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Abstract In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10−10, OR 3.11, 95% CI 2.2–4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Background. By 2009, two decades of war and widespread displacement left the majority of the population of Northern Uganda impoverished. Methods. This study used a cluster-randomized design to test the hypothesis that a poverty alleviation program would improve economic security and reduce symptoms of depression in a sample of mostly young women. Roughly 120 villages in Northern Uganda were invited to participate. Community committees were asked to identify the most vulnerable women (and some men) to participate. The implementing agency screened all proposed participants, and a total of 1800 were enrolled. Following a baseline survey, villages were randomized to a treatment or wait-list control group. Participants in treatment villages received training, start-up capital, and follow-up support. Participants, implementers, and data collectors were not blinded to treatment status. Results. Villages were randomized to the treatment group (60 villages with 896 participants) or the wait-list control group (60 villages with 904 participants) with an allocation ration of 1:1. All clusters participated in the intervention and were included in the analysis. The intent-to-treat analysis included 860 treatment participants and 866 control participants (4.1% attrition). Sixteen months after the program, monthly cash earnings doubled from UGX 22 523 to 51 124, non-household and non-farm businesses doubled, and cash savings roughly quadrupled. There was no measurable effect on a locally derived measure of symptoms of depression. Conclusions. Despite finding large increases in business, income, and savings among the treatment group, we do not find support for an indirect effect of poverty alleviation on symptoms of depression.

Objectives: Understanding the long-term effects of severe COVID-19 illness on survivors is essential for effective pandemic recovery planning. Therefore, we investigated impairments among hospitalized adults discharged to long-term acute care hospitals (LTACHs) for prolonged severe COVID-19 illness who survived 1 year., Design: The Recovery After Transfer to an LTACH for COVID-19 (RAFT COVID) study was a national, multicenter, prospective longitudinal cohort study., Setting and Patients: We included hospitalized English-speaking adults transferred to one of nine LTACHs in the United States between March 2020 and February 2021 and completed a survey., Interventions: None., Measurements and Main Results: Validated instruments for impairments and free response questions about recovering. Among 282 potentially eligible participants who provided permission to be contacted, 156 (55.3%) participated (median age, 65; 38.5% female; 61.3% in good prior health; median length of stay of 57 d; 77% mechanically ventilated for a median of 26 d; 42% had a tracheostomy). Approximately two-thirds (64%) had a persistent impairment, including physical (57%), respiratory (49%; 19% on supplemental oxygen), psychiatric (24%), and cognitive impairments (15%). Nearly half (47%) had two or more impairment types. Participants also experienced persistent debility from hospital-acquired complications, including mononeuropathies and pressure ulcers. Participants described protracted recovery, attributing improvements to exercise/rehabilitation, support, and time. While considered life-altering with 78.7% not returning to their usual health, participants expressed gratitude for recovering; 99% returned home and 60% of previously employed individuals returned to work., Conclusions: Nearly two-thirds of survivors of among the most prolonged severe COVID-19 illness had persistent impairments at 1 year that resembled post-intensive care syndrome after critical illness plus debility from hospital-acquired complications., Competing Interests: Dr. Makam’s institution received funding from the University of California, San Francisco Research Evaluation and Allocation Committee Carson and Hampton Research Funds and the National Association of Long Term Hospitals (NALTH). Drs. Makam’s and Covinsky’s institutions received funding from the National Institute on Aging. Drs. Makam, Ely, Jackson, and Convinsky received support for article research from the National Institutes of Health. Dr. Prettyman disclosed that he is President of the NALTH. Dr. Espejo’s institution received funding from the Donaghue Foundation. Dr. Votto received funding from the NALTH; he disclosed that he is the Chief Medical Officer of NALTH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objective: To evaluate the association of blood pressure category < 20 weeks according to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) criteria with adverse perinatal outcomes., Study Design: A retrospective cohort study of singleton deliveries between 1/2014 and 10/2017 was undertaken. Blood pressure category assigned by 2017 ACC/AHA criteria applied to blood pressures prior to 20 weeks gestation: normal (systolic < 120 and diastolic < 80), elevated blood pressure (systolic 120-129 and diastolic < 80 mmHg), stage 1 hypertension (systolic 130-139 and/or diastolic 80-89), stage 2 hypertension (prior diagnosis of chronic hypertension or systolic ≥ 140 or diastolic ≥ 90 mmHg)., Main Outcome Measures: The primary outcome was preeclampsia. Secondary outcomes included preterm birth and postpartum readmission. Chi-square, ANOVA and Kruskal-Wallis tests and multivariable Poisson regression were used for analysis., Results: Of the 6,067 eligible pregnancies, 3,855 (63.5%) had normotensive blood pressure, 1,224 (20.2%) elevated blood pressure, 624 (10.3%) stage 1 hypertension, and 364 (6.0%) stage 2 hypertension. Compared to 4.6% prevalence of preeclampsia among normotensive pregnancies, higher categories were associated with higher preeclampsia prevalence: elevated blood pressure (10.7%, adjusted relative risk (aRR) 2.2, 95% confidence interval (CI) 1.8-2.6), stage 1 hypertension (15.1%, aRR 2.7, 95% CI 2.2-3.4) and stage 2 hypertension (38.7%, aRR 6.2, 95% CI 5.1-7.4). Non-normal categories were also associated with a higher risk of preterm birth and postpartum readmission., Conclusion: Patients with elevated blood pressure and stage 1 and 2 hypertension at < 20 weeks are at increased risk of adverse obstetric perinatal outcomes., (Copyright © 2022. Published by Elsevier B.V.)

Access to recreational physical activities, particularly in outdoor spaces, has been a crucial outlet for physical and mental health during the COVID-19 pandemic. There is a need to understand how conducting these activities modulates the risk of SARS-CoV-2 infection. In this case-control study of unvaccinated individuals conducted in San Francisco, California, the odds of testing positive to SARS-CoV-2 were lower for those who conducted physical activity in outdoor locations (adjusted odds ratio [aOR]: 0.16, 95% confidence interval [CI]: 0.05, 0.40) in the two weeks prior to testing than for those who conducted no activity or indoor physical activity only. Individuals who visited outdoor parks, beaches, or playgrounds also had lower odds of testing positive to SARS-CoV-2 (aOR: 0.28, 95% CI: 0.11, 0.68) as compared with those who did not visit outdoor parks, beaches, or playgrounds. These findings, albeit in an unvaccinated population, offer observational data to support pre-existing ecological studies that suggest that activity in outdoor spaces lowers COVID-19 risk.

Background: External cephalic version (ECV) is a technique used to reduce the incidence of cesarean deliveries due to malpresentation. Nitrous oxide is an inhaled analgesic that may be used for pain relief for women undergoing external cephalic version., Objective: To compare the conversion rate of non-cephalic to cephalic presentation in ECV with and without nitrous oxide., Study Design: A retrospective cohort analysis was performed including all singleton, term gestation ECVs between January 2016 and June 2017 at a single institution. Multivariable logistic regression was used to compare women who had ECV with nitrous oxide versus ECV without nitrous oxide. The primary outcome was successful rate of conversion to cephalic presentation and the secondary outcome was the rate of vaginal delivery., Results: During the study period, 167 women underwent ECV: 77 with nitrous oxide and 90 without nitrous oxide. Of the 77 women who used nitrous oxide, 25 (32.5%) were successful and 17 of these women delivered vaginally (68%). Of the women who underwent ECV without nitrous oxide, 29 (32.2%) successfully converted and 21 of these delivered vaginally (72%). After controlling for confounders, the use of nitrous oxide had no clinically or statistically significant difference on ECV success rates (OR 1.08, 95% CI 0.52-2.23)., Conclusion: Nitrous oxide does not seem to affect conversion rate to cephalic presentation in ECV. Further studies are needed to determine the impact of nitrous oxide on women's decision to undergo ECV and on patient satisfaction and tolerability., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The combined burden of geriatric conditions, comorbidities, and HIV requires a model of HIV care that offers a comprehensive clinical approach with people 50 years or older with HIV. Golden Compass is an outpatient, multidisciplinary HIV-geriatrics program with an onsite HIV geriatrician, cardiologist, pharmacist, and social worker, offering specialist referrals, care navigation, and classes on improving functional status and cognition. Participants (13 patients and 11 primary care providers) were recruited using a non-probability sampling method to participate in semi-structured interviews on the perceived impact of Golden Compass on care delivered to older people with HIV. Interviews were transcribed verbatim and framework analysis used to analyze the transcripts. The perceived impacts of Golden Compass by patients and providers were organized by the Compass points (Northern: Heart and Mind, Eastern: Bones and Strength, Southern: Navigation and Network, Western: Dental, Hearing, and Vision). Overall, patients valued the focus on functional health and whole-person care, leading to greater trust in the ability of providers. Providers gained new skills through the geriatrics, cardiology and/or pharmacist consultations. The HIV-geriatrics specialty approach of Golden Compass improved functional ability and quality of life for older adults with HIV. Few integrated care programs for older people with HIV have been evaluated. This study adds to the limited literature demonstrating high patient and provider satisfaction with a HIV-care model that incorporated principles of geriatric medicine emphasizing a comprehensive approach to sustaining functional ability and improving quality of life., (© 2021. The Author(s).)

Objective: Twin vaginal deliveries (VDs) are often performed in the operating room (OR) given the risk of conversion to cesarean delivery (CD) for the aftercoming twin. We aim to investigate the rates of conversion to CD for planned twin VDs and identify predictors and outcomes of conversion., Study Design: A retrospective cohort study of all women who underwent a planned twin VD at two large academic medical centers over 4 years. Demographic and outcome data were chart abstracted. Various statistical tests were used to evaluate the influence of perinatal variables on mode of delivery and identify possible predictors of conversion., Results: Eight hundred and eighty-five twin deliveries were identified, of which 725 (81.9%) were possible candidates for VD. Of those, 237 (32.7%) underwent successful VD of twin A. Ninety-five (40.1%) had a nonvertex second twin at time of delivery. Conversion to CD occurred in 10 planned VDs (4.2%). Conversions were higher with spontaneous labor (relative risk [RR]: 2.1; 95% confidence interval [CI] 1.6-2.7; p  = 0.003), and having an intertwin delivery interval greater than 60 minutes (RR: 5.1; 95% CI: 2.5-10.8; p  < 0.001). Nonvertex presentation of twin B, type of delivery provider, or years out in practice of delivery provider were not significantly different between groups. There were no significant differences in neonatal outcomes between VD and conversion groups. There was a significant association between use of forceps for twin B and successful VD ( p  = 0.02), with 84.6% in the setting of a nonvertex twin B., Conclusion: Successful VD was achieved in planned VD of twins in 95.8% of cases, and there were no significant differences in maternal and fetal outcomes between successful VD and conversion to CD for twin B. With the optimal clinical scenario and shared decision-making, performing vaginal twin deliveries in labor and delivery rooms should be discussed., Key Points: · There is a propensity to perform twin vaginal deliveries in the operating room.. · Rates of conversion to cesarean section are very low.. · There are no significant differences in perinatal outcomes with conversion.., Competing Interests: None declared., (Thieme. All rights reserved.)

Pediatric HIV remains a significant global concern, with 160,000 new infections annually. Accelerating Children's HIV/AIDS Treatment (ACT) provided a strategic response to the "treatment gap" for children. We examined whether activities under ACT increased testing and identification of youth living with HIV (YLWH). Family AIDS Care & Education Services implemented ACT across 130 health facilities in western Kenya between October 2015 and September 2016, providing: HIV-testing counselors and space; training on the Family Information Table (FIT) and chart audits; community outreach testing; and text message reminders for pregnant women. We analyzed the number of youths tested and identified with HIV over time and between intervention and control sites using interrupted time series analysis. We tested 268,312 youths (7,183 infants <18 months; 145,833 children 18 months to 9 years; and 115,296 adolescents 10-14 years). Mean monthly number tested per health facility increased from 2.8 to 7.2 ( p  < 0.0001) in infants, 44.8-142.0 ( p  < 0.0001) in children, and 30.1-123.3 ( p  < 0.0001) in adolescents. Mean monthly number identified with HIV per facility increased from 0.06 to 0.37 ( p  < 0.0001) in infants; 0.34-0.62 ( p  = 0.008) in children; and 0.17-0.26 ( p  = 0.04) in adolescents, resulting in 1,328 diagnoses. Among infants, FIT training was associated with increased HIV testing over time, incidence rate ratio (IRR) = 3.85 (95% confidence interval [CI] 2.16-6.84; p  < 0.0001). Text messaging increased testing, IRR = 2.10 (95% CI 1.57-2.80; p  < 0.0001) and identification of HIV in infants, IRR = 1.83 (95% CI 1.06-3.18; p  = 0.0381) and older children, IRR = 2.25 (95% CI 1.62, 3.13; p  < 0.0001). Chart audits increased testing over time among adolescents (IRR = 2.11; 95% CI 1.21-3.66; p  = 0.0082). Outreach was associated with identification of adolescents with HIV, IRR = 1.58 (95% CI 1.22-2.06; p  = 0.0005). In lower-income settings, targeted interventions effective at reaching YLWH can help optimize resource allocation to address gaps in testing and identification to further reduce HIV-related morbidity and mortality.

Objective: This study aimed to identify differences in sequential integrated screening and early ultrasound markers in monochorionic/diamniotic (MC/DA) pregnancies complicated by twin-to-twin transfusion syndrome (TTTS) and unequal placental sharing (UPS)., Study Design: Retrospective cohort study of MC/DA pregnancies evaluated between January 2012 and July 2017 at the University of California San Francisco. MC/DA pregnancies with ultrasound surveillance up to 26 weeks who participated in the California Prenatal Screening Program (CPSP) were included. Pregnancies with structural or genetic anomalies were excluded. UPS was defined as an intertwin growth discordance ≥20%. Intertwin nuchal translucency (NT) discordance was calculated by the absolute value of the difference of the NT of cotwins. Kruskal-Wallis or ANOVA testing was performed where appropriate, and negative binomial regression models were chosen to test for differences in mean biomarker levels by outcome group., Results: A total of 191 MC/DA pregnancies were included; 85 were affected by TTTS, 35 by UPS, and 71 controls. Significant differences in intertwin NT discordance in pregnancies complicated by TTTS and UPS compared with controls ( p  = 0.007) were found. TTTS cases had a mean NT discordance greater than two times that of controls ( p  = 0.04), while UPS cases had a value more than three times greater ( p  = 0.003). There was a statistically significant difference in mean second trimester human chorionic gonadotropin (hCG) between the cohorts ( p  = 0.0002) with TTTS cases having a mean second trimester hCG value 1.5 greater than both controls ( p  < 0.001) and UPS cases ( p  = 0.001). Analysis showed a significant difference in mean second trimester inhibin between the three cohorts ( p  = 0.029). Pregnancies complicated by UPS had a mean second trimester inhibin 1.5 times greater than controls ( p  = 0.010)., Conclusion: Our study shows that there are unique differences in early ultrasound and sequential integrated serum markers between MC/DA gestations complicated by TTTS and UPS versus those unaffected., Key Points: · Differences exist in sequential integrated screening markers in monochorionic-diamniotic twin pregnancies.. · Early risk stratification of monochorionic-diamniotic twin pregnancies may be possible.. · Sequential integrated screening testing can provide useful information to clinicians when evaluating monochorionic-diamnitoic twin pregnancies.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: This study aimed to assess the association of preimplantation genetic testing (PGT) with abnormal placentation among a cohort of pregnancies conceived after frozen embryo transfer (FET)., Study Design: This is a retrospective cohort study of women who conceived via FET at the University of California, San Francisco from 2012 to 2016 with resultant delivery at the same institution. The primary outcome was abnormal placentation, including placenta accreta, retained placenta, abruption, placenta previa, vasa previa, marginal or velamentous cord insertion, circumvallate placenta, circummarginate placenta, placenta membranacea, bipartite placenta, and placenta succenturiata. Diagnosis was confirmed by reviewing imaging, delivery, and pathology reports. Our secondary outcome was hypertensive disease of pregnancy., Results: A total of 311 pregnancies were included in analysis; 158 (50.8%) underwent PGT. Baseline demographic characteristics were similar between groups except for age at conception and infertility diagnosis. Women with PGT were more likely to undergo single embryo transfer (82.3 vs. 64.1%, p  < 0.001). There were no statistically significant differences in the rate of the primary outcome (26.6 vs. 27.4%, p  = 0.86) or hypertensive disorders of pregnancy (33.5 vs. 33.3%, p  = 0.97), which remained true after multivariate analysis was performed., Conclusion: Among pregnancies conceived after FET, PGT is not associated with a statistically significant increased risk of abnormal placentation or hypertensive disorders of pregnancy., Key Points: · In pregnancies conceived by FET, PGT is not associated with increased risk of abnormal placentation.. · In pregnancies conceived by FET, PGT is not associated with increased risk of hypertensive disorders.. · Differences in outcomes of PGT pregnancies may be related to FET rather than trophectoderm biopsy.., Competing Interests: None declared., (Thieme. All rights reserved.)

Importance: Reducing cesarean delivery rates in the US is an important public health goal; despite evidence of the safety of vaginal birth after cesarean delivery, most women have scheduled repeat cesarean deliveries. A decision support tool could help increase trial-of-labor rates., Objective: To analyze the effect of a patient-centered decision support tool on rates of trial of labor and vaginal birth after cesarean delivery and decision quality., Design, Setting, and Participants: Multicenter, randomized, parallel-group clinical trial conducted in Boston, Chicago, and the San Francisco Bay area. A total of 1485 English- or Spanish-speaking women with 1 prior cesarean delivery and no contraindication to trial of labor were enrolled between January 2016 and January 2019; follow-up was completed in June 2019., Interventions: Participants were randomized to use a tablet-based decision support tool prior to 25 weeks' gestation (n=742) or to receive usual care (without the tool) (n=743)., Main Outcomes and Measures: The primary outcome was trial of labor; vaginal birth was the main secondary outcome. Other secondary outcomes focused on maternal and neonatal outcomes and decision quality., Results: Among 1485 patients (mean age, 34.0 [SD, 4.5] years), 1470 (99.0%) completed the trial (n = 735 in both randomization groups) and were included in the analysis. Trial-of-labor rates did not differ significantly between intervention and control groups (43.3% vs 46.2%, respectively; adjusted absolute risk difference, -2.78% [95% CI, -7.80% to 2.25%]; adjusted relative risk, 0.94 [95% CI, 0.84-1.05]). There were no statistically significant differences in vaginal birth rates (31.8% in both groups; adjusted absolute risk difference, -0.04% [95% CI, -4.80% to 4.71%]; adjusted relative risk, 1.00 [95% CI, 0.86-1.16]) or in any of the other 6 clinical maternal and neonatal secondary outcomes. There also were no significant differences between the intervention and control groups in the 5 decision quality measures (eg, mean decisional conflict scores were 17.2 and 17.5, respectively; adjusted mean difference, -0.38 [95% CI, -1.81 to 1.05]; scores >25 are considered clinically important)., Conclusions and Relevance: Among women with 1 previous cesarean delivery, use of a decision support tool compared with usual care did not significantly change the rate of trial of labor. Further research may be needed to assess the efficacy of this tool in other clinical settings or when implemented at other times in pregnancy.

The population with HIV is aging and has unique health needs. We present findings from an evaluation of the geriatric-HIV program, Golden Compass, at San Francisco General Hospital. We used the implementation science framework, RE-AIM ( Reach, Effectiveness, Adoption, Implementation, Maintenance ) to guide the evaluation and used quantitative and qualitative methods to assess RE-AIM dimensions. From January 2017 to June 2018, 198 adults age ≥50 years participated in the program, with an estimated reach of 17%. Providers and patients indicated high acceptability of the program and were satisfied with clinics and classes. Colocation of services, specific pharmacy and geriatric assessments, and social support from classes were valued ( effectiveness ). Provider adoption was high, and the program was implemented as originally designed. Areas for improvement included challenges of framing aging services to patients. Future efforts will focus on expanding the reach of the program and examining long-term outcomes.

Objective: To evaluate the association of patient preferences and attitudes with TOLAC., Study Design: Prospective observational study of TOLAC-eligible women at 26-34 weeks gestation. Preferences (utilities) were elicited using the time trade-off and standard gamble metrics. Logistic regression was used to identify preference- and attitude-based factors associated with TOLAC., Results: Of the 231 participants, most (n = 197, 85%) preferred vaginal delivery, but only 40% (n = 93) underwent TOLAC. Utilities for uterine rupture outcomes did not differ based on delivery approach. In multivariable analysis, strength of preference for vaginal delivery, value for the experience of labor, and the opinion of the person whom the participant thought of as most important to this decision were associated with TOLAC., Conclusions: Future decision support interventions incorporating individualized information regarding the likelihood of vaginal birth and empowering patients to express their preferences and engage their families in the decision-making process may improve decision quality and increase TOLAC rates.

Purpose: Human papillomavirus (HPV) testing is being more widely used in simplified cervical cancer screening protocols in low-resource settings. One challenge to successful implementation is the multiple visits necessary to provide results and follow-up. mHealth strategies may reduce visit burden by providing information through text message., Methods: As part of a cluster-randomized trial to compare HPV testing in clinics and community health campaigns in western Kenya, we carried out a mixed-methods study to assess women's preferences and experiences with different strategies to receive their results. Women could opt to receive their HPV results via text message, cell phone call, home visit, or return clinic visit. We examined overall receipt of results, follow-up rates, and acceptability by notification method., Results: Among the 4,947 women who underwent HPV-based cervical cancer screening, 1,596 (32%) received results via text message, 1,181 (24%) via cell phone call, 1,563 (32%) via clinic visit, and 605 (12%) via home visit. Women opting for texts or calls were younger and had higher rates of prior cervical cancer screening, HIV testing, and modern contraceptive use ( P < .001 for all). Home visits were associated with a significantly higher rate of treatment acquisition (45%) than texts (38%), cell phone calls (38%), and clinic visits (23%; P < .001). In a model controlling for age, prior screening, HIV testing, and contraceptive use, clinic visits remained significantly associated with decreased odds of treatment (adjusted odds ratio, 0.45; 95% CI, 0.29 to 0.69) compared with texts. Among treated women, there was no difference in time to treatment by notification method., Conclusion: Cell phone-based results notification strategies were preferred by women with greater health-seeking behavior; however, HPV-positive women who received results via home visit were more likely to pursue for treatment.

Objective: This article evaluates gender differences in academic rank and National Institutes of Health (NIH) funding among academic maternal-fetal medicine (MFM) physicians., Study Design: This was a cross-sectional study of board-certified academic MFM physicians. Physicians were identified in July 2017 from the MFM fellowship Web sites. Academic rank and receipt of any NIH funding were compared by gender. Data on potential confounders were collected, including years since board certification, region of practice, additional degrees, number of publications, and h-index., Results: We identified 659 MFM physicians at 72 institutions, 312 (47.3%) male and 347 (52.7%) female. There were 246 (37.3%) full, 163 (24.7%) associate, and 250 (37.9%) assistant professors. Among the 154 (23.4%) MFM physicians with NIH funding, 89 (57.8%) were male and 65 (42.2%) were female ( p  = 0.003). Adjusting for potential confounders, male MFM physicians were twice as likely to hold a higher academic rank than female MFM physicians (adjusted odds ratio [aOR], 2.04 [95% confidence interval, 1.39-2.94], p  < 0.001). There was no difference in NIH funding between male and female MFM physicians (aOR, 1.23 [0.79-1.92], p  = 0.36)., Conclusion: Compared with female academic MFM physicians, male academic MFM physicians were twice as likely to hold a higher academic rank but were no more likely to receive NIH funding., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Kenya introduced universal antiretroviral treatment (ART) for pregnant and breastfeeding women living with HIV (Option B+) in 2014. A retrospective study was conducted to review consecutive records for HIV positive pregnant women presenting for antenatal care (ANC) at five clinics in western Kenya. Known positive women (KP :HIV diagnosis prior to current pregnancy) were compared to newly positive (NP) women regarding virologic suppression and retention in care. Among 165 women included, 71 (43%) NP and 94 (57%) KP, NP were younger (24.5 years (SD 4.6) vs. 28.1 years (SD 5.6) compared to KP (p < .001). Almost all NP (97%) were initiated on Option B+ while over half of KP (59%) started ART for clinical/immunological criteria (p < .0001). KPs were more likely than NPs to have a VL performed following Kenyan guidelines (64% vs. 31%; p < .001). Among those tested, virologic suppression was high in both groups (92% KP vs. 100% NP; p = .31). More KPs (82%) vs. NPs (66%) remained active in care at 15-18 months of follow-up (p = .02). Women newly diagnosed with HIV during pregnancy show poorer uptake of VL testing and worse retention in care than those diagnosed prior to pregnancy.

Objective: To examine the relationship between cardiomediastinal shift angle (CMSA) and adverse perinatal outcomes and hydrops in cases of congenital pulmonary airway malformation (CPAM)., Study Design: This retrospective study evaluated CPAM cases referred to our institution from 2008 to 2015. The primary outcome was a composite score for adverse perinatal outcome. CMSA was measured for each case and evaluated for its association with the primary outcome. The prediction accuracy of CMSA for adverse perinatal outcome was assessed using receiver operator characteristic (ROC) curves., Results: Eighteen (21.2%) of the 85 cases experienced an adverse perinatal outcome. Increases in CMSA were associated with adverse perinatal outcomes and hydrops in bivariate analyses. Adjusted analyses found each 10-degree increase in CMSA to be associated with increased odds of an adverse perinatal outcome (adjusted odds ratio [aOR] 2.2, 95% confidence interval [CI]: 1.4-3.3) and hydrops (aOR 3.0, 95% CI: 1.5-6.1). CMSA performed well and was comparable to CPAM volume ratio in predicting adverse perinatal outcomes (area under the curve 0.81 and 0.84, respectively)., Conclusion: We describe a novel measurement of mediastinal shift in cases of CPAM and its relationship with adverse perinatal outcomes and hydrops. These findings may shape the evaluation and management of CPAMs, improve our understanding of their prognosis, and influence patient counseling., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Access to routine virologic monitoring, critical to ensuring treatment success, remains limited in low- and middle-income countries. We report on implementation of routine viral load (VL) monitoring and risk factors for virologic failure among HIV-infected children on antiretroviral treatment (ART) in Western Kenya., Methods: Routine VL testing was introduced in western Kenya in November 2013. We performed a case-control study among 1190 HIV-infected children ≤15 years on ART who underwent routine VL testing June 2014-May 2015. A random sample of 98 cases (virologic failure define as VL >1000 cps/mL) and 201 controls (VL <1000 cps/mL) from five facilities in three high HIV prevalence counties in Kenya were followed for a minimum of 12 months. Data from patient charts were analyzed using logistic regression to determine factors associated with failure to attain virologic suppression at initial routine and subsequent VL testing among cases., Results: Overall, 1190 (94%) children with a median age of 8 years underwent routine VL testing of whom (37%) had virological failure. Among the 299 cases and controls, WHO stage, baseline CD4 count and time since ART initiation were not associated with virologic failure during the follow-up period. In multivariable analysis, unsuppressed children at initial test were more likely to be male (adjusted Odds Ratio (aOR) 2.1, 95% Confidence Interval (CI) 2.1-3.6) and have had an ART regimen change (aOR 2.0, CI 1.0-3.7) than controls. Of the two-thirds of children 201/299 who had a subsequent VL performed, VL suppression was greater among those suppressed at initial test 126/135 (93.3%) compared to children with virologic failure 15/66 (22.7%, p<0.0001). Among those failing at first test who achieved viral suppression in follow up, 12/15 (80%) were on a protease inhibitor (PI)-based regimen. In the multivariable analysis of children with subsequent VL testing, children on PI-based 2nd line regimens were 10-fold more likely to achieve viral suppression than children on first-line NNRTI-based ART (adjusted Odds Ratio [aOR] 0.1; 95%CI 0.0-0.4)., Conclusion: Coverage of initial routine viral load testing among children on ART in western Kenya is high. However, subsequent testing and virologic suppression are low in children with virologic failure on initial routine viral load test. There is an urgent need to improve management and viral load monitoring of children living with HIV experiencing treatment failure to ensure improved long-term outcomes., Competing Interests: The authors have declared that no competing interests exist.

Background: The incidence of cervical cancer in Kenya is among the highest in the world. Few Kenyan women are able to access screening, thus fueling the high cervical cancer burden. Self-collected human papilloma Virus (HPV) tests, administered during community-health campaigns in rural areas may be a way to expand access to screening., Methods: In December 2015, we carried out a four-day community health campaign (CHC) to educate participants about cervical cancer prevention and offer self-administered HPV screening. Community enumeration, outreach and mobilization preceded the CHC. Samples were sent to Migori County Hospital for HPV DNA testing using careHPV Test Kits. Women were notified of results through their choice of short message service (SMS), phone call, home visit or clinic visit. HPV positive women were referred for cryotherapy following a screen-and-treat strategy., Results: Door-to-door enumeration identified approximately 870 eligible women in Ngodhe Community in Migori County. Among the 267 women attending the campaign, 255 women enrolled and collected samples: 243 tests were successfully resulted and 12 were indeterminate. Of the 243 resulted tests, 47 (19%) were positive for HPV, with young age being the only significant predictor of positivity. In multivariate analysis, each additional year of age conferred about a 4% decrease in the odds of testing positive (95% CI 0.1 to 7%, p = 0.046). Just over three-quarters of all women (195/255), were notified of their results. Those who were unable to be reached were more likely to prefer receiving results from clinic (54/60, 90%) and were less likely to have mobile phones (24/60, 73%). Although 76% of HPV positive women were notified of their results, just half (51%) of those testing positive presented for treatment. HPV positive women who successfully accessed the treatment facility did not differ from their non-presenting counterparts by demographics, health history, desired route of notification or access to a mobile phone., Conclusion: Nearly a third of eligible women in Ngodhe Community attended the CHC and were screened for cervical cancer. Nearly all women who attended the CHC underwent cervical cancer screening by self-collected HPV tests. Three-quarters of all participants received results, but just half of HPV positive participants presented for treatment in a timely fashion, suggesting that linkage to treatment remains a major challenge., Trial Registration: NCT02124252 , Registered 25 April 2014.

Objective: To determine the effectiveness of community health campaigns (CHCs) as a strategy for human papillomavirus (HPV)-based cervical cancer screening in rural western Kenya., Methods: Between January and November 2016, a cluster-randomized trial was carried out in 12 communities in western Kenya to investigate high-risk HPV testing offered via self-collection to women aged 25-65 years in CHCs versus government health facilities. Outcome measures were the total number of women accessing cervical cancer screening and the proportion of HPV-positive women accessing treatment., Results: In total, 4944 women underwent HPV-based cervical cancer screening in CHCs (n=2898) or health facilities (n=2046). Screening uptake as a proportion of total eligible women in the population was greater in communities assigned to CHCs (60.0% vs 37.0%, P<0.001). Rates of treatment acquisition were low in both arms (CHCs 39.2%; health facilities 31.5%; P=0.408)., Discussion: Cervical cancer screening using HPV testing of self-collected samples reached a larger proportion of women when offered through periodic CHCs compared with health facilities. The community-based model is a promising strategy for cervical cancer prevention. Lessons learned from this trial can be used to identify ways of maximizing the impact of such strategies through greater community participation and improved linkage to treatment. ClinicalTrials.gov registration: NCT02124252., (© 2017 International Federation of Gynecology and Obstetrics.)

BACKGROUND Prader-Willi syndrome (PWS) is a genetic disorder characterized by initial muscular hypotonia and feeding difficulties, and later an insatiable appetite, hyperphagia and obesity along with mild to moderate intellectual impairment. Affected individuals' food-seeking behavior and suspected delayed gastric emptying can lead to gastric dilatation with subsequent necrosis and perforation. CASE REPORT We present the case of a 5-year-old boy diagnosed with Prader-Willi syndrome at neonatal age due to muscular hypotonia, who started growth hormone therapy at 20 months. He presented with two episodes of a rapidly progressing gastric dilatation that led to abdominal hypertension and secondary shock at the age of 2 and 5. No large amount of food was eaten before any of the episodes, and he had abdominal pain and vomiting on both occasions. On arrival at the emergency room, a nasogastric tube was placed and aspiration of food material was performed. Abdominal X-ray and CT scan revealed massive gastric dilatation. He was admitted at the Pediatric Intensive Care Unit and after a variable period of fasting, tolerated oral intake and could be discharged. CONCLUSIONS Gastric dilatation due to gastroparesis in PWS is a rare complication. However, it is a life-threatening situation and physicians should therefore maintain a high level of suspicion for gastric dilatation when patients present with warning symptoms such as abdominal pain or discomfort and vomiting.

Objectives: To determine if integration of family planning (FP) and HIV services led to increased use of more effective contraception (i.e. hormonal and permanent methods, and intrauterine devices) and decreased pregnancy rates., Design: Cohort analysis following cluster randomized trial, when the Kenya Ministry of Health led integration of the remaining control (delayed integration) sites and oversaw integrated services at the original intervention (early integration) sites., Setting: Eighteen health facilities in Kenya., Subjects: Women aged 18-45 receiving care: 5682 encounters at baseline, and 11628 encounters during the fourth quarter of year 2., Intervention: "One-stop shop" approach to integrating FP and HIV services., Main Outcome Measures: Use of more effective contraceptive methods and incident pregnancy across two years of follow-up., Results: Following integration of FP and HIV services at the six delayed integration clinics, use of more effective contraception increased from 31.7% to 44.2% of encounters (+12.5%; Prevalence ratio (PR) = 1.39 (1.19-1.63). Among the twelve early integration sites, the proportion of encounters at which women used more effective contraceptive methods was sustained from the end of the first to the second year of follow-up (37.5% vs. 37.0%). Pregnancy incidence including all 18 integrated sites in year two declined in comparison to the control arm in year one (rate ratio: 0.72; 95% CI 0.60-0.87)., Conclusions: Integration of FP services into HIV clinics led to a sustained increase in the use of more effective contraceptives and decrease in pregnancy incidence 24 months following implementation of the integrated service model., Trial Registration: ClinicalTrials.gov NCT01001507.

HIV treatment is life-long, yet many patients travel or migrate for their livelihoods, risking treatment interruption. We examine timely reengagement in care among patients who transferred-out or were lost-to-follow-up (LTFU) from a rural HIV facility. We conducted a cohort study among 369 adult patients on antiretroviral therapy between November 2011 and November 2013 on Mfangano Island, Kenya. Patients who transferred or were LTFU (i.e., missed a scheduled appointment by ≥90 days) were traced to determine if they reengaged or accessed care at another clinic. We report cumulative incidence and time to reengagement using Cox proportional hazards models adjusted for patient demographic and clinical characteristics. Among 369 patients at the clinic, 23(6%) requested an official transfer and 78(21%) were LTFU. Among official transfers, cumulative incidence of linkage to their destination facility was 91% at three months (95%CI (confidence intervals) 69-98%). Among LTFU, cumulative incidence of reengagement in care at the original or a new clinic was 14% at three months (95%CI 7-23%) and 60% at six months (95%CI 48-69%). In the adjusted Cox model, patients who left with an official transfer reengaged in care six times faster than those who did not (adjusted hazard ratio 6.2, 95%CI 3.4-11.0). Patients who left an island-based HIV clinic in Kenya with an official transfer letter reengaged in care faster than those who were LTFU, although many in both groups had treatment gaps long enough to risk viral rebound. Better coordination of transfers between clinics, such as assisting patients with navigating the process or improving inter-clinic communication surrounding transfers, may reduce delays in treatment during transfer and improve overall clinical outcomes.

Background. Kenyan antiretroviral (ART) guidelines encourage treatment buddies (TBy) to maximize treatment adherence. This study examined the effect of TBys on clinic attendance in men and women on ART. Methods. This retrospective cohort study included all adult patients initiating ART from August 2007 to December 2011 at four health facilities in Kenya. Data were abstracted from electronic medical records and analyzed using Poisson regression. Results. Of 2,430 patients, 2,199 (91%) had a TBy. Relationship between TBy and clinic attendance differed in females and males (interaction p = 0.09). After demographic and clinic factor adjustment, females with a TBy were 28% more likely to adhere to all appointments than those without (adjusted aRR = 1.28; 95% CI 1.08-1.53), whereas males were no more likely to adhere (aRR = 1.01; 95% CI 0.76-1.32). Males reported partner/spouse (33%) or brother (11%) as the TBy while females reported sister (17%), partner/spouse (14%), or another family member (12%). Multivariable analysis found no association between clinic attendance and TBy relationship in either gender. Conclusion. Clinic attendance was higher among women with TBys but not men. Results support TBys to help women achieve ART success; alternate strategies to bolster TBy benefits are needed for men.

Youth are particularly vulnerable to acquiring HIV, yet reaching them with HIV prevention interventions and engaging and retaining those infected in care and treatment remains a challenge. We sought to determine the incidence rate of loss to follow-up (LTFU) and explore socio-demographic and clinical characteristics associated with LTFU among HIV-positive youth aged 15-21 years accessing outpatient care and treatment clinics in Kisumu, Kenya. Between July 2007 and September 2010, youth were enrolled into two different HIV care and treatment clinics, one youth specific and the other family oriented. An individual was defined as LTFU when absent from the HIV treatment clinic for ≥ 4 months regardless of their antiretroviral treatment status. The incidence rate of LTFU was calculated and Cox regression analysis used to identify factors associated with LTFU. A total of 924 youth (79% female) were enrolled, with a median age of 20 years (IQR 18-21). Over half, (529 (57%)), were documented as LTFU, of whom 139 (26%) were LTFU immediately after enrolment. The overall incidence rate of LTFU was 52.9 per 100 person-years (p-y). Factors associated with LTFU were pregnancy during the study period (crude HR 0.68, 95% CI 0.53-0.89); CD4 cell count >350 (adjusted hazard ratios (AHR) 0.59, 95% CI 0.39-0.90); not being on antiretroviral therapy (AHR 4.0, 95% CI 2.70-5.88); and non-disclosure of HIV infection status (AHR 1.43, 95% CI 1.10-1.89). The clinic of enrolment, age, marital status, employment status, WHO clinical disease stage and education level were not associated with LTFU. Interventions to identify and enrol youth into care earlier, support disclosure, and initiate ART earlier may improve retention of youth and need further investigation. Further research is also needed to explore the reasons for LTFU from care among HIV-infected youth and the true outcomes of these patients.

Background: Concerns have been raised about efavirenz reducing the effectiveness of contraceptive implants. We aimed to establish whether pregnancy rates differ between HIV-positive women who use various contraceptive methods and either efavirenz-based or nevirapine-based antiretroviral therapy (ART) regimens., Methods: We did this retrospective cohort study of HIV-positive women aged 15-45 years enrolled in 19 HIV care facilities supported by Family AIDS Care and Education Services in western Kenya between Jan 1, 2011, and Dec 31, 2013. Our primary outcome was incident pregnancy diagnosed clinically. The primary exposure was a combination of contraceptive method and efavirenz-based or nevirapine-based ART regimen. We used Poisson models, adjusting for repeated measures, and demographic, behavioural, and clinical factors, to compare pregnancy rates among women receiving different contraceptive and ART combinations., Findings: 24,560 women contributed 37,635 years of follow-up with 3337 incident pregnancies. In women using implants, adjusted pregnancy incidence was 1.1 per 100 person-years (95% CI 0.72-1.5) for nevirapine-based ART users and 3.3 per 100 person-years (1.8-4.8) for efavirenz-based ART users (adjusted incidence rate ratio [IRR] 3.0, 95% CI 1.3-4.6). In women using depot medroxyprogesterone acetate, adjusted pregnancy incidence was 4.5 per 100 person-years (95% CI 3.7-5.2) for nevirapine-based ART users and 5.4 per 100 person-years (4.0-6.8) for efavirenz-based ART users (adjusted IRR 1.2, 95% CI 0.91-1.5). Women using other contraceptive methods, except for intrauterine devices and permanent methods, had 3.1-4.1 higher rates of pregnancy than did those using implants, with 1.6-2.8 higher rates in women using efavirenz-based ART., Interpretation: Although HIV-positive women using implants and efavirenz-based ART had a three-times higher risk of contraceptive failure than did those using nevirapine-based ART, these women still had lower contraceptive failure rates than did those receiving all other contraceptive methods except for intrauterine devices and permanent methods. Guidelines for contraceptive and ART combinations should balance the failure rates for each contraceptive method and ART regimen combination against the high effectiveness of implants., Funding: None., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Despite progress in the global scale-up of antiretroviral therapy, sustained engagement in HIV care remains challenging. Social capital is an important factor for sustained engagement, but interventions designed to harness this powerful social force are uncommon., Methods: We conducted a quasiexperimental study evaluating the impact of the Microclinic Social Network intervention on engagement in HIV care and medication adherence on Mfangano Island, Kenya. The intervention was introduced into 1 of 4 similar communities served by this clinic; comparisons were made between communities using an intention-to-treat analysis. Microclinics, composed of patient-defined support networks, participated in 10 biweekly discussion sessions covering topics ranging from HIV biology to group support and group HIV status disclosure. Nevirapine concentrations in hair were measured before and after study., Results: One hundred thirteen (74%) intervention community participants joined a microclinic group, 86% of whom participated in group HIV status disclosure. Over 22-month follow-up, intervention community participants experienced one-half the rate of ≥ 90-day clinic absence as those in control communities (adjusted hazard ratio: 0.48; 95% confidence interval: 0.25 to 0.92). Nevirapine hair levels declined in both study arms; in adjusted linear regression analysis, the decline was 6.7 ng/mg less severe in the intervention arm than control arm (95% confidence interval: -2.7 to 16.1)., Conclusions: The microclinic intervention is a promising and feasible community-based strategy to improve long-term engagement in HIV care and possibly medication adherence. Reducing treatment interruptions using a social network approach has important implications for individual patient virologic suppression, morbidity, and mortality and for broader community empowerment and engagement in healthcare.

Objective: To determine if a health talk on family planning (FP) by community clinic health assistants (CCHAs) will improve knowledge, attitudes and behavioral intentions about contraception in HIV-infected individuals., Methods: A 15-min FP health talk was given by CCHAs in six rural HIV clinics to a sample of 49 HIV-infected men and women. Effects of the health talk were assessed through a questionnaire administered before the health talk and after completion of the participant's clinic visit., Results: Following the health talk, there was a significant increase in knowledge about contraceptives (p<.0001), side-effects (p<.0001), and method-specific knowledge about IUCDs (p<.001), implants (p<.0001), and injectables (p<.05). Out of 31 women and 18 men enrolled, 14 (45%) women and 6 (33%) men intended to try a new contraceptive. Participant attitudes toward FP were high before and after the health talk (median 4 of 4)., Conclusion: A health talk delivered by CCHAs can increase knowledge of contraception and promote the intention to try new more effective contraception among HIV-infected individuals., Practice Implications: FP health talks administered by lay-health providers to HIV-infected individuals as they wait for HIV services can influence FP knowledge and intention to use FP., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Effective strategies to identify and screen children at risk for HIV are needed. The objectives of this study were to evaluate the utilization of a family information table (FIT) to identify and test at-risk children in Kenya and identify factors associated with child testing., Methods: A cross-sectional study was conducted among HIV-infected adults with children at five Kenyan clinics. HIV testing status for children aged ≤18 years was gathered from the patients' FITs and compared to reports from in-person clinic visits as the gold standard. Generalized estimating equations were used to assess predictors for HIV testing of children adjusted for confounders and within parent correlation., Results: Our sample included 384 HIV-infected adults enrolled in care with 933 reported children. Overall, 323 FITs (84%) correctly listed all children in the family and 340 (89%) documented an HIV testing status (including untested) for all children. Seventy-five percent of parents verbally reported all children tested, compared to only 46% of FITs (OR=13.5, 95% CI 6.5-27.8). Verbal reports identified 739 (79%) children tested, with 55 (7.4%) HIV-positive and 17 (2.3%) HIV-exposed infants (HEI). Of 63 adults with HIV-positive children or HEI, 60 (95%) reported enrolling children into care. Likelihood that children had been tested was higher for younger children (≤4y vs. > 4y, aOR=2.0; 95% CI 1.4-2.9) and lower if the partner's serostatus was unknown vs. seropositive (aOR=0.3; 95% CI: 0.1-0.8)., Conclusions: Although the FIT may be a useful tool to identify children at risk for HIV, this study found underutilization by providers. To maximize impact of this tool, documentation of follow-up for untested and positive children is essential., Global Health Implications: Through early documentation of at-risk children and follow up of untested and infected children, the FIT may serve as an effective resource for improving HIV testing and linkage to care.

Objective: To evaluate whether HIV-infected women and men in HIV care and not using highly effective methods of contraception thought they would be more likely to use contraception if it were available at the HIV clinic., Methods: A face-to-face survey assessing family-planning knowledge, attitudes, and practices was conducted among 976 HIV-infected women and men at 18 public-sector HIV clinics in Nyanza, Kenya. Data were analyzed using logistic regression and generalized estimating equations., Results: The majority of women (73%) and men (71%) thought that they or their partner would be more likely to use family planning if it were offered at the HIV clinic. In multivariable analysis, women who reported making family-planning decisions with their partner (adjusted odds ratio [aOR] 3.22; 95% confidence interval [CI], 1.53-6.80) and women aged 18-25 years who were not currently using family planning (aOR 4.76; 95% CI, 2.28-9.95) were more likely to think they would use contraception if integrated services were available. Women who perceived themselves to be infertile (aOR 0.07; 95% CI, 0.02-0.31) and had access to a cell phone (aOR 0.40; 95% CI, 0.25-0.63) were less likely to think that integrated services would change their contraceptive use. Men who were not taking antiretroviral medications (aOR 3.30; 95% CI, 1.49-7.29) were more likely, and men who were unsure of their partner's desired number of children (aOR 0.36; 95% CI, 0.17-0.76), were not currently using family planning (aOR 0.40; 95% CI, 0.22-0.73), and were living in a peri-urban setting (aOR 0.46; 95% CI, 0.21-0.99) were less likely to think their partner would use contraception if available at the HIV clinic., Conclusions: Integrating family planning into HIV care would probably have a broad impact on the majority of women and men accessing HIV care and treatment. Integrated services would offer the opportunity to involve men more actively in the contraceptive decision-making process, potentially addressing 2 barriers to family planning: access to contraception and partner uncertainty or opposition., (© 2013.)

Objective: To determine whether integrating family planning services into HIV care is associated with increased use of more effective contraceptive methods (sterilization, intrauterine device, implant, injectable or oral contraceptives)., Design: Cluster-randomized trial., Setting: Eighteen public HIV clinics in Nyanza Province, Kenya., Participants: Women aged 18-45 years receiving care at participating HIV clinics; 5682 clinical encounters from baseline period (December 2009-February 2010) and 12,531 encounters from end-line period (July 2011-September 2011, 1 year after site training)., Intervention: Twelve sites were randomized to integrate family planning services into the HIV clinic, whereas six clinics were controls where clients desiring contraception were referred to family planning clinics at the same facility., Main Outcome Measures: Increase in use of more effective contraceptive methods between baseline and end-line periods. Pregnancy rates during the follow-up year (October 2010-September 2011) were also compared., Results: Women seen at integrated sites were significantly more likely to use more effective contraceptive methods at the end of the study [increased from 16.7 to 36.6% at integrated sites, compared to increase from 21.1 to 29.8% at controls; odds ratio (OR) 1.81, 95% confidence interval (CI) 1.24-2.63]. Condom use decreased non-significantly at intervention sites compared to controls (OR 0.64, 95% CI 0.35-1.19). No difference was observed in incident pregnancy in the first year after integration comparing intervention to control sites (incidence rate ratio 0.90; 95% CI 0.68-1.20)., Conclusions: Integration of family planning services into HIV care clinics increased use of more effective contraceptive methods with a non-significant reduction in condom use. Although no significant reduction in pregnancy incidence was observed during the study, 1 year may be too short a period of observation for this outcome.

Objective: To evaluate costs, cost-efficiency and cost-effectiveness of integration of family planning into HIV services., Intervention: Integration of family planning services into HIV care and treatment clinics., Design: A cluster-randomized trial., Setting: Twelve health facilities in Nyanza, Kenya were randomized to integrate family planning into HIV care and treatment; six health facilities were randomized to (nonintegrated) standard-of-care with separately delivered family planning and HIV services., Main Outcome Measures: We assessed costs, cost-efficiency (cost per additional use of more effective family planning), and cost-effectiveness (cost per pregnancy averted) associated with the first year of integration of family planning into HIV care. More effective family planning methods included oral and injectable contraceptives, subdermal implants, intrauterine device, and female and male sterilization., Patients and Participants: We collected cost data through interviews with study staff and review of financial records to determine costs of service integration., Results: Integration of services was associated with an average marginal cost of $841 per site and $48 per female patient. Average overall and marginal costs of integration were associated with personnel costs [initial ($1003 vs. $872) and refresher ($498 vs. $330) training, mentoring ($1175 vs. $902) and supervision ($1694 vs. $1636)], with fewer resources required for other fixed ($18 vs. $0) and recurring expenses ($471 vs. $287). Integration was associated with a marginal cost of $65 for each additional use of more effective family planning and $1368 for each pregnancy averted., Conclusion: Integration of family planning and HIV services is feasible, inexpensive to implement, and cost-efficient in the Kenyan setting, and thus supports current Kenyan integration policy.

The vulnerability of neurons and the irreversibility of loss make discoveries of neuroprotective compounds fundamentally important. Here, the complete coding sequence of a novel protein (828 amino acids, pI 5.99), derived from mouse neuroglial cells, is revealed. The sequence contained (1) a neuroprotective peptide, NAPVSIPQ, sharing structural and immunological homologies with the previously reported, activity-dependent neurotrophic factor; (2) a glutaredoxin active site; and (3) a zinc binding domain. Gene expression was enriched in the mouse hippocampus and cerebellum and augmented in the presence of the neuropeptide vasoactive intestinal peptide, in cerebral cortical astrocytes. In mixed neuron-astrocyte cultures, NAPVSIPQ provided neuroprotection at subfemtomolar concentrations against toxicity associated with tetrodotoxin (electrical blockade), the beta-amyloid peptide (the Alzheimer's disease neurotoxin), N-methyl-D-aspartate (excitotoxicity), and the human immunodeficiency virus envelope protein. Daily NAPVSIPQ injections to newborn apolipoprotein E-deficient mice accelerated the acquisition of developmental reflexes and prevented short-term memory deficits. Comparative studies suggested that NAPVSIPQ was more efficacious than other neuroprotective peptides in the apolipoprotein E-deficiency model. A potential basis for rational drug design against neurodegeneration is suggested with NAPVSIPQ as a lead compound. The relative enrichment of the novel mRNA transcripts in the brain and the increases found in the presence of vasoactive intestinal peptide, an established neuroprotective substance, imply a role for the cloned protein in neuronal function.

Up until now the phenomenon of density dependent inhibition of growth has remained unexplained; one hypothesis suggests that autocrine growth inhibitory molecules are secreted in the medium of dense cultures and inhibit cell growth. From medium conditioned by mouse fibroblasts we purified a 45-kDa inhibitory factor which is an insulin-like growth factor binding protein (IGFBP-3). Based on different results we assumed that IGFBP-3 is a bifunctional molecule and has inhibitory function independent of its known function of binding IGF. In the present publication we attempted to verify whether IGFBP-3 is involved in DDI of growth. IGFBP-3 was secreted by mouse embryo fibroblasts (MEF). Its concentration in the medium increased with the cell density of the culture and was large at saturation density when DNA synthesis was minimum. Medium conditioned (CM) by dense culture was inhibitory compared to fresh medium and this inhibition disappeared when CM was preincubated with anti-IGFBP-3 IgG. Addition of FGFb to MEF dense cultures increased but transiently DNA synthesis which decreased as soon as 24 h after growth factor addition. By contrast accumulation of IGFBP-3 in the medium increased with time and was large at the time when DNA synthesis was minimum. Our results suggest that the rapid decrease of DNA synthesis in stimulated dense culture was the result of both depletion of the medium (particularly of FGFb) and the increase in concentration of inhibitory molecules like IGFBP-3. Addition of FGFb and preincubation of CM with anti-IGFBP-3 IgG were able to greatly reduce the inhibition.

IGF Binding Protein-3 (IGFBP-3), the major IGF carrier in the blood, undergoes limited proteolysis which reduces its affinity for IGFs, thus facilitating dissociation. The functional effects of this at the cellular level were studied by comparing two serum pools, one from healthy adults, one from women during late pregnancy when IGFBP-3 proteolysis is increased. Sera were mixed to yield identical IGF-I and IGF-II concentrations in the two pools. Western ligand and immunoblotting gave the characteristic IGFBP patterns for the two types of serum. Both pools dose-dependently stimulated DNA synthesis in cultured chick embryo fibroblasts. Stimulation by pregnancy serum was twice that by normal serum at 0.05-0.2% concentrations (P < 0.001). In the presence of excess monoclonal anti-IGF-I and -II antibodies, stimulation by both (0.1-0.2%) pools was 70-80% reduced and residual stimulation was similar. Addition of recombinant human (rh) IGFBP-3 dose-dependently depressed both pools' activity, more so for normal serum at 25 and 50 ng/ml, equally for each at 100 ng/ml. At the latter concentration, slight proteolysis of the rhIGFBP-3 was detectable in the presence of 0.2% pregnancy serum, but at 25 ng/ml, proteolysis was absent. These results suggest that IGFs are released more readily from pregnancy serum, accounting for the weaker inhibitory effect of low rhIGFBP-3 concentrations. For identical IGF concentrations, pregnancy serum's greater biological activity therefore reflects greater IGF availability to the cells. This study demonstrates the functional consequences at cellular level of serum IGFBP-3 proteolysis, underlining its significance in regulating serum IGF bioavailability.

Insulin-like growth factor binding proteins 1 and 3 are essentially known as regulators of IGF bioactivity. However, we previously showed that IGFBP-3 was able, in chick embryo fibroblast (CEF), to 100% inhibit DNA synthesis stimulated by calf serum, while the maximal inhibition found with IGFBP-1 was 60%, suggesting a difference between the two IGFBPs in their biological functions. Results of the present work agree with this assumption: (a) Recombinant human IGFBP-3, like rat IGFBP-3, was able to 100% inhibit DNA synthesis stimulation induced by human serum, while this stimulation was 75% decreased by IGFBP-1. However, the most striking difference was observed when the effects of the two IGFBPs were compared for stimulation induced by a serum growth factor (SGF) fraction depleted in IGFs. Stimulation induced by the SFG fraction was more significantly decreased (p < 0.001) by IGFBP-3 than by IGFBP-1. The mean percent inhibition +/- SEM was 67.1 +/- 2.5 in the presence of IGFBP-3 (200 ng/ml) and 29.3 +/- 2.7 and 34.2 +/- 4 in the presence of 200 and 400 ng/ml IGFBP-1 respectively. Inhibition by 200 ng/ml IGFBP-1 and inhibition by 6 ng/ml IGFBP-3 were additive. However, inhibition by IGFBP-3 and that by IGFBP-1 were no longer additive at high concentrations of IGFBP-3, which might thus replace IGFBP-1. (b) FGF stimulation of CEF was similarly inhibition (65% and 70%) by IGFBP-1 and IGFBP-3. (c) TGF beta stimulation of CEF was more strongly decreased by IGFBP-3 (90%) than by IGFB-1 (60%).(ABSTRACT TRUNCATED AT 250 WORDS)

Deregulation of growth in malignant cells has been suggested to be the result of increased secretion by these cells, of autocrine growth factors; alternatively, this deregulation has been assumed to be related to loss of sensitivity by malignant cells to secreted inhibitory molecules. The results of the present publication lend new support to both hypotheses. We recently showed that human prostate adenocarcinoma cells (PC-3 cells) secreted insulin-like growth factor binding proteins (IGFBP) of 45, 34 and 25 kDa. From medium conditioned by dense cultures of PC-3 cells, we have now purified two IGFBPs of M(r) 45 kDa and 34 kDa. The N-amino terminal sequences were determined, and it was shown that they are IGFBP-3. IGFBP-34 appeared to be a deglycosylated form of IGFBP-45. The two IGFBPs had more affinity for IGF-II than for IGF-I. IGFBP-45 and IGFBP-34 were growth-inhibitory factors of chick embryo fibroblasts (CEF): they totally inhibited DNA synthesis stimulated by serum in CEF. Our results point to a clear difference between the effects of these IGFBPs upon growth of normal prostate cells and malignant PC-3 cells. At a concentration of 150 ng/ml, they inhibited growth of normal prostate cells even in the presence of 1 microgram/ml insulin. This suggests that such inhibition was not simply the result of a decrease by the IGFBP of stimulation induced by serum IGF or IGF secreted by the cells. At a concentration of 150 ng/ml, IGFBP did not modify the growth of PC-3 cells. In contrast, it stimulated growth of PC-3 cells when added at a concentration lower than 50 ng/ml (about 1 nM). Our results thus provide new insight concerning the regulation of growth in PC-3 cells.

Our results show that an insulin-like growth factor binding protein, IGFBP-3, purified from rat serum, is an inhibitor of chick embryo fibroblast (CEF) growth. It abolished DNA synthesis in CEF stimulated by IGF-I as well as by human serum. Rat IGFBP-3 and IDF45 (an inhibitory diffusible factor secreted by mouse cells) had the same activities, confirming that they have an intrinsic capacity to inhibit serum stimulation and may be considered as growth inhibitors. Our data show that inhibition by IGFBP-3 of serum stimulation was not simply the result of its inhibition of IGF present in the serum: 1) While anti-IGF-I IgG was able to completely inhibit stimulation induced by added IGF-I, it did not decrease stimulation induced by 1% human serum. Anti-IGF-II IgG inhibited the stimulation induced by added IGF-II, but only 25% decreased the stimulation induced by 0.7% serum. The percent inhibition was not significantly increased when the concentration of serum was decreased to 0.2%, which induced 140% stimulation of DNA synthesis; 2) stimulation by 0.2% serum was much more inhibited by IGFBP-3 than by IgG anti IGF-II; 3) after separation of IGF-I and IGF-II from serum by chromatography of acidified serum proteins on BioGel P150, the remaining serum proteins (with a molecular mass greater than 45 kDa) which were depleted in IGF-I and -II (verified by RIA determination) still stimulated DNA synthesis, and this stimulation was 80% inhibited by IGFBP-3.

From medium conditioned by 3T3 cells, we had previously purified an inhibitory factor of Mr 45 kDa which we termed IDF45 (inhibitory diffusible factor). The protein was able to 100% inhibit stimulation induced in CEF by 1% calf serum and to reversibly prevent cell growth. We then demonstrated that IDF45 was an IGF-binding protein. Our results suggested that IDF45 was a bifunctional molecule able to bind IGF and to inhibit DNA synthesis stimulated by this hormone, but also to inhibit stimulation of DNA synthesis induced by another growth factor in serum. Indeed, its N terminal amino acid sequence has great homology with that of IGFBP-3 and IDF45 is now proposed to be named IGFBP-3 (mouse IGF binding protein). Present results show that Ha-ras transfected 3T3 cells (EJ cells), like 3T3 cells, secrete a mIGFBP-3 molecule. In addition, transfected cells secrete a doublet of an IGF-binding protein (IGFBP-28) of Mr 28 kDa which is not secreted by untransformed 3T3 cells. IGFBP-28 has been purified and characterized in this work. Various results suggest that IGFBP-28 is not a degradation product of mIGFBP-3. Its N terminal amino acid sequence was different from that of mIGFBP-3. IGFBP-28 inhibited DNA synthesis stimulated by IGF-I, but much more IGFBP-28 protein than mIGFBP-3 was required to prevent this stimulation. In agreement with this result, IGFBP-28 has low affinity for IGF-I. In contrast, IGFBP-28 has high affinity for IGF-II. Like mIGFBP-3, IGFBP-28 was able to inhibit the stimulation induced by serum in CEF and to reversibly prevent growth, though with a specific activity lower than that of mIGFBP-3. It has also the capacity to inhibit stimulation of DNA synthesis induced by high molecular weight serum proteins depleted in IGF-I and II. In conclusion we have shown that transformation of 3T3 cells with Ha-ras induced the synthesis of a new IGF binding protein in medium conditioned by normal 3T3 cells. Our results suggest that IGFBP-28 like mIGFBP-3 is a bifunctional protein able to inhibit stimulation induced by IGF and by serum proteins different from IGFs.

Our results show that stimulation by serum of dense cultures of 3T3 cells rapidly induced increased synthesis of a growth inhibitor (mIGFBP-3) capable of binding IGF. mIGFBP-3 was secreted by stimulated cells immediately after its synthesis, and accumulated in the medium. Accumulation of mIGFBP-3 in the medium increased, as a function of growth factor (bFGF, PDGF, insulin) concentrations and time. bFGF was the best stimulatory factor for both DNA synthesis and accumulation of mIGFBP-3 in the first 24 h of incubation. DNA synthesis was arrested after 48 h of incubation with bFGF when accumulation of mIGFBP-3 was maximal. Since we showed that mIGFBP-3 is able to inhibit bFGF stimulation of DNA synthesis in mouse fibroblasts, it is possible that the accumulation of mIGFBP-3 induces a feedback regulation of cell growth.

We purified to homogeneity a growth inhibiting diffusible factor (IDF45) secreted by dense cultures of mouse 3T3 cells and which was able to inhibit 100% of DNA synthesis stimulated by serum in chick embryo fibroblasts (CEF) (Blat et al., 1989a). We then demonstrated that this factor was an IGF-binding protein (Blat et al., 1989b). Indeed, its N-terminal amino acid sequence was homologous to that of rat IGFBP-3. Our present results show that basic fibroblast growth factor (bFGF) induced, respectively, a fivefold and threefold increase in DNA synthesis in mouse embryo fibroblasts (MEF) and CEF. IDF-45 inhibited the stimulation induced by bFGF by about 65%, while stimulation induced by insulin, PDGF, or EGF was only weakly or not at all inhibited by IDF45. When bFGF stimulation was determined in the presence of a high concentration of insulin in conditions which minimize the effect of endogenous IGF-I or -II, this stimulation was decreased by about 50% in the presence of IDF45. This result suggests that addition of bFGF stimulates IGF secretion, thereby resulting in partial loss of inhibition, by IDF45, of bFGF stimulation.