0.93 and a likelihood ratio (positive) of 8.2. For the Edinburgh Postnatal Depression Scale, the diagnostic accuracy was as follows: a weighted sensitivity of 0.59, a specificity of 0.94, a positive predictive value of 0.52, a negative predictive value of 0.95 and a likelihood ratio (positive) of 9.8. Most women reported that asking about depression at the antenatal booking appointment was acceptable, although this was reported as being less acceptable for women with mental disorders and/or experiences of abuse. Cost-effectiveness analysis suggested that both the Whooley depression screening questions and the Edinburgh Postnatal Depression Scale were more cost-effective than with the Whooley depression screening questions followed by the Edinburgh Postnatal Depression Scale or no-screen option. WP1(ii) – 53 women with depression in pregnancy were randomised. Twenty-six women received modified guided self-help [with 18 (69%) women attending four or more sessions] and 27 women received usual care. Three women were lost to follow-up (follow-up for primary outcome: 92%). At 14 weeks post randomisation, women receiving guided self-help reported fewer depressive symptoms than women receiving usual care (adjusted effect size −0.64, 95% confidence interval −1.30 to 0.06). Costs and quality-adjusted life-years were similar, resulting in a 50% probability of guided self-help being cost-effective compared with usual care at National Institute for Health and Care Excellence cost per quality-adjusted life-year thresholds. The slow recruitment rate means that a future definitive larger trial is not feasible. WP2 – qualitative findings indicate that women valued clinicians with specialist perinatal expertise across all services, but for some women generic services were able to provide better continuity of care. Involvement of family members and care post discharge from acute services were perceived as poor across services, but there was also ambivalence among some women about increasing family involvement because of a complex range of factors. WP3(i) – for the perinatal VOICE, measures from exploratory factor analysis suggested that two factors gave an adequate fit (comparative fit index = 0.97). Items loading on these two dimensions were (1) those concerning aspects of the service relating to the care of the mother and (2) those relating to care of the baby. The factors were positively correlated (0.49; p < 0.0001). Total scores were strongly associated with service (with higher satisfaction for mother and baby units, 2 degrees of freedom; p < 0.0001) and with the ‘gold standard’ Client Service Questionnaire total score (test–retest intraclass correlation coefficient 0.784, 95% confidence interval 0.643 to 0.924; p < 0.0001). WP3(ii) – 263 of 279 women could be included in the primary analysis, which shows that the odds of being readmitted to acute care was 0.95 times higher for women who were admitted to a mother and baby unit than for those not admitted to a mother and baby unit (0.95, 95% confidence interval 0.86 to 1.04; p = 0.29). Sensitivity analysis using an instrumental variable found a markedly more significant effect of admission to mother and baby units (p < 0.001) than the primary analysis. Mother and baby units were not found to be cost-effective at 1 month post discharge because of the costs of care in a mother and baby unit. Cost-effectiveness advantages may exist if the cost of mother and baby units is offset by savings from reduced readmissions in the longer term. Limitations Policy and service changes had an impact on recruitment. In observational studies, residual confounding is likely. Conclusions Services adapted for the perinatal period are highly valued by women and may be more effective than generic services. Mother and baby units have a low probability of being cost-effective in the short term, although this may vary in the longer term. Future work Future work should include examination of how to reduce relapses, including in after-care following discharge, and how better to involve family members. Trial registration This trial is registered as ISRCTN83768230 and as study registration UKCRN ID 16403. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 10, No. 5. See the NIHR Journals Library website for further project information

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio