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Abstract Background and aims Refugees are at higher risk for hepatitis B (HBV) and hepatitis C (HCV), but often face unique healthcare barriers to vaccination, testing, and treatment. This scoping review aimed to identify and characterize HBV and HCV prevention and care services serving refugee populations globally. Methods A literature search was conducted on Embase, Cochrane, and PubMed databases. Research studies published in English between January 2010 to July 2022 describing an HBV or HCV prevention, testing, or treatment intervention for refugees were included. Results There were a total of 69 articles reporting viral hepatitis prevalence, implementation of services, or economic modelling. Of the 38 implementation studies, 14 were stand-alone HBV and/or HCV interventions, while 24 studies included HBV and/or HCV in an intervention targeting multiple infectious diseases and/or parasitic infections. Interventions commonly included a testing (n = 30) or referral (n = 24) component. Frequently reported features to promote program accessibility included bilingual services (n = 25), community partnerships (n = 21), and multidisciplinary staff members (n = 18), such as cultural and/or linguistic mediators, community health workers, community health leaders, lay health workers, local health staff, members of the refugee community, and social workers. The most commonly reported challenge was the transience of refugees (n = 5). Twenty studies noted funding sources, of which twelve reported governmental funding (not including national health insurance) and eight reported that refugees received national health insurance. Conclusions This is the first scoping review to characterize the types of hepatitis prevention, screening, and treatment interventions serving refugee populations globally. Published experiences of HBV and HCV services for refugee populations remain limited. Additional efforts are needed to disseminate models of hepatitis interventions for refugees to ensure access to care for this key population. To achieve hepatitis elimination globally, best practices must be identified and shared to expand access to hepatitis services for refugee populations.

This article details a correction to: Klassen, S.L., Okello, E., Ferrer, J.M.E., Alizadeh, F., Barango, P., Chillo, P., Chimalizeni, Y., Dagnaw, W.W., Eiselé, J.-L., Eberly, L., Gomanju, A., Gupta, N., Koirala, B., Kpodonu, J., Kwan, G.F., Mailosi, B.G.D., Mbau, L., Mutagaywa, R., Pfaff, C., Piñero, D., Pinto, F., Rusingiza, E., Sanni, U.A., Sanyahumbi, A., Shakya, U., Sharma, S.K., Sherpa, K., Sinabulya, I., Wroe, E.B., Bukhman, G. and Mocumbi, A. (2024) ‘Decentralization and Integration of Advanced Cardiac Care for the World’s Poorest Billion Through the PEN-Plus Strategy for Severe Chronic Non-Communicable Disease’, Global Heart. 2024; 19(1): 33. Available at: https://doi.org/10.5334/gh.1313.

Introduction The Package of Essential Noncommunicable Disease Interventions—Plus (PEN-Plus) is a strategy decentralising care for severe non-communicable diseases (NCDs) including type 1 diabetes, rheumatic heart disease and sickle cell disease, to increase access to care. In the PEN-Plus model, mid-level clinicians in intermediary facilities in low and lower middle income countries are trained to provide integrated care for conditions where services traditionally were only available at tertiary referral facilities. For the upcoming phase of activities, 18 first-level hospitals in 9 countries and 1 state in India were selected for PEN-Plus expansion and will treat a variety of severe NCDs. Over 3 years, the countries and state are expected to: (1) establish PEN-Plus clinics in one or two district hospitals, (2) support these clinics to mature into training sites in preparation for national or state-level scale-up, and (3) work with the national or state-level stakeholders to describe, measure and advocate for PEN-Plus to support development of a national operational plan for scale-up.Methods and analysis Guided by Proctor outcomes for implementation research, we are conducting a mixed-method evaluation consisting of 10 components to understand outcomes in clinical implementation, training and policy development. Data will be collected through a mix of quantitative surveys, routine reporting, routine clinical data and qualitative interviews.Ethics and dissemination This protocol has been considered exempt or covered by central and local institutional review boards. Findings will be disseminated throughout the project’s course, including through quarterly M&E discussions, semiannual formative assessments, dashboard mapping of progress, quarterly newsletters, regular feedback loops with national stakeholders and publication in peer-reviewed journals.

Rheumatic and congenital heart disease, cardiomyopathies, and hypertensive heart disease are major causes of suffering and death in low- and lower middle-income countries (LLMICs), where the world’s poorest billion people reside. Advanced cardiac care in these counties is still predominantly provided by specialists at urban tertiary centers, and is largely inaccessible to the rural poor. This situation is due to critical shortages in diagnostics, medications, and trained healthcare workers. The Package of Essential NCD Interventions – Plus (PEN-Plus) is an integrated care model for severe chronic noncommunicable diseases (NCDs) that aims to decentralize services and increase access. PEN-Plus strategies are being initiated by a growing number of LLMICs. We describe how PEN-Plus addresses the need for advanced cardiac care and discuss how a global group of cardiac organizations are working through the PEN-Plus Cardiac expert group to promote a shared operational strategy for management of severe cardiac disease in high-poverty settings.

Iatrogenic retention of surgical drains following drain entrapment and breakage is a never event and a preventable complication. The traditional approach for removing a fractured drain from the intra-peritoneal cavity involves exploratory laparotomy. However, over the last few decades, minimal access surgery has been a more popular retrieval method for retained surgical items from peritoneal and extraperitoneal cavities. We report a case of a 32-year-old woman with a fractured pelvic drain post-caesarean section. Postoperatively, the patient developed the signs of infection and features of bowel obstruction. The mechanical obstruction was ruled out by computed tomography scan. Multiple attempts were made to pull the pelvic drain out but the tube snapped, leaving about a quarter of its length. The drain remnant was retrieved using a non-invasive, inexpensive interventional radiology technique. We could not find any such report in the literature describing this innovative approach for retrieving a fractured pelvic drain.

The current burden of Hepatitis C virus infection and the availability of HCV-related services in Ghana are not well described. Previous estimates on HCV seroprevalence in the country are outdated. This study investigated the HCV seroprevalence and testing and treatment capacity in Ghana. A multi-centre cross-sectional study was conducted in which laboratory and blood bank registers from 17 public healthcare institutions in Ghana were reviewed. A survey on cost and availability of HCV-related testing and treatment was also performed. Crude and pooled estimates of HCV seroprevalence, frequency and median cost of available diagnostic tests and medicines were described. The crude HCV seroprevalence was 2.62% (95% CI 2.53-2.72) and the pooled estimate was 4.58% (95% CI 4.06-5.11) among 103,609 persons tested in laboratories. Age (OR 1.02 95% CI 1.01-1.02) and male sex (OR 1.26 95% CI 1.08-1.48) were predictors of a positive anti-HCV RDT test. Northern administrative regions in Ghana had the highest HCV seroprevalence ranging from 8.3-14.4%. Among 55, 458 potential blood donors, crude HCV seroprevalence was 3.57% (95% CI 3.42-3.72). Testing was through Rapid Diagnostic Test (RDT) kits in most facilities, and only 2 of 17 centres were performing HCV RNA testing. The median cost of an anti-HCV RDT test was $0.97 (0-1.61) and $3.23 (1.61-7.58) for persons with and without government health insurance respectively. The median cost of a 12-week course of the pan-genotypic direct-acting antiviral therapy sofosbuvir-daclatasvir was $887.70. In conclusion, there are significant regional differences in HCV burden across Ghana. Limited access to and cost of HCV RNA and DAA therapy hinders testing and treatment capability, and consequently HCV elimination efforts. A national HCV program supported with a sustainable financing plan is required to accelerate HCV elimination in Ghana.

Summary: Background: There has been increasing awareness about the importance of type 1 diabetes (T1D) globally. Diabetic ketoacidosis (DKA) is a life-threatening complication of T1D in low-income settings. Little is known about health system capacity to manage DKA in low- and lower-middle income countries (LLMICs). As such, we describe health system capacity to diagnose and manage DKA across nine LLMICs using data from Service Provision Assessments. Methods: In this cross-sectional study, we used data from Service Provision Assessment (SPA) surveys, which are part of the Demographic and Health Survey (DHS) Program. We defined an item set to diagnose and manage DKA in higher-level (tertiary or secondary) facilities, and a set to assess and refer patients presenting to lower-level (primary) facilities. We quantified each item's availability by service level in Bangladesh (Survey 1: May 22 2014–Jul 20 2014; Survey 2: Jul 2017–Oct 2017), the Democratic Republic of the Congo (DRC) (Oct 16 2017–Nov 24 2017 in Kinshasha; Aug 08 2018–Apr 20 2018 in rest of country), Haiti (Survey 1: Mar 05 2013–Jul 2013; Survey 2: Dec 16 2017–May 09 2018), Ethiopia (Feb 06 2014–Mar 09 2014), Malawi (Phase 1: Jun 11 2013–Aug 20 2013; Phase 2: Nov 13 2013–Feb 7 2014), Nepal (Phase 1: Apr 20 2015–Apr 25 2015; Phase 2: Jun 04 2015–Nov 05 2015), Senegal (Survey 1: Jan 2014–Oct 2014; Survey 2: Feb 09 2015–Nov 10 2015; Survey 3: Feb 2016–Nov 2016; Survey 4: Mar 13 2017–Dec 15 2017; Survey 5: Apr 15 2018–Dec 31 2018; Survey 6: Apr 15 2019–Feb 28 2020), Tanzania (Oct 20 2014–Feb 21 2015), and Afghanistan (Nov 1 2018–Jan 20 2019). Variation in secondary facilities’ capacity and trends over time were also explored. Findings: We examined data from 2028 higher-level and 7534 lower-level facilities. Of these, 1874 higher-level and 6636 lower-level facilities’ data were eligible for analysis. Availability of all item sets were low at higher-level facilities, where less than 50% had the minimal set of supplies, less than 20% had the full minimal set, and less than 15% had the ideal set needed to diagnose and manage DKA. Across countries in lower-level facilities, less than 14% had the minimal set of supplies and less than 9% the full set of supplies for diagnosis and transfer of DKA patients. No country had more than 20% of facilities with the minimal set of items needed to assess or manage DKA. Where data were available for more than one survey (Bangladesh, Senegal, and Haiti), changes in availability of the minimal set and ideal set of items did not exceed 15%. Tertiary facilities performed best in Haiti, Ethiopia, Malawi, Nepal, Senegal, Tanzania, and Afghanistan. Secondary facilities that were rural, public, and had fewer staff had lower capacity. Interpretation: Health system capacity to manage DKA was low across these nine LLMICs. Although efforts are underway to strengthen health systems, a specific focus on DKA management is still needed. Funding: Leona M. and Harry B. Helmsley Charitable Trust, and Juvenile Diabetes Research Foundation Ltd.

Abstract Background Antimicrobial resistance is a global health emergency. Persons colonized with multidrug-resistant organisms (MDROs) are at risk for developing subsequent multidrug-resistant infections, as colonization represents an important precursor to invasive infection. Despite reports documenting the worldwide dissemination of MDROs, fundamental questions remain regarding the burden of resistance, metrics to measure prevalence, and determinants of spread. We describe a multi-site colonization survey protocol that aims to quantify the population-based prevalence and associated risk factors for colonization with high-threat MDROs among community dwelling participants and patients admitted to hospitals within a defined population-catchment area. Methods Researchers in five countries (Bangladesh, Chile, Guatemala, Kenya, and India) will conduct a cross-sectional, population-based prevalence survey consisting of a risk factor questionnaire and collection of specimens to evaluate colonization with three high-threat MDROs: extended-spectrum cephalosporin-resistant Enterobacteriaceae (ESCrE), carbapenem-resistant Enterobacteriaceae (CRE), and methicillin-resistant Staphylococcus aureus (MRSA). Healthy adults residing in a household within the sampling area will be enrolled in addition to eligible hospitalized adults. Colonizing isolates of these MDROs will be compared by multilocus sequence typing (MLST) to routinely collected invasive clinical isolates, where available, to determine potential pathogenicity. A colonizing MDRO isolate will be categorized as potentially pathogenic if the MLST pattern of the colonizing isolate matches the MLST pattern of an invasive clinical isolate. The outcomes of this study will be estimates of the population-based prevalence of colonization with ESCrE, CRE, and MRSA; determination of the proportion of colonizing ESCrE, CRE, and MRSA with pathogenic characteristics based on MLST; identification of factors independently associated with ESCrE, CRE, and MRSA colonization; and creation an archive of ESCrE, CRE, and MRSA isolates for future study. Discussion This is the first study to use a common protocol to evaluate population-based prevalence and risk factors associated with MDRO colonization among community-dwelling and hospitalized adults in multiple countries with diverse epidemiological conditions, including low- and middle-income settings. The results will be used to better describe the global epidemiology of MDROs and guide the development of mitigation strategies in both community and healthcare settings. These standardized baseline surveys can also inform future studies seeking to further characterize MDRO epidemiology globally.

Direct‐acting antivirals for hepatitis C virus (HCV) are highly effective and well‐tolerated. However, only a small percentage of HCV‐infected individuals globally have received therapy. Reducing the complexity of monitoring during HCV therapy, if shown to be safe, could facilitate greater access to HCV services, particularly in resource‐limited settings such as sub‐Saharan Africa. We enrolled a total of 300 patients who were chronically infected with genotype 4 HCV in Rwanda and treated them with fixed‐dose ledispasvir/sofosbuvir for 12 weeks. For 60 consecutive participants enrolled, we blinded the study clinician to on‐treatment laboratory results. We compared the efficacy, safety, and tolerability in those with blinded laboratory results to those with standard laboratory monitoring. Baseline characteristics among those with blinded laboratory values were comparable to those with standard monitoring. Among both groups, the median age was 63 years, and the median HCV viral load was 5.9 log (versus 64 years and 6.0 log, respectively). Sustained virologic response rates at 12 weeks after treatment completion were similar in those with blinded laboratories (87%) compared to those with standard laboratory monitoring (87%). There was no increase in adverse events in those with blinded laboratory results, and no participants discontinued the study medication because of an adverse event. Conclusion: On‐treatment laboratory monitoring did not improve patient outcomes in those treated with ledispasvir/sofosbuvir. Eliminating this monitoring in treatment programs in resource‐limited settings may facilitate and accelerate scale‐up of HCV therapy.

Abstract Background The epidemiology and risk factors for hepatitis C virus (HCV) infection in Rwanda are not well known; however, this information is crucial to shaping the country’s public health approach to hepatitis C control. Methods A HCV screening campaign was conducted in the general population in 24 districts previously identified to have a high HCV disease burden. At the time of sample collection, sociodemographic information and self-reported risk factors were collected. Bivariate and multivariate logistic regressions were conducted to assess risk factors independently associated with hepatitis C antibodies (HCVAb) seroprevalence. Results Out of a total of 326,263 individuals screened for HCVAb, 22,183 (6.8%) were positive. In multivariate analysis, risk factors identified as statistically associated with HCVAb Seroprevalence include history of traditional operation or scarification (OR = 1.09, 95% CI: 1.05–1.14), presence of viral hepatitis in the family (OR = 1.27, 95% CI: 1.15–1.40), widowed or separated/divorced (OR = 1.36, 95% CI: 1.26–1.47), Southern province (OR = 1.98, 95% CI: 1.88–2.08) and aged 65 years and older (OR = 4.86, 95% CI: 4.62–5.11). Ubudehe category 3 (OR = 0.97, 95% CI: 0.93–1.01) and participants using RAMA (Health insurances for employees of public and private sectors) insurance (OR = 0.76, 95% CI: 0.70–0.85) had lower odds of HCV seroprevalence. Conclusions Our findings provide important information for Rwanda’s strategy on prevention and case-finding. Future prevention interventions should aim to reduce transmission through targeted messaging around traditional healing practices and case-finding targeting individuals with a history of exposure or advanced age.

Abstract Although critical to prevent healthcare-associated infections, hand hygiene (HH) compliance is poor in resource-limited settings. In 2012, three Kenyan hospitals began onsite production of alcohol-based handrub (ABHR) and HH promotion. Our aim is to determine the impact of local production of ABHR on HH compliance and perceptions of ABHR. We observed 25,738 HH compliance opportunities and conducted 15 baseline and post-intervention focus group discussions. Hand Hygiene compliance increased from 28% (baseline) to 38% (post-intervention, p = 0.0003). Healthcare workers liked the increased accessibility of ABHR, but disliked its smell, feel, and sporadic availability. Onsite production and promotion of ABHR resulted in modest HH improvement. Enhancing the quality of ABHR and addressing logistical barriers could improve program impact.

Abstract Background Rwanda has dramatically reduced child mortality, but the causes and sociodemographic drivers for mortality are poorly understood. Methods We conducted a matched case-control study of all children who died before 5 years of age in eastern Rwanda between 1st March 2013 and 28th February 2014 to identify causes and risk factors for death. We identified deaths at the facility level and via a community health worker reporting system. We used verbal social autopsy to interview caregivers of deceased children and controls matched by area and age. We used InterVA4 to determine probable causes of death and cause-specific mortality fractions, and utilized conditional logistic regression to identify clinical, family, and household risk factors for death. Results We identified 618 deaths including 174 (28.2%) in neonates and 444 (71.8%) in non-neonates. The most commonly identified causes of death were pneumonia, birth asphyxia, and meningitis among neonates and malaria, acute respiratory infections, and HIV/AIDS-related death among non-neonates. Among neonates, 54 (31.0%) deaths occurred at home and for non-neonates 242 (54.5%) deaths occurred at home. Factors associated with neonatal death included home birth (aOR: 2.0; 95% CI: 1.4–2.8), multiple gestation (aOR: 2.1; 95% CI: 1.3–3.5), both parents deceased (aOR: 4.7; 95% CI: 1.5–15.3), mothers non-use of family planning (aOR: 0.8; 95% CI: 0.6–1.0), lack of accompanying person (aOR: 1.6; 95% CI: 1.1–2.1), and a caregiver who assessed the medical services they received as moderate to poor (aOR: 1.5; 95% CI: 1.2–1.9). Factors associated with non-neonatal deaths included multiple gestation (aOR: 2.8; 95% CI: 1.7–4.8), lack of adequate vaccinations (aOR: 1.7; 95% CI: 1.2–2.3), household size (aOR: 1.2; 95% CI: 1.0–1.4), maternal education levels (aOR: 1.9; 95% CI: 1.2–3.1), mothers non-use of family planning (aOR: 1.6; 95% CI: 1.4–1.8), and lack of household electricity (aOR: 1.4; 95% CI: 1.0–1.8). Conclusion In the context of rapidly declining childhood mortality in Rwanda and increased access to health care, we found a large proportion of remaining deaths occur at home, with home deliveries still representing a significant risk factor for neonatal death. The major causes of death at a population level remain largely avoidable communicable diseases. Household characteristics associated with death included well-established socioeconomic and care-seeking risk factors.

Background:Kenya has implemented a robust response to non-communicable diseases and injuries (NCDIs); however, key gaps in health services for NCDIs still exist in the attainment of Universal Health Coverage (UHC). The Kenya Non-Communicable Diseases and Injury (NCDI) Poverty Commission was established to estimate the burden of NCDIs, determine the availability and coverage of health services, prioritize an expanded set of NCDI conditions, and propose cost-effective and equity-promoting interventions to avert the health and economic consequences of NCDIs in Kenya. Methods:Burden of NCDIs in Kenya was determined using desk review of published literature, estimates from the Global Burden of Disease Study, and secondary analysis of local health surveillance data. Secondary analysis of nationally representative surveys was conducted to estimate current availability and coverage of services by socioeconomic status. The Commission then conducted a structured priority setting process to determine priority NCDI conditions and health sector interventions based on published evidence. Findings:There is a large and diverse burden of NCDIs in Kenya, with the majority of disability-adjusted life-years occurring before age of 40. The poorest wealth quintiles experience a substantially higher deaths rate from NCDIs, lower coverage of diagnosis and treatment for NCDIs, and lower availability of NCDI-related health services. The Commission prioritized 14 NCDIs and selected 34 accompanying interventions for recommendation to achieve UHC. These interventions were estimated to cost $11.76 USD per capita annually, which represents 15% of current total health expenditure. This investment could potentially avert 9,322 premature deaths per year by 2030. Conclusions and Recommendations:An expanded set of priority NCDI conditions and health sector interventions are required in Kenya to achieve UHC, particularly for disadvantaged socioeconomic groups. We provided recommendations for integration of services within existing health services platforms and financing mechanisms and coordination of whole-of-government approaches for the prevention and treatment of NCDIs.

BackgroundThe health of populations living in extreme poverty has been a long-standing focus of global development efforts, and continues to be a priority during the Sustainable Development Goal era. However, there has not been a systematic attempt to quantify the magnitude and causes of the burden in this specific population for almost two decades. We estimated disease rates by cause for the world's poorest billion and compared these rates to those in high-income populations.MethodsWe defined the population in extreme poverty using a multidimensional poverty index. We used national-level disease burden estimates from the 2017 Global Burden of Disease Study and adjusted these to account for within-country variation in rates. To adjust for within-country variation, we looked to the relationship between rates of extreme poverty and disease rates across countries. In our main modeling approach, we used these relationships when there was consistency with expert opinion from a survey we conducted of disease experts regarding the associations between household poverty and the incidence and fatality of conditions. Otherwise, no within-country variation was assumed. We compared results across multiple approaches for estimating the burden in the poorest billion, including aggregating national-level burden from the countries with the highest poverty rates. We examined the composition of the estimated disease burden among the poorest billion and made comparisons with estimates for high-income countries.ResultsThe composition of disease burden among the poorest billion, as measured by disability-adjusted life years (DALYs), was 65% communicable, maternal, neonatal, and nutritional (CMNN) diseases, 29% non-communicable diseases (NCDs), and 6% injuries. Age-standardized DALY rates from NCDs were 44% higher in the poorest billion (23,583 DALYs per 100,000) compared to high-income regions (16,344 DALYs per 100,000). Age-standardized DALY rates were 2,147% higher for CMNN conditions (32,334 DALYs per 100,000) and 86% higher for injuries (4,182 DALYs per 100,000) in the poorest billion, compared to high-income regions.ConclusionThe disease burden among the poorest people globally compared to that in high income countries is highly influenced by demographics as well as large disparities in burden from many conditions. The comparisons show that the largest disparities remain in communicable, maternal, neonatal, and nutritional diseases, though NCDs and injuries are an important part of the "unfinished agenda" of poor health among those living in extreme poverty.

Context and objectives Non-communicable diseases and injuries (NCDIs) comprise a large share of mortality and morbidity in low-income countries (LICs), many of which occur earlier in life and with greater severity than in higher income settings. Our objective was to assess availability of essential equipment and medications required for a broad range of acute and chronic NCDI conditions.Design Secondary analysis of existing cross-sectional survey data.Setting We used data from Service Provision Assessment surveys in Bangladesh, the Democratic Republic of the Congo, Ethiopia, Haiti, Malawi, Nepal, Senegal and Tanzania, focusing on public first-referral level hospitals in each country.Outcome measures We defined sets of equipment and medications required for diagnosis and management of four acute and nine chronic NCDI conditions and determined availability of these items at the health facilities.Results Overall, 797 hospitals were included. Medication and equipment availability was highest for acute epilepsy (country estimates ranging from 40% to 95%) and stage 1–2 hypertension (28%–83%). Availability was low for type 1 diabetes (1%–70%), type 2 diabetes (3%–57%), asthma (0%–7%) and acute presentations of diabetes (0%–26%) and asthma (0%–4%). Few hospitals had equipment or medications for heart failure (0%–32%), rheumatic heart disease (0%–23%), hypertensive emergencies (0%–64%) or acute minor surgical conditions (0%–5%). Data for chronic pain were limited to only two countries. Availability of essential medications and equipment was lower than previous facility-reported service availability.Conclusions Our findings demonstrate low availability of essential equipment and medications for diverse NCDIs at first-referral level hospitals in eight LICs. There is a need for decentralisation and integration of NCDI services in existing care platforms and improved assessment and monitoring to fully achieve universal health coverage.

Objectives This study describes the burden of the hepatitis B, C and HIV co-infections and assesses associated risk factors.Setting This analysis used data from a viral hepatitis screening campaign conducted in six districts in Rwanda from April to May 2019. Ten health centres per district were selected according to population size and distance.Participants The campaign collected information from 156 499 participants (51 496 males and 104 953 females) on sociodemographic, clinical and behavioural characteristics. People who were not Rwandan by nationality or under 15 years old were excluded.Primary and secondary outcomes The outcomes of interest included chronic hepatitis C virus (HCV) infection, chronic hepatitis B virus (HBV) infection, HIV infection, co-infection HIV/HBV, co-infection HIV/HCV, co-infection HBV/HCV and co-infection HCV/HBV/HIV. Multivariable logistic regressions were used to assess factors associated with HBV, HCV and HIV, mono and co-infections.Results Of 156 499 individuals screened, 3465 (2.2%) were hepatitis B surface antigen positive and 83% (2872/3465) of them had detectable HBV desoxy-nucleic acid (HBV DNA). A total of 4382 (2.8%) individuals were positive for antibody-HCV (anti-HCV) and 3163 (72.2%) had detectable HCV ribo-nucleic acid (RNA). Overall, 36 (0.02%) had HBV/HCV co-infection, 153 (0.1%) HBV/HIV co-infection, 238 (0.15%) HCV/HIV co-infection and 3 (0.002%) had triple infection. Scarification or receiving an operation from traditional healer was associated with all infections. Healthcare risk factors—history of surgery or transfusion—were associated with higher likelihood of HIV infection with OR 1.42 (95% CI 1.21 to 1.66) and OR 1.48 (1.29 to 1.70), respectively, while history of physical traumatic assault was associated with a higher likelihood of HIV and HBV/HIV co-infections with OR 1.69 (95% CI 1.51 to 1.88) and OR 1.82 (1.08 to 3.05), respectively.Conclusions Overall, mono-infections were common and there were differences in significant risk factors associated with various infections. These findings highlight the magnitude of co-infections and differences in underlying risk factors that are important for designing prevention and care programmes.

Background: In rural sub-Saharan Africa, access to care for severe non-communicable diseases (NCDs) is limited due to myriad delivery challenges. We describe the implementation, patient characteristics, and retention rate of an integrated NCD clinic inclusive of cancer services at a district hospital in rural Rwanda. Methods: In 2006, the Rwandan Ministry of Health at Rwinkwavu District Hospital (RDH) and Partners In Health established an integrated NCD clinic focused on nurse-led care of severe NCDs, within a single delivery platform. Implementation modifications were made in 2011 to include cancer services. For this descriptive study, we abstracted medical record data for 15 months after first clinic visit for all patients who enrolled in the NCD clinic between 1 July 2012 and 30 June 2014. We report descriptive statistics of patient characteristics and retention. Results: Three hundred forty-seven patients enrolled during the study period: oncology – 71.8%, hypertension – 10.4%, heart failure – 11.0%, diabetes – 5.5%, and chronic respiratory disease (CRD) – 1.4%. Twelve-month retention rates were: oncology – 81.6%, CRD – 60.0%, hypertension – 75.0%, diabetes – 73.7%, and heart failure – 47.4%. Conclusions: The integrated NCD clinic filled a gap in accessible care for severe NCDs, including cancer, at rural district hospitals. This novel approach has illustrated good retention rates.

Although a large part of the symptomology of coronavirus disease 2019 (COVID-19) has been attributed to its effects in the lungs, the virus has also been shown to cause extensive cardiovascular complications in a small subset of patients. In this case report, we describe a 29-year-old nonobese hospital food service associate who presented with diffuse abdominal and chest pain; he was found to be positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with significantly elevated levels of troponin T and multiple acute phase reactants; his EKG demonstrated ST-elevations consistent with anterolateral infarction. Despite having no significant past medical history or atherosclerotic risk factors, he was found to have a complete occlusion of his left anterior descending artery that required cardiac catheterization. This case demonstrates that cardiovascular complications must be considered in the COVID-19 population, even without the clear presence of other risk factors for heart disease.

Abstract Background Despite worldwide efforts to reduce neonatal mortality, 44% of under-five deaths occur in the first 28 days of life. The primary causes of neonatal death are preventable or treatable. This study describes the presentation, management and outcomes of hospitalized newborns admitted to the neonatal units of two rural district hospitals in Rwanda after the 2012 launch of a national neonatal protocol and standards. Methods We retrospectively reviewed routinely collected data for all neonates (0 to 28 days) admitted to the neonatal units at Rwinkwavu and Kirehe District Hospitals from January 1, 2013 to December 31, 2014. Data on demographic and clinical characteristics, clinical management, and outcomes were analyzed using median and interquartile ranges for continuous data and frequencies and proportions for categorical data. Clinical management and outcome variables were stratified by birth weight and differences between low birth weight (LBW) and normal birth weight (NBW) neonates were assessed using Fisher’s exact or Wilcoxon rank-sum tests at the α = 0.05 significance level. Results A total of 1723 neonates were hospitalized over the two-year study period; 88.7% were admitted within the first 48 h of life, 58.4% were male, 53.8% had normal birth weight and 36.4% were born premature. Prematurity (27.8%), neonatal infection (23.6%) and asphyxia (20.2%) were the top three primary diagnoses. Per national protocol, vital signs were assessed every 3 h within the first 48 h for 82.6% of neonates (n = 965/1168) and 93.4% (n = 312/334) of neonates with infection received antibiotics. The overall mortality rate was 13.3% (n = 185/1386) and preterm/LBW infants had similar mortality rate to NBW infants (14.7 and 12.2% respectively, p = 0.131). The average length of stay in the neonatal unit was 5 days. Conclusions Our results suggest that it is possible to provide specialized neonatal care for both LBW and NBW high-risk neonates in resource-limited settings. Despite implementation challenges, with the introduction of the neonatal care package and defined clinical standards these most vulnerable patients showed survival rates comparable to or higher than neighboring countries.

Abstract Background Breast cancer is the most common malignancy encountered during pregnancy. However, the burden of pregnancy-associated breast cancer (PABC) and subsequent care is understudied in sub-Saharan Africa (SSA). Here, we describe the characteristics, diagnostic delays and treatment of women with PABC seeking care at a rural cancer referral facility in Rwanda. Methods Data from female patients aged 18–50 years with pathologically confirmed breast cancer who presented for treatment between July 1, 2012 and February 28, 2014 were retrospectively reviewed. PABC was defined as breast cancer diagnosed in a woman who was pregnant or breastfeeding. Numbers and frequencies are reported for demographic and diagnostic delay variables and Wilcoxon rank sum and Fisher’s exact tests are used to compare characteristics of women with PABC to women with non-PABC at the alpha = 0.05 significance level. Treatment and outcomes are described for women with PABC only. Results Of the 117 women with breast cancer, 12 (10.3%) had PABC based on medical record review. The only significant demographic differences were that women with PABC were younger (p = 0.006) and more likely to be married (p = 0.035) compared to women with non-PABC. There were no significant differences in diagnostic delays or stage at diagnosis between women with PABC and women with non-PABC women. Eleven of the women with PABC received treatment, three had documented treatment delays or modifications due to their pregnancy or breastfeeding, and four stopped breastfeeding to initiate treatment. At the end of the study period, six patients were alive, three were deceased and three patients were lost to follow-up. Conclusions PABC was relatively common in our cohort but may have been underreported. Although patients with PABC did not experience greater diagnostic delays, most had treatment modifications, emphasizing the potential value of PABC-specific treatment protocols in SSA. Larger prospective studies of PABC are needed to better understand particular challenges faced by these patients and inform policies and practices to optimize care for women with PABC in Rwanda and similar settings.

BackgroundRwanda has been a leader in the global effort to reduce infant mortality, particularly in regions of sub-Saharan Africa. Although rates have dropped, deaths still occur.ObjectiveTo explore the care pathways and barriers taken by infant caregivers before the death of their infant through a verbal social autopsy study in 2 districts in eastern Rwanda.MethodsWe adapted the World Health Organization verbal socialautopsy tools to reflect local context and priorities. Caregivers of infants in the 2 districts were interviewed using the adapted quantitative survey and semistructured interview guide. Interviews were recorded and thematic analysis employed on a subsample (n = 133) to extract the content relevant to understanding the drivers of infant death and inform results of the quantitative data until saturation was reached (66). Results were interpreted through a driver diagram framework to explore caregiver-reported challenges in knowledge and experiences with care access and delivery.FindingsMost study participants (82%) reported accessing the formal health system at some point before the infant's death. The primary caregiver-reported drivers for infant death included challenges in accessing care in a timely manner, concerns about the technical quality of care received, and poor responsiveness of the system and providers. The 2 most commonly discussed drivers were gaps in communication between providers and patients and challenges obtaining and using the community-based health insurance. The framework of the driver diagram was modified to identify the factors where change was needed to further reduce mortality.ConclusionThis study provides important information on the experiential quality of care received by infants and their caregivers within the current health care space in rural Rwanda. By listening to the individual stories of so many caregivers regarding the gaps and challenges they faced, appropriate action may be taken to bolster the existing health care system.

Objectives We analysed data collected during programmatic screening activities conducted in 2017 to describe hepatitis C virus (HCV) seroprevalence in the general population and identify associated factors.Design We analysed data collected between June and September 2017. For both seroprevalence and viraemia, variations across demographic and geographic factors were assessed and multivariate regression models were fit to identify factors independently associated with each marker. Geospatial data were examined for visualisation.Setting HCV screening was organised within each of the 30 districts in Rwanda. One designated location in each district was selected as the screening site and screening took place for 1 week at each site.Participants This study included 124 223 male and female volunteers. Anti-HCV-positive individuals were followed up with HCV RNA viral load (VL) testing for infection confirmation.Main outcome measures Two markers were examined: the presence of HCV antibodies and HCV RNA VL.Results Among 124 223 individuals screened, 11 003 (8.86%, 95% CIs: 8.70% to 9.02%) were positive for anti-HCV. Anti-HCV prevalence varied by age with the oldest age group (>55 year olds) having a prevalence of 16.46% (95% CIs: 16.14% to 16.80%) and the youngest age group (

Background: Performance-based financing (PBF) has demonstrated a range of successes and failures in improving health outcomes across low- and middle-income countries. Evidence indicates that the success of PBF depends, in large part, on the model selected, in relation to a variety of contextual factors. Objective: Partners In Health∣Inshuti Mu Buzima aimed to evaluate health outcomes associated with a novel capacity-building model of PBF at health centers throughout Kirehe district, Rwanda. Design: Thirteen health centers in Kirehe district, which provide healthcare to a population of over 300,000 people, agreed to participate in a PBF initiative scheme that integrated data feedback, quality improvement coaching, peer-to-peer learning, and district-level priority setting. Health centers’ progress toward collectively agreed upon site-specific health targets was assessed every 6 months for 18 months. Incentives were awarded only when health centers met goals on all three priorities health centers had collectively agreed upon: 90% coverage of community-based health insurance, 70% contraceptive prevalence rate, and zero acute severe malnutrition cases. Improvement across all four time points and facilities was measured using mixed-effects linear regression. Findings: At 6-month follow-up, 4 of 13 health centers had met 1 target. At 12-month follow-up, 7 centers had met 1 target, and by 18-month follow-up, 6 centers had met 2 targets and 2 centers had met all 3. Average health center performance had improved significantly across the district for all three targets: mean insurance coverage increased from 68% at baseline to 93% (p

Upon food intake, insulin stimulates de novo lipogenesis (DNL) in hepatocytes via the AKT-mTORC1-sterol regulatory element-binding protein (SREBP)-1c pathway. How insulin maintains the maximal SREBP-1c activities during the entire feeding state remains elusive. We previously reported that insulin induced b-ZIP transcription factor, E4-binding protein 4 (E4BP4), in hepatocytes. In the current study, we show that insulin injection increases hepatic E4bp4 expression by activating the AKT-mTORC1-SREBP-1c pathway in hepatocytes. E4bp4-deficient hepatocytes not only fail to maintain robust DNL but also become resistant to SREBP-1c-induced lipogenesis. In vivo, acute depletion of E4bp4 in the liver by adenoviral shRNA reduces the expression of lipogenic enzymes and results in reduced levels of serum triglycerides and cholesterol during the postprandial phase. In hepatocytes, E4BP4 interacts with nuclear SREBP-1c to preserve its acetylation, and subsequently protects it from ubiquitination-dependent degradation. In conclusion, the current studies uncover a novel positive feedback pathway mediated by E4BP4 to augment SREBP-1c-mediated DNL in the liver during the fed state.

The severe epidemic of Ebola virus disease in Liberia started in March 2014. On May 9, 2015, the World Health Organization declared Liberia free of Ebola, 42 days after safe burial of the last known case-patient. However, another 6 cases occurred during June–July; on September 3, 2015, the country was again declared free of Ebola. Liberia had by then reported 10,672 cases of Ebola and 4,808 deaths, 37.0% and 42.6%, respectively, of the 28,103 cases and 11,290 deaths reported from the 3 countries that were heavily affected at that time. Essential components of the response included government leadership and sense of urgency, coordinated international assistance, sound technical work, flexibility guided by epidemiologic data, transparency and effective communication, and efforts by communities themselves. Priorities after the epidemic include surveillance in case of resurgence, restoration of health services, infection control in healthcare settings, and strengthening of basic public health systems.

Over half of under-five deaths occur in sub-Saharan Africa and appropriate, timely, quality care is critical for saving children's lives. This study describes the context surrounding children's deaths from the time the illness was first noticed, through the care-seeking patterns leading up to the child's death, and identifies factors associated with care-seeking for these children in rural Rwanda.Secondary analysis of a verbal and social autopsy study of caregivers who reported the death of a child between March 2013 to February 2014 that occurred after discharge from the child's birth facility in southern Kayonza and Kirehe districts in Rwanda. Bivariate analyses using Fisher's exact tests were conducted to identify child, caregiver, and household factors associated with care-seeking from the formal health system (i.e., community health worker or health facility). Factors significant at α = 0.10 significance level were considered for backwards stepwise multivariate logistic regression, stopping when remaining factors were significantly associated with care-seeking at α = 0.05 significance level.Among the 516 eligible deaths among children under-five, 22.7% (n = 117) did not seek care from the health system. For those who did, the most common first point of contact was community health workers (45.8%). In multivariate logistic regression, higher maternal education (OR = 3.36, 95% CI: 1.89, 5.98), having diarrhea (OR = 4.21, 95%CI: 1.95, 9.07) or fever (OR = 2.03, 95%CI: 1.11, 3.72), full household insurance coverage (3.48, 95%CI: 1.79, 6.76), and longer duration of illness (OR = 22.19, 95%CI: 8.88, 55.48) were significantly associated with formal care-seeking.Interventions such as community health workers and insurance promote access to care, however a gap remains as many children had no contact with the health system prior to death and those who sought formal care still died. Further efforts are needed to respond to urgent cases in communities and further understand remaining barriers to accessing appropriate, quality care.

Nearly a quarter of a million children have acquired HIV, prompting the implementation of new protocols-Option B and B+-for treating HIV+ pregnant women. While efficacy has been demonstrated in randomized trials, there is limited real-world evidence on the impact of these changes. Using longitudinal, routinely collected data we assessed the impact of the adoption of WHO Option B in Rwanda on mother to infant transmission.We used interrupted time series analysis to evaluate the impact of Option B on mother-to-child HIV transmission in Rwanda. Our primary outcome was the proportion of HIV tests in infants with positive results at six weeks of age. We included data for 20 months before and 22 months after the 2010 policy change.Of the 15,830 HIV tests conducted during our study period, 392 tested positive. We found a significant decrease in both the level (-2.08 positive tests per 100 tests conducted, 95% CI: -2.71 to -1.45, p < 0.001) and trend (-0.11 positive tests per 100 tests conducted per month, 95% CI: -0.16 to -0.07, p < 0.001) of test positivity. This represents an estimated 297 fewer children born without HIV in the post-policy period or a 46% reduction in HIV transmission from mother to child.The adoption of Option B in Rwanda contributed to an immediate decrease in the rate of HIV transmission from mother to child. This suggests other countries may benefit from adopting these WHO guidelines.

Background and Objectives: Despite recent improvements in accessibility of services to prevent mother-to-child transmission of HIV, maternal retention in HIV care remains a challenge in the postpartum period. This study assessed service utilization, program retention, and linkage to routine services, as well as clinical outcomes for mothers and infants, following implementation of an integrated mother-infant clinic in rural Rwanda. Methods: We conducted a retrospective cohort study of all HIV-positive mothers and their infants enrolled in the integrated clinics in two rural districts between July 1, 2012, and June 30, 2013. At 18 months post-partum, data on mother-infant service utilization and program outcomes were reported. Results: Of the 185 mother-infant pairs in the clinics, 98.4% of mothers were on antiretroviral therapy (ART) and 30.3% used modern contraception at enrollment. At 18 months post-partum, 98.4% of mothers were retained and linked back to adult HIV program. All mothers were on ART and 72.0% on modern contraception. For infants, 93.0% completed follow-up. Two (1.1%) infants tested HIV positive. Conclusion and Global Health Implication: An integrated clinic was successfully implemented in rural Rwanda with high mother retention in care and low mother to child HIV transmission rates. This model of integration of services may contribute to improved mother-infant retention in care during post-partum period and should be considered as one approach to addressing this challenge in similar settings. Key words: HIV • Integrated Clinic • Combined Clinic • Antiretroviral Therapy • Post-partum Retention • Linkages • ART • PMTCT • Option B+ • Africa Copyright © 2017 Neza Guillaine et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.affect economic and health promotion.

BACKGROUND:Access to treatment for hepatitis C virus (HCV) in sub-Saharan Africa is extremely limited. With the advent of direct acting antivirals (DAAs), highly effective and easy-to-deliver oral regimens are now available on the global market. This study was conducted to understand the background and characteristics of a national cohort of patients with HCV infection enrolled in care and awaiting therapy with DAAs. METHODS AND FINDINGS:We conducted a retrospective chart review of all adult patients with confirmed HCV infection who were currently enrolled in care and treatment at the four existing hepatitis referral centers in Rwanda. Patient charts at these centers were reviewed, and routinely collected data were recorded and analyzed. Overall, 253 patients were identified; median age was 56 years (IQR: 43, 65), and 149 (58.9%) were female. Median viral load was 688,736 IU/ml and 96.7% were HCV genotype 4. As classified by FIB-4 score, 64.8% of the patients had moderate to severe fibrosis. Fibrosis stage was associated with age (OR 1.12, CI 1.09-1.17), but not with time since diagnosis, gender, treatment center, or type of insurance. There was a low frequency of documented co-morbid conditions, including hypertension, diabetes, HIV, and hepatitis B virus. CONCLUSIONS:Compared to an estimated 55,000 patients eligible for HCV treatment in Rwanda, this study identified only 253 patients currently diagnosed and engaged in care, highlighting an immense treatment gap in HCV, likely due to the lack of accessible and affordable screening, diagnostic, and treatment modalities. The patients that were enrolled in care had a disproportionately advanced fibrosis stage, possibly indicating late presentation to care or lack of treatment options. In the context of newly available and effective treatment options, this study supports the overall need to accelerate access to HCV screening, diagnostics, and care and treatment services in resource-limited settings in sub-Saharan Africa.

Background: The American Society of Gastrointestinal Endoscopy (ASGE) published updated guidelines in 2009 to help endoscopists manage the treatment of their patients who have been prescribed antiplatelet therapy (APT). Study aim: To assess the use of APT among endoscopists, and to identify factors guiding their use of APT while treating their patients. Method: A survey questionnaire was distributed to endoscopists at two national meetings to assess their usage of APT while treating patients during the peri-endoscopic period. Results: The survey was provided to 400 attendees of whom 239 (60 %) responded. Only 30 % of respondents followed the ASGE guidelines for treating their patients and 26 % percent of respondents withheld all APT before engaging in any patient procedure. Endoscopists’ decisions appeared to be influenced by their own particular experiences rather than any specific APT usage guidelines (46 % vs 22 %; P

Introduction: The American Society for Gastrointestinal Endoscopy (ASGE) has published a Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) statement on incorporating an imaging-guided surveillance protocol to replace the current practice of four-quadrant biopsies every two centimeters for Barrett’s esophagus (BE) surveillance. We sought to determine if current gastroenterologists would be willing to apply these changes to their practice and identify any barriers to implementation. Methods: We collected data using surveys that were distributed at two national meetings and using a random selection process emailed surveys to members listed in the American Gastroenterological Association directory. Physicians from a variety of practice settings participated. Primary outcomes of our study included determining whether clinicians would be willing to accept an imaging-based surveillance protocol, their reasons for not doing so, and whether a financial incentive would be persuade them to implement the protocol. Continuous variables were reported as mean ± standard deviation. Categorical variables were summarized with percentages and 95 % confidence intervals. Results: Gastroenterologists (172) completed the survey; and 140 (81.4 %) of them stated they would implemented the PIVI recommendations into practice. Using a multivariate analysis of the data, physicians who reported a financial incentive for submitting biopsy specimens to pathology were less likely to implement the PIVI recommendations. The two main barriers to implementation of the protocol were medical-legal and financial reasons. Of the 32 gastroenterologists who were not willing to implement the imaging-guided surveillance protocol, 20 (62.5 %) stated that they would implement it if there were a financial incentive. Discussion: The PIVI statement focuses on re-evaluating our current method of surveillance for BE. The results of our survey show that gastroenterologists may be willing to implement an imaging-guided surveillance program, but concerns regarding financial compensation and proper training in advanced imaging techniques remain.

Background and study aims: It has been postulated that the endoscopic ablation of Barrett’s esophagus can lead to complete eradication of the disease. This study was undertaken to evaluate the efficacy of endoscopic eradication therapy for Barrett’s esophagus and the rates of recurrence of intestinal metaplasia. Patients and methods: As part of an initial randomized controlled trial, patients with nondysplastic or low grade dysplastic Barrett’s esophagus underwent mucosal ablation. Following ablation, the patients had annual surveillance endoscopies. Recurrence was defined as the presence of intestinal metaplasia after initial complete eradication had been achieved. Results: A total of 28 patients with Barrett’s esophagus were followed for a mean of 6.4 years after ablation therapy. At baseline, the majority of the patients had nondysplastic Barrett’s esophagus (79 %). Initial complete eradication of intestinal metaplasia was achieved at a mean of 4.1 months. During long-term follow-up, initial recurrence of intestinal metaplasia was seen in 14 of the 28 of patients (50 %) at a mean of 40 months, and further maintenance ablation therapy was applied. At the final follow-up, 36 % of the patients had complete eradication of intestinal metaplasia, 18 % of the patients had intestinal metaplasia, and 21 % had died of unrelated causes; invasive esophageal adenocarcinoma had developed in 1 patient. Conclusions: The long-term results of this study demonstrate a recurrence rate of 50 % after complete eradication of Barrett’s esophagus with endoscopic eradication therapy. In addition, re-recurrence (in 36 %), even after further maintenance endoscopic eradication therapy, and deaths unrelated to the disease (21 %) occurred. Complete remission of Barrett’s esophagus appears to be a difficult goal to achieve. These results call into question the role of ablation in patients with low risk Barrett’s esophagus.

Henoch-Schönlein purpura (HSP) is a small vessel systemic vasculitis, predominantly affecting children, characterized by a tetrad of manifestations, specifically palpable purpura, arthralgia, abdominal pain, and renal disease. HSP in the adult population is rare, and no case has been described of HSP in liver cirrhosis with spontaneous bacterial peritonitis (SBP). We present the case of a 58-year-old male with liver cirrhosis, who was subsequently diagnosed with SBP and later HSP. In this patient, the diagnosis of HSP was demonstrated clinically by his palpable purpura, diarrhea, hematuria, and abdominal pain and confirmed pathologically by his renal and skin biopsies demonstrating leukocytoclastic vasculitis and IgA complexes. We believe that this is an example of altered IgA processing in cirrhosis leading to the development of IgA immune complexes and ultimately HSP. The patient additionally had SBP, which may have increased his risk for developing HSP given antigen processing by mucosa-associated lymphoid tissues leading to immune complex deposition, which may not have been effectively cleared in the context of his liver disease. The patient unfortunately died of gastrointestinal hemorrhage, which is unclear to be due to his underlying cirrhosis or a gastrointestinal manifestation of HSP itself.

Elevated levels of serum saturated fatty acid palmitate have been shown to promote insulin resistance, increase cellular ROS production, and trigger cell apoptosis in hepatocytes during the development of obesity. However, it remains unclear whether palmitate directly impacts the circadian clock in hepatocytes, which coordinates nutritional inputs and hormonal signaling with downstream metabolic outputs. Here we presented evidence that the molecular clock is a novel target of palmitate in hepatocytes. Palmitate exposure at low dose inhibits the molecular clock activity and suppresses the cyclic expression of circadian targets including Dbp, Nr1d1 and Per2 in hepatocytes. Palmitate treatment does not seem to alter localization or reduce protein expression of BMAL1 and CLOCK, the two core components of the molecular clock in hepatocytes. Instead, palmitate destabilizes the protein-protein interaction between BMAL1-CLOCK in a dose and time-dependent manner. Furthermore, we showed that SIRT1 activators could reverse the inhibitory action of palmitate on BMAL1-CLOCK interaction and the clock gene expression, whereas inhibitors of NAD synthesis mimic the palmitate effects on the clock function. In summary, our findings demonstrated that palmitate inhibits the clock function by suppressing SIRT1 function in hepatocytes.

The CUL4-DDB1 E3 ligase complex serves as a critical regulator in various cellular processes, including cell proliferation, DNA damage repair, and cell cycle progression. However, whether this E3 ligase complex regulates clock protein turnover and the molecular clock activity in mammalian cells is unknown. Here we show that CUL4-DDB1-CDT2 E3 ligase ubiquitinates CRY1 and promotes its degradation both in vitro and in vivo. Depletion of the major components of this E3 ligase complex, including Ddb1, Cdt2, and Cdt2-cofactor Pcna, leads to CRY1 stabilization in cultured cells or in the mouse liver. CUL4A-DDB1-CDT2 E3 ligase targets lysine 585 within the C-terminal region of CRY1 protein, shown by the CRY1 585KA mutant's resistance to ubiquitination and degradation mediated by the CUL4A-DDB1 complex. Surprisingly, both depletion of Ddb1 and over-expression of Cry1-585KA mutant enhance the oscillatory amplitude of the Bmal1 promoter activity without altering its period length, suggesting that CUL4A-DDB1-CDT2 E3 targets CRY1 for degradation and reduces the circadian amplitude. All together, we uncovered a novel biological role for CUL4A-DDB1-CDT2 E3 ligase that regulates molecular circadian behaviors via promoting ubiquitination-dependent degradation of CRY1.

Non-adherence is one of the primary obstacles to successful antiretroviral therapy in HIV+ patients worldwide. In Brazil, the Domiciliary Therapeutic Assistance is a multidisciplinary and integrated home-based assistance program provided for HIV+ patients confined in their homes due to physical deficiency. This study investigated ADT's ability to monitor and promote appropriate adherence to ARV therapy. Fifty-six individuals were recruited from three study groups: Group 1 - patients currently in the ADT program, Group 2 - 21 patients previously treated by the ADT program, and Group 3 - 20 patients who have always been treated using conventional ambulatory care. Using multivariable self-reporting to evaluate adherence, patients in the ADT program had significantly better adherence than patients in ambulatory care (F = 6.66, p = 0.003). This effect was independent of demographic and socioeconomic characteristics as well as medical history. Patients in the ADT program also showed a trend towards greater therapeutic success than ambulatory patients. These results suggest the incorporation of characteristics of ADT in conventional ambulatory care as a strategy to increase adherence to ARV therapy.O sucesso da terapia antiretroviral depende da adesão ao tratamento. A Assistência Domiciliar Terapêutica é um programa de atendimento multidisciplinar a pacientes com HIV/AIDS e com dificuldades de se deslocar para atendimento ambulatorial. Este estudo compara a adesão de pacientes ao esquema ARV em um programa ADT com aqueles em tratamento ambulatorial convencional. Foram estudados: Grupo 1 - 15 pacientes no programa de ADT, Grupo 2 - 21 pacientes em tratamento ambulatorial convencional, Grupo 3 - 20 pacientes em tratamento ambulatorial convencional que nunca freqüentaram o programa ADT. Os pacientes inscritos no programa ADT apresentaram significativamente maior adesão ao tratamento do que pacientes ambulatoriais (F = 6.66, p= 0,003). Os resultados observados não foram influenciados pelas características demográficas, características socioeconômicas, ou histórico médico. Pacientes em programa de ADT também mostraram uma tendência a melhor resposta terapêutica do que os ambulatoriais. Este estudo sugere a utilização das características do ADT como estratégia para melhorar a adesão à terapia antiretroviral.

Amyloid is a complex pathology associated with a growing number of diseases including Alzheimer's disease, type 2 diabetes, rheumatoid arthritis, and myeloma. The distribution and extent of amyloid deposition in body organs establishes the prognosis and can define treatment options; therefore, determining the amyloid load by using non-invasive molecular imaging is clinically important. We have identified a heparin-binding peptide designated p5 that, when radioiodinated, was capable of selectively imaging systemic visceral AA amyloidosis in a murine model of the disease. The p5 peptide was posited to bind effectively to amyloid deposits, relative to similarly charged polybasic heparin-reactive peptides, because it adopted a polar α helix secondary structure. We have now synthesized a variant, p5R, in which the 8 lysine amino acids of p5 have been replaced with arginine residues predisposing the peptide toward the α helical conformation in an effort to enhance the reactivity of the peptide with the amyloid substrate. The p5R peptide had higher affinity for amyloid and visualized AA amyloid in mice by using SPECT/CT imaging; however, the microdistribution, as evidenced in micro-autoradiographs, was dramatically altered relative to the p5 peptide due to its increased affinity and a resultant "binding site barrier" effect. These data suggest that radioiodinated peptide p5R may be optimal for the in vivo detection of discreet, perivascular amyloid, as found in the brain and pancreatic vasculature, by using molecular imaging techniques; however, peptide p5, due to its increased penetration, may yield more quantitative imaging of expansive tissue amyloid deposits.