Maternal plasma soluble neuropilin-1 is downregulated in fetal growth restriction complicated by abnormal umbilical artery Doppler: a pilot study.

OBJECTIVES: Placental expression of neuropilin-1 (NRP1), a proangiogenic member of the vascular endothelial growth factor receptor family involved in sprouting angiogenesis, was recently discovered to be downregulated in pregnancies with fetal growth restriction (FGR) and abnormal umbilical artery (UA) Doppler. Soluble NRP1 (sNRP1) is an antagonist to NRP1; however, little is known about its role in normal and FGR pregnancies. This study tested the hypotheses that, first, sNRP1 would be detectable in maternal circulation and, second, its concentration would be upregulated in FGR pregnancies compared to those with normal fetal growth and this would correlate with the severity of the disease as assessed by UA Doppler. METHODS: This was a prospective case-control pilot study of 40 singleton pregnancies (20 FGR cases and 20 uncomplicated controls) between 24 + 0 and 40 + 0 weeks' gestation followed in an academic perinatal center from January 2015 to May 2017. FGR was defined as an ultrasound-estimated fetal weight < 10th percentile for gestational age. The control group was matched to the FGR group for maternal age and gestational age at assessment. Fetal ultrasound biometry and UA Doppler were performed using standard protocols. Maternal plasma sNRP1 measurements were performed using a commercially available ELISA. RESULTS: Contrary to the study hypothesis, maternal plasma sNRP1 levels were significantly decreased in FGR pregnancies as compared to those with normal fetal growth (137.4 ± 44.8 pg/mL vs 166.7 ± 36.9 pg/mL; P = 0.03). However, there was no significant difference in sNRP1 concentration between the control group and FGR pregnancies that had normal UA Doppler. Plasma sNRP1 was downregulated in FGR pregnancies with elevated UA systolic/diastolic ratio (P = 0.023) and those with UA absent or reversed end-diastolic flow (P = 0.005) in comparison to FGR pregnancies with normal UA Doppler. This suggests that biometrically small fetuses without hemodynamic compromise are small-for-gestational age rather than FGR. CONCLUSIONS: This study demonstrated a significant decrease in maternal plasma sNRP1 concentration in growth-restricted pregnancies with fetoplacental circulatory compromise. These findings suggest a possible role of sNRP1 in modulating fetal growth and its potential as a biomarker for FGR. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

A religiously-tailored, multilevel intervention in African American churches to increase HIV testing: Rationale and design of the Taking It to the Pews cluster randomized trial.

HIV continues to disproportionately impact African American (AA) communities. Due to delayed HIV diagnosis, AAs tend to enter HIV treatment at advanced stages. There is great need for increased access to regular HIV testing and linkage to care services for AAs. AA faith institutions are highly influential and have potential to increase the reach of HIV testing in AA communities. However, well-controlled full-scale trials have not been conducted in the AA church context. We describe the rationale and design of a 2-arm cluster randomized trial to test a religiously-tailored HIV testing intervention (Taking It to the Pews [TIPS]) against a standard information arm on HIV testing rates among AA church members and community members they serve. Using a community-engaged approach, TIPS intervention components are delivered by trained church leaders via existing multilevel church outlets using religiously-tailored HIV Tool Kit materials and activities (e.g., sermons, responsive readings, video/print testimonials, HIV educational games, text messages) to encourage testing. Church-based HIV testing events and linkage to care services are conducted by health agency partners. Control churches receive standard, non-tailored HIV information via multilevel church outlets. Secondarily, HIV risk/protective behaviors and process measures on feasibility, fidelity, and dose/exposure are assessed. This novel study is the first to fully test an HIV testing intervention in AA churches - a setting with great reach and influence in AA communities. It could provide a faith-community engagement model for delivering scalable, wide-reaching HIV prevention interventions by supporting AA faith leaders with religiously-appropriate HIV toolkits and health agency partners.

Pre-operative assessment of muscle mass to predict surgical complications and prognosis in patients with endometrial cancer.

BACKGROUND: Sarcopenia or loss of skeletal muscle mass is an objective measure of frailty associated with functional impairment and disability. This study aimed to examine the impact of sarcopenia on surgical complications and survival outcomes in patients with endometrial cancer. METHODS: A retrospective review of endometrial cancer patients who underwent surgery between 2005 and 2009 was performed. Sarcopenia was assessed on preoperative computed tomography (CT) scan by measurement of the lumbar psoas muscle cross-sectional area and defined as any value below the median (<4.33 cm(2)). Sarcopenic obesity was defined as sarcopenia plus a body mass index (BMI) of 30 kg/m(2) or higher. Microsatellite instability (MSI) was analyzed using the National Cancer Institute (NCI) consensus markers and tumor from hysterectomy specimens. RESULTS: Of 122 patients, 27 (22%) met the criteria for sarcopenic obesity. Sarcopenic patients were older than patients with normal muscle mass (mean age, 69.7 vs. 62.1 years; p < 0.001), had a lower BMI (31.1 vs. 39.4 kg/m(2); p < 0.001), and had more comorbidities (p = 0.048). Sarcopenia was not associated with tumor MSI, hospital stay, 90-day readmission rate, or early/late complications. Patients with sarcopenia had a shorter recurrence-free survival than nonsarcopenic patients (median 23.5 vs. 32.1 months; log-rank p = 0.02), but did not differ in terms of overall survival (log-rank p = 0.25). After adjustment for race, BMI, lymphocyte count, and tumor histology, sarcopenia was associated with a fourfold shorter recurrence-free survival (adjusted hazard ratio [HRadj], 3.99; 95% confidence interval [CI], 1.42-11.3). CONCLUSIONS: Sarcopenia has an impact on recurrence-free survival, but does not appear to have a negative impact on surgical outcomes or overall survival among endometrial cancer patients who undergo preoperative CT scan.

Adiponectin and adiponectin receptors in the mouse preimplantation embryo and uterus.

BACKGROUND: Adiponectin (Adipoq), a protein secreted by adipocytes in inverse proportion to the adipose mass present, modulates energy homeostasis and increases insulin sensitivity. Tissue Adipoq signaling decreases in settings of maternal diabetes, polycystic ovary syndrome (PCOS) and endometriosis, conditions which are associated with reproductive difficulty. Our objective was to define the expression and hormonal regulation of Adipoq and its receptors in the mouse preimplantation embryo and uterus. METHODS AND RESULTS: By real-time quantitative PCR, mRNA transcripts for Adipoq, AdipoR1, AdipoR2, Ppara, Ppard, FATP1 (SLC27A1) and acyl CoA oxidase (Acox1) were identified in mouse 2-cell and 8-cell embryos, while blastocyst stage embryos and trophoblast stem (TS) cells expressed mRNA for all genes except Adipoq. Protein expression of Adipoq, AdipoR1, AdipoR2, the insulin sensitive transporters GLUT8 (Slc2A8), GLUT12 (Slc2A12) and p-PRKAA1 was identified by immunofluorescence staining in all stages of preimplantation embryos including the blastocyst. In situ hybridization demonstrated the presence of Adipoq, AdipoR1 and AdipoR2 mRNA in the mouse decidual cells of the implantation site and in artificially decidualized cells, and the expression of these proteins was confirmed by western blotting. Flow cytometry confirmed cell surface expression of AdipoR1 and AdipoR2 in TS cells and decidual cells. CONCLUSIONS: These results suggest for the first time that Adipoq signaling may play an important role in preimplantation embryo development and uterine receptivity by autocrine and paracrine methods in the mouse. Implantation failures and pregnancy loss, specifically those experienced in women with maternal metabolic conditions such as diabetes, obesity and PCOS, may be the result of aberrant Adipoq and AdipoR1 and AdipoR2 expression and suboptimal decidualization in the uterus.

Prognostic factors associated with response in platinum retreatment of platinum-resistant ovarian cancer.

The goal of this study was to determine the factors associated with response to platinum retreatment in patients with platinum-resistant ovarian cancer. A review of patients with epithelial ovarian cancer retreated with cisplatin or carboplatin between 2002 and 2004 was performed. The platinum-free interval (PFI) and treatment-free interval (TFI) were determined for each patient. Response was based on serial CA125 levels using a modification of the Rustin criteria. Patients with clinical benefit ([CB] those who attained at least stable disease) were compared to patients with disease progression (PD). An analysis was performed to determine factors associated with CB in platinum-resistant patients retreated with platinum. Of 48 patients identified, 37 were evaluable included in this analysis. CB was observed in 27 (73%) while disease progression was noted in 10 (27%) women. The PFI was longer in those women who achieved CB (12.3 vs 6.9 months; P = 0.02). The TFI was 7.1 months for patients benefited from platinum retreatment vs 3.5 months for those with disease progression (P = 0.06). There was no statistically significant difference in the number of cytotoxic agents between the time of platinum retreatment and the prior platinum regimen (2 vs 1.5 months; P = 0.61). A prolonged PFI was associated with an improved chance of achieving CB with platinum retreatment. There was no association between the response to platinum retreatment and the number of intervening cytotoxic agents utilized. Further prospective study is warranted to define the optimal timing of platinum retreatment.

The effect of female tobacco smoking on IVF outcomes.

BACKGROUND: Cigarette smoking is widely believed to be associated with decreased fecundity in naturally conceiving populations; however, the effect of female smoking on pregnancy outcomes in patients undergoing IVF is unclear. METHODS: A retrospective analysis of 389 consecutive patients undergoing first cycle IVF was performed. Outcomes of peak estradiol (E(2)) levels, log mean ovarian volume, number of oocytes retrieved, oocyte maturity in ICSI, fertilization rate, cleavage rate, embryo quality, percentage of high-quality embryos, pregnancy and live birth were assessed in patients reported as never smokers, past smokers and current smokers. Potential confounding variables evaluated included day 3 FSH, number of oocytes retrieved, embryo quality, caffeine and alcohol consumption. The population was also stratified by female age (<35 and >or=35 years). RESULTS: A total of 9.3% of our patients reported current smoking and 12.1% reported a history of smoking. Smoking status did not significantly affect pregnancy outcome, live birth rate or any other indicated outcome. CONCLUSIONS: A total of 21.4% of IVF patients in this study had past or present exposure to cigarette smoking with no measurable effect on IVF outcome.

Assessing menstrual cycles with urinary hormone assays.

The Study of Women's Health Across the Nation (SWAN) is a multiethnic cohort study of middle-aged women enrolled at seven US sites. A subset of 848 women completed a substudy in which their urinary gonadotropins and sex steroid metabolites were assessed during one complete menstrual cycle or up to 50 consecutive days. Urine was analyzed for LH, FSH, estrone conjugates (E1c), and pregnanediol glucuronide (Pdg). To prepare for serial analysis of this large, longitudinal database in a population of reproductively aging women, we examined the performance of algorithms designed to identify features of the normal menstrual cycle in midreproductive life. Algorithms were based on existing methods and were compared with a "gold standard" of ratings of trained observers on a subset of 396 cycles from the first collection of Daily Hormone Substudy samples. In evaluating luteal status, overall agreement between and within raters was high. Only 17 of the 396 cycles evaluated were considered indeterminate. Of the 328 cycles rated as containing evidence of luteal activity (ELA), 320 were considered ELA by use of a Pdg threshold detection algorithm. Of 51 cycles that were rated as no evidence of luteal activity, only 2 were identified by this algorithm as ELA. Evaluation of the day of the luteal transition with methods that detected a change in the ratio of E1c to Pdg provided 85-92% agreement for day of the luteal transition within 3 days of the raters. Adding further conditions to the algorithm increased agreement only slightly, by 1-8%. We conclude that reliable, robust, and relatively simple objective methods of evaluation of the probability and timing of ovulation can be used with urinary hormonal assays in early perimenopausal women.

Ovarian function in late reproductive years in relation to lifetime experiences of abuse.

The objective of this study was to investigate the relation between violence victimization and levels of ovarian hormones during women's late reproductive years, as measured by serum levels of follicle-stimulating hormone and estradiol, which respectively rise and fall with onset of menopause. In March 1999, 732 women 36-45 years of age from the Harvard Study of Moods and Cycles cohort completed a survey of lifetime experiences of physical and sexual harm. Follicle-stimulating hormone and estradiol levels were measured during the menstrual period after entry into the cohort. Associations for violence and follicle-stimulating hormone and estradiol levels were estimated using crude and adjusted risk differences. Overall, women who experienced abuse during childhood or adolescence relative to never-abused women had a slight positive association of violence with high follicle-stimulating hormone. However, a positive association with high follicle-stimulating hormone was not observed among women whose first abuse occurred during adulthood. Age stratification indicated modification of the association between violence and low estradiol. Women 36-40 years of age had no evidence of a positive association between violence before adulthood and low estradiol, whereas first violence in adulthood was associated with an 11% increase in the estimate of risk difference [95% confidence limits (CL) = -0.14, 0.36]. Among women 41-45 years, there was a 17-23% increase in the estimate of risk difference for low estradiol, regardless of life stage at first experience of abuse (before adulthood, 95% CL = 0.06, 0.28; during adulthood, 95% CL = 0.01, 0.46). This investigation supports the credibility of a hypothesis that physical and sexual abuse may lead to neuroendocrine disruption, thereby affecting ovarian function and potentially leading to altered age at perimenopausal transition.

Maintaining reliability in a long-term psychiatric study: an ongoing inter-rater reliability monitoring program using the longitudinal interval follow-up evaluation.

The Longitudinal Interval Follow-up Evaluation (LIFE), has been shown to be a valid and reliable instrument for characterizing the week-by-week course of anxiety disorders examined retrospectively over the period of 1 year. Due to the chronic nature of these disorders, there is a need for reliable, valid instruments for measuring course over periods of several years if we are to learn more about the natural history of these disorders. This paper describes a rater-monitoring program designed to ensure long-term inter-rater reliability and prevent "rater drift". In this program, clinical interviewers score taped interviews and are required to maintain a median intra-class correlation coefficient (ICC) of at least 0.80 with the other raters. Raters also assess tapes from previous years, to ensure that they are using the same diagnostic criteria as earlier generations of interviewers. A reliability study was conducted to compare psychiatric status ratings (PSRs) collected using biweekly telephone interviews with the semi-annual interviews. The ICCs for panic, agoraphobia, social phobia, and generalized anxiety disorder were very good to excellent. Another reliability study examined the PSRs of subjects who had been previously lost to follow-up. ICCs for panic, agoraphobia, generalized anxiety disorder and depression were good to excellent. These results show that the LIFE, when used in conjunction with an intensive training and rater monitoring system, is a reliable instrument for use in longitudinal studies of the course of anxiety disorders.

Chronicity in posttraumatic stress disorder (PTSD) and predictors of course of comorbid PTSD in patients with anxiety disorders.

The purpose of this study was to examine the course of comorbid posttraumatic stress disorder (PTSD) in 54 patients with another anxiety disorder. Using a prospective longitudinal design, the present study found that during the first 5 years of follow-up the probability of full remission from a chronic episode of PTSD was .18. Findings from this and other research confirm clinical impressions that a substantial number of people never fully remit from their PTSD even after many years. Variables associated with a longer time to remit from an episode of chronic PTSD were a history of alcohol abuse and a history of childhood trauma.

Simple phobia as a comorbid anxiety disorder.

This study sought to describe clinical and demographic characteristics differentiating patients with DSM-III-R simple phobias comorbid with one or more of five DSM-III-R index anxiety disorders as compared with those with the index diagnoses alone. From 711 subjects participating in a multicenter, longitudinal, naturalistic study of anxiety disorders, 115 subjects with comorbid simple phobias were compared with 596 subjects without simple phobias in terms of demographic data, comorbidity with other disorders, somatic and psychosocial treatment received, and quality of life. In addition, episode characteristics, types of simple phobias found, and course of illness were specified. Subjects with simple phobias had more additional comorbid anxiety disorders by history than did those without. Mean length of intake episode was 22.43 years and severity was typically moderate. Fears of heights and animals were the most commonly represented simple phobias. Subjects with uncomplicated panic disorder were less likely to have comorbid simple phobias than were subjects with other index diagnoses, and subjects with simple phobia were more likely to have comorbid posttraumatic stress disorder than were these without simple phobia. Subjects with and without simple phobias did not differ by somatic or psychosocial treatment received or in terms of quality of life. Simple phobia appeared in this study to be a chronic illness of moderate severity for which behavioral treatment methods of recognized efficacy were not being frequently utilized. Uncomplicated panic disorder may reflect some type of resistance to phobia development.

Is the course of panic disorder the same in women and men?

OBJECTIVE: Panic disorder with or without agoraphobia has a chronic relapsing course. Factors associated with poor outcome include early onset of illness and phobic avoidance. Several, but not all, authors have found a worse clinical course for women. Using observational, longitudinal data from the Harvard/Brown Anxiety Disorders Research Program, the authors analyzed remission and symptom recurrence rates in panic patients with respect to sex. METHOD: Male and female patients (N = 412) in an episode of panic with or without agoraphobia were assessed by structured interview and prospectively followed for up to 5 years. Data on remission, symptom recurrence, and comorbid psychiatric conditions for each sex were compared. RESULTS: There were no significant differences between men and women in panic symptoms or level of severity at baseline. Women were more likely to have panic with agoraphobia (85% versus 75%), while men were more likely to have uncomplicated panic (25% versus 15%). The rates of remission for panic with or without agoraphobia at 5 years were equivalent in men and women (39%). Of the subjects who achieved remission, 25% of the women and 15% of the men reexperienced symptoms by 6 months. Recurrence of panic symptoms continued to be higher in women (82%) than men (51%) during the follow-up period and was not influenced by concurrent agoraphobia. CONCLUSIONS: This study extends previous findings by showing that not only are women more likely to have panic with concurrent agoraphobia, but they are more likely than men to suffer a recurrence of panic symptoms after remission of panic.