Confirmatory Factor Analysis and Validation of the Sexual and Reproductive Empowerment Scale for Adolescents and Young Adults in Kenya.

Understanding the levels of power that adolescent girls and young women exercise in their sexual and reproductive lives is imperative to inform interventions to help them meet their goals. We implemented an adapted version of the Sexual and Reproductive Health Empowerment (SRE) Scale for Adolescents and Young Adults among 500 adolescent girls and young women aged 15-20 in Kisumu, Kenya. We used confirmatory factor analysis (CFA) to assess factor structure, and logistic regression to examine construct validity through the relationship between empowerment scores and ability to mitigate risk of undesired pregnancy through consistent contraceptive use. Participants had a mean age of 17.5, and most were students (61 percent), were currently partnered (94 percent), and reported having sex in the past 3 months (70 percent). The final, 26-item CFA model had acceptable fit. All subscales had Cronbach's alpha scores >0.7, and all items had rotated factor loadings >0.5, indicating good internal consistency and robust factor-variable associations. The total SRE-Kenya (SRE-K) score was associated with increased odds of the consistent method used in the past three months (adjusted odds ratio: 1.98, 95 percent CI: 1.29-3.10). The SRE-K scale is a newly adapted and valid measure of sexual and reproductive empowerment specific to adolescent girls and young women in an East African setting.

Individuals' experiences in genetic counseling and predictive testing for familial amyotrophic lateral sclerosis.

As clinical genetic testing in the amyotrophic lateral sclerosis (ALS) diagnostic setting increases, the identification of at-risk family members has also expanded. No practice guidelines specifically for predictive genetic testing exist, and few studies about the psychological impacts of testing in this subgroup have occurred, limiting the ability to tailor recommendations and counseling in this community. We surveyed asymptomatic individuals at risk for inheriting an ALS-associated gene mutation. The 80-question survey was designed using a combination of validated measures (General Anxiety Disorder; FACToR; Decision Regret Scale) and original items. Ninety participants completed the survey, including those who completed predictive genetic testing (N = 42) and those who did not (N = 48). Gene positive individuals experienced greater negativity, uncertainty, and overall psychological impairment (p = 0.002; p < 0.001; p = 0.001). Individuals who had not undergone testing reported thinking about their risk multiple times per day and experiencing more decisional regret than those who tested (p = 0.006). In terms of decision-making, being prepared for potential clinical drug trials was a more important potential benefit among those who underwent testing (p = 0.026). Participants valuing preparedness for clinical drug trials supports the concept that genetic testing for ALS will increase as research in gene-targeted therapeutics progresses. This study describes factors relevant to the genetic testing decision-making process and adaptation to results from the perspective of at-risk individuals, which can ultimately guide genetic counseling practice in this population.

The landscape of BRCA1 and BRCA2 large rearrangements in an international cohort of over 20 000 ovarian tumors identified using next-generation sequencing.

BACKGROUND: Approximately half of ovarian tumors have defects within the homologous recombination repair pathway. Tumors carrying pathogenic variants (PVs) in BRCA1/BRCA2 are more likely to respond to poly-ADP ribose polymerase (PARP) inhibitor treatment. Large rearrangements (LRs) are a challenging class of variants to identify and characterize in tumor specimens and may therefore be underreported. This study describes the prevalence of pathogenic BRCA1/BRCA2 LRs in ovarian tumors and discusses the importance of their identification using a comprehensive testing strategy. METHODS: Sequencing and LR analyses of BRCA1/BRCA2 were conducted in 20 692 ovarian tumors received between March 18, 2016 and February 14, 2023 for MyChoice CDx testing. MyChoice CDx uses NGS dosage analysis to detect LRs in BRCA1/BRCA2 genes using dense tiling throughout the coding regions and limited flanking regions. RESULTS: Of the 2217 PVs detected, 6.3% (N = 140) were LRs. Overall, 0.67% of tumors analyzed carried a pathogenic LR. The majority of detected LRs were deletions (89.3%), followed by complex LRs (5.7%), duplications (4.3%), and retroelement insertions (0.7%). Notably, 25% of detected LRs encompassed a single or partial single exon. This study identified 84 unique LRs, 2 samples each carried 2 unique LRs in the same gene. We identified 17 LRs that occurred in multiple samples, some of which were specific to certain ancestries. Several cases presented here illustrate the intricacies involved in characterizing LRs, particularly when multiple events occur within the same gene. CONCLUSIONS: Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.

Occupational therapy practice for post-acute COVID-19 inpatients requiring rehabilitation.

INTRODUCTION: COVID-19 caused significant occupational disruption to people's life roles, with some people requiring an inpatient rehabilitation admission. Occupational therapists assessed and treated these patients using previous knowledge of similar conditions due to limited specificity in available guidelines to inform practice. The aim of this study was to investigate current practice with post-acute COVID-19 (PAC) patients within an inpatient rehabilitation setting in Australia, to better understand the role and impact of occupational therapy. METHODS: A mixed-method study was conducted, including electronic medical record audits (October 2021 October 2022) and descriptive patient interviews at a large metropolitan subacute service. Descriptive statistics and qualitative analysis were used to summarise and interpret data. CONSUMER AND COMMUNITY INVOLVEMENT: No involvement. RESULTS: A total of 24 patient electronic medical records were audited, and 10 patient interviews were completed. Three overarching categories were identified within the 685 occasions of occupational therapy service audited-occupational engagement, education provision and discharge planning. Patients identified the value of occupational therapy by reflecting on their lived experiences of engaging with occupational therapists and associated changes in occupational performance between COVID-19 diagnoses and discharge home. CONCLUSION: Occupational therapists possess a unique skill set that directly addresses the occupational needs and priorities of PAC patients. This study adds to the growing body of evidence supporting the contribution of occupational therapy to the management of COVID-19; however, further research is needed to develop evidence-based practice resources and advocate for system changes that improve quality of life for COVID-19 patients. PLAIN LANGUAGE SUMMARY: During the COVID-19 pandemic, a lot of people got very sick. Some of these people needed more time and support to get better. Occupational therapists were important during this time because they helped these people to do their daily activities again. Because there were not many resources on how to do this, we looked into what occupational therapists were doing to help these people. We looked at patient hospital files and also talked to them to understand this better. We found that occupational therapists focused on three main areas: helping patients do activities that were important to them, teaching them about COVID-19 and helping them plan to leave the hospital. This study shows that occupational therapists are skilled at helping people with COVID-19. But more research is needed to make resources and also help with changing the healthcare system to further help people get better from COVID-19.

Prevalence and correlates of condom use at last sexual intercourse pre- and post-COVID-19 lockdown among adolescent girls and young women in central and western Kenya.

We investigated condom use at last sexual intercourse among adolescent girls and young women (AGYW) to determine the prevalence and correlates of condom use pre- and post-COVID-19 lockdown. Condom use was compared pre- and post-COVID-19 lockdown using a single group interrupted time series analysis. Multivariable Poisson regression was used to determine the correlates of condom use at last sexual intercourse. We found a statistically significant decrease in prevalence of condom use at last sexual intercourse post-COVID-19 lockdown. Condom use at last sexual intercourse was associated with younger age, current contraceptive use, and higher education. AGYW in concurrent relationships were less likely to use condoms, as were owners of mobile phones. These findings suggest a disconnect between youth knowledge of HIV prevention and their actual condom use, particularly in concurrent sexual partnerships. Future research should explore how dynamic fertility intentions, mobile phone access, concurrent sexual partnerships and empowerment influence condom use among sub-Saharan AGYW.

Natriuretic peptide receptor-C mediates the inhibitory effect of atrial natriuretic peptide on neutrophil recruitment to the lung during acute lung injury.

Atrial natriuretic peptide (ANP) protects against acute lung injury (ALI), but the receptor that mediates this effect is not known. Transgenic mice with 0 (knockout), 1 (heterozygote), or 2 (wild-type) functional copies of Npr3, the gene that encodes for natriuretic peptide receptor-C (NPR-C), were treated with intravenous infusion of ANP or saline vehicle before oropharyngeal aspiration of Pseudomonas aeruginosa (PA103) or saline vehicle. Lung injury was assessed 4 h following aspiration by measurement of lung wet/dry (W/D) weight, whole lung leukocyte and cytokine levels, and protein, leukocyte, and cytokine concentration in bronchoalveolar lavage fluid (BALF). PA103 induced acute lung injury as evidenced by increases in lung W/D ratio and protein concentration in BALF. The severity of PA103-induced lung injury did not differ between NPR-C genotypes. Treatment with intravenous ANP infusion reduced PA103-induced increases in lung W/D and BALF protein concentration in all three NPRC genotypes. PA103 increased the percentage of leukocytes that were neutrophils and cytokine levels in whole lung and BALF in NPR-C wild-type and knockout mice. This effect was blunted by ANP in wild-type mice but not in the NPR-C knockout mice. NPR-C does not mediate the protective effect of ANP on endothelial cell permeability in settings of PA103-induced injury but may mediate the effect of ANP on inhibition of the recruitment of neutrophils to the lung and thereby attenuate the release of inflammatory cytokines.

Landscape of homologous recombination deficiencies in solid tumours: analyses of two independent genomic datasets.

BACKGROUND: DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types. METHODS: Germline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different candidate homologous recombination repair (HRR) genes, and their relationship with the genetic events of bi-allelic loss, loss of heterozygosity (LOH) and tumour mutation burden (TMB). RESULTS: Approximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations, identifying potentially 50% more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types. CONCLUSIONS: Our results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.

Patient, Caregiver, and Oncologist Experiences With and Perceptions of Racial Bias and Discrimination in Cancer Care Delivery.

BACKGROUND: Cancer prevention and treatment systems are significantly impacted by interpersonal, organizational, and structural and systemic racism. A wide body of research has found that racial disparities in access to guideline-adherent cancer care are pervasive throughout the United States and contributing factors include social determinants of health, insurance status, and bias and discrimination in care delivery. Although the existence of racial disparities in cancer care and outcomes is well established, there has been limited research exploring the patient and caregiver experience with bias and discrimination in cancer care. METHODS: Two national surveys were conducted, one of patients and caregivers and one of oncologists. The surveys examined patient and caregiver experiences with and oncologist perceptions of racial disparities in cancer care. RESULTS: The surveys found that when patients and caregivers were asked about negative care experiences, differences across race were observed. Patients and caregivers identifying as African American/Black (AA/B) or Hispanic/Latino (H/L) were more likely to report at least one negative care experience than patients and caregivers identifying as White (W). Patients who were AA/B or H/L were also more likely than W patients to report that the healthcare system treats people unfairly based on their racial or ethnic background and that racial bias occurs often or very often when a patient and doctor are of different racial/ethnic background. A slight majority of oncologists reported that the healthcare system treats people unfairly based on their racial or ethnic background. CONCLUSIONS: The survey results highlight a need for improved racial representation in the oncology professional workforce, improved implicit bias training, and improved clinical trial recruitment efforts.

Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response.

BACKGROUND: The absence of the putative DNA/RNA helicase Schlafen11 (SLFN11) is thought to cause resistance to DNA-damaging agents (DDAs) and PARP inhibitors. METHODS: We developed and validated a clinically applicable SLFN11 immunohistochemistry assay and retrospectively correlated SLFN11 tumour levels to patient outcome to the standard of care therapies and olaparib maintenance. RESULTS: High SLFN11 associated with improved prognosis to the first-line treatment with DDAs platinum-plus-etoposide in SCLC patients, but was not strongly linked to paclitaxel-platinum response in ovarian cancer patients. Multivariate analysis of patients with relapsed platinum-sensitive ovarian cancer from the randomised, placebo-controlled Phase II olaparib maintenance Study19 showed SLFN11 tumour levels associated with sensitivity to olaparib. Study19 patients with high SLFN11 had a lower progression-free survival (PFS) hazard ratio compared to patients with low SLFN11, although both groups had the benefit of olaparib over placebo. Whilst caveated by small sample size, this trend was maintained for PFS, but not overall survival, when adjusting for BRCA status across the olaparib and placebo treatment groups, a key driver of PARP inhibitor sensitivity. CONCLUSION: We provide clinical evidence supporting the role of SLFN11 as a DDA therapy selection biomarker in SCLC and highlight the need for further clinical investigation into SLFN11 as a PARP inhibitor predictive biomarker.

1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA).

PURPOSE: To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. METHODS: A modified 1-13C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment (13CO2/12CO2) was measured in exhaled breath after an enteral bolus of sodium-1-13C-propionate, and normalized for CO2 production. 1-13C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. RESULTS: Lower propionate oxidation was observed in patients with the severe mut0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut- forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-13C-propionate oxidation to control levels. 1-13C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. CONCLUSION: Propionate oxidative capacity, as measured with 1-13C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. TRIAL REGISTRATION: This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078.

Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial.

OBJECTIVE: Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor. METHODS: Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined. RESULTS: 289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off. CONCLUSIONS: Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

COVID contingencies: Early epicenter experiences of different genetics clinics at a New York City institution inform emergency adaptation strategies.

The unique situational challenges of the COVID-19 pandemic have demanded creative modifications to the delivery of genetic services. Institutions across the country have adapted workflows to continue to provide quality care while minimizing the need for physical visits. As the first epicenter of the pandemic in the country, New York City healthcare workers and residents had to make rapid, unprecedented changes to their way of life. This article describes the workflow adaptations of genetic counselors across various clinical settings at New York Presbyterian/Columbia University Irving Medical Center, the largest provider of genetics care in New York City, during the height of the COVID-19 pandemic. The authors observe how the adaptations impacted clinical care and the genetic counselors. Our lived experience and account can provide guidance for others during the current and future pandemics.

Culture of pulmonary artery endothelial cells from pulmonary artery catheter balloon tips: considerations for use in pulmonary vascular disease.

Endothelial dysfunction is a hallmark of pulmonary arterial hypertension (PAH) but there are no established methods to study pulmonary artery endothelial cells (PAECs) from living patients. We sought to culture PAECs from pulmonary artery catheter (PAC) balloons used during right-heart catheterisation (RHC) to characterise successful culture attempts and to describe PAEC behaviour.PAECs were grown in primary culture to confluence and endothelial cell phenotype was confirmed. Standard assays for apoptosis, migration and tube formation were performed between passages three to eight. We collected 49 PAC tips from 45 subjects with successful PAEC culture from 19 balloons (39%).There were no differences in subject demographic details or RHC procedural details in successful versus unsuccessful attempts. However, for subjects who met haemodynamic criteria for PAH, there was a higher but nonsignificant (p=0.10) proportion amongst successful attempts (10 out of 19, 53%) versus unsuccessful attempts (nine out of 30, 30%). A successful culture was more likely in subjects with a lower cardiac index (p=0.03) and higher pulmonary vascular resistance (p=0.04). PAECs from a subject with idiopathic PAH were apoptosis resistant compared to commercial PAECs (p=0.04) and had reduced migration compared to PAECs from a subject with portopulmonary hypertension with high cardiac output (p=0.01). PAECs from a subject with HIV-associated PAH formed fewer (p=0.01) and shorter (p=0.02) vessel networks compared to commercial PAECs.Sustained culture and characterisation of PAECs from RHC balloons is feasible, especially in PAH with high haemodynamic burden. This technique may provide insight into endothelial dysfunction during PAH pathogenesis.

A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are unfit for or relapsed postautologous stem-cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitor vistusertib in an intermittent dosing schedule of 125 mg b.d. for 2 days per week. Thirty patients received vistusertib and six received vistusertib-rituximab for up to six cycles (28-day cycles). Two partial responses were achieved on monotherapy. Durations of response were 57 and 62 days, respectively, for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression-free survival was1.69 (95% confidence interval [CI] 1.61-2.14) months and median overall survival was 6.58 (95% CI 3.81-not reached) months, respectively. The median duration of response or stable disease across the trial duration was 153 days (95% CI 112-not reached). Tumour responses according to positron emission tomography/computed tomography versus computed tomography were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib ± rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1-2. Common vistusertib-related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1-2), diarrhoea (27% G1-2, 6% G3), fatigue (30% G1-2, 3% G3), mucositis (25% G1-2, 6% G3), vomiting (17% G1-2), and dyspepsia (14% G1-2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.

An mHealth SMS intervention on Postpartum Contraceptive Use Among Women and Couples in Kenya: A Randomized Controlled Trial.

Objectives. To assess the effect of 2-way short message service (SMS) with a nurse on postpartum contraceptive use among individual women and couples. Methods. From 2016 to 2017, we conducted a randomized controlled trial at 2 public hospitals in western Kenya. We assigned eligible pregnant women to receive 2-way SMS with a nurse or no SMS, with the option to include male partners. We delivered automated family planning-focused SMS messages weekly until 6 months postpartum. Women and men receiving SMS could interact with nurses via SMS. In intention-to-treat analysis, we compared highly effective contraceptive (HEC) use at 6 months postpartum between groups using the χ2 test. We used Poisson regression in adjusted analysis. Results. We randomized 260 women to 2-way SMS or control, and we enrolled 103 male partners. At 6 months postpartum, 69.9% women receiving SMS reported HEC use, compared with 57.4% in control (relative risk = 1.22; 95% confidence interval [CI] = 1.01, 1.47; P = .04). In analysis adjusted for baseline demographic differences, the adjusted relative risk for HEC use in the SMS group was 1.26 (95% CI = 1.04, 1.52; P = .02). Conclusions. Two-way SMS with a nurse, including optional male participation, increased postpartum contraceptive use. Trial Registration. ClinicalTrials.gov; identifier: NCT02781714.

Utilizing perspectives from HIV-infected women, male partners and healthcare providers to design family planning SMS in Kenya: a qualitative study.

BACKGROUND: Short message service (SMS) presents an opportunity to expand the reach of care and improve reproductive health outcomes. SMS could increase family planning (FP) use through education, support and demand generation. The purpose of this analysis is to determine the perspectives of potential FP users to inform design of SMS. METHODS: We conducted focus group discussions (FGD) with HIV-infected women and in-depth interviews (IDI) with male partners and health care workers (HCW) at urban and rural clinics in Kenya to design SMS content for a randomized controlled trial. RESULTS: Women and men indicated SMS could be used as a tool to discuss FP with their partners, and help decrease misconceptions about FP. Women stated SMS could make them more comfortable discussing sensitive topics with HCWs compared to in-person discussions. However, some women expressed concerns about FP SMS particularly if they used FP covertly or feared partner disapproval of FP use. These findings were common among women who had not disclosed their status. Providers viewed SMS as an important tool for tracking patients and clinical triage in conjunction with routine clinical visits. CONCLUSION: Our findings suggest that SMS has the potential to facilitate FP education, counselling, and interaction with HCWs around FP.

Engaging men in an mHealth approach to support postpartum family planning among couples in Kenya: a qualitative study.

BACKGROUND: Involving male partners in family planning (FP) education and counseling may improve FP utilization and help meet couples' reproductive health needs in the postpartum period. We aimed to explore Kenyan men's and women's perspectives on an interactive short message service (SMS) approach to support postpartum FP decision-making, and inform intervention content for a randomized controlled trial (RCT). METHODS: We conducted four focus group discussions (FGD) among men (n = 35) and two among pregnant/postpartum women (n = 15) in western Kenya. Female participants were recruited at antenatal clinics; male participants were referred by antenatal attendees. FGDs included participant critique of pilot theory-based SMS messages. FGD transcripts were coded by two investigators and analyzed using an iterative, modified grounded theory approach. These data informed the intervention and RCT design, in which women had the option to refer male partners for trial enrollment. RESULTS: Men strongly desired inclusion in FP programs, and frequently discussed negative relationship consequences of women's covert contraceptive use. Female and male participants voiced a variety of concerns about contraceptive side effects and potential harms, which were central to narratives of community influence on personal contraceptive choices. Most participants felt that receiving FP-focused SMS and including men would be beneficial. They perceived that SMS dialogue with a nurse about FP could reduce misperceptions and may stimulate communication within couples, thereby improving contraceptive access and continuation. Shared decision-making around FP within couple relationships, in consultation with clinicians, was highly valued. CONCLUSIONS: Health concerns about FP and limited couple communication are perceived contributors to postpartum unmet contraceptive need. With women's consent, the inclusion of male partners in FP services, and specifically in an mHealth SMS intervention, is acceptable and desired. Receiving SMS may trigger communication about postpartum FP within couples. SMS content should address contraceptive knowledge gaps, anticipated side effects and FP misperceptions, and allow for real-time method choice assistance.

Activation of the sweet taste receptor, T1R3, by the artificial sweetener sucralose regulates the pulmonary endothelium.

A hallmark of acute respiratory distress syndrome (ARDS) is pulmonary vascular permeability. In these settings, loss of barrier integrity is mediated by cell-contact disassembly and actin remodeling. Studies into molecular mechanisms responsible for improving microvascular barrier function are therefore vital in the development of therapeutic targets for reducing vascular permeability in ARDS. The sweet taste receptor T1R3 is a G protein-coupled receptor, activated following exposure to sweet molecules, to trigger a gustducin-dependent signal cascade. In recent years, extraoral locations for T1R3 have been identified; however, no studies have focused on T1R3 within the vasculature. We hypothesize that activation of T1R3, in the pulmonary vasculature, plays a role in regulating endothelial barrier function in settings of ARDS. Our study demonstrated expression of T1R3 within the pulmonary vasculature, with a drop in expression levels following exposure to barrier-disruptive agents. Exposure of lung microvascular endothelial cells to the intensely sweet molecule sucralose attenuated LPS- and thrombin-induced endothelial barrier dysfunction. Likewise, sucralose exposure attenuated bacteria-induced lung edema formation in vivo. Inhibition of sweet taste signaling, through zinc sulfate, T1R3, or G-protein siRNA, blunted the protective effects of sucralose on the endothelium. Sucralose significantly reduced LPS-induced increased expression or phosphorylation of the key signaling molecules Src, p21-activated kinase (PAK), myosin light chain-2 (MLC2), heat shock protein 27 (HSP27), and p110α phosphatidylinositol 3-kinase (p110αPI3K). Activation of T1R3 by sucralose protects the pulmonary endothelium from edemagenic agent-induced barrier disruption, potentially through abrogation of Src/PAK/p110αPI3K-mediated cell-contact disassembly and Src/MLC2/HSP27-mediated actin remodeling. Identification of sweet taste sensing in the pulmonary vasculature may represent a novel therapeutic target to protect the endothelium in settings of ARDS.

pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry.

BACKGROUND: AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage. METHODS: We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue. RESULTS: We found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34-72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors. CONCLUSION: Together these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.

Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience.

PurposeTo describe the frequency and nature of differences in variant classifications between clinicians and genetic testing laboratories.MethodsRetrospective review of variants identified through genetic testing ordered in routine clinical care by clinicians in the Stanford Center for Inherited Cardiovascular Disease. We compared classifications made by clinicians, the testing laboratory, and other laboratories in ClinVar.ResultsOf 688 laboratory classifications, 124 (18%) differed from the clinicians' classifications. Most differences in classification would probably affect clinical care of the patient and/or family (83%, 103/124). The frequency of discordant classifications differed depending on the testing laboratory (P < 0.0001) and the testing laboratory's classification (P < 0.00001). For the majority (82/124, 66%) of discordant classifications, clinicians were more conservative (less likely to classify a variant pathogenic or likely pathogenic). The clinicians' classification was discordant with one or more submitter in ClinVar in 49.1% (28/57) of cases, while the testing laboratory's classification was discordant with a ClinVar submitter in 82.5% of cases (47/57, P = 0.0002).ConclusionThe clinical team disagreed with the laboratory's classification at a rate similar to that of reported disagreements between laboratories. Most of this discordance was clinically significant, with clinicians tending to be more conservative than laboratories in their classifications.