Effect of Integrated Capacity-Building Interventions on Malaria Case Management by Health Professionals in Uganda: A Mixed Design Study with Pre/Post and Cluster Randomized Trial Components

Background

The Integrated Infectious Diseases Capacity Building Evaluation (IDCAP) designed two interventions: Integrated Management of Infectious Disease (IMID) training program and On-Site Support (OSS). We evaluated their effects on 23 facility performance indicators, including malaria case management.

Methodology

IMID, a three-week training with two follow-up booster courses, was for two mid- level practitioners, primarily clinical officers and registered nurses, from 36 primary care facilities. OSS was two days of training and continuous quality improvement activities for nine months at 18 facilities, to which all health workers were invited to participate. Facilities were randomized as clusters 1∶1 to parallel OSS “arm A” or control “arm B”. Outpatient data on four malaria case management indicators were collected for 14 months. Analysis compared changes before and during the interventions within arms (relative risk = RR). The effect of OSS was measured with the difference in changes across arms (ratio of RR = RRR).

Findings

The proportion of patients with suspected malaria for whom a diagnostic test result for malaria was recorded decreased in arm B (adjusted RR (aRR) = 0.97; 99%CI: 0.82,1.14) during IMID, but increased 25% in arm A (aRR = 1.25; 99%CI:0.94, 1.65) during IMID and OSS relative to baseline; (aRRR = 1.28; 99%CI:0.93, 1.78). The estimated proportion of patients that received an appropriate antimalarial among those prescribed any antimalarial increased in arm B (aRR = 1.09; 99%CI: 0.87, 1.36) and arm A (aRR = 1.50; 99%CI: 1.04, 2.17); (aRRR = 1.38; 99%CI: 0.89, 2.13). The proportion of patients with a negative diagnostic test result for malaria prescribed an antimalarial decreased in arm B (aRR = 0.96; 99%CI: 0.84, 1.10) and arm A (aRR = 0.67; 99%CI: 0.46, 0.97); (aRRR = 0.70; 99%CI: 0.48, 1.00). The proportion of patients with a positive diagnostic test result for malaria prescribed an antibiotic did not change significantly in either arm.

Interpretation

The combination of IMID and OSS was associated with statistically significant improvements in malaria case management.     

Improving Facility Performance in Infectious Disease Care in Uganda: A Mixed Design Study with Pre/Post and Cluster Randomized Trial Components

BackgroundThe effects of two interventions, Integrated Management of Infectious Disease (IMID) training program and On-Site Support (OSS), were tested on 23 facility performance indicators for emergency triage assessment and treatment (ETAT), malaria, pneumonia, tuberculosis, and HIV.MethodsThe trial was implemented in 36 primary care facilities in Uganda. From April 2010, two mid-level practitioners per facility participated in IMID training. Eighteen of 36 facilities were randomly assigned to Arm A, and received OSS in 2010 (nine monthly two-day sessions); 18 facilities assigned to Arm B did not receive OSS in 2010. Data were collected from Nov 2009 to Dec 2010 using a revised Ministry of Health outpatient medical form and nine registers. We analyzed the effect of IMID training alone by measuring changes before and during IMID training in Arm B, the combined effect of IMID training and OSS by measuring changes in Arm A, and the incremental effect of OSS by comparing changes across Arms A and B.ResultsIMID training was associated with statistically significant improvement in three indicators: outpatients triaged (adjusted relative risks (aRR) = 1.29, 99%CI = 1.01,1.64), emergency and priority patients admitted, detained, or referred (aRR = 1.59, 99%CI = 1.04,2.44), and pneumonia suspects assessed (aRR = 2.31, 99%CI = 1.50,3.55). IMID training and OSS combined was associated with improvements in six indicators: three ETAT indicators (outpatients triaged (aRR = 2.03, 99%CI = 1.13,3.64), emergency and priority patients admitted, detained or referred (aRR = 3.03, 99%CI = 1.40,6.56), and emergency patients receiving at least one appropriate treatment (aRR = 1.77, 99%CI = 1.10,2.84)); two malaria indicators (malaria cases receiving appropriate antimalarial (aRR = 1.50, 99%CI = 1.04,2.17), and patients with negative malaria test results prescribed antimalarial (aRR = 0.67, 99%CI = 0.46,0.97)); and enrollment in HIV care (aRR = 1.58, 99%CI = 1.32,1.89). OSS was associated with incremental improvement in emergency patients receiving at least one appropriate treatment (adjusted ratio of RR = 1.84,99%CI = 1.09,3.12).ConclusionThe trial showed that the OSS intervention significantly improved performance in one of 23 facility indicators.     

Responding to Young People’s Health Risks in Primary Care: A Cluster Randomised Trial of Training Clinicians in Screening and Motivational Interviewing

Objective

To evaluate the effectiveness of a complex intervention implementing best practice guidelines recommending clinicians screen and counsel young people across multiple psychosocial risk factors, on clinicians’ detection of health risks and patients’ risk taking behaviour, compared to a didactic seminar on young people’s health.

Design

Pragmatic cluster randomised trial where volunteer general practices were stratified by postcode advantage or disadvantage score and billing type (private, free national health, community health centre), then randomised into either intervention or comparison arms using a computer generated random sequence. Three months post-intervention, patients were recruited from all practices post-consultation for a Computer Assisted Telephone Interview and followed up three and 12 months later. Researchers recruiting, consenting and interviewing patients and patients themselves were masked to allocation status; clinicians were not.

Setting

General practices in metropolitan and rural Victoria, Australia

Participants

General practices with at least one interested clinician (general practitioner or nurse) and their 14–24 year old patients.

Intervention

This complex intervention was designed using evidence based practice in learning and change in clinician behaviour and general practice systems, and included best practice approaches to motivating change in adolescent risk taking behaviours. The intervention involved training clinicians (nine hours) in health risk screening, use of a screening tool and motivational interviewing; training all practice staff (receptionists and clinicians) in engaging youth; provision of feedback to clinicians of patients’ risk data; and two practice visits to support new screening and referral resources. Comparison clinicians received one didactic educational seminar (three hours) on engaging youth and health risk screening.

Outcome Measures

Primary outcomes were patient report of (1) clinician detection of at least one of six health risk behaviours (tobacco, alcohol and illicit drug use, risks for sexually transmitted infection, STI, unplanned pregnancy, and road risks); and (2) change in one or more of the six health risk behaviours, at three months or at 12 months. Secondary outcomes were likelihood of future visits, trust in the clinician after exit interview, clinician detection of emotional distress and fear and abuse in relationships, and emotional distress at three and 12 months. Patient acceptability of the screening tool was also described for the intervention arm. Analyses were adjusted for practice location and billing type, patients’ sex, age, and recruitment method, and past health risks, where appropriate. An intention to treat analysis approach was used, which included multilevel multiple imputation for missing outcome data.

Results

42 practices were randomly allocated to intervention or comparison arms. Two intervention practices withdrew post allocation, prior to training, leaving 19 intervention (53 clinicians, 377 patients) and 21 comparison (79 clinicians, 524 patients) practices. 69% of patients in both intervention (260) and comparison (360) arms completed the 12 month follow-up. Intervention clinicians discussed more health risks per patient (59.7%) than comparison clinicians (52.7%) and thus were more likely to detect a higher proportion of young people with at least one of the six health risk behaviours (38.4% vs 26.7%, risk difference [RD] 11.6%, Confidence Interval [CI] 2.93% to 20.3%; adjusted odds ratio [OR] 1.7, CI 1.1 to 2.5). Patients reported less illicit drug use (RD -6.0, CI -11 to -1.2; OR 0·52, CI 0·28 to 0·96), and less risk for STI (RD -5.4, CI -11 to 0.2; OR 0·66, CI 0·46 to 0·96) at three months in the intervention relative to the comparison arm, and for unplanned pregnancy at 12 months (RD -4.4; CI -8.7 to -0.1; OR 0·40, CI 0·20 to 0·80). No differences were detected between arms on other health risks. There were no differences on secondary outcomes, apart from a greater detection of abuse (OR 13.8, CI 1.71 to 111). There were no reports of harmful events and intervention arm youth had high acceptance of the screening tool.

Conclusions

A complex intervention, compared to a simple educational seminar for practices, improved detection of health risk behaviours in young people. Impact on health outcomes was inconclusive. Technology enabling more efficient, systematic health-risk screening may allow providers to target counselling toward higher risk individuals. Further trials require more power to confirm health benefits.

Trial Registration

ISRCTN.com ISRCTN16059206.     

A Randomized Trial of Time-Limited Antiretroviral Therapy in Acute/Early HIV Infection

Background

It has been proposed that initiation of antiretroviral treatment (ART) very soon after establishment of HIV infection may be beneficial by improving host control of HIV replication and delaying disease progression.

Methods

People with documented HIV infection of less than 12 months’ duration in Baltimore MD and seven Canadian sites were randomized to either a) observation and deferred ART, or b) immediate treatment with ART for 12 months. All subjects not receiving ART were followed quarterly and permanent ART was initiated according to contemporaneous treatment guidelines. The endpoint of the trial was total ART-free time from study entry until initiation of permanent ART.

Results

One hundred thirteen people were randomized, 56 to the observation arm and 57 to the immediate treatment arm. Twenty-three had acute (<2 months) infection and 90 early (2–12 months) infection. Of those randomized to the immediate treatment arm, 37 completed 12 months of ART according to protocol, 9 declined to stop ART after 12 months, and 11 were nonadherent to the protocol or lost to follow-up. Comparing those in the observation arm to either those who completed 12 months of ART or all 56 who were randomized to immediate ART, there was no significant difference between the arms in treatment-free interval after study entry, which was about 18 months in both arms.

Conclusions

This study did not find a benefit from administration of a brief, time-limited (12-month) course of ART in acute or early HIV infection.

Trial Registration

ClinicalTrials.gov NCT00106171     

Potentially Modifiable Factors Associated with Death of Infants and Children with Severe Pneumonia Routinely Managed in District Hospitals in Malawi

Objective

To investigate recognised co-morbidities and clinical management associated with inpatient pneumonia mortality in Malawian district hospitals.

Methods

Prospective cohort study, of patient records, carried out in Malawi between 1^st October 2000 and 30^th June 2003. The study included all children aged 0-59 months admitted to the paediatric wards in sixteen district hospitals throughout Malawi with severe and very severe pneumonia. We compared individual factors between those that survived (n = 14 076) and those that died (n = 1 633).

Results

From logistic regression analysis, predictors of death in hospital, adjusted for age, sex and severity grade included comorbid conditions of meningitis (OR =2.49, 95% CI 1.50-4.15), malnutrition (OR =2.37, 95% CI 1.94-2.88) and severe anaemia (OR =1.41, 95% CI 1.03-1.92). Requiring supplementary oxygen (OR =2.16, 95% CI 1.85-2.51) and intravenous fluids (OR =3.02, 95% CI 2.13-4.28) were associated with death while blood transfusion was no longer significant (OR =1.10, 95% CI 0.77-1.57) when the model included severe anaemia.

Conclusions

This study identified a number of challenges to improve outcome for Malawian infants and children hospitalised with pneumonia. These included improved assessment of co-morbidities and more rigorous application of standard case management.     

Factors Influencing Health Facility Delivery in Predominantly Rural Communities across the Three Ecological Zones in Ghana: A Cross-Sectional Study

Background

Maternal and neonatal mortality indicators remain high in Ghana and other sub-Saharan African countries. Both maternal and neonatal health outcomes improve when skilled personnel provide delivery services within health facilities. Determinants of delivery location are crucial to promoting health facility deliveries, but little research has been done on this issue in Ghana. This study explored factors influencing delivery location in predominantly rural communities in Ghana.

Methods

Data were collected from 1,500 women aged 15–49 years with live or stillbirths that occurred between January 2011 and April 2013. This was done within the three sites operating Health and Demographic Surveillance Systems, i.e., the Dodowa (Greater Accra Region), Kintampo (Brong Ahafo Region), and Navrongo (Upper-East Region) Health Research Centers in Ghana. Multivariable logistic regression was used to identify the determinants of delivery location, controlling for covariates that were statistically significant in univariable regression models.

Results

Of 1,497 women included in the analysis, 75.6% of them selected health facilities as their delivery location. After adjusting for confounders, the following factors were associated with health facility delivery across all three sites: healthcare provider’s influence on deciding health facility delivery, (AOR = 13.47; 95% CI 5.96–30.48), place of residence (AOR = 4.49; 95% CI 1.14–17.68), possession of a valid health insurance card (AOR = 1.90; 95% CI 1.29–2.81), and socio-economic status measured by wealth quintiles (AOR = 2.83; 95% CI 1.43–5.60).

Conclusion

In addition to known factors such as place of residence, socio-economic status, and possession of valid health insurance, this study identified one more factor associated with health facility delivery: healthcare provider’s influence. Ensuring care provider’s counseling of clients could improve the uptake of health facility delivery in rural communities in Ghana.     

Capacity-Building and Clinical Competence in Infectious Disease in Uganda: A Mixed-Design Study with Pre/Post and Cluster-Randomized Trial Components

Trial Design

Best practices for training mid-level practitioners (MLPs) to improve global health-services are not well-characterized. Two hypotheses were: 1) Integrated Management of Infectious Disease (IMID) training would improve clinical competence as tested with a single arm, pre-post design, and 2) on-site support (OSS) would yield additional improvements as tested with a cluster-randomized trial.

Methods

Thirty-six Ugandan health facilities (randomized 1∶1 to parallel OSS and control arms) enrolled two MLPs each. All MLPs participated in IMID (3-week core course, two 1-week boost sessions, distance learning). After the 3-week course, OSS-arm trainees participated in monthly OSS. Twelve written case scenarios tested clinical competencies in HIV/AIDS, tuberculosis, malaria, and other infectious diseases. Each participant completed different randomly-assigned blocks of four scenarios before IMID (t0), after 3-week course (t1), and after second boost course (t2, 24 weeks after t1). Scoring guides were harmonized with IMID content and Ugandan national policy. Score analyses used a linear mixed-effects model. The primary outcome measure was longitudinal change in scenario scores.

Results

Scores were available for 856 scenarios. Mean correct scores at t0, t1, and t2 were 39.3%, 49.1%, and 49.6%, respectively. Mean score increases (95% CI, p-value) for t0–t1 (pre-post period) and t1–t2 (parallel-arm period) were 12.1 ((9.6, 14.6), p<0.001) and −0.6 ((−3.1, +1.9), p = 0.647) percent for OSS arm and 7.5 ((5.0, 10.0), p<0.001) and 1.6 ((−1.0, +4.1), p = 0.225) for control arm. The estimated mean difference in t1 to t2 score change, comparing arm A (participated in OSS) vs. arm B was −2.2 ((−5.8, +1.4), p = 0.237). From t0–t2, mean scores increased for all 12 scenarios.

Conclusions

Clinical competence increased significantly after a 3-week core course; improvement persisted for 24 weeks. No additional impact of OSS was observed. Data on clinical practice, facility-level performance and health outcomes will complete assessment of overall impact of IMID and OSS.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01190540","term_id":"NCT01190540"}}NCT01190540     

Vitamin D Status Is an Independent Risk Factor for Global Cognitive Impairment in Peritoneal Dialysis Patients

Objective

Vitamin D (VD) deficiency is an independent risk factor for cognitive impairment (CI) in the general population, but VD status in peritoneal dialysis (PD) patients has not been investigated. In this study, we aimed to investigate the relationship between serum VD levels and global and specific cognitive functions in PD patients.

Design and Setting

Cross-sectional study, simultaneously conducted at two PD centers.

Patients

Clinically stable patients (n = 273) undergoing PD for at least 3 months were enrolled over a period of one year.

Main outcome Measures

Demographic and comorbidity data were recorded, and routine biochemical parameters and serum 25-hydroxyvitamin D (25(OH) D) levels of overnight fasted patients were determined. Global cognitive function was assessed by the Modified Mini-Mental State Examination (3MS) score; executive function, by the trail making tests (Trails A and B); and immediate memory, delayed memory, and language ability by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) sub-tests.

Results

In the univariate analysis, serum 25(OH) D levels significantly correlated with 3MS scores (r = -0.139; P = 0.02), and Trail A (r = -0.188; P = 0.002) and B (r = -0.154; P = 0.01) completion times. In the multivariate analysis, 25(OH) D was found to be independently associated with global CI, but not with executive dysfunction. Serum 25(OH) D could not predict scores of immediate/delayed memory and language ability.

Conclusions

VD deficiency is highly prevalent in PD patients and is an independent risk factor for global CI in this patient cohort.     

Access to HIV Services at Non-Governmental and Community-Based Organizations among Men Who Have Sex with Men (MSM) in Cameroon: An Integrated Biological and Behavioral Surveillance Analysis

Background

Men who have sex with men (MSM) are more likely to be living with HIV than other adult men in low- and middle-income countries. MSM experience barriers to accessing HIV services including a lack of available specialized care, and community-level stigma and discrimination. This study aims to examine the uptake of HIV services at non-governmental and community-based organizations (NGOs/CBOs) to identify ways to improve coverage of HIV prevention and treatment among MSM.

Methods

An Integrated Biological and Behavioral Surveillance (IBBS) survey was conducted in Yaoundé and Douala, Cameroon in 2011 using the respondent driven sampling (RDS) method to recruit and interview 239 MSM in Yaoundé and 272 MSM in Douala.

Results

MSM in Yaoundé were statistically significantly more likely to have accessed NGO/CBO services or been reached by an outreach worker in the past 12 months if they had any STI symptoms (aOR 2.17 CI 1.02-4.59. p=0.04), or if they had a larger MSM social network (aOR 1.02 CI 1.01-1.04. p<0.01). MSM in Douala were more likely to have accessed NGO/CBO services or been reached by an outreach worker in the past 12 months if they were living with HIV (aOR 3.60 CI 1.35-9.60. p=0.01), or if they reported higher numbers of male sexual partners (aOR 1.17 CI 1.00-1.36. p=0.046). Compared to men in Douala, MSM in Yaoundé were significantly less likely to have accessed NGO/CBO services or been reached by an outreach worker in the past 12 months (aOR 0.22 CI 0 .14-0.34. p=<0.01).

Conclusions

With appropriate funding and resources, community-based organizations that provide care specifically for MSM can improve access to HIV prevention, treatment, and care services. Additionally, using social networks to reach MSM can connect greater numbers of the population to effective HIV interventions, which will improve health outcomes and decrease onward transmission of HIV.     

Pre-Dialysis Visits to a Nephrology Department and Major Cardiovascular Events in Patients Undergoing Dialysis

Background and Objectives

Pre-dialysis care by a nephrology out-patient department (OPD) may affect the outcomes of patients who ultimately undergo maintenance dialysis. This study examined the effect of pre-dialysis care by a nephrology OPD on the incidence of one-year major cardiovascular events after initiation of dialysis.

Design, Setting Participants, & Measurements

The study consisted of Taiwanese patients with chronic kidney disease (CKD) who commenced dialysis from 2006 to 2008. The number of nephrology OPD visits during the critical care period (within 6 months of initiation of dialysis) and the early care period (6–36 months before initiation of dialysis) were analyzed. The primary outcome measure was one-year major cardiovascular events.

Results

A total of 1191 CKD patients who initiated dialysis from 2006 to 2008 were included. Binary logistic regression showed that patients with ≧3 visits during the critical care period and those with ≧11 visits during the early care period had fewer composite major cardiovascular events than those with 0 visits. Patients with early referral are less likely to experience composite major cardiovascular events than those with late referral, with aOR 0.574 (95% CI = 0.43–0.77, P<0.001). Patients with both ≧3 visits during critical care period and ≧11 visits during early care period were less likely to experience composite major cardiovascular events (aOR = 0.25, 95% CI = 0.16–0.39, P < 0.001).

Conclusions

Patients with adequate pre-dialysis nephrology OPD visits, not just early referral, may had fewer one-year composite major cardiovascular events after initiation of dialysis. This information may be important to medical care providers and public health policy makers in their efforts to improve the well-being of CKD patients.     

Institutional Delivery and Satisfaction among Indigenous and Poor Women in Guatemala,Mexico, and Panama

Indigenous women in Mesoamerica experience disproportionately high maternal mortality rates and are less likely to have institutional deliveries. Identifying correlates of institutional delivery, and satisfaction with institutional deliveries, may help improve facility utilization and health outcomes in this population. We used baseline surveys from the Salud Mesoamérica Initiative to analyze data from 10,895 indigenous and non-indigenous women in Guatemala and Mexico (Chiapas State) and indigenous women in Panama. We created multivariable Poisson regression models for indigenous (Guatemala, Mexico, Panama) and non-indigenous (Guatemala, Mexico) women to identify correlates of institutional delivery and satisfaction. Compared to their non-indigenous peers, indigenous women were substantially less likely to have an institutional delivery (15.2% vs. 41.5% in Guatemala (P<0.001), 29.1% vs. 73.9% in Mexico (P<0.001), and 70.3% among indigenous Panamanian women). Indigenous women who had at least one antenatal care visit were more than 90% more likely to have an institutional delivery (adjusted risk ratio (aRR) = 1.94, 95% confidence interval (CI): 1.44–2.61), compared to those who had no visits. Indigenous women who were advised to give birth in a health facility (aRR = 1.46, 95% CI: 1.18–1.81), primiparous (aRR = 1.44, 95% CI: 1.24–1.68), informed that she should have a Caesarean section (aRR = 1.41, 95% CI: 1.21–1.63), and had a secondary or higher level of education (aRR = 1.36, 95% CI: 1.04–1.79) also had substantially higher likelihoods of institutional delivery. Satisfaction among indigenous women was associated with being able to be accompanied by a community health worker (aRR = 1.15, 95% CI: 1.05–1.26) and facility staff speaking an indigenous language (aRR = 1.10, 95% CI: 1.02–1.19). Additional effort should be exerted to increase utilization of birthing facilities by indigenous and poor women in the region. Improving access to antenatal care and opportunities for higher-level education may increase institutional delivery rates, and providing culturally adapted services may improve satisfaction.     

Efficacy of Enhanced HIV Counseling for Risk Reduction during Pregnancy and in the Postpartum Period: A Randomized Controlled Trial

Introduction

Pregnancy and the postpartum period present important intervention opportunities. Counseling can leverage the motivation women have during this time to change behaviors that may negatively affect their health and the heath of their infants.

Methods

Pregnant women attending an antenatal clinic in South Africa were randomly allocated to treatment (n = 733) and control arms (n = 747). Treatment arm participants received enhanced HIV pre- and post-test counseling, legal support and access to support groups at baseline, which occurred at the first antenatal visit, and then six and ten weeks postpartum. Control arm participants received standard HIV testing and counseling (HTC) and two postpartum attention control sessions. Outcomes were incidence of sexually transmitted infection (STI) by 14 weeks postpartum and past 30-day inconsistent condom use at 14 weeks and 9 months postpartum.

Results

There were no intervention effects on incident STIs for either HIV-negative (adjusted risk ratio (aRR) 1.01, 95% CI 0^.71–1^.44) or HIV-positive participants (aRR 0^.86, 95% CI 0^.61–1^.23). The intervention was associated with a 28% decrease in risk of past 30-day inconsistent condom use at nine-months among HIV-negative women (aRR 0^.72,95% CI 0^.59–0^.88), but did not affect inconsistent condom use among HIV-positive women (aRR1.08; 95% CI 0.67–1.75).

Discussion

An enhanced counseling intervention during pregnancy and the postpartum period can lead to reductions in inconsistent condom use among HIV-negative women. Results underscore the importance of the counseling that accompanies HIV HTC. More work is needed to understand how to promote and sustain risk reduction among HIV-positive women.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01683461","term_id":"NCT01683461"}}NCT01683461     

Etiology and Factors Associated with Pneumonia in Children under 5 Years of Age in Mali: A Prospective Case-Control Study

Background

There are very limited data on children with pneumonia in Mali. The objective was to assess the etiology and factors associated with community-acquired pneumonia in hospitalized children <5 years of age in Mali.

Methods

A prospective hospital-based case-control study was implemented in the Pediatric department of Gabriel Touré University Hospital at Bamako, Mali, between July 2011-December 2012. Cases were children with radiologically-confirmed pneumonia; Controls were hospitalized children without respiratory features, matched for age and period. Respiratory specimens, were collected to identify 19 viruses and 5 bacteria. Whole blood was collected from cases only. Factors associated with pneumonia were assessed by multivariate logistic regression.

Results

Overall, 118 cases and 98 controls were analyzed; 44.1% were female, median age was 11 months. Among pneumonia cases, 30.5% were hypoxemic at admission, mortality was 4.2%. Pneumonia cases differed from the controls regarding clinical signs and symptoms but not in terms of past medical history. Multivariate analysis of nasal swab findings disclosed that S. pneumoniae (adjusted odds ratio [aOR] = 3.4, 95% confidence interval [95% CI]: 1.6–7.0), human metapneumovirus (aOR = 17.2, 95% CI: 2.0–151.4), respiratory syncytial virus [RSV] (aOR = 7.4, 95% CI: 2.3–23.3), and influenza A virus (aOR = 10.7, 95% CI: 1.0–112.2) were associated with pneumonia, independently of patient age, gender, period, and other pathogens. Distribution of S. pneumoniae and RSV differed by season with higher rates of S. pneumoniae in January-June and of RSV in July-September. Pneumococcal serotypes 1 and 5 were more frequent in pneumonia cases than in the controls (P = 0.009, and P = 0.04, respectively).

Conclusions

In this non-PCV population from Mali, pneumonia in children was mainly attributed to S. pneumoniae, RSV, human metapneumovirus, and influenza A virus. Increased pneumococcal conjugate vaccine coverage in children could significantly reduce the burden of pneumonia in sub-Saharan African countries.     

Cotrimoxazole Prophylaxis Discontinuation among Antiretroviral-Treated HIV-1-Infected Adults in Kenya: A Randomized Non-inferiority Trial

Background

Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings.

Methods and Findings

Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ≥18 mo with CD4 count > 350 cells/mm³ in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity (malaria, pneumonia, and diarrhea) and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression.Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm (IRR = 2.27, 95% CI 1.52–3.38; p < 0.001), driven by malaria morbidity. There were 34 cases of malaria, with 33 in the CTX discontinuation arm (IRR = 33.02, 95% CI 4.52–241.02; p = 0.001). Diarrhea and pneumonia rates did not differ significantly between arms (IRR = 1.36, 95% CI 0.82–2.27, and IRR = 1.43, 95% CI 0.54–3.75, respectively). Study limitations include a lack of placebo and a lower incidence of morbidity events than expected.

Conclusions

CTX discontinuation among ART-treated, immune-reconstituted adults in a malaria-endemic region resulted in increased incidence of malaria but not pneumonia or diarrhea. Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence. These data support the 2014 WHO CTX guidelines.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01425073","term_id":"NCT01425073"}}NCT01425073     

The Effect of Single or Repeated Home Visits on the Hanging and Use of Insecticide-Treated Mosquito Nets following a Mass Distribution Campaign - A Cluster Randomized,Controlled Trial

Background

Study objective was to evaluate the effectiveness of commonly used post-campaign hang-up visits on the hanging and use of campaign nets.

Methods

A cluster-randomized trial was carried out in Uganda following an ITN distribution campaign. Five clusters (parishes, consisting of ∼11 villages each) were randomly selected for each of the three study arms with between 7,534 and 9,401 households per arm. Arm 1 received one hang-up visit, while Arm 2 received two visits by volunteers four and seven months after the campaign. Visits consisted of assistance hanging the net and education on net use. The control arm was only exposed to messages during the campaign itself. Three cross-sectional surveys with a two-stage cluster sampling design, representative of the study populations, were carried out to capture the two key outcome variables of net hanging and ITN use. Sample size was calculated to detect at least a 15 percentage-points change in net use, and was 1811 at endline. The analysis used an intention-to-treat approach.

Findings

Both hanging and use of ITN increased during follow-up in a similar way in all three study arms. The proportion of the population using an ITN the previous night was 64.0% (95% CI 60.8, 67.2), for one additional visit, 68.2% (63.8, 72.2) for two visits and 64.0% (59.4, 68.5) for the control. The proportion of households with all campaign nets hanging increased from 55.7% to 72.5% at endline (p<0.0005 for trend), with no difference between study arms. Financial cost per household visited was estimated as USD 2.33 for the first visit and USD 2.24 for the second.

Conclusions

Behavior change communication provided during the campaign or through other channels was sufficient to induce high levels of net hanging and use and additional “hang-up” activities were not cost-effective.     

Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial

Background

Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%).

Methods and Findings

This randomized controlled trial included children (0.5–10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan–Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7g/dl 7 d or more after admission.The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI −7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI −12, 1; p = 0.24). Delayed parasite clearance was associated with the ^N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms.A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner.

Conclusions

A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children.

Trial registration

Pan African Clinical Trials Registry PACTR201102000277177     

Facility Delivery,Postnatal Care and Neonatal Deaths in India: Nationally-Representative Case-Control Studies

Objective

Clinical studies demonstrate the efficacy of interventions to reduce neonatal deaths, but there are fewer studies of their real-life effectiveness. In India, women often seek facility delivery after complications arise, rather than to avoid complications. Our objective was to quantify the association of facility delivery and postnatal checkups with neonatal mortality while examining the “reverse causality” in which the mothers deliver at a health facility due to adverse perinatal events.

Methods

We conducted nationally representative case-control studies of about 300,000 live births and 4,000 neonatal deaths to examine the effect of, place of delivery and postnatal checkup on neonatal mortality. We compared neonatal deaths to all live births and to a subset of live births reporting excessive bleeding or obstructed labour that were more comparable to cases in seeking care.

Findings

In the larger study of 2004–8 births, facility delivery without postnatal checkup was associated with an increased odds of neonatal death (Odds ratio = 2.5; 99% CI 2.2–2.9), especially for early versus late neonatal deaths. However, use of more comparable controls showed marked attenuation (Odds ratio = 0.5; 0.4–0.5). Facility delivery with postnatal checkup was associated with reduced odds of neonatal death. Excess risks were attenuated in the earlier study of 2001–4 births.

Conclusion

The combined effect of facility deliveries with postnatal checks ups is substantially higher than just facility delivery alone. Evaluation of the real-life effectiveness of interventions to reduce child and maternal deaths need to consider reverse causality. If these associations are causal, facility delivery with postnatal check up could avoid about 1/3 of all neonatal deaths in India (~100,000/year).     

Fluoroquinolones versus β-Lactam/β-Lactamase Inhibitors in Outpatients with Chronic Obstructive Pulmonary Disease and Pneumonia: A Nationwide Population-Based Study

Background

Studies on the association between antibiotic treatment and outcomes in outpatients with chronic obstructive pulmonary disease (COPD) and pneumonia are scarce. This study aimed to evaluate the effectiveness of fluoroquinolones and β-lactam/β-lactamase inhibitors for pneumonia in COPD outpatients.

Methods

We conducted a retrospective cohort study and identified 4,851 episodes of pneumonia among COPD outpatients treated with fluoroquinolones or β-lactam/β-lactamase inhibitors from the Taiwan National Health Insurance Research Database during 2002–2011. Using the propensity score analysis, 1,296 pairs of episodes were matched for the demographic and clinical characteristics. The primary outcome was pneumonia/empyema-related hospitalization or emergency department (ED) visits, and the secondary outcomes were treatment failure, all-cause mortality and medical costs within 30 days.

Results

Compared with episodes treated with β-lactam/β-lactamase inhibitors, episodes treated with fluoroquinolones had similar clinical outcomes. The rates of pneumonia/empyema-related hospitalization or ED visits were 3.9% and 3.5% in the fluoroquinolone and β-lactam/β-lactamase inhibitor groups, respectively (adjusted hazard ratio [aHR], 1.11; 95% confidence interval [CI], 0.74–1.66). The percentage of treatment failure and all-cause mortality were 28.2% versus 31.3% (adjusted odds ratio, 0.86; 95% CI, 0.73–1.02) and 0.5% versus 0.4% (aHR, 1.40; 95% CI, 0.45–4.41) in the fluoroquinolone and β-lactam/β-lactamase inhibitor groups, respectively. The medical expenditures, including total medical costs (528 versus 455 US dollars) and pneumonia-related costs (202 vs. 155 USD) were also balanced between the two treatment groups (both P >0.05).

Conclusions

For pneumonia in COPD outpatients, fluoroquinolones were associated with similar clinical outcomes and medical expenditures compared with β-lactam/β-lactamase inhibitors.     

National Trends in the Ambulatory Treatment of Hypertension in the United States, 1997-2012

Importance

Hypertension is common and costly. Over the past decade, new antihypertensive therapies have been developed, several have lost patent protection and additional evidence regarding the safety and effectiveness of these agents has accrued.

Objective

To examine trends in the use of antihypertensive therapies in the United States between 1997 and 2012.

Design, Setting and Participants

We used nationally representative audit data from the IMS Health National Disease and Therapeutic Index to examine the ambulatory pharmacologic treatment of hypertension.

Outcome Measures

Our primary unit of analysis was a visit where hypertension was a reported diagnosis and treated with a pharmacotherapy (treatment visit). We restricted analyses to the use of six therapeutic classes of antihypertensive medications among individuals 18 years or older.

Results

Annual hypertension treatment visits increased from 56.9 million treatment visits (95% confidence intervals [CI], 53.9–59.8) in 1997 to 83.3 million visits (CI 79.2–87.3) in 2008, then declined steadily to 70.9 million visits (CI 66.7–75.0) by 2012. Angiotensin receptor blocker utilization increased substantially from 3% of treatment visits in 1997 to 18% by 2012, whereas calcium channel blocker use decreased from 27% to 18% of visits. Rates of diuretic and beta-blocker use remained stable and represented 24%–30% and 14–16% of visits, respectively. Use of direct renin inhibitor accounted for fewer than 2% of annual visits. The proportion of visits treated using fixed-dose combination therapies increased from 28% to 37% of visits.

Conclusions

Several important changes have occurred in the landscape of antihypertensive treatment in the United States during the past decade. Despite their novel mechanism of action, the adoption rate of direct renin inhibitors remains low.     

Intentional Weight Loss and All-Cause Mortality: A Meta-Analysis of Randomized Clinical Trials

Background

Obesity is associated with increased mortality, and weight loss trials show rapid improvement in many mortality risk factors. Yet, observational studies typically associate weight loss with higher mortality risk. The purpose of this meta-analysis of randomized controlled trials (RCTs) of weight loss was to clarify the effects of intentional weight loss on mortality.

Methods

2,484 abstracts were identified and reviewed in PUBMED, yielding 15 RCTs reporting (1) randomization to weight loss or non-weight loss arms, (2) duration of ≥18 months, and (3) deaths by intervention arm. Weight loss interventions were all lifestyle-based. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12), a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials.

Results

Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30–46 kg/m², follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95% CI: 0.73–1.00). There was no evidence for heterogeneity of effect (Cochran’s Q = 5.59 (11 d.f.; p = 0.90); I² = 0). Results were similar in trials with a mean age at randomization ≥55 years (RR = 0.84; 95% CI 0.71–0.99) and a follow-up time of ≥4 years (RR = 0.85; 95% CI 0.72–1.00).

Conclusions

In obese adults, intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality.