Hypertensive Disorders of Pregnancy:A Systematic Review of International Clinical Practice Guidelines

Background Clinical practice guidelines (CPGs) are developed to assist health care providers in decision-making. We systematically reviewed existing CPGs on the HDPs (hypertensive disorders of pregnancy) to inform clinical practice. Methodology & Principal Findings MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessments, and Database of Abstracts of Reviews of Effects (Ovid interface), Grey Matters, Google Scholar, and personal records were searched for CPGs on the HDPs (Jan/03 to Nov/13) in English, French, Dutch, or German. Of 13 CPGs identified, three were multinational and three developed for community/midwifery use. Length varied from 3–1188 pages and three guidelines did not formulate recommendations. Eight different grading systems were identified for assessing evidence quality and recommendation strength. No guideline scored ≧80% on every domain of the AGREE II, a tool for assessing guideline methodological quality; two CPGs did so for 5/6 domains. Consistency was seen for (i) definitions of hypertension, proteinuria, chronic and gestational hypertension; (ii) pre-eclampsia prevention for women at increased risk: calcium when intake is low and low-dose aspirin, but not vitamins C and E or diuretics; (iii) antihypertensive treatment of severe hypertension; (iv) MgSO4 for eclampsia and severe pre-eclampsia; (v) antenatal corticosteroids a

Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary

Objective: This executive summary presents in brief the current evidence assessed in the clinical practice guideline prepared by the Canadian Hypertensive Disorders of Pregnancy Working Group and published by Pregnancy Hypertension (. http://www.pregnancyhypertension.org/article/S2210-7789(14)00004-X/fulltext) to provide a reasonable approach to the diagnosis, evaluation, and treatment of the hypertensive disorders of pregnancy. Evidence: Published literature was retrieved through searches of Medline, CINAHL, and The Cochrane Library in March 2012 using appropriate controlled vocabulary (e.g., pregnancy, hypertension, pre-eclampsia, pregnancy toxemias) and key words (e.g., diagnosis, evaluation, classification, prediction, prevention, prognosis, treatment, postpartum follow-up). Results were restricted to systematic reviews, randomized control trials, controlled clinical trials, and observational studies published in French or English between January 2006 and February 2012. Searches were updated on a regular basis and incorporated in the guideline to September 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values: The quality of evidence in the guideline summarized here was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (. Table 1)

Role of cGMP-dependent protein kinase in the negative inotropic effects of cGMP-elevating agents in the mammalian ventricle

The role of guanosine 3':5'-cyclic monophosphate (cGMP) and cGMPdependent protein kinase (PKG) in the regulation of cardiac contractility is controversial. There is evidence in the literature which suggests that cGMP is involved in the muscarinic receptor agonist-mediated antagonism of the positive inotropic effects of cAMP-elevating agents in the mammalian ventricle. Support for this relationship includes observations that a.) acetylcholine elevates cGMP and mediates a negative inotropic effect in (3-adrenoceptor-stimulated ventricular tissue in a time- and concentration-dependent manner and b.) some of the contractile effects of muscarinic receptor agonists can be mimicked by cGMP analogues and inhibited cGMP-lowering agents. The proposal that cGMP can mediate negative inotropic effects is difficult to reconcile with reports the nitrovasodilator sodium nitroprusside (SNP) markedly increased tissue cGMP levels in several ventricular preparations but had no effect on contractile activity (Rodger and Shahid, 1984; Lincoln and Keely, 1980, 1981). A possible explanation for these conflicting results was proposed by Lincoln and Keely (1980, 1981). They hypothesized that some cGMP-elevating agents, such as muscarinic receptor agonists, increase cGMP in a functional pool which can specifically activate PKG and, thereby, mediate a negative inotropic effect. Cyclic GMP-elevating agents, such as SNP, which fail to elevate cGMP in the requisite pool would be unable to activate PKG and, as a result, would not reduce ventricular contractility. The aim of the present study was to test this hypothesis. The experimental approach was to compare the effects of carbachol, SNP and atrial natriuretic peptide (ANP) on contractility, cGMP content and PKG activity in rat intact ventricular tissue and freshly isolated rat ventricular cardiomyocytes. Carbachol induced a marked negative inotropic effect in intact, perfused hearts, ventricular strips and isolated cardiomyocytes in the presence of isoproterenol. The negative inotropic effect of carbachol in the intact ventricle was associated with insignificant changes in tissue cGMP content but, in isolated cardiac myocytes, with significant, although small, increases in cellular cGMP levels. SNP and ANP had no effect on isoproterenol-stimulated contractility in ventricular strips and intact hearts. Furthermore, SNP did not change the positive inotropic effect of isoproterenol in isolated cardiomyocytes. The absence of negative inotropic effects by ANP and SNP was observed in the presence of marked increases in intact ventricular cGMP levels. SNP also increased cGMP levels by up to 8-fold in isolated cardiomyocytes. The presence of PKG in both the intact ventricle and in isolated ventricular cardiomyocytes confirmed by MonoQ anion exchange chromatography and Western blotting. The elution profile indicated that the conditions of the PKG assay were very selective for measuring PKG activity. Attempts were made to confirm the reliability of the PKG assay, after which agonist-mediated PKG activation was assessed. Carbachol had no significant effect on PKG activity at a concentration which exerted a marked negative inotropic effect in isoproterenol-stimulated ventricular tissue and cardiomyocytes. Conversely, PKG was activated in the presence of SNP or ANP in ventricular tissue and was activated by SNP in myocytes and this activation occurred without changes in the positive inotropic effects of isoproterenol. PKG activation may have occurred in the presence of carbachol but may have been underestimated by the conditions of the assay. The results of this study demonstrate that the negative inotropic effects of muscarinic receptor agonists occur in the presence of a small increase in cGMP levels and in the absence of significant activation of PKG. Larger increases in ventricular cGMP content and PKG activity were not sufficient to mediate a negative inotropic effect in the presence of SNP or ANP. Under the conditions of this study, PKG activation cannot be ruled out as playing a role in the negative inotropic effects of muscarinic receptor agonists but elevation of cGMP content and activation of PKG are not sufficient to inhibit contractility in the rat ventricle.Pharmaceutical Sciences, Faculty ofGraduat

Relationship between cyclic AMP-dependent protein kinase activation and smooth muscle relaxation by cyclic AMP and analogs

It is generally held that adenosine 3',5'-cyclic monophosphate (cAMP) mediates smooth muscle relaxation by the activation of cAMP-dependent protein kinase (PKA). This hypothesis was tested in two intact smooth muscle preparations, the rat vas deferens and the bovine coronary artery, using exogenously applied cAMP and cAMP analogs. After 30 minutes of incubation, N⁶,2'-0-dibutyryl-cAMP (dBu-cAMP) (1 - 100 μM) inhibited phenylephrine (PE)-induced tension generation in the rat vas deferens in a dose-dependent manner. This analog (10 μM) also activated the soluble fraction of PKA but did not activate the particulate fraction kinase. In contrast, 8-bromo-cAMP (8Br-cAMP) (10 -100 μM) did not have any significant effect on inhibition of PE-induced tension after 30 minutes of incubation but, at a concentration of 10 μM, significantly activated both the soluble and particulate fractions of PKA. The time course of activation of soluble PKA activation by 8Br-cAMP (10 μM) demonstrated that the kinase was significantly activated only after 30 minutes of exposure to the analog. In the bovine coronary artery, cAMP (10 - 100 μM) relaxed potassium-depolarized helical strips and significantly activated soluble PKA in a dose-dependent manner. dBu-cAMP (10 - 100 μM) affected neither tension nor soluble PKA activity. 8Br-cAMP (10 - 100 μM) did not affect the coronary artery tension but did activate soluble PKA. Both smooth muscle preparations were homogenized with charcoal prior to the determination of PKA activity in order to minimize artifactual assay results. As a further precaution, extracellularly associated cAMP and analogs were also washed from bovine coronary artery strips after the incubation period. These controls allowed for a valid assessment of PKA activity in the cyclic nucleotide-treated tissues. The results of the tension and kinase studies demonstrate a lack of correlation between activation of PKA and inhibition of rat vas deferens contraction or relaxation of bovine coronary artery. This does not support the hypothesis that the kinase is responsible for cAMP-induced relaxation of vascular and non-vascular smooth muscle. While the mechanism by which exogenous cAMP and specific analogs induce relaxation in some smooth muscle preparations remains unclear, it can be suggested that PKA activation is not necessarily required for the final functional effect.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat

Pediatric subspecialty healthcare providers' views of recruitment during a randomized controlled trial of a mobile health intervention

Background: Randomized clinical trials (RCTs) enrolling pediatric populations often struggle with recruitment. Engaging healthcare providers in the recruitment process may increase patients' and caregivers' willingness to participate in research. The purpose of this study was to understand the perspectives of pediatric subspecialty healthcare providers considering recruiting patients to participate in an mobile health (mHealth) RCT. Methods: We conducted 9 semi-structured interviews and 1 focus group with a total of N = 11 providers from various disciplines before the initiation of an mHealth RCT addressing medication nonadherence. Then, we conducted 5 follow-up interviews and 1 follow-up focus group with a total of 8 of these providers several months later. We used thematic analysis to generate themes describing providers' views of the RCT and patient recruitment. Results: Providers indicated that they were willing to recruit for this study because they believed that the intervention sought to address a significant problem. They also thought it made sense to intervene using technology for this age group. However, many providers thought that certain patients (e.g., those with mild, shorter-lasting adherence difficulties) were the most appropriate to recruit. They described how keeping the trial front of mind facilitated recruitment, and they advised researchers to use strategies to promote their ongoing awareness of the study if conducting similar research in the future. Conclusion: Pediatric healthcare providers are important stakeholders in mHealth intervention research. Engaging them in participant recruitment is a complex endeavor that might promote patient enrollment, but their views of research and demanding clinical roles are important to understand when designing study procedures

Adapting Effective mHealth Interventions to Improve Uptake and Adherence to HIV Pre-Exposure Prophylaxis Among Thai Young Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial

BackgroundYoung men who have sex with men (YMSM) are the fastest-growing HIV-positive population worldwide. Thailand has the highest adult HIV seroprevalence in Asia; over 25% of men having sex with men in Bangkok are HIV positive. Pre-exposure prophylaxis (PrEP) is an efficacious HIV prevention strategy recommended for all at-risk individuals. PrEP is highly effective when taken as prescribed, but PrEP utilization rate has been low, and adherence is often inadequate. ObjectiveWe propose to develop and pilot a multicomponent, technology-based intervention to promote motivation to begin PrEP (“uptake”) and sustained adherence to PrEP among HIV-negative Thai YMSM. We will adapt an existing 2-session technology-delivered, motivational interviewing–based intervention to focus on PrEP use in YMSM in Thailand. The resulting intervention is called the Motivational Enhancement System for PrEP Uptake and Adherence (MES-PrEP). We will also develop motivational text messaging (MTM) to send two-way motivational messages to promote PrEP use. MethodsThe proposed study includes 3 phases. Phase 1 includes in-depth interviews with HIV-negative Thai YMSM and providers to explore barriers and facilitators of PrEP initiation and adherence, aiming to inform intervention content. Phase 2 consists of adapting and beta-testing MES-PrEP and MTM for functionality and feasibility using a youth advisory board of Thai YMSM. In Phase 3, we will conduct a pilot randomized controlled trial to evaluate the feasibility, acceptability, and preliminary efficacy of MES-PrEP and MTM to increase PrEP uptake and adherence among Thai YMSM. A total of 60 HIV-negative Thai YMSM who have not started PrEP and 60 YMSM who are on PrEP but not adherent to it will be randomized 2:1 to receive MES-PrEP and MTM (n=40) or standard PrEP counseling (n=20). The feasibility and acceptability of the intervention will be assessed through usage patterns and the System Usability Scale. The preliminary impact will be assessed by evaluating the proportion of PrEP initiation and level of adherence to PrEP. Participants will complete the assessments at baseline and at 1-, 3-, and 6-month postintervention. Biomarkers of adherence to PrEP and biomarkers of HIV and sexually transmitted infections will be collected. ResultsRecruitment for this study began in January 2022 for phase 1. Qualitative interviews were completed with 30 YMSM and 5 clinical providers in May 2022. Phase 3, the pilot feasibility and acceptability trial, began in July 2023. Upon project completion, we shall have developed a highly innovative mobile health intervention to support YMSM using PrEP, which will be ready for testing in a larger efficacy trial. ConclusionsThis study addresses a critical problem (ie, high HIV incidence and low PrEP use) among Thai YMSM. We are developing 2 potentially synergistic technology-based, theory-driven interventions aimed at maximizing PrEP use. The proposed project has the potential to make significant contributions to advancing HIV prevention research and implementation science. Trial RegistrationClinicalTrials.gov NCT05243030; https://clinicaltrials.gov/ct2/show/NCT05243030 International Registered Report Identifier (IRRID)DERR1-10.2196/4643

Examining Recruitment Strategies in the Enrollment Cascade of Youth Living With HIV: Descriptive Findings From a Nationwide Web-Based Adherence Protocol

BackgroundDigital strategies and broadened eligibility criteria may optimize the enrollment of youth living with HIV in mobile health adaptive interventions. Prior research suggests that digital recruitment strategies are more efficient than traditional methods for overcoming enrollment challenges of youth living with HIV in the United States. ObjectiveThis study highlights the challenges and strategies that explain screening and enrollment milestones in a national web-based adherence protocol for youth living with HIV. MethodsBaseline data from a national web-based HIV adherence protocol for youth living with HIV, collected from July 2018 to February 2021, were analyzed. A centralized recruitment procedure was developed, which used web-based recruitment via Online Master Screener; paid targeted advertisements on social media platforms (eg, Facebook and Reddit) and geosocial networking dating apps (eg, Grindr and Jack’d); and site and provider referrals from Subject Recruitment Venues and other AIDS service organizations, website referrals, and text-in recruitment. ResultsA total of 3 distinct cohorts of youth living with HIV were identified, marked by changes in recruitment strategies. Overall, 3270 individuals consented to screening, 2721 completed screening, 581 were eligible, and 83 completed enrollment. We examined sociodemographic and behavioral differences in completing milestones from eligibility to full enrollment (ie, submitting antiretroviral therapy and viral load data and completing the baseline web-based survey). Those with the most recent viral load tests >6 months ago were half as likely to enroll (odds ratio 0.45, 95% CI 0.21-0.94). Moreover, eligible participants with self-reported antiretroviral therapy adherence (SRA) between 50% and 80% were statistically significant (P80%. ConclusionsThe findings add to our knowledge on the use of digital technologies for youth living with HIV before and during the COVID-19 pandemic and provide insight into the impact of expanding eligibility criteria on enrollment. As the COVID-19 pandemic continues and the use of and engagement with social media and dating apps among youth living with HIV changes, these platforms should continue to be investigated as potential recruitment tools. Using a wide variety of recruitment strategies such as using social media and dating apps as well as provider referral mechanisms, increasing compensation amounts, and including SRA in enrollment criteria should continue to be studied with respect to their ability to successfully recruit and enroll eligible participants. International Registered Report Identifier (IRRID)RR2-10.2196/1118