A comprehensive genome-wide cross-trait analysis of sexual factors and uterine leiomyoma.

Age at first sexual intercourse (AFS) and lifetime number of sexual partners (NSP) may influence the pathogenesis of uterine leiomyoma (UL) through their associations with hormonal concentrations and uterine infections. Leveraging summary statistics from large-scale genome-wide association studies conducted in European ancestry for each trait (NAFS = 214,547; NNSP = 370,711; NUL = 302,979), we observed a significant negative genomic correlation for UL with AFS (rg = -0.11, P = 7.83×10-4), but not with NSP (rg = 0.01, P = 0.62). Four specific genomic regions were identified as contributing significant local genetic correlations to AFS and UL, including one genomic region further identified for NSP and UL. Partitioning SNP-heritability with cell-type-specific annotations, a close clustering of UL with both AFS and NSP was identified in immune and blood-related components. Cross-trait meta-analysis revealed 15 loci shared between AFS/NSP and UL, including 7 novel SNPs. Univariable two-sample Mendelian randomization (MR) analysis suggested no evidence for a causal association between genetically predicted AFS/NSP and risk of UL, nor vice versa. Multivariable MR adjusting for age at menarche or/and age at natural menopause revealed a significant causal effect of genetically predicted higher AFS on a lower risk of UL. Such effect attenuated to null when age at first birth was further included. Utilizing participant-level data from the UK Biobank, one-sample MR based on genetic risk scores yielded consistent null findings among both pre-menopausal and post-menopausal females. From a genetic perspective, our study demonstrates an intrinsic link underlying sexual factors (AFS and NSP) and UL, highlighting shared biological mechanisms rather than direct causal effects. Future studies are needed to elucidate the specific mechanisms involved in the shared genetic influences and their potential impact on UL development.

Genetic contribution of reproductive traits to risk of uterine leiomyomata: a large-scale, genome-wide, cross-trait analysis.

BACKGROUND: Although phenotypic associations between female reproductive characteristics and uterine leiomyomata have long been observed in epidemiologic investigations, the shared genetic architecture underlying these complex phenotypes remains unclear. OBJECTIVE: We aimed to investigate the shared genetic basis, pleiotropic effects, and potential causal relationships underlying reproductive traits (age at menarche, age at natural menopause, and age at first birth) and uterine leiomyomata. STUDY DESIGN: With the use of large-scale, genome-wide association studies conducted among women of European ancestry for age at menarche (n=329,345), age at natural menopause (n=201,323), age at first birth (n=418,758), and uterine leiomyomata (ncases/ncontrols=35,474/267,505), we performed a comprehensive, genome-wide, cross-trait analysis to examine systematically the common genetic influences between reproductive traits and uterine leiomyomata. RESULTS: Significant global genetic correlations were identified between uterine leiomyomata and age at menarche (rg, -0.17; P=3.65×10-10), age at natural menopause (rg, 0.23; P=3.26×10-07), and age at first birth (rg, -0.16; P=1.96×10-06). Thirteen genomic regions were further revealed as contributing significant local correlations (P<.05/2353) to age at natural menopause and uterine leiomyomata. A cross-trait meta-analysis identified 23 shared loci, 3 of which were novel. A transcriptome-wide association study found 15 shared genes that target tissues of the digestive, exo- or endocrine, nervous, and cardiovascular systems. Mendelian randomization suggested causal relationships between a genetically predicted older age at menarche (odds ratio, 0.88; 95% confidence interval, 0.85-0.92; P=1.50×10-10) or older age at first birth (odds ratio, 0.95; 95% confidence interval, 0.90-0.99; P=.02) and a reduced risk for uterine leiomyomata and between a genetically predicted older age at natural menopause and an increased risk for uterine leiomyomata (odds ratio, 1.08; 95% confidence interval, 1.06-1.09; P=2.30×10-27). No causal association in the reverse direction was found. CONCLUSION: Our work highlights that there are substantial shared genetic influences and putative causal links that underlie reproductive traits and uterine leiomyomata. The findings suggest that early identification of female reproductive risk factors may facilitate the initiation of strategies to modify potential uterine leiomyomata risk.

Interpersonal Trauma and Substance Use Severity: The Serial Mediation of Emotional Intolerance and Emotional Dysregulation.

Substance use is highly prevalent in those with trauma histories, especially in women, which may be in part explained by high rates of interpersonal trauma in this population. Research examining the potential mechanisms underlying the relationship between co-occurring interpersonal trauma histories and substance use disorders (SUDs) is in its infancy. The current study examined whether the relationship between interpersonal trauma and SUD severity could be understood via the sequential ordering of two transdiagnostic emotional vulnerability factors: 1) emotional intolerance (anxiety sensitivity, distress intolerance), and 2) emotional dysregulation (negative urgency, lack of clarity, nonacceptance, limited strategies, difficulties with goal-directed behavior). A sample of 130 adult community-based women self-identifying as experiencing substance use problems completed the online survey. Mediation analyses suggest that as women's lifetime interpersonal trauma increases, so does their SUD severity by way of emotional intolerance and subsequent difficulties regulating their emotions. The findings suggests that transdiagnostic interventions targeting tolerance of aversive emotions may facilitate the ability to learn and employ healthy emotion regulation strategies among women with interpersonal trauma histories and SUDs.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Value of ultrasound in assessing response to neoadjuvant chemotherapy in breast cancer.

AIM: To analyse the utility of ultrasound in assessing response to neoadjuvant chemotherapy (NAC) and predicting residual cancer burden (RCB) index and pathological complete response (pCR) MATERIALS AND METHODS: This was a retrospective study with 417 patients over 7 years. The difference in longest diameter (LD) of the index lesion from baseline to end, baseline to mid, and mid to end was evaluated with respect to RCB class using logistic regression and ordered logistic regression. RESULTS: Change in LD measurements from baseline to end, baseline to mid, and mid to end of chemotherapy as a predictor of RCB class show a negative relationship with a statistically significant association. This would suggest that a smaller change in LD measurements would be associated with an eventual higher RCB class. Change in LD measurements from baseline to end and baseline to mid chemotherapy as a predictor of pCR class show a negative relationship with a statistically significant association (p<0.05). This similarly indicates an inversely proportional relationship between changes in LD measurements and RCB class 0 for baseline to end and baseline to mid. CONCLUSION: This study has shown significance in reducing LD measurements on ultrasound as a predictor of PCR and RCB class. This adds weight to the current practice of using ultrasound at the start, mid and end of chemotherapy cycles to monitor NACT responses.

Heterogeneity In Women's Trauma Histories: Impact On Substance Use Disorder Severity.

Trauma and substance use disorders (SUDs) frequently co-occur, especially in women. Previous studies have attempted to determine if individual differences in trauma histories could be meaningfully categorized but few studies have focused solely on women, especially those reporting substance use problems. A total of 130 women (M age = 30.7, SD = 7.9) self reporting past-year substance use problems completed comprehensive measures assessing lifetime exposure to a variety of traumatic events as well as substance use patterns and severity. Using latent class analysis, three classes emerged, a Low Lifetime Interpersonal Trauma class (40%, n = 52), a Moderate Lifetime Interpersonal Trauma class (23.8%, n = 31) and a High Lifetime Interpersonal Trauma class (36.2%, n = 47). Groups did not vary on daily/almost daily use of different types of substances and polysubstance use frequency but were significantly different on SUD severity, with the Moderate and the High Lifetime Interpersonal Trauma classes reporting severe SUD severity in comparison to moderate severity for the Low Interpersonal Trauma class. The findings of the current study indicate that women experiencing substance use problems should receive SUD treatment in a trauma-informed manner but that not all may require integrated trauma and substance use interventions.

Tailoring the refractive index of impedance-matched ferrite composites.

Independent control of the magnetic and electric properties of two-part and three-part ferrite composites is demonstrated through variation of particle size and volume fraction of ferrite inclusions. This provides a route to creating broadband impedance-matched composites with tailored high refractive-index values. A two-part composite comprising NiZn ferrite in a PTFE dielectric host with approximately equal values of relative real permittivity and permeability up to 100 MHz is manufactured. The refractive index for NiZn-PTFE composites, measured at 20 MHz, is 6.1 for NiZn volume fraction of 50%vol. and 6.9 for NiZn volume fraction of 70%vol. Similarly, we have characterised a three-part composite with a refractive index of approximately 16 up to 60 MHz. The three-part composite comprises NiZn and MnZn ferrites in a PTFE dielectric host matrix with a percentage volume ratio of 65%: 15%: 20%, respectively.

Investigating the shared genetic architecture of uterine leiomyoma and breast cancer: A genome-wide cross-trait analysis.

Little is known regarding the shared genetic architecture or causality underlying the phenotypic association observed for uterine leiomyoma (UL) and breast cancer (BC). Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) conducted in each trait, we investigated the genetic overlap and causal associations of UL with BC overall, as well as with its subtypes defined by the status of estrogen receptor (ER). We observed a positive genetic correlation between UL and BC overall (rg = 0.09, p = 6.00 × 10-3), which was consistent in ER+ subtype (rg = 0.06, p = 0.01) but not in ER- subtype (rg = 0.06, p = 0.08). Partitioning the whole genome into 1,703 independent regions, local genetic correlation was identified at 22q13.1 for UL with BC overall and with ER+ subtype. Significant genetic correlation was further discovered in 9 out of 14 functional categories, with the highest estimates observed in coding, H3K9ac, and repressed regions. Cross-trait meta-analysis identified 9 novel loci shared between UL and BC. Mendelian randomization demonstrated a significantly increased risk of BC overall (OR = 1.09, 95% CI = 1.01-1.18) and ER+ subtype (OR = 1.09, 95% CI = 1.01-1.17) for genetic liability to UL. No reverse causality was found. Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis, pleiotropic loci, as well as a putative causal relationship between UL and BC, highlighting an intrinsic link underlying these two complex female diseases.

Assessing the quality of cardiac rehabilitation programs by measuring adherence to the Australian quality indicators.

BACKGROUND: Every year, over 65,000 Australians experience an acute coronary syndrome (ACS) and around one-third occur in people with prior coronary heart disease. Cardiac rehabilitation (CR) aims to prevent a repeat ACS by supporting patients' return to an active and fulfilling lifestyle. CR programs are efficacious, but audits of clinical practice show variability of program delivery, which may compromise patient outcomes. Core components, quality indicators and accreditation of programs have been introduced internationally to increase program standardisation. With Australian quality indicators (QIs) for cardiac rehabilitation recently introduced, we aimed to conduct a survey in one state of Australia to assess the extent to which programs adhere to the measurement of QIs comparing country, metropolitan, telephone and face to face programs. METHODS: A cross- sectional survey design with face validity testing was used to formulate questions to evaluate cardiac rehabilitation program and personnel characteristics and QI adherence. Between October 2020- December 2021, 23 cardiac rehabilitation programs across country and metropolitan areas were invited to participate. Quality improvement was defined as adherence to the Australian Quality Indicators, and we developed an objective score to calculate program performance categorised by quartiles. Significance of CR completion and time to enrolment between program type (telephone versus face to face) and location (country versus metropolitan were compared using Pearson's Chi-square and Mann-Whitney U tests. RESULTS: Among the 23 CR programs, 15 were country and 8 metropolitan-based and 22 were face to face and 1 telephone-based. Median wait time from discharge was 27.0 days, (interquartile range 19.3-46.0) across all programs and country completions of enrolled were 76.9% versus metropolitan 56.5%, p < 0.001 and telephone versus face to face 92.9% versus 59.6% p < 0.001. Pre-program QI adherence was higher than post program for depression, medication adherence, health-related quality of life and comprehensive re-assessment. Seventy four percent of programs were ranked at a medium level of performance (mean score: 11.4/16, SD ± 0.79). CONCLUSIONS: A survey of 23 cardiac rehabilitation programs, showed variability in adherence to measurement of the Australian Cardiovascular and Rehabilitation Association and Australian Heart Foundation Cardiac Rehabilitation Quality Indicators. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12621000222842 , registered 03/03/2021.

Effect of plasma rich in growth factors on quality of life following mandibular third molar removal: a double-blind randomized controlled trial.

The objective of this study was to investigate the effect of plasma rich in growth factors (PRGF) on patient- and clinician-reported outcomes following mandibular third molar removal. Seventy-four patients requiring surgical removal of a unilateral impacted mandibular third molar under local anaesthesia were recruited into the study. PRGF was prepared for all patients irrespective of study arm allocation. Reviews were conducted 3 days (T1) and 7 days (T2) postoperatively. Primary outcome measures were pain (numerical rating scale, NRS), OHIP-14 (Oral Health Impact Profile-14), and postoperative symptom severity scale (PoSSe) data. Secondary outcome measures including mouth opening, dry socket, socket healing, and analgesic consumption were also explored. The statistical analysis was performed using analysis of covariance and the χ2 test. NRS pain scores were higher in the PRGF group at T1, demonstrating borderline significance (mean difference 1.0; P = 0.06), with no difference at T2. PoSSe scores did not differ between the groups, with the exception of the 'interference with daily activities' subscale at T1, where PRGF group patients scored 1.2 units higher (P = 0.02). OHIP-14 scores demonstrated a 25% increased likelihood of PRGF patients reporting discomfort on eating at T1 (P = 0.02), with no statistical significance at T2. Secondary outcomes did not differ between the groups. No difference in clinical or quality of life outcomes was observed for patients receiving adjunctive PRGF in third molar sockets.

Confidence of Irish dermatologists in caring for patients with skin of colour.

To assess Irish dermatologists' confidence with dermatology in patients with skin of colour (SOC), an online survey was distributed to all members of the Irish Association of Dermatology (IAD) by email. Half (50%) of respondents were 'not confident' or 'not at all confident' in diagnosing skin conditions and one-third (33.9%) were 'not confident' or 'not at all confident' in managing skin conditions in patients with SOC. Irish dermatologists have low confidence with skin pathology in SOC, and specific training could reduce this disparity.

Mid-pass whole genome sequencing enables biomedical genetic studies of diverse populations.

BACKGROUND: Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at "mid-pass" 1-7x coverage. RESULTS: Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). CONCLUSION: Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.

Anakinra for recalcitrant pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is an autoinflammatory neutrophilic dermatosis characterized by rapidly enlarging, painful ulcers. Anakinra is a recombinant interleukin (IL)-1 receptor antagonist that blocks the activity of IL-1α and IL-1ß by competitively inhibiting IL-1 binding to the IL-1 type 1 receptor. We present a series of two patients with recalcitrant PG, who had limited therapeutic options and multiple comorbidities and multiple previous treatment failures, who obtained 100% healing with anakinra. Compared with conventional first-line therapies for PG, the safety profile of anakinra may be preferable for patients with multiple comorbidities. Further research is needed to assess the safety and efficacy of anakinra for PG.

Bare necessities? The utility of full skin examination in the COVID-19 era.

Full skin examination (FSE) may improve the detection of malignant melanoma (MM). The objective of this study was to assess the safety of targeted lesion examination (TLE) compared with FSE in our Pigmented Lesion Clinic (PLC). Patients attending the PLC were randomized in a 2 : 1 ratio to FSE (intervention) or TLE (standard care). Demographic details and risk factors were documented, and the time taken to perform FSE and TLE was noted. Of 763 participants, 520 were assigned to FSE and 243 were assigned to TLE. On average, FSE took 4.02 min and TLE took 30 s to perform. Of the 520 participants assigned to FSE, 37 (7.1%) had incidental findings, of whom 12 patients (2.3%) had additional lesions biopsied. No additional melanomas were detected that would have been missed by use of the standard protocol. This study suggests that in low-risk patients referred to a PLC with a lesion of concern, the possibility of missing incidental cutaneous malignancies using lesion-directed examination is low.