Diffuse myocardial fibrosis is uncommon in people with perinatally acquired human immunodeficiency virus infection.

BACKGROUND: Cardiovascular disease (CVD) remains a leading cause of death in people living with HIV. Myocardial fibrosis is well-described in HIV infection acquired in adulthood. We evaluate the burden of fibrosis by cardiac magnetic resonance in people with perinatal HIV infection. METHODS: Individuals with perinatally acquired HIV (pnHIV) diagnosed before 10 years-old and on antiretroviral treatment for ≥ 6 months were matched with uninfected controls. Patients with significant cardiometabolic co-morbidities and pregnancy were excluded. Diffuse fibrosis was assessed by cardiac magnetic resonance (CMR) with native T1 mapping for calculation of extracellular volume fraction (ECV). Viability was assessed with late gadolinium enhancement. The normality of fibrosis was assessed using the Komogrov-Smirnov test. Fibrosis between the groups was analyzed using a Mann-Whitney U test, as the data was not normally distributed. Statistical significance was defined as a p-valve < 0.05. RESULTS: Fourteen adults with pnHIV group and 26 controls (71% female and 86% Black race) were assessed. The average (± standard deviation) age in the study group was 29 (± 4.3) years-old. All pnHIV had been on ART for decades. Demographic data, CMR functional/volumetric data, and pre-contrast T1 mapping values were similar between groups. Diastolic function was normal in 50% of pnHIV patients and indeterminate in most of the remainder (42%). There was no statistically significant difference in ECV between groups; p = 0.24. CONCLUSION: Perinatally-acquired HIV was not associated with diffuse myocardial fibrosis. Larger prospective studies with serial examinations are needed to determine whether pnHIV patients develop abnormal structure or function more often than unaffected controls.

Impact of Policy Change on Access to Medication for Opioid Use Disorder in Primary Care.

OBJECTIVES: The opioid overdose epidemic is escalating. Increasing access to medications for opioid use disorder in primary care is crucial. The impact of the US Department of Health and Human Services' policy change removing the buprenorphine waiver training requirement on primary care buprenorphine prescribing remains unclear. We aimed to investigate the impact of the policy change on primary care providers' likelihood of applying for a waiver and the current attitudes, practices, and barriers to buprenorphine prescribing in primary care. METHODS: We used a cross-sectional survey with embedded educational resources disseminated to primary care providers in a southern US academic health system. We used descriptive statistics to aggregate survey data, logistic regression models to evaluate whether buprenorphine interest and familiarity correlate with clinical characteristics, and a χ2 test to evaluate the effect of the educational intervention on screening. RESULTS: Of the 54 respondents, 70.4% reported seeing patients with opioid use disorder, but only 11.1% had a waiver to prescribe buprenorphine. Few nonwaivered providers were interested in prescribing, but perceiving buprenorphine to be beneficial to the patient population was associated with interest (adjusted odds ratio 34.7, P < 0.001). Two-thirds of nonwaivered respondents reported the policy change having no impact on their decision to obtain a waiver; however, among interested providers, it increased their likelihood of obtaining a waiver. Barriers to buprenorphine prescribing included lack of clinical experience, clinical capacity, and referral resources. Screening for opioid use disorder did not increase significantly after the survey. CONCLUSIONS: Although most primary care providers reported seeing patients with opioid use disorder, interest in prescribing buprenorphine was low and structural barriers remained the dominant obstacles. Providers with a preexisting interest in buprenorphine prescribing reported that removing the training requirement was helpful.

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.

PURPOSE: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions. METHODS: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation. RESULTS: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression. CONCLUSION: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.

Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis.

RATIONALE & OBJECTIVE: Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes. STUDY DESIGN: Multicenter, pragmatic, cluster-randomized clinical trial. SETTING & PARTICIPANTS: HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis. INTERVENTION: Phosphate binder prescriptions and dietary recommendations to achieve the "Hi" serum phosphate target (≥6.5 mg/dL) or the "Lo" serum phosphate target (<5.5 mg/dL). OUTCOMES: Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome. RESULTS: The trial is currently enrolling. LIMITATIONS: HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes. CONCLUSIONS: HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04095039.

Preexposure Prophylaxis Outcomes in an Urban Community in North Carolina: Discontinuation of Care and Sexually Transmitted Infections.

BACKGROUND: Few studies have examined long-term outcomes among persons who initiate preexposure prophylaxis (PrEP) in the South, including PrEP discontinuation and sexually transmitted infection (STI) rates. METHODS: Care discontinuation (>6 months without a PrEP appointment) and incident STIs were evaluated for patients at 2 PrEP clinics in Durham, NC. We tested for predictors of discontinuation as a binary variable using logistic regression. Model covariates included age, race/ethnicity, sex, known HIV-positive partner, commercial sex work, men who have sex with men (MSM) versus not MSM, type of insurance, and clinic site. A similar analysis was completed for STI incidence, controlling for days in the study. RESULTS: Among 271 patients, mean age was 33.2 years, 46.9% were Black and 11.1% were Latino, 81.2% were MSM, and 32% were uninsured. Preexposure prophylaxis was discontinued in 47%, and another 11% had intermittent care. Sexually transmitted infection incidence was 45.4/100 person-years, and 5 patients were diagnosed with HIV at baseline or in follow-up. Men who have sex with men were less likely to discontinue PrEP relative to non-MSM (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.10-0.64). Baseline STI was associated with a higher likelihood of incident STI (OR, 8.19; 95% CI, 3.69-19.21), whereas care discontinuation was associated with a lower likelihood of STI (OR, 0.28; 95% CI, 0.11-0.65). CONCLUSIONS: Preexposure prophylaxis programs in the Southern United States are reaching uninsured and predominantly Black and Latino MSM, but discontinuation rates are high despite elevated rates of incident STI and HIV. Further work is required to elucidate causes of PrEP discontinuation and encourage persistence in care.

Annexin A1 is a Potential Novel Biomarker of Congestion in Acute Heart Failure.

OBJECTIVES: This study sought to identify the role of annexin A1 (AnxA1) as a congestion marker in acute heart failure (AHF) and to identify its putative role in predicting clinical outcomes. BACKGROUND: AnxA1 is a protein that inhibits inflammation following ischemia-reperfusion injury in cardiorenal tissues. Because AHF is a state of tissue hypoperfusion, we hypothesized that plasma AnxA1 levels are altered in AHF. METHODS: In the Renal Optimization Strategies Evaluation (ROSE) trial, patients hospitalized for AHF with kidney injury were randomized to receive dopamine, nesiritide, or placebo for 72 hours in addition to diuresis. In a subanalysis, plasma AnxA1 levels were measured at baseline and at 72 hours in 275 patients. Participants were divided into 3 tertiles based on their baseline AnxA1 levels. RESULTS: The prevalence of peripheral edema 2+ increased with increasing AnxA1 levels (P < .007). Cystatin C, blood urea nitrogen, and kidney injury molecule-1 plasma levels were higher among participants in tertile 3 vs tertiles 1 or 2 (P< .05). Patients with a congestion score of 4 had a mean baseline AnxA1 level 8.63 units higher than those with a congestion score of 0 (P = .03). Patients in tertiles 2 and 3 were twice as likely to experience creatinine elevation as patients in tertile 1 (P = .03). Patients in tertiles 2 and 3 were at a higher risk of 60-day all-cause mortality or heart failure hospitalization and 180-day all-cause mortality (P < .05). CONCLUSIONS: Among patients hospitalized for AHF with impaired kidney function, elevated AnxA1 levels are associated with worse congestion, higher risk for further creatinine elevation, and higher rates of 60-day morbidity or all-cause mortality and 180-day all-cause mortality. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01132846.

Cumulus cell pappalysin-1, luteinizing hormone/choriogonadotropin receptor, amphiregulin and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 mRNA levels associate with oocyte developmental competence and embryo outcomes.

PURPOSE: To determine whether a selected set of mRNA biomarkers expressed in individual cumulus granulosa cell (CC) masses show association with oocyte developmental competence, embryo ploidy status, and embryo outcomes. METHODS: This prospective observational cohort pilot study assessed levels of mRNA biomarkers in 163 individual CC samples from 15 women stimulated in antagonist cycles. Nineteen mRNA biomarker levels were measured by real-time PCR and related to the development of their corresponding individually cultured oocytes and subsequent embryos, embryo ploidy status, and live birth outcomes. RESULTS: PAPPA mRNA levels were significantly higher in CC from oocytes that led to euploid embryos resulting in live births and aneuploid embryos compared to immature oocytes by ANOVA. LHCGR mRNA levels were significantly higher in CC of oocytes resulting in embryos associated with live birth compared to immature oocytes and oocytes resulting in arrested embryos by ANOVA. Using a general linearized mixed model to assess ploidy status, CC HSD3B mRNA levels in oocytes producing euploid embryos were significantly lower than other oocyte outcomes, collectively. When transferred euploid embryos outcomes were analyzed by ANOVA, AREG mRNA levels were significantly lower and PAPPA mRNA levels significantly higher in CC from oocytes that produced live births compared to transferred embryos that did not form a pregnancy. CONCLUSIONS: Collectively, PAPPA, LHCGR, and AREG mRNA levels in CC may be able to identify oocytes with the best odds of resulting in a live birth, and HSD3B1 mRNA levels may be able to identify oocytes capable of producing euploid embryos.

Comparing behavioral health models for reducing risky drinking among older male veterans.

BACKGROUND: Screening older veterans in Veterans Affairs Medical Center (VAMC) primary care clinics for risky drinking facilitates early identification and referral to treatment. OBJECTIVE: This study compared two behavioral health models, integrated care (a standardized brief alcohol intervention co-located in primary care clinics) and enhanced referral care (referral to specialty mental health or substance abuse clinics), for reducing risky drinking among older male VAMC primary care patients. VAMC variation was also examined. METHOD: A secondary analysis of longitudinal data from the Primary Care Research in Substance Abuse and Mental Health for Elderly (PRISM-E) study, a multisite randomized controlled trial, was conducted with a sample of older male veterans (n = 438) who screened positive for risky drinking and were randomly assigned to integrated or enhanced referral care at five VAMCs. RESULTS: Generalized estimating equations revealed no differences in either behavioral health model for reducing risky drinking at a 6-month follow-up (AOR: 1.46; 95% CI: 0.42-5.07). Older veterans seen at a VAMC providing geriatric primary care and geriatric evaluation and management teams had lower odds of risky drinking (AOR: 0.24; 95% CI: 0.07-0.81) than those seen at a VAMC without geriatric primary care services. CONCLUSIONS: Both integrated and enhanced referral care reduced risky drinking among older male veterans. However, VAMCs providing integrated behavioral health and geriatric specialty care may be more effective in reducing risky drinking than those without these services. Integrating behavioral health into geriatric primary care may be an effective public health approach for reducing risky drinking among older veterans.

Rural-urban differences in HIV viral loads and progression to AIDS among new HIV cases.

OBJECTIVE: The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic in the United States has shifted to the South, where an increasing proportion is occurring in rural areas. We sought to gain a better understanding of the affected rural population in this region. METHODS: The statewide HIV/AIDS Electronic Reporting System database was used to examine the epidemiological characteristics of newly diagnosed HIV cases in South Carolina from 2005 to 2011. Rural-urban differences were examined in sociodemographic and clinical characteristics, including progression to AIDS and a decline in HIV viral load (VL) to undetectable levels within 1 year of diagnosis. RESULTS: Of the 5336 individuals newly diagnosed as having HIV, 1433 (26.9%) were from rural areas. Compared with urban residents, a higher proportion of rural residents were black, non-Hispanic (80.1% vs 68.5%; P ≤ 0.0001) and reported heterosexual risk (28.8% vs 22.9%; P = 0.0007). The proportion of female patients was higher in rural areas (29.7% vs 26.4%; P = 0.016). No significant rural-urban differences were found in initial CD4(+) T-cell and VL counts or proportion obtaining an undetectable VL at 1 year. Rural residents were significantly more likely than urban residents to have AIDS at diagnosis or within 1 year of the HIV diagnosis (adjusted odds ratio 1.15; 95% confidence interval 1.007-1.326). CONCLUSIONS: The reasons behind differences in proportions of rural and urban residents who were diagnosed as having AIDS or progressed to AIDS despite similar initial CD4(+) T-cell counts and VL suppression at 1 year are unclear and should be explored in future studies. Future prevention and treatment efforts may need to consider the unique characteristics of rural populations in the South.

Dose of early intervention treatment during children's first 36 months of life is associated with developmental outcomes: an observational cohort study in three low/low-middle income countries.

BACKGROUND: The positive effects of early developmental intervention (EDI) on early child development have been reported in numerous controlled trials in a variety of countries. An important aspect to determining the efficacy of EDI is the degree to which dosage is linked to outcomes. However, few studies of EDI have conducted such analyses. This observational cohort study examined the association between treatment dose and children's development when EDI was implemented in three low and low-middle income countries as well as demographic and child health factors associated with treatment dose. METHODS: Infants (78 males, 67 females) born in rural communities in India, Pakistan, and Zambia received a parent-implemented EDI delivered through biweekly home visits by trainers during the first 36 months of life. Outcome was measured at age 36 months with the Mental (MDI) and Psychomotor (PDI) Development Indices of the Bayley Scales of Infant Development-II. Treatment dose was measured by number of home visits completed and parent-reported implementation of assigned developmental stimulation activities between visits. Sociodemographic, prenatal, perinatal, and child health variables were measures as correlates. RESULTS: Average home visits dose exceeded 91% and mothers engaged the children in activities on average 62.5% of days. Higher home visits dose was significantly associated with higher MDI (mean for dose quintiles 1-2 combined = 97.8, quintiles 3-5 combined = 103.4, p = 0.0017). Higher treatment dose was also generally associated with greater mean PDI, but the relationships were non-linear. Location, sociodemographic, and child health variables were associated with treatment dose. CONCLUSIONS: Receiving a higher dose of EDI during the first 36 months of life is generally associated with better developmental outcomes. The higher benefit appears when receiving ≥91% of biweekly home visits and program activities on ≥67% of days over 3 years. It is important to ensure that EDI is implemented with a sufficiently high dose to achieve desired effect. To this end groups at risk for receiving lower dose can be identified and may require special attention to ensure adequate effect.

Folic Acid Fortification and Women's Folate Levels in Selected Communities in Brazil - A First Look.

BACKGROUND: Several countries have implemented mandatory folic acid fortification of wheat flour and selected grain products to increase the folate intake of reproductive-aged women. Brazil implemented a folic acid fortification program in 2004. No previous studies have examined folate differences among Brazilian women following the mandate. OBJECTIVE: We evaluate differences in serum and red blood cell (RBC) folate concentrations between two samples of women of childbearing age from selective communities in Brazil, one tested before (N = 116) and the other after the mandate (N = 240). METHODS: We compared the baseline folate levels of women enrolled in a prevention study shortly before the fortification mandate was implemented, to baseline levels of women from the same communities enrolled in the same study shortly after fortification began. The participants were women enrolled in a folate supplementation clinical trial, at a hospital specializing in treating craniofacial anomalies in the city of Bauru from January 29, 2004 to April 27, 2005. We only compared baseline folate levels before the women received oral cleft prevention program (OCPP) folic acid supplements. RESULTS: Women enrolled after the fortification mandate had higher means of serum folate (20.3 versus 11.2 nmol/L; p < 0.001) and RBC folate (368.3 versus 177.6 nmol/L; p < 0.001) than women enrolled before the mandate. Differences in folate levels between the two groups remained after adjusting for several co-variables. CONCLUSIONS: The results suggest that serum and RBC folate levels among women of childbearing age increased after implementing the folic acid fortification mandate in Brazil.

Solubilization of tricalcium phosphate by P(3HB) accumulating Azotobacter chroococcum MAL-201.

Cells of Azotobacter chroococcum MAL-201 (MTCC 3853) are capable of accumulating the intracellular poly(3-hydroxybutyric acid) [P(3HB)], accounting for 65-71 % of its cell dry weight and also capable of synthesizing the enzyme alkaline phosphatase (APase), when grown in glucose and tricalcium phosphate containing nitrogen-free modified Stockdale medium. The concentration of insoluble phosphate in broth medium was optimized as 0.25 % (w/v) for growth and biosynthesis of APase. However, the suboptimal concentration of phosphate (0.1 %, w/v) appeared as the best suited for accumulation of P(3HB) by the strain. The significant differences were observed in biosynthesis of polymer and APase enzyme under variable phosphate concentrations. Glucose, 3.0 % (w/v) was recorded as the optimum concentration for all of the three parameters. The continuation of APase biosynthesis was observed during the period of significant decline in the cellular content of the polymer in the late phase of growth. In order to study the role of P(3HB), the rate of autodigestion of biopolymer and phosphate solubilization rate (k, mineralization constant) were determined in carbon-free medium under batch cultivation process and the parameters were found to be positively correlated. The maximum phosphate solubilization rate (k = 0.0154) by the strain MAL-201 timed at the 10th hour of incubation when the rate of polymer degradation concomitantly attained its peak corresponding to 87 mg/l/h and then declined gradually. Only a negligible amount of residual polymer remained undigested. These data strongly support the functional role of P(3HB) in response to multinutritional stress condition.

Design and Rationale of the Phase 2 Baricitinib Study in Apolipoprotein L1-Mediated Kidney Disease (JUSTICE).

Introduction: Individuals of recent West African ancestry develop focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (HTN-ESKD) at 4 times the rate of White Americans. Two protein-coding variants of the Apolipoprotein L1 (APOL1) gene, G1 and G2, explain 50% to 70% of the excess risk of HTN-ESKD and FSGS among this group. Increased expression of G1 and G2 in the kidney, mediated by Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling, drive pathogenesis of these kidney diseases. Baricitinib is an orally active inhibitor of JAK1/2 that blocks APOL1 synthesis. The Janus kinase-STAT Inhibition to Reduce APOL1-Associated Kidney Disease (JUSTICE) trial is evaluating the antiproteinuric efficacy and safety of baricitinib in patients with APOL1-associated FSGS and HTN-attributed chronic kidney disease (HTN-CKD). Methods: JUSTICE is a single-center, randomized, double-blind, placebo-controlled, pilot phase 2 trial of baricitinib in patients with proteinuria, APOL1-associated FSGS or APOL1-associated HTN-CKD without diabetes. A total of 75 African American patients with APOL1-associated CKD, including 25 with FSGS and 50 with HTN-CKD, aged 18 to 70 years will be randomized 2:1 to daily treatment with baricitinib or placebo, respectively. Results: The primary efficacy end point will be percent change in urine albumin-to-creatinine ratio (UACR) from baseline to end of month 6. The primary safety end point will be incidence of clinically significant decreases in hemoglobin of ≥ 1g/dl. Conclusion: The phase 2 JUSTICE study will characterize the antiproteinuric efficacy and safety of JAK1/2 inhibition with baricitinib in patients with APOL1-associated FSGS and APOL1-associated HTN-CKD.

Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

Newborn-care training and perinatal mortality in developing countries.

BACKGROUND: Of the 3.7 million neonatal deaths and 3.3 million stillbirths each year, 98% occur in developing countries. An evaluation of community-based interventions designed to reduce the number of these deaths is needed. METHODS: With the use of a train-the-trainer model, local instructors trained birth attendants from rural communities in six countries (Argentina, Democratic Republic of Congo, Guatemala, India, Pakistan, and Zambia) in the World Health Organization Essential Newborn Care course (which focuses on routine neonatal care, resuscitation, thermoregulation, breast-feeding, "kangaroo" [skin-to-skin] care, care of the small baby, and common illnesses) and (except in Argentina) in a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (which teaches basic resuscitation in depth). The Essential Newborn Care intervention was assessed among 57,643 infants with the use of a before-and-after design. The Neonatal Resuscitation Program intervention was assessed as a cluster-randomized, controlled trial involving 62,366 infants. The primary outcome was neonatal death in the first 7 days after birth. RESULTS: The 7-day follow-up rate was 99.2%. After birth attendants were trained in the Essential Newborn Care course, there was no significant reduction from baseline in the rate of neonatal death from all causes in the 7 days after birth (relative risk with training, 0.99; 95% confidence interval [CI], 0.81 to 1.22) or in the rate of perinatal death; there was a significant reduction in the rate of stillbirth (relative risk with training, 0.69; 95% CI, 0.54 to 0.88; P=0.003). In clusters of births in which attendants had been randomly assigned to receive training in the Neonatal Resuscitation Program, as compared with control clusters, there was no reduction in the rates of neonatal death in the 7 days after birth, stillbirth, or perinatal death. CONCLUSIONS: The rate of neonatal death in the 7 days after birth did not decrease after the introduction of Essential Newborn Care training of community-based birth attendants, although the rate of stillbirths was reduced. Subsequent training in the Neonatal Resuscitation Program did not significantly reduce the mortality rates. (ClinicalTrials.gov number, NCT00136708.)

Randomized trial of early developmental intervention on outcomes in children after birth asphyxia in developing countries.

OBJECTIVE: To determine if early developmental intervention (EDI) improves developmental abilities in resuscitated children. STUDY DESIGN: This was a parallel group, randomized controlled trial of infants unresponsive to stimulation who received bag and mask ventilation as part of their resuscitation at birth and infants who did not require any resuscitation born in rural communities in India, Pakistan, and Zambia. Intervention infants received a parent-implemented EDI delivered with home visits by parent trainers every other week for 3 years starting the first month after birth. Parents in both intervention and control groups received health and safety counseling during home visits on the same schedule. The main outcome measure was the Mental Development Index (MDI) of the Bayley Scales of Infant Development, 2nd edition, assessed at 36 months by evaluators unaware of treatment group and resuscitation history. RESULTS: MDI was higher in the EDI (102.6 ± 9.8) compared with the control resuscitated children (98.0 ± 14.6, 1-sided P = .0202), but there was no difference between groups in the nonresuscitated children (100.1 ± 10.7 vs 97.7 ± 10.4, P = .1392). The Psychomotor Development Index was higher in the EDI group for both the resuscitated (P = .0430) and nonresuscitated children (P = .0164). CONCLUSIONS: This trial of home-based, parent provided EDI in children resuscitated at birth provides evidence of treatment benefits on cognitive and psychomotor outcomes. MDI and Psychomotor Development Index scores of both nonresuscitated and resuscitated infants were within normal range, independent of early intervention.

Strain echocardiography in predicting LV dysfunction in RV apical pacing.

Right ventricular (RV) pacing is associated with a reduction in left ventricular (LV) systolic function, thought to be mediated by pacing-induced ventricular dyssynchrony. The prevalence of heart failure after RV pacing is reported to range from 31±3%. We studied 60 subjects with high-grade atrioventricular block and Complete Heart Block (CHB) scheduled to undergo right ventricular apical pacing. 2D echocardiography was done at baseline, 1 month and 12 months. Pacing-induced cardiomyopathy was defined as a reduction in LVEF to <45%. Strain was evaluated off-line from digitally stored images using all advanced software package (cardiac wall motion quantification (CMQ); Toshiba Medical Systems). Longitudinal strain for individual myocardial segments was measured from the apical four-chamber, two-chamber and long axis views (16 segment AHA/ASE model). None had LV dysfunction at baseline based on 2D and strain echo imaging. Subsequently 18 patients were detected to develop low GLS score (less than -14.5) at 1 month. On subsequent follow up at 1 year, all 18 patients developed LV dysfunction on 2D Echocardiography. Thus Strain imaging with GLS score helped in early detection of LV dysfunction in RV apical pacing subjects. Pacing-induced cardiomyopathy had significant association with high grade AV block with pacemaker dependency. It had no significant associations with other comorbidities like diabetes, hypertension, ischemic heart disease or with the type of medication intake. However there was a statistically significant association with heart failure.

Diffuse Myocardial Fibrosis is Uncommon in People with Perinatally Acquired Human Immunodeficiency Virus Infection.

Background: Cardiovascular disease (CVD) remains a leading cause of death in people living with HIV. Myocardial fibrosis is well-described in HIV infection acquired in adulthood. We evaluate the burden of fibrosis by cardiac magnetic resonance in people with perinatal HIV infection. Methods: Individuals with perinatally acquired HIV (pnHIV) diagnosed before 10 years-old and on antiretroviral treatment for ≥ 6 months were matched with uninfected controls. Patients with significant cardiometabolic co-morbidities and pregnancy were excluded. Diffuse fibrosis was assessed by cardiac magnetic resonance (CMR). with native T1 mapping for calculation of extracellular volume fraction (ECV). Viability was assessed with late gadolinium enhancement. The normality of fibrosis was assessed using the Komogrov-Smirnov test. Fibrosis between the groups was analyzed using a Mann-Whitney U test, as the data was not normally distributed. Statistical significance was defined as a p-valve < 0.05. Results: Fourteen adults with pnHIV group and 26 controls (71% female and 86% Black race) were assessed. The average (± standard deviation) age in the study group was 29 (± 4.3) years-old. All pnHIV had been on ART for decades. Demographic data, CMR functional/volumetric data, and pre-contrast T1 mapping values were similar between groups. Diastolic function was normal in 50% of pnHIV patients and indeterminate in most of the remainder (42%). There was no statistically significant difference in ECV between groups; p = 0.24. Conclusion: Perinatally-acquired HIV was not associated with diffuse myocardial fibrosis. Early exposure to ART may be cardioprotective against development of myocardial fibrosis in patients with perinatal HIV.

Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension.

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network.