Correspondence Between Clinician Ratings of Vulvovaginal Health and Patient-Reported Sexual Function After Cancer

BackgroundTools for diagnosing sexual dysfunction and for tracking outcomes of interest include clinician interviews, physical exam, and patient self-report. Limited work has described relationships among these three sources of information regarding female sexual dysfunction and vulvovaginal health.AimWe describe correlations among data collected from clinician interviews, clinical gynecological examination, and patient self-report.MethodsData are from a single-site, single-arm, prospective trial in 100 postmenopausal patients with a history of breast or endometrial cancer who sought treatment for vulvovaginal symptoms. The trial collected a standardized clinical gynecologic exam, clinician-reported outcome (ClinRO) measures of vulvovaginal dryness and pain, and patient-reported outcome (PRO) measures of sexual function, including PROMIS Sexual Function and Satisfaction (SexFS) lubrication, vaginal discomfort, labial discomfort, and clitoral discomfort and Female Sexual Function Index (FSFI) lubrication and pain. We examined polyserial correlations between measures with bootstrapped 95% confidence intervals from the baseline and 12–14-week timepoints.ResultsAll of the relationships between the ClinRO variables and the PRO variables were in the expected direction (ie, positive), but the strength of the relationships varied substantially. At 12–14 weeks, there were medium-to-large correlations between ClinRO vaginal dryness and SexFS Lubrication (0.64), ClinRO vulvar dryness and SexFS Lubrication (0.46), ClinRO vulvar discomfort and SexFS Labial Discomfort (0.70), and ClinRO vulvar discomfort and SexFS Clitoral Discomfort (0.43). With one exception, the correlations between the exam variables and the corresponding PRO scores were small (range 0.01–0.27).Strengths & LimitationsOur study included a comprehensive, standardized gynecologic exam designed specifically to evaluate sexual dysfunction as well as established PRO measures with significant evidence for validity. A limitation of our findings is that the sample size was relatively small, and our sample was restricted to women who received cancer treatments known to have dramatic effects on vulvovaginal tissue quality.ConclusionPatient- and clinician-reported vulvovaginal dryness and discomfort were moderately correlated with each other but not with clinical gynecologic exam findings. Understanding the relationships among these different types of data highlights the distinct contributions of each to understand vulvovaginal tissue quality and patient sexual function after cancer. Flynn KE, Lin L, Carter J, et al. Correspondence Between Clinician Ratings of Vulvovaginal Health and Patient-Reported Sexual Function After Cancer. J Sex Med 2021;18:1768–1774.     

Metabolic memory in diabetes – from in vitro oddity to in vivo problem: Role of Apoptosis

Retinal capillary cells undergo apoptosis before pathology characteristic of retinopathy can be observed, and the appearance of apoptotic capillary cell can predict the development of pathology. The purpose of this study is to investigate the effect of reversal of hyperglycemia on retinal capillary cell apoptosis, and identify the apoptosis encoding genes. Streptozotocin-diabetic rats were maintained either in poor glycemic control (PC, glycated hemoglobin, GHb >11%) or in good glycemic control (GC, GHb <6%) for 12 months, or allowed to be in PC for 6 months followed by GC for 6 additional months (PC–GC). Capillary cell apoptosis was determined in the trypsin-digested retinal microvasculature by TUNEL staining, and the genes encoding apoptosis were identified by Oligo GEArray rat apoptosis microarray that profiles 113 genes. Six months of good glycemic control that followed 6 months of poor control failed to attenuate the number of TUNEL-positive capillary cells in the retinal microvasculature. Twenty-three retinal genes, mainly from TNF ligand and receptor, caspase, Bcl-2 and death domain subfamilies that were upregulated by least a two-fold in PC rats remain upregulated after reversal of hyperglycemia. Thus, the continued activation of apoptosis plays a major role in the resistance of retinopathy to halt after re-institution of good glycemic control, and the regulation apoptosis machinery could help retard the progression of diabetic retinopathy.     

Endothelial cell surface vimentin binding peptide induces angiogenesis under hypoxic/ischemic conditions

We have previously identified several angiogenic peptides that bind cell surface proteins by screening a phage display peptide library on human umbilical endothelial cells exposed to hypoxic conditions. In this study we describe one of the selected peptides, SP. We found by protein precipitation of endothelial cell lysates that the 12 amino acid SP peptide binds cell surface vimentin. Surprisingly, vimentin was detected on the cell surface of about 30% of intact endothelial cells under both normoxic and hypoxic conditions, as was demonstrated by fluorocytometric analysis on viable cells. The assessment of SP in the induction of angiogenesis was established by a significant increase in endothelial cell proliferation and tube formation under hypoxic conditions and not under normoxic conditions. Cell proliferation and tube length increased two-fold in endothelial cells in the presence of 10 ng/ml SP peptide when compared to controls. The specificity of SP binding to vimentin was demonstrated by SP inhibition of anti-vimentin binding and by the inhibition of tube formation in cells transfected with siRNA against vimentin. Local intramuscular administrations of the peptide SP to ischemic hind limbs using the mouse hind limb ischemia model, demonstrated that SP inoculated at 1 and 10 μg, improved blood perfusion compared to inoculations with an irrelevant peptide or PBS. The recovery of blood perfusion correlated with the increase in the number of detectable capillaries in the ischemic limb. The development of novel peptides for the induction of pro-angiogenic activity may pave the way for new therapeutic strategies in the treatment of cardiovascular ischemic diseases.     

Risk Factors for Silent Brain Infarcts and White Matter Disease in a Real-World Cohort Identified by Natural Language Processing

ObjectiveTo assess the frequency of silent brain infarcts (SBIs) and white matter disease (WMD) and associations with stroke risk factors (RFs) in a real-world population.Patients and MethodsThis was an observational study of patients 50 years or older in the Kaiser Permanente Southern California health system from January 1, 2009, through June 30, 2019, with head computed tomography or magnetic resonance imaging for nonstroke indications and no history of stroke, transient ischemic attack, or dementia. A natural language processing (NLP) algorithm was applied to the electronic health record to identify individuals with reported SBIs or WMD. Multivariable Poisson regression estimated risk ratios of demographic characteristics, RFs, and scan modality on the presence of SBIs or WMD.ResultsAmong 262,875 individuals, the NLP identified 13,154 (5.0%) with SBIs and 78,330 (29.8%) with WMD. Stroke RFs were highly prevalent. Advanced age was strongly associated with increased risk of SBIs (adjusted relative risks [aRRs], 1.90, 3.23, and 4.72 for those aged in their 60s, 70s, and ≥80s compared with those in their 50s) and increased risk of WMD (aRRs, 1.79, 3.02, and 4.53 for those aged in their 60s, 70s, and ≥80s compared with those in their 50s). Magnetic resonance imaging was associated with a reduced risk of SBIs (aRR, 0.87; 95% CI, 0.83 to 0.91) and an increased risk of WMD (aRR, 2.86; 95% CI, 2.83 to 2.90). Stroke RFs had modest associations with increased risk of SBIs or WMD.ConclusionAn NLP algorithm can identify a large cohort of patients with incidentally discovered SBIs and WMD. Advanced age is strongly associated with incidentally discovered SBIs and WMD.     

Polygenic risk scores and risk-stratified breast cancer screening: Familiarity and perspectives of health care professionals

PurposeHealth care professionals are expected to take on an active role in the implementation of risk-based cancer prevention strategies. This study aimed to explore health care professionals’ (1) self-reported familiarity with the concept of polygenic risk score (PRS), (2) perceived level of knowledge regarding risk-stratified breast cancer (BC) screening, and (3) preferences for continuing professional development.MethodsA cross-sectional survey was conducted using a bilingual—English/French—online questionnaire disseminated by health care professional associations across Canada between November 2020 and May 2021.ResultsA total of 593 professionals completed more than 2 items and 453 responded to all questions. A total of 432 (94%) participants were female, 103 (22%) were physicians, and 323 (70%) were nurses. Participants reported to be unfamiliar with (20%), very unfamiliar (32%) with, or did not know (41%) the concept of PRS. Most participants reported not having enough knowledge about risk-stratified BC screening (61%) and that they would require more training (77%). Online courses and webinar conferences were the preferred continuing professional development modalities.ConclusionThe study indicates that health care professionals are currently not familiar with the concept of PRS or a risk-stratified approach for BC screening. Online information and training seem to be an essential knowledge transfer modality.     

Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest

PurposeThe genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test.MethodsThrough comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes.ResultsA total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg1381], c.282C>A [p.Cys941]; c.257dup [p.Tyr861]; and c.180del, [p.Ser61Profs130]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes.ConclusionBy combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.     

Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome

PurposeRABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.MethodsThrough GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped.ResultsWe report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly.ConclusionCollectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1.     

Genetic findings in patients with primary fibrotic atrial cardiomyopathy

Primary fibrotic atrial cardiomyopathy (PF-ACM) is a novel type of cardiomyopathy characterized by primary atrial fibrosis with arrhythmogenicity and increased stroke risk without ventricular myocardium involvement. However, genetic analysis regarding PF-ACM and genotype–phenotype correlations is lacking. A cohort of PF-ACM patients was recruited and followed up. Whole-exome sequencing (WES) was applied, and genes were screened using a cardiovascular disease (CVD)-related gene panel. Echocardiography and cardiac magnetic resonance (CMR) were performed. The pathogenicity of the identified mutations was evaluated using in silico analysis. Thirty-three unrelated patients were referred for WES. Thirty-three rare variants of 19 CVD-related genes were identified in 21 patients, with 10 patients harboring more than one variation. TTN was the most frequent gene observed. Further analysis demonstrated that variations in sarcomeric (SV) or non-sarcomeric (NSV) genes were found in 16 and 10 patients, respectively. Patients carrying variants regardless of SV or NSV had larger left atrial dimensions determined by echo and larger left atrium areas determined by CMR. There was no discrepancy in disease severity between SV carriers and NSV carriers. Our genetic investigation into PF-ACM has identified several genetic culprits, providing further insight into its underlying pathophysiology and emphasizing a potential role for genetic testing for this condition.