Family planning needs of young adults with sickle cell disease.

Sexual and reproductive healthcare standards for adolescents and young adults with sickle cell disease (SCD) are not established. A total of 50 young adults entering adult SCD care completed a Family Planning Survey assessing sexual and reproductive health needs from March 2019 to July 2020. Clinical data were abstracted from respondents' electronic medical records. Linear and logistic regression was applied to explore associations between clinical characteristics and survey results. Few respondents (8%) wished to be pregnant in the coming year, and 46% answered yes to at least one of four needs assessment questions. Those who were not employed full time were more likely to endorse needing help with getting sickle cell trait testing for a partner (ORadj = 9.59, p-value = 0.05). Contraceptive use was associated with having an obstetrician-gynecologist (OR = 6.8, p-value = 0.01). Young adults with SCD entering adult care have diverse reproductive health needs, highlighting opportunities to provide multidisciplinary, SCD-specific reproductive healthcare.

Post-sequelae symptoms and comorbidities after COVID-19.

The frequency, severity, and forms of symptoms months after coronavirus 2019 (COVID-19) are poorly understood, especially in community settings. To better understand and characterize symptoms months after community-based COVID-19, a retrospective cohort analysis was conducted. Three hundred and twenty-eight consecutive persons with a positive test for SARS-CoV-2 in the Johns Hopkins Health System, Maryland, March-May 2020, were selected for the study. Symptom occurrence and severity were measured through questionnaires. Of 328 persons evaluated, a median of 242 days (109-478 days) from the initial positive SARS-CoV-2 test, 33.2% reported not being fully recovered and 4.9% reported symptoms that constrained daily activities. Compared to those who reported being fully recovered, those with post-acute sequelae were more likely to report a prior history of heart attack (p < 0.01). Among those reporting long-term symptoms, men and women were equally represented (men = 34.8%, women = 34.6%), but only women reported symptoms that constrained daily activities, and 56% of them were caregivers. The types of new or persistent symptoms varied, and for many, included a deviation from prior COVID-19 health, such as being less able to exercise, walk, concentrate, or breathe. A limitation is that self-report of symptoms might be biased and/or caused by factors other than COVID-19. Overall, even in a community setting, symptoms may persist months after COVID-19 reducing daily activities including caring for dependents.

Delirium Prevention, Detection, and Treatment in Emergency Medicine Settings: A Geriatric Emergency Care Applied Research (GEAR) Network Scoping Review and Consensus Statement.

BACKGROUND: Older adult delirium is often unrecognized in the emergency department (ED), yet the most compelling research questions to overcome knowledge-to-practice deficits remain undefined. The Geriatric Emergency care Applied Research (GEAR) Network was organized to identify and prioritize delirium clinical questions. METHODS: GEAR identified and engaged 49 transdisciplinary stakeholders including emergency physicians, geriatricians, nurses, social workers, pharmacists, and patient advocates. Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews, clinical questions were derived, medical librarian electronic searches were conducted, and applicable research evidence was synthesized for ED delirium detection, prevention, and management. The scoping review served as the foundation for a consensus conference to identify the highest priority research foci. RESULTS: In the scoping review, 27 delirium detection "instruments" were described in 48 ED studies and used variable criterion standards with the result of delirium prevalence ranging from 6% to 38%. Clinician gestalt was the most common "instrument" evaluated with sensitivity ranging from 0% to 81% and specificity from 65% to 100%. For delirium management, 15 relevant studies were identified, including one randomized controlled trial. Some intervention studies targeted clinicians via education and others used clinical pathways. Three medications were evaluated to reduce or prevent ED delirium. No intervention consistently prevented or treated delirium. After reviewing the scoping review results, the GEAR stakeholders identified ED delirium prevention interventions not reliant on additional nurse or physician effort as the highest priority research. CONCLUSIONS: Transdisciplinary stakeholders prioritize ED delirium prevention studies that are not reliant on health care worker tasks instead of alternative research directions such as defining etiologic delirium phenotypes to target prevention or intervention strategies.

A Survey-Based Needs Assessment of Barriers to Optimal Sickle Cell Disease Care in the Emergency Department.

STUDY OBJECTIVE: Guided by an implementation science framework, this needs assessment identifies institutional-, provider-, and patient-level barriers to care of sickle cell disease (SCD) in the emergency department (ED) to inform future interventions conducted by the multicenter Sickle Cell Disease Implementation Consortium. METHODS: The consortium developed and implemented a validated needs assessment survey administered to a cross-sectional convenience sample of patients with SCD and ED providers caring for them. In total, 516 adolescents and adults with SCD and 243 ED providers from 7 and 5 regions of the United States, respectively, responded to the ED care delivery for SCD survey. RESULTS: Survey results demonstrated that 84.5% of respondents with SCD have an outpatient provider who treats many patients with SCD. In the ED, 54.3% reported not receiving care fast enough and 46.0% believed physicians did not care about them and believed similarly of nurses (34.9%). Consequently, 48.6% of respondents were "never" or "sometimes" satisfied with their ED care. Of surveyed ED providers, 75.1% were unaware of the National Heart, Lung, and Blood Institute recommendations for vaso-occlusive crises, yet 98.1% were confident in their knowledge about caring for patients with SCD. ED providers identified the following factors as barriers to care administration: opioid epidemic (62.1%), patient behavior (60.9%), crowding (58.0%), concern about addiction (47.3%), and implicit bias (37.0%). CONCLUSION: The results underscore that many patients with SCD are dissatisfied with their ED care and highlight challenges to optimal care on the practice, provider, and patient levels. Exploring these differences may facilitate improvements in ED care.

Publication of data collection forms from NHLBI funded sickle cell disease implementation consortium (SCDIC) registry.

BACKGROUND: Sickle cell disease (SCD) is an autosomal recessive blood disorder affecting approximately 100,000 Americans and 3.1 million people globally. The scarcity of relevant knowledge and experience with rare diseases creates a unique need for cooperation and infrastructure to overcome challenges in translating basic research advances into clinical advances. Despite registry initiatives in SCD, the unavailability of descriptions of the selection process and copies of final data collection tools, coupled with incomplete representation of the SCD population hampers further research progress. This manuscript describes the SCDIC (Sickle Cell Disease Implementation Consortium) Registry development and makes the SCDIC Registry baseline and first follow-up data collection forms available for other SCD research efforts. RESULTS: Study data on 2400 enrolled patients across eight sites was stored and managed using Research Electronic Data Capture (REDCap). Standardized data collection instruments, recruitment and enrollment were refined through consensus of consortium sites. Data points included measures taken from a variety of validated sources (PHENX, PROMIS and others). Surveys were directly administered by research staff and longitudinal follow-up was coordinated through the DCC. Appended registry forms track medical records, event-related patient invalidation, pregnancy, lab reporting, cardiopulmonary and renal functions. CONCLUSIONS: The SCDIC Registry strives to provide an accurate, updated characterization of the adult and adolescent SCD population as well as standardized, validated data collecting tools to guide evidence-based research and practice.

RhoE is regulated by cyclic AMP and promotes fusion of human BeWo choriocarcinoma cells.

Fusion of placental villous cytotrophoblasts with the overlying syncytiotrophoblast is essential for the maintenance of successful pregnancy, and disturbances in this process have been implicated in pathological conditions such as pre-eclampsia and intra-uterine growth retardation. In this study we examined the role of the Rho GTPase family member RhoE in trophoblast differentiation and fusion using the BeWo choriocarcinoma cell line, a model of villous cytotrophoblast fusion. Treatment of BeWo cells with the cell permeable cyclic AMP analogue dibutyryl cyclic AMP (dbcAMP) resulted in a strong upregulation of RhoE at 24 h, coinciding with the onset of fusion. Using the protein kinase A (PKA)-specific cAMP analogue N(6)-phenyl-cAMP, and a specific inhibitor of PKA (14-22 amide, PKI), we found that upregulation of RhoE by cAMP was mediated through activation of PKA signalling. Silencing of RhoE expression by RNA interference resulted in a significant decrease in dbcAMP-induced fusion. However, expression of differentiation markers human chorionic gonadotrophin and placental alkaline phosphatase was unaffected by RhoE silencing. Finally, we found that RhoE upregulation by dbcAMP was significantly reduced under hypoxic conditions in which cell fusion is impaired. These results show that induction of RhoE by cAMP is mediated through PKA and promotes BeWo cell fusion but has no effect on functional differentiation, supporting evidence that these two processes may be controlled by separate or diverging pathways.

Downregulation of caveolin-1 enhances fusion of human BeWo choriocarcinoma cells.

BACKGROUND: Fusion of placental villous cytotrophoblasts with the overlying syncytiotrophoblast is essential for the maintenance of successful pregnancy, and disturbances in this process have been implicated in pathological conditions such as pre-eclampsia and intra-uterine growth retardation. Caveolin-1 has been shown to be expressed in human villous cytotrophoblast and to be downregulated during fusion into syncytiotrophoblast but it is unclear whether it plays a role in this process. METHODOLOGY/PRINCIPAL FINDINGS: We used RNA interference to determine whether caveolin-1 plays a role in differentiation and fusion in the BeWo choriocarcinoma cell line, a model of villous cytotrophoblast fusion. Assessment of cell fusion by desmosomal protein immunostaining revealed that cells transfected with caveolin-1 siRNA showed significantly enhanced fusion in response to treatment with dibutyryl cyclic AMP compared with cells transfected with a non-silencing control. Furthermore, caveolin-1 knockdown alone was sufficient to promote spontaneous fusion. In addition, biochemical differentiation, assessed by expression of placental alkaline phosphatase, was upregulated in caveolin-1 siRNA-transfected cells, with or without dbcAMP treatment. Assessment of Akt phosphorylation showed that caveolin-1 knockdown resulted in a significant reduction in phosphorylation at Thr(308). CONCLUSIONS/SIGNIFICANCE: Taken together, these results suggest that caveolin-1 regulates BeWo cell differentiation and fusion, possibly through a mechanism involving modulation of Akt activity.

Prediction of preterm delivery based on maternal plasma urocortin.

CONTEXT: Preterm birth still remains a significant management problem, and a large number of markers of the disease have been investigated. OBJECTIVE: We measured plasma levels of urocortin, a neuropeptide expressed by gestational tissues, in women with threatened preterm labor (TPTL) to evaluate whether the measurement may predict preterm delivery (PTD). DESIGN: We studied patients as part of an open observational study. SETTING: The study was conducted at a tertiary referral center for obstetric care. PATIENTS: Eighty-five women with singleton pregnancies between 28 and 34 completed gestational weeks with TPTL participated in the study. INTERVENTIONS: Interventions included clinical examination and urocortin measurement. MAIN OUTCOME MEASURES: Pregnancy outcome and evaluation of sensitivity, specificity, and predictive values of urocortin as diagnostic test for PTD were measured. RESULTS: Thirty of 85 patients (35.3%) had PTD: 23 of 30 delivered within 7 d from admission (delivery time interval: 2.91 +/- 1.62 d; gestational weeks at delivery: 32.12 +/- 1.7); the remaining delivered later (delivery time interval: 11.71 +/- 4.27 d; gestational weeks at delivery: 33.5 +/- 2.18). Urocortin was significantly higher in women who delivered preterm (median 131.2 pg/ml, interquartile interval 115.1-139.4 pg/ml) than in those who progressed to term delivery [95.4 (69.9-101.3) pg/ml, P < 0.0001] and still higher in those delivering within 7 d from admission [137.7 (124.8-141.2) pg/ml]. Receiver operating characteristic curve analysis revealed that urocortin at the cutoff of 113.9 pg/ml had sensitivity of 80%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 90% as a marker for PTD. CONCLUSIONS: Maternal plasma urocortin concentration is increased in patients with TPTL who have PTD, and its measurement may be a promising new biochemical marker of PTD.

Plasma urocortin levels in the diagnosis of ovarian endometriosis.

OBJECTIVE: Urocortin is a neuropeptide, member of the corticotropin-releasing hormone family, that is produced by the human endometrium. Ovarian endometrioma is a prevalent gynecologic disorder still lacking specific serum markers. In the present study we measured systemic levels of urocortin to assess the diagnostic performance of its determination in distinguishing endometriomas from other benign ovarian cysts. METHODS: Plasma urocortin was measured by radioimmunoassay in women with ovarian endometrioma (n=40) and in women with benign, nonendometriotic ovarian cysts (n=40). The diagnostic accuracy of urocortin measurement was evaluated by receiver operating characteristic curve and compared with the standard marker, CA 125. To support the local origin of the peptide, we also evaluated its localization in endometriomas by immunohistochemistry and its concentrations in cyst fluid and peritoneal fluid of 12 women with endometrioma. RESULTS: Plasma urocortin levels were twice as high in women with endometrioma (median 49 pg/mL, interquartile range 41-63 pg/mL) than in the control group (19 [15-23] pg/mL, P<.001) and significantly higher in the cystic content of endometriomas than in the peritoneal fluid and plasma (P<.05). The peptide was immunolocalized in endometrioma glands and stromal capillary vessels. Elevated plasma urocortin levels detected 88% of the cases of endometrioma with 90% specificity, whereas CA 125 detected only 65% of the cases with the same specificity. CONCLUSION: Plasma urocortin is increased in women with endometriomas, and its measurement may be useful for the differential diagnosis of endometrioma compared with other benign ovarian cysts. LEVEL OF EVIDENCE: II.

High maternal and fetal plasma urocortin levels in pregnancies complicated by hypertension.

OBJECTIVE: We evaluated maternal and fetal plasma levels and placental mRNA expression of urocortin, a placental vasoactive neuropeptide, in singleton pregnancies (n = 70) complicated by hypertensive disorders classified as gestational hypertension (n = 36), pre-eclampsia (n = 19), and pre-eclampsia complicated by intrauterine growth restriction (PE/IUGR, n = 15), and in 70 healthy normotensive singleton pregnancies. METHODS: Plasma levels were assayed by radioimmunoassay, fetal biometry by ultrasound scans, utero-placental and fetal perfusion by Doppler velocimetry, and placental urocortin mRNA expression by quantitative real time reverse transcriptase-polymerase chain reaction. The main outcome measures were the correlation of urocortin concentrations with patterns of the utero-placental and fetal circulation, and the early prediction of a poor neonatal outcome such as the occurrence of perinatal death and intraventricular hemorrhage. RESULTS: Maternal and fetal urocortin levels were significantly (both P < 0.001) higher in gestational hypertension, pre-eclampsia and PE/IUGR women than in controls, and correlated with Doppler velocimetry patterns. Fetal concentrations were significantly (P < 0.0001) higher than and significantly (P < 0.0001) correlated to maternal levels. Placental mRNA expression did not change. Ten out of 140 newborns had a poor neonatal outcome, with an overall prevalence of 7.14% (pretest probability). Using the receiver operator characteristics curve analysis cut-off values, the probability of a poor neonatal outcome was 66.7% when urocortin was used, and was 0% if levels were unaltered. CONCLUSIONS: Maternal and fetal urocortin levels are increased in hypertensive disorders of pregnancy. Since urocortin has vasoactive properties, the evidence of increased urocortin levels in hypertensive disorders may represent an adaptive fetal response.

Maternal plasma corticotrophin-releasing factor and urocortin levels in post-term pregnancies.

OBJECTIVE: Corticotrophin-releasing factor (CRF) and urocortin are two placental neuropeptides that are involved in the mechanisms of labour by modulating myometrial activity. Maternal plasma levels of both CRF and urocortin are increased at term and preterm labour, whilst those of CRF are reduced in women who are destined to experience post-term delivery. The present study evaluated maternal plasma levels in term and post-term pregnancies out of labour. DESIGN: A group of healthy pregnant women was enrolled and subdivided as follows: (i) at term out of labour (n = 19; 276 +/- 0.7 days of gestation; samples collected at the time of elective caesarean section due to previous uterine surgery); (ii) post-term (n = 19; 291 +/- 1.4 days of gestation), from whom samples were collected before induction of labour. METHODS: Urocortin and CRF measurements by radioimmunoassay; digital palpatory cervical examination and Bishop score computation; cervical length and funnelling presence assessment by transvaginal ultrasonography. RESULTS: Maternal plasma CRF concentrations were significantly (P < 0.05) lower whilst those of urocortin were unchanged in post-term compared with term pregnancy. However, CRF and urocortin levels were both significantly (P < 0.05 and P < 0.001 respectively) higher in pregnancies delivered within 12 h of labour induction than in those that remained undelivered, and were significantly correlated with the induction-delivery interval (CRF: r = -0.676, P = 0.0015; urocortin: r = -0.783, P < 0.0001). CONCLUSIONS: CRF and urocortin levels are decreased and unchanged, respectively, in post-term pregnancy when compared with term pregnancy. Both CRF and urocortin correlate with the time of labour onset after induction. Since CRF derives from the placenta, and urocortin from the fetus, the concerted expression of these neuropeptides appears to be relevant in determining the length of human gestation.

Reduced maternal plasma urocortin concentrations and impaired uterine artery blood flow at human mid pregnancy.

OBJECTIVE: Urocortin is a placental neuropeptide belonging to the family of corticotropin-releasing factors (CRFs), playing a role in the uteroplacental blood flow regulation through the binding to specific CRF receptors. Since CRF receptors are expressed in the uterine vascular bed of pregnant rats, and because urocortin has a relaxant effect on uterine vasculature, we evaluated mid-gestation plasma urocortin levels in women with impaired blood flow through uterine arteries. METHODS: Maternal plasma urocortin was assayed by specific radioimmunoassay and uterine artery resistance index (RI) by Doppler evaluation at 22-24 weeks' gestation in 57 healthy pregnant women, of which 29 showed a monolateral or bilateral uterine artery notch. Statistical analysis was performed by one-way analysis of variance (ANOVA), followed by post-hoc Tukey test for multiple comparison and Pearson correlation coefficient test. RESULTS: The mean uterine artery RI was significantly (P <.001) higher in women with a notch than healthy controls. Mean +/- SEM maternal plasma urocortin levels were significantly (P <.001) lower in women with unilateral (52.03 +/- 3.25 pg/mL) or bilateral (47.01 +/- 4.16 pg/mL) uterine artery notch than in healthy control pregnant women (84.01 +/- 3.5 pg/mL). While no difference was found in urocortin levels between patients with unilateral or bilateral uterine artery notch, urocortin concentrations inversely correlated with the mean RI (Pearson r = -0.7318; 95% confidence interval -0.8334 to -0.5822; P <.0001). CONCLUSIONS: The present findings suggest that reduced levels of circulating urocortin are associated with increased uterine artery resistances and support the hypothesis that urocortin may regulate uterine artery tone at mid gestation.

Levels of maternal plasma corticotropin-releasing factor and urocortin during labor.

OBJECTIVE: Corticotropin-releasing factor (CRF) is produced by the placenta and intrauterine tissues and secreted in increasing amounts from early to term pregnancy. In the presence of labor, a more incisive increase in CRF levels has been described, and women with preterm labor or those destined to have premature delivery have higher midpregnancy CRF levels than those who deliver at term. Urocortin is a 40-amino acid peptide belonging to the CRF family, expressed by human trophoblast and fetal membranes, which has the same biologic effects as CRF. Acting on the same CRF receptors, urocortin stimulates myometrial contractility and ACTH and prostaglandin release from cultured human placental cells. Because no data exist about urocortin levels in the maternal circulation at parturition, we investigated whether maternal plasma urocortin and CRF levels change according to cervical dilatation in healthy pregnant women at term labor. METHODS: In a cross-sectional study of labor, a single maternal blood sample was collected from healthy pregnant women at term (n = 40); in a second longitudinal study, plasma samples were collected longitudinally in a subset of patients (n = 8) throughout labor, according to a Bishop score evaluation. RESULTS: Both maternal plasma CRF and urocortin levels were higher in labor than those previously reported during pregnancy, but they did not change significantly during the different stages of labor when evaluated longitudinally. Some patients showed a trend toward increasing levels, whereas others had variable concentrations. CONCLUSION: Neither CRF nor urocortin levels changed during the progression of spontaneous labor.