Analysis of exome data in a UK cohort of 603 patients with syndromic orofacial clefting identifies causal molecular pathways.

Orofacial cleft (OC) is a common congenital anomaly in humans, which has lifelong implications for affected individuals. This disorder can be classified as syndromic or non-syndromic depending on the presence or absence of additional physical or neurodevelopmental abnormalities, respectively. Non-syndromic cleft is often non-familial in nature and has a complex aetiology, whereas syndromic forms tend to be monogenic. Although individual OC-related syndromes have been frequently described in the medical literature, there has not been a comprehensive review across syndromes, thereby leaving a gap in our knowledge, which this paper aims to address. Six hundred and three patients with cleft-related human phenotype ontology terms were identified within the Deciphering Developmental Disorders study. Genes carrying pathogenic/likely pathogenic variants were identified and reviewed enabling a diagnostic yield of 36.5%. In total, 124 candidate genes for syndromic OC were identified, including 34 new genes that should be considered for inclusion in clinical clefting panels. Functional enrichment and gene expression analyses identified three key processes that were significantly overrepresented in syndromic OC gene lists: embryonic morphogenesis, protein stability and chromatin organization. Comparison with non-syndromic OC gene networks led us to propose that chromatin remodelling specifically contributes to the aetiology of syndromic OC. Disease-driven gene discovery is a valid approach to gene identification and curation of gene panels. Through this approach, we have started to unravel common molecular pathways contributing to syndromic orofacial clefting.

Mapping HIV prevalence in sub-Saharan Africa between 2000 and 2017.

HIV/AIDS is a leading cause of disease burden in sub-Saharan Africa. Existing evidence has demonstrated that there is substantial local variation in the prevalence of HIV; however, subnational variation has not been investigated at a high spatial resolution across the continent. Here we explore within-country variation at a 5 × 5-km resolution in sub-Saharan Africa by estimating the prevalence of HIV among adults (aged 15-49 years) and the corresponding number of people living with HIV from 2000 to 2017. Our analysis reveals substantial within-country variation in the prevalence of HIV throughout sub-Saharan Africa and local differences in both the direction and rate of change in HIV prevalence between 2000 and 2017, highlighting the degree to which important local differences are masked when examining trends at the country level. These fine-scale estimates of HIV prevalence across space and time provide an important tool for precisely targeting the interventions that are necessary to bringing HIV infections under control in sub-Saharan Africa.

Patient-Reported Bowel, Urinary, and Sexual Outcomes After Laparoscopic-Assisted Resection or Open Resection for Rectal Cancer: The Australasian Laparoscopic Cancer of the Rectum Randomized Clinical Trial (ALaCart).

OBJECTIVE: The aim of this study was to compare patient-reported urinary, bowel, and sexual functioning of ALaCaRT Trial participants randomized to open or laparoscopic surgery for rectal cancer. SUMMARY BACKGROUND DATA: The primary endpoint, noninferiority of laparoscopic surgical resection adequacy, was not established. METHODS: Participants completed QLQ-CR29 at baseline, 3, and 12 months post-surgery. Additionally, women completed Rosen's Female Sexual Functioning Index (FSFI). Men completed the International Index of Erectile Function (IIEF) and QLQ-PR25. We compared the proportions of participants in each group who experienced moderate/severe symptoms/dysfunction at each time-point and compared mean difference scores from baseline to 12 months between groups. All analyses were intention-to-treat. Sexual functioning analyses included only the participants who expressed sexual interest at baseline. RESULTS: Baseline PRO compliance of 475 randomized participants was 88%. At 12 months, a lower proportion of open surgery participants experienced moderate-severe fecal incontinence and sore skin, compared to Laparoscopic participants, and a lower proportion of men randomized to open surgery experienced moderate-severe urinary symptoms. There were no differences at 3 months for bowel or urinary symptoms. Sexual functioning among sexually interested participants was similar between groups at 3 and 12 months; however, a lower proportion of women reported moderate to severe sexual dissatisfaction at 3 months in the open as compared to the laparoscopic group, (Rebecca.mercieca@sydney.edu.au., 95% CI 0.03-0.39). DISCUSSION: Despite the slightly lower proportions of open surgery participants self-reporting moderate-severe symptoms for 3 of 16 urinary/bowel domains, and lack of differences in sexual domains, it remains difficult to recommend one surgical approach over another for rectal resection.

Angiotensin receptor blockers and ß blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials.

BACKGROUND: Angiotensin receptor blockers (ARBs) and ß blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. METHODS: In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus ß blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus ß blocker; and indirectly, ß blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. FINDINGS: We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference -0·07 [95% CI -0·12 to -0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with ß-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with ß blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase -0·08 [SE 0·03] in ARB groups vs -0·11 [SE 0·02] in ß-blocker groups; absolute difference 0·03 [95% CI -0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between ß blockers and control was -0·09 (95% CI -0·18 to 0·00; p=0·042). INTERPRETATION: In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a ß blocker. The effects of ß blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and ß blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery. FUNDING: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.

Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.

Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Condom Use Behaviors, Risk Perception, and Partner Communication Following Oral HIV Self-testing Among Adolescents and Young Adults in Kenya: A Cohort Study.

HIV self-testing (HIVST) can improve testing completion among adolescents and young adults (AYA), although its influence on sexual behaviors is unclear. We evaluated whether HIVST was associated with changes in talking with sexual partners about HIVST, condom use, and HIV risk perception among AYA ages 15-24 years in a study of HIVST distribution through homes, pharmacies, and nightclubs in Nairobi, Kenya. All participants had negative HIVST results. Regression models were used to evaluate changes between pre-HIVST and 4 months post-HIVST. Overall, there was a significant increase in talking with sexual partners about HIVST. There was a significant reduction in number of condomless sex acts among AYA recruited through pharmacies and homes. Unexpectedly, among females, there was a significant decrease in consistent condom use with casual partners. HIVST services for AYA may benefit from including strategies to support condom use and partner communication about self-testing adapted to specific populations and partnerships.

"They have given you the morale and confidence:" adolescents and young adults want more community-based oral HIV self-testing options in Kenya.

Community-based delivery of oral HIV self-testing (HIVST) may expand access to testing among adolescents and young adults (AYA). Eliciting youth perspectives can help to optimize these services. We conducted nine focus group discussions (FGDs) with HIV negative AYA aged 15-24 who had completed oral HIVST following community-based distribution through homes, pharmacies, and bars. FGDs were stratified by distribution point and age (15-17, 18-24). Participants valued HIVST because it promoted greater autonomy and convenience compared to traditional clinic-based testing. AYA noted how HIVST could encourage positive behavior change, including using condoms to remain HIV negative. Participants recommended that future testing strategies include individualized, ongoing support during and after testing. Support examples included access to trained peer educators, multiple community-based distribution points, and post-test support via phones and websites. Multiple distribution points and trained peer educators' involvement in all steps of distribution, testing, and follow-up can enhance future community-based HIVST programs.

Abandoning the word Caucasian.

Traditionally, the field of genetics has used patient-reported genetic ancestry to assist in risk assessment, calculate detection rates, and understand residual risks for recessive or X-linked genetic diseases. Patient-reported genetic ancestry is useful for variant curation, based on practice guidelines from medical societies. Words used to describe a person's race, ethnicity, and genetic ancestry have changed over the last few centuries, especially in the last few decades. The origin and use of Caucasian to describe people of European ancestry have come into question. With recommendations from the Department of Health and Human Services (HHS) and the American College of Medical Genetics and Genomics (ACMG), among other organizations, the medical and genetics communities are moving away from using this term altogether. The purpose of this article is to review the history of the word Caucasian and to provide evidence that it should be avoided when documenting genetic ancestry in medical records, laboratory forms, and medical research.

Healthcare Costs of Laparoscopic versus Open Surgery for Rectal Cancer Patients in the First 12 Months: A Secondary Endpoint Analysis of the Australasian Laparoscopic Cancer of the Rectum Trial (ALaCaRT).

BACKGROUND: Laparoscopic-assisted surgery for rectal cancer is widely used, however the healthcare costs are thought to be higher than for open resection. This secondary endpoint analysis of a randomized controlled trial aimed to evaluate total healthcare costs of laparoscopic-assisted surgery compared with open resection for rectal cancer over a 12-month period. METHODS: Patients in the Australasian Laparoscopic Cancer of the Rectum Trial (ALaCaRT) were included in a prospective costing analysis. All healthcare use for the index surgery and hospital admission, readmissions, and follow-up care over 12 months were included. Unit costs were valued in Australian dollars (AUD$) using scheduled Medicare fees and hospital cost weights. The primary outcome was mean per patient cost. Non-parametric bootstrapping with 10,000 replications was undertaken for robustness checks. RESULTS: Data from 468 patients indicated that the laparoscopic-assisted surgical procedure incurred a mean cost of AUD$4542 (standard deviation [SD] AUD$1050)-AUD$521 higher than the open procedure mean cost of AUD$4021 (SD AUD$804) due to longer operative time and involvement of more costly equipment (95% confidence interval [CI] AUD$354-AUD$692). At 12 months, the average cost for the laparoscopic-assisted and open groups was AUD$43,288 (SD AUD$40,883) and AUD$45,384 (SD AUD$38,659), respectively, due to the shorter subsequent hospital stays. No overall significant cost difference between groups was found (95% CI -AUD$9358 to AUD$5003). One-way sensitivity analyses confirmed the robustness of the results. CONCLUSION: While initially higher, the costs of laparoscopic-assisted surgery for rectal cancer were similar to open resection at 12 months. Clinicians may choose a surgical approach based on clinical need. TRIAL REGISTRATION: The Australasian Gastro-Intestinal Trials Group (AGITG) was the legal sponsor and trial coordination was performed by the NHMRC Clinical Trials Centre. The trial was registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12609000663257).

High Acceptance and Completion of HIV Self-testing Among Diverse Populations of Young People in Kenya Using a Community-Based Distribution Strategy.

Oral HIV self-testing (HIVST) may expand access to testing among hard-to-reach reach adolescents and young adults (AYA). We evaluated community-based HIVST services for AYA in an urban settlement in Kenya. Peer-mobilizers recruited AYA ages 15-24 through homes, bars/clubs, and pharmacies. Participants were offered oral HIVST, optional assistance and post-test counseling. Outcomes were HIVST acceptance and completion (self-report and returned kits). Surveys were given at enrollment, post-testing, and 4 months. Log-binomial regression evaluated HIVST preferences by venue. Among 315 reached, 87% enrolled. HIVST acceptance was higher in bars/clubs (94%) than homes (86%) or pharmacies (75%). HIVST completion was 97%, with one confirmed positive result. Participants wanted future HIVST at multiple locations, include PrEP, and cost ≤ $5USD. Participants from bars/clubs and pharmacies were more likely to prefer unassisted testing and peer-distributers compared to participants from homes. This differentiated community-based HIVST strategy could facilitate engagement in HIV testing and prevention among AYA.

'They can stigmatize you': a qualitative assessment of the influence of school factors on engagement in care and medication adherence among adolescents with HIV in Western Kenya.

School-related factors may influence retention in care and adherence to antiretroviral therapy (ART) among adolescents with human immunodeficiency virus (HIV). We analyzed data from in-depth interviews with 40 adolescents with HIV (aged 14 -19 years), 40 caregivers of adolescents with HIV, and 4 focus group discussions with healthcare workers to evaluate contextual factors affecting adherence to ART and clinic attendance among adolescents, with a focus on the school environment. Informed by Anderson's Model of Health Services Utilization, transcripts were systematically coded and synthesized to identify school-related themes. All groups identified the school environment as a critical barrier to engagement in HIV care and medication adherence for adolescents with HIV. Adolescent participants reported inflexible school schedules and disclosure to school staff as the biggest challenges adhering to clinic appointments and ART. Adolescents described experiencing stigma and discrimination by peers and school staff and would adjust when, where and how often they took ART to avoid inadvertent disclosure. Boarding school students faced challenges because they had limited private space or time. Caregivers were often instrumental in navigating school permissions, including identifying a treatment supporter among school staff. Additional research engaging school staff may guide interventions for schools to reduce stigma and improve adherence and retention.

MONARCC: a randomised phase II study of panitumumab monotherapy and panitumumab plus 5-fluorouracil as first-line therapy for RAS and BRAF wildtype metastatic colorectal cancer: a study by the Australasian Gastrointestinal Trials Group (AGITG).

BACKGROUND: Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a "lighter" treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population. METHODS/DESIGN: MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies. DISCUSSION: MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN12618000233224 , prospectively registered 14 February 2018.

AGITG MASTERPLAN: a randomised phase II study of modified FOLFIRINOX alone or in combination with stereotactic body radiotherapy for patients with high-risk and locally advanced pancreatic cancer.

BACKGROUND: Among patients with non-metastatic pancreatic cancer, 80% have high-risk, borderline resectable or locally advanced cancer, with a 5-year overall survival of 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in these patients. METHODS AND DESIGN: MASTERPLAN is a multi-centre randomised phase II trial of 120 patients with histologically confirmed potentially operable pancreatic cancer (POPC) or inoperable pancreatic cancer (IPC). POPC includes patients with borderline resectable or high-risk tumours; IPC is defined as locally advanced or medically inoperable pancreatic cancer. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy alone (control arm) by minimisation and stratified by patient cohort (POPC v IPC), planned induction chemotherapy and institution. Chemotherapy can have been commenced ≤28 days prior to randomisation. Both arms receive 6 × 2 weekly cycles of modified FOLFIRINOX (oxaliplatin (85 mg/m2 IV), irinotecan (150 mg/m2), 5-fluorouracil (2400 mg/m2 CIV), leucovorin (50 mg IV bolus)) plus SBRT in the investigational arm. Gemcitabine+nab-paclitaxel is permitted for patients unsuitable for mFOLFIRINOX. SBRT is 40Gy in five fractions with planning quality assurance to occur in real time. Following initial chemotherapy ± SBRT, resectability will be evaluated. For resected patients, adjuvant chemotherapy is six cycles of mFOLFIRINOX. Where gemcitabine+nab-paclitaxel was used initially, the adjuvant treatment is 12 weeks of gemcitabine and capecitabine or mFOLFIRINOX. Unresectable or medically inoperable patients with stable/responding disease will continue with a further six cycles of mFOLFIRINOX or three cycles of gemcitabine+nab-paclitaxel, whatever was used initially. The primary endpoint is 12-month locoregional control. Secondary endpoints are safety, surgical morbidity and mortality, radiological response rates, progression-free survival, pathological response rates, surgical resection rates, R0 resection rate, quality of life, deterioration-free survival and overall survival. Tertiary/correlative objectives are radiological measures of nutrition and sarcopenia, and serial tissue, blood and microbiome samples to be assessed for associations between clinical endpoints and potential predictive/prognostic biomarkers. Interim analysis will review rates of locoregional recurrence, distant failure and death after 40 patients complete 12 months follow-up. Fifteen Australian and New Zealand sites will recruit over a 4-year period, with minimum follow-up period of 12 months. DISCUSSION: MASTERPLAN evaluates SBRT in both resectable and unresectable patients with pancreatic ductal adenocarcinoma. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12619000409178 , 13/03/2019. Protocol version: 2.0, 19 May 2019.

The Psychosocial Effects of the COVID-19 Pandemic on Youth Living with HIV in Western Kenya.

The objective of this study was to assess psychosocial effects of COVID-19 among adolescents living with HIV (ALHIV) in Kenya and to assess the feasibility of conducting behavioral surveys by phone. We adapted our protocol to administer telephone rather than in-person follow-up surveys and included questions about COVID-19. The majority of participants (99%) reported having heard of COVID-19; 23% reported no longer being able to go outside, 17% reported that they could no longer go to their regular clinic for medical care, and 3% reported that they could no longer get medication refills. PHQ-9 screening identified 9% (n = 45) with mild depression symptoms, and 1% (n = 3) with moderate-to-severe depression symptoms. Young adults 20-24 years old had more mild to severe depressive symptoms than the younger age groups (p < 0.001). Offering remote peer-support or mental health care, continuing to offer differentiated care services, and considering financial support will support the health and well-being of ALHIV.

Mapping male circumcision for HIV prevention efforts in sub-Saharan Africa.

BACKGROUND: HIV remains the largest cause of disease burden among men and women of reproductive age in sub-Saharan Africa. Voluntary medical male circumcision (VMMC) reduces the risk of female-to-male transmission of HIV by 50-60%. The World Health Organization (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) identified 14 priority countries for VMMC campaigns and set a coverage goal of 80% for men ages 15-49. From 2008 to 2017, over 18 million VMMCs were reported in priority countries. Nonetheless, relatively little is known about local variation in male circumcision (MC) prevalence. METHODS: We analyzed geo-located MC prevalence data from 109 household surveys using a Bayesian geostatistical modeling framework to estimate adult MC prevalence and the number of circumcised and uncircumcised men aged 15-49 in 38 countries in sub-Saharan Africa at a 5 × 5-km resolution and among first administrative level (typically provinces or states) and second administrative level (typically districts or counties) units. RESULTS: We found striking within-country and between-country variation in MC prevalence; most (12 of 14) priority countries had more than a twofold difference between their first administrative level units with the highest and lowest estimated prevalence in 2017. Although estimated national MC prevalence increased in all priority countries with the onset of VMMC campaigns, seven priority countries contained both subnational areas where estimated MC prevalence increased and areas where estimated MC prevalence decreased after the initiation of VMMC campaigns. In 2017, only three priority countries (Ethiopia, Kenya, and Tanzania) were likely to have reached the MC coverage target of 80% at the national level, and no priority country was likely to have reached this goal in all subnational areas. CONCLUSIONS: Despite MC prevalence increases in all priority countries since the onset of VMMC campaigns in 2008, MC prevalence remains below the 80% coverage target in most subnational areas and is highly variable. These mapped results provide an actionable tool for understanding local needs and informing VMMC interventions for maximum impact in the continued effort towards ending the HIV epidemic in sub-Saharan Africa.

De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.

PURPOSE: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. METHODS: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. RESULTS: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. CONCLUSION: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

Psychosocial Factors, Condomless Sex, and Detectable Viral Load in HIV-Positive Women in Serodiscordant Couples in Nairobi, Kenya.

This prospective study of HIV-positive Kenyan women in serodiscordant couples examined relationships between psychosocial factors, viral suppression, and condomless sex. Participants were screened for alcohol use disorders and intimate partner violence (IPV) annually and depressive symptoms every 6 months. Prostate specific antigen (PSA) detection was used as a marker for condomless sex. A total of 151 participants contributed 349 person-years of follow-up. Hazardous/harmful alcohol use was associated with increased risk of detecting PSA in vaginal secretions (aRR 1.99, 95%CI 1.08-3.66, χ2 = 4.85 (1)), while IPV and depression were not. Events representing HIV transmission potential, where there was biological evidence of condomless sex at a visit with a detectable plasma viral load, were observed at 2% of visits. The high prevalence of IPV and association between alcohol use and sexual risk suggest the need for monitoring and support for these conditions as part of comprehensive HIV care for women.

Impacts of genesurance considerations on genetic counselors' practice and attitudes.

Genesurance counseling has been identified as an integral part of many genetic counseling sessions, but little is known about the workflow impacts and genetic counselor perceptions of genesurance-related tasks. In this study, we aimed to characterize how insurance and billing considerations for genetic testing are being incorporated into genetic counselors' practice in the United States, as well as describe current attitudes and challenges associated with their integration. An electronic survey was sent by email to members of the National Society of Genetic Counselors (NSGC). A total of 325 American Board of Genetic Counselors-certified genetic counselors who provide direct patient care in the United States for at least 50% of their time were included in data analysis. Results showed that the frequency and timing of various insurance- and billing-related tasks were not consistent among respondents, even those practicing in similar settings. Inadequate training to complete tasks was reported by 64% of respondents, and 47% reported a lack of resources from their employer and/or institution to complete genesurance tasks. Additionally, only 38% of respondents agreed that insurance- and billing-related tasks were within the scope of the genetic counseling practice, and there was little consensus on who respondents believe is the most appropriate person to complete these tasks. When asked how genesurance considerations affected job satisfaction, 85% of respondents reported a negative impact. This study found an inconsistent genesurance workflow among genetic counselors practicing in the United States, a lack of consensus on who should be responsible for genesurance tasks, several challenges associated with completing these tasks, and identifies genesurance considerations as potential risk factors for genetic counselor burnout.

Developing a quality assurance program for transvaginal cervical length measurement at 18-21 weeks' gestation.

BACKGROUND: Preterm birth is the leading cause of death in children under the age of five years. Transvaginal cervical length (TVCL) assessment can be used to predict preterm delivery risk at the mid-trimester scan. To optimise the screening tool, developing and maintaining quality standards is important. AIMS: To develop an Australian reference range for TVCL at 18.0-21.0 weeks' gestation, quality standards for measurement and audit mechanisms for ultrasound operators. MATERIALS AND METHODS: A retrospective audit was performed of consecutive patients scanned at 18.0-21.0 weeks' gestation. Each TVCL measurement ultrasound image was reviewed, and exclusions were made based on a defined set of quality criteria. Fractional polynomial Bayesian methodology was used to establish a reference range. Central tendency, dispersion plots and cumulative sum charts for operators in the original reference range cohort were created. These plots were then applied to a second validation cohort of operators to establish the efficacy of this quality assurance audit tool. RESULTS: Median TVCL from 1031 participants was 36.0 mm (interquartile range 32.7-40.0 mm), which was independent of gestational age. The quality audit tool was applied to 15 operators from the reference cohort with a mean cervix length multiple of the median of 1.01 and a mean SD log10 cervix length multiple of the median of 0.06. Of the 22 operators in the validation cohort, 20 (90.9%) demonstrated ideal or acceptable central tendency results, and 19 (86.4%) remained in the appropriate cumulative sum zone. CONCLUSION: An Australian cervix length measurement reference range at 18.0-21.0 weeks' gestation has been developed along with a validated quality assurance audit tool for ultrasound operators.

Disease-free Survival and Local Recurrence After Laparoscopic-assisted Resection or Open Resection for Rectal Cancer: The Australasian Laparoscopic Cancer of the Rectum Randomized Clinical Trial.

OBJECTIVE: The aim of the study was to determine the efficacy of laparoscopic rectal resection (Lap) versus open laparotomy and rectal resection (Open) for rectal cancer on locoregional recurrence (LRR) and disease-free survival (DFS) at 2 years. SUMMARY BACKGROUND DATA: Although a Lap approach to colon cancer surgery may offer similar oncological outcomes to Open with potentially less morbidity, this remains to be clearly established for the treatment of rectal cancer. METHODS: A randomized, multicenter noninferiority phase 3 trial of 475 patients with T1 to T3 rectal adenocarcinoma <15 cm from anal verge, given Lap or Open and followed for a minimum 2 years to assess LRR, DFS, and overall survival (OS). RESULTS: Secondary endpoint analyses included 450 patients (95%) without metastases at baseline (mean age 64; 34% women) who received Lap (n = 225) or Open (n = 225). Median follow-up was 3.2 years (range: 0.1-5.4 yrs). LRR cumulative incidence at 2 years: Lap 5.4%; Open 3.1% [difference, 2.3%; 95% confidence interval (CI), -1.5% to 6.1%; hazard ratio (HR) 1.7; 95% CI, 0.74-3.9]. DFS at 2 years: Lap 80%; Open 82% (difference, 2.0%; 95% CI, -9.3% to 5.4%; HR for recurrence or death, 1.17; 95% CI, 0.81-1.68; P = 0.41). After adjustment for baseline factors HR = 1.07 (95% CI, 0.7-1.6). OS at 2 years: Lap 94%; Open 93% (difference 0.9%; 95% CI, -3.6% to 5.4%). CONCLUSIONS: Laparoscopic surgery for rectal cancer did not differ significantly from open surgery in effects on 2-year recurrence or DFS and OS. Confidence intervals included potentially clinically important differences favoring open resection, so that the combination of primary and secondary study endpoints may not support laparoscopic resection of rectal cancer as a routine standard of care and further follow-up is required.