Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Cost-effectiveness and public health impact of typhoid conjugate vaccine introduction strategies in Bangladesh.

PURPOSE: Typhoid fever causes substantial morbidity and mortality in Bangladesh. The government of Bangladesh plans to introduce typhoid conjugate vaccines (TCV) in its expanded program on immunization (EPI) schedule. However, the optimal introduction strategy in addition to the costs and benefits of such a program are unclear. METHODS: We extended an existing mathematical model of typhoid transmission to integrate cost data, clinical incidence data, and recently conducted serosurveys in urban, semi-urban, and rural areas. In our primary analysis, we evaluated the status quo (i.e., no vaccination) and eight vaccine introduction strategies including routine and 1-time campaign strategies, which differed by age groups targeted and geographic focus. Model outcomes included clinical incidence, seroincidence, deaths, costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for each strategy. We adopted a societal perspective, 10-year model time horizon, and 3 % annual discount rate. We performed probabilistic, one-way, and scenario sensitivity analyses including adopting a healthcare perspective and alternate model time horizons. RESULTS: We projected that all TCV strategies would be cost saving compared to the status quo. The preferred strategy was a nationwide introduction of TCV at 9-12 months of age with a single catch-up campaign for children ages 1-15, which was cost saving compared to all other strategies and the status quo. In the 10 years following implementation, we projected this strategy would avert 3.77 million cases (95 % CrI: 2.60 - 5.18), 11.31 thousand deaths (95 % CrI: 3.77 - 23.60), and save $172.35 million (95 % CrI: -14.29 - 460.59) compared to the status quo. Our findings were broadly robust to changes in parameter values and willingness-to-pay thresholds. CONCLUSIONS: We projected that nationwide TCV introduction with a catch-up campaign would substantially reduce typhoid incidence and very likely be cost saving in Bangladesh.

Community-based asthma assessment in young children: adaptations for a multicentre longitudinal study in South Asia.

Background: Systematic assessment of childhood asthma is challenging in low- and middle-income country (LMIC) settings due to the lack of standardised and validated methodologies. We describe the contextual challenges and adaptation strategies in the implementation of a community-based asthma assessment in four resource-constrained settings in Bangladesh, India, and Pakistan. Method: We followed a group of children of age 6-8 years for 12 months to record their respiratory health outcomes. The study participants were enrolled at four study sites of the 'Aetiology of Neonatal Infection in South Asia (ANISA)' study. We standardised the research methods for the sites, trained field staff for uniform data collection and provided a 'Child Card' to the caregiver to record the illness history of the participants. We visited the children on three different occasions to collect data on respiratory-related illnesses. The lung function of the children was assessed in the outreach clinics using portable spirometers before and after 6-minute exercise, and capillary blood was examined under light microscopes to determine eosinophil levels. Results: We enrolled 1512 children, 95.5% (1476/1512) of them completed the follow-up, and 81.5% (1232/1512) participants attended the lung function assessment tests. Pre- and post-exercise spirometry was performed successfully in 88.6% (1091/1232) and 85.7% (1056/1232) of children who attempted these tests. Limited access to health care services, shortage of skilled human resources, and cultural diversity were the main challenges in adopting uniform procedures across all sites. Designing the study implementation plan based on the local contexts and providing extensive training of the healthcare workers helped us to overcome these challenges. Conclusion: This study can be seen as a large-scale feasibility assessment of applying spirometry and exercise challenge tests in community settings of LMICs and provides confidence to build capacity to evaluate children's respiratory outcomes in future translational research studies.

Derivation and validation of a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality in 20 countries.

INTRODUCTION: Existing risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality across various settings. METHODS: We used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool. RESULTS: A total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84). CONCLUSIONS: The PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality.

Invasive Bacterial Vaccine-Preventable Disease Surveillance: Successes and Lessons Learned in Bangladesh for a Sustainable Path Forward.

We have made considerable progress in setting and scaling up surveillance systems to drive evidence-based policy decisions, but the recent epidemics highlight that current systems are not optimally designed. Good surveillance systems should be coordinated, comprehensive, and adaptive. They should generate data in real time for immediate analysis and intervention, whether for endemic diseases or potential epidemics. Such systems are especially needed in low-resource settings where disease burden is the highest, but tracking systems are the weakest here due to competing priorities and constraints on available resources. In this article, using the examples of 3 large, and mostly successful, infectious disease surveillance studies in Bangladesh, we identify 2 core limitations-the pathogen bias and the vaccine bias-in the way current surveillance programs are designed for low-resource settings. We highlight the strengths of the current Global Invasive Bacterial Vaccine Preventable Disease Surveillance Network of the World Health Organization and present case studies from Bangladesh to illustrate how this surveillance platform can be leveraged to overcome its limitations. Finally, we propose a set of criteria for building a comprehensive infectious disease surveillance system with the hope of encouraging current systems to use the limited resources as optimally as possible to generate the maximum amount of knowledge.

Metabolic gestational age assessment in low resource settings: a validation protocol.

Preterm birth is the leading global cause of neonatal morbidity and mortality. Reliable gestational age estimates are useful for quantifying population burdens of preterm birth and informing allocation of resources to address the problem. However, evaluating gestational age in low-resource settings can be challenging, particularly in places where access to ultrasound is limited. Our group has developed an algorithm using newborn screening analyte values derived from dried blood spots from newborns born in Ontario, Canada for estimating gestational age within one to two weeks. The primary objective of this study is to validate a program that derives gestational age estimates from dried blood spot samples (heel-prick or cord blood) collected from health and demographic surveillance sites and population representative health facilities in low-resource settings in Zambia, Kenya, Bangladesh and Zimbabwe. We will also pilot the use of an algorithm to identify birth percentiles based on gestational age estimates and weight to identify small for gestational age infants. Once collected from local sites, samples will be tested by the Newborn Screening Ontario laboratory at the Children's Hospital of Eastern Ontario (CHEO) in Ottawa, Canada. Analyte values will be obtained through laboratory analysis for estimation of gestational age as well as screening for other diseases routinely conducted at Ontario's newborn screening program. For select conditions, abnormal screening results will be reported back to the sites in real time to facilitate counseling and future clinical management. We will determine the accuracy of our existing algorithm for estimation of gestational age in these newborn samples. Results from this research hold the potential to create a feasible method to assess gestational age at birth in low- and middle-income countries where reliable estimation may be otherwise unavailable.

The role of immune correlates of protection on the pathway to licensure, policy decision and use of group B Streptococcus vaccines for maternal immunization: considerations from World Health Organization consultations.

The development of a group B Streptococcus (GBS) vaccine for maternal immunization constitutes a global public health priority, to prevent GBS-associated early life invasive disease, stillbirth, premature birth, maternal sepsis, adverse neurodevelopmental consequences, and to reduce perinatal antibiotic use. Sample size requirements for the conduct of a randomized placebo-controlled trial to assess vaccine efficacy against the most relevant clinical endpoints, under conditions of appropriate ethical standards of care, constitute a significant obstacle on the pathway to vaccine availability. Alternatively, indirect evidence of protection based on immunologic data from vaccine and sero-epidemiological studies, complemented by data from opsonophagocytic in vitro assays and animal models, could be considered as pivotal data for licensure, with subsequent confirmation of effectiveness against disease outcomes in post-licensure evaluations. Based on discussions initiated by the World Health Organization we present key considerations about the potential role of correlates of protection towards an accelerated pathway for GBS vaccine licensure and wide scale use. Priority activities to support progress to regulatory and policy decision are outlined.

Disparities by sex in care-seeking behaviors and treatment outcomes for pneumonia among children admitted to hospitals in Bangladesh.

BACKGROUND: Incidence of community acquired pneumonia is high globally. In Bangladesh, more male children than female children are brought to hospitals for pneumonia. We examined if there was disparities in the severity of illness and outcome by sex among children who were admitted with pneumonia to hospitals in Bangladesh. METHODS: Hospitalized children, aged 2 to 59 months, meeting a case definition of pneumonia were recruited in seven hospitals following parental consent. At baseline, study doctors obtained socio-demographic characteristics and care seeking behaviors for pneumonia, and then clinical data were collected throughout the hospital stay. Multivariate analysis was performed to determine if the sex of the child had a relationship with either illness severity on admission or outcome in the hospital. RESULTS: Between May 2004 and December 2008, 6,856 children, including 35% females, were recruited. A total of 1,371 (19.9%) children had non-severe pneumonia, 4,118 (60.0%) had severe pneumonia, and 1,367 (19.9%) had very severe pneumonia. A higher proportion of hospitalized females had very severe pneumonia as compared to males (21.5% versus 19.1%; P = 0.01), but there was no difference by sex in the proportion of children with severe or non-severe pneumonia. There was no difference by sex observed in the clinical management provided in the hospital, but a greater proportion of females (4.7%) as compared to males (3.6%) died in hospitals (P = 0.04). In multivariate analyses, female sex was associated with very severe pneumonia on admission (OR: 1.26, 95% CI: 1.09-1.47) and fatal outcome in the hospitals (OR: 1.31, 95% CI: 1.01-1.71). Death in female children admitted with very severe pneumonia was 4 times higher than that reported in males (OR: 4.37, 95% CI: 3.24-5.89). CONCLUSION: Our data demonstrates a sex-based disparity in the severity of pneumonia and deaths among children admitted to hospitals in Bangladesh, despite no existing disparity by sex in hospital treatment. These findings call for further investigations to explore the determinants of health seeking behavior by parents with children with pneumonia in a community that favors males to females, and to understand the role of differences by sex in childhood pneumonia outcomes in Bangladesh.

Typhoid conjugate vaccines: a new tool in the fight against antimicrobial resistance.

Typhoid fever is an acute systemic infectious disease responsible for an estimated 12-20 million illnesses and over 150 000 deaths annually. In March, 2018, a new recommendation was issued by WHO for the programmatic use of typhoid conjugate vaccines in endemic countries. Health economic analyses of typhoid vaccines have informed funding decisions and national policies regarding vaccine rollout. However, by focusing only on averted typhoid cases and their associated costs, traditional cost-effectiveness analyses might underestimate crucial benefits of typhoid vaccination programmes, because the potential effect of typhoid vaccines on the treatment of patients with non-specific acute febrile illnesses is not considered. For every true case of typhoid fever, three to 25 patients without typhoid disease are treated with antimicrobials unnecessarily, conservatively amounting to more than 50 million prescriptions per year. Antimicrobials for suspected typhoid might therefore be an important selective pressure for the emergence and spread of antimicrobial resistance globally. We propose that large-scale, more aggressive typhoid vaccination programmes-including catch-up campaigns in children up to 15 years of age, and vaccination in lower incidence settings-have the potential to reduce the overuse of antimicrobials and thereby reduce antimicrobial resistance in many bacterial pathogens. Funding bodies and national governments must therefore consider the potential for broad reductions in antimicrobial use and resistance in decisions related to the rollout of typhoid conjugate vaccines.

Pneumococcal Conjugate Vaccine impact assessment in Bangladesh.

The study examines the impact of the introduction of 10-valent Pneumococcal Conjugate Vaccine (PCV10) into Bangladesh's national vaccine program. PCV10 is administered to children under 1 year-old; the scheduled ages of administration are at 6, 10, and 18 weeks. The study is conducted in ~770,000 population containing ~90,000 <5 children in Sylhet, Bangladesh and has five objectives: 1) To collect data on community-based pre-PCV incidence rates of invasive pneumococcal diseases (IPD) in 0-59 month-old children in Sylhet, Bangladesh; 2) To evaluate the effectiveness of PCV10 introduction on Vaccine Type (VT) IPD in 3-59 month-old children using an incident case-control study design. Secondary aims include measuring the effects of PCV10 introduction on all IPD in 3-59 month-old children using case-control study design, and quantifying the emergence of Non Vaccine Type IPD; 3) To evaluate the effectiveness of PCV10 introduction on chest radiograph-confirmed pneumonia in children 3-35 months old using incident case-control study design. We will estimate the incidence trend of clinical and radiologically-confirmed pneumonia in 3-35 month-old children in the study area before and after introduction of PCV10; 4) To determine the feasibility and utility of lung ultrasound for the diagnosis of pediatric pneumonia in a large sample of children in a resource-limited setting. We will also evaluate the effectiveness of PCV10 introduction on ultrasound-confirmed pneumonia in 3-35 month-old children using an incident case-control design and to examine the incidence trend of ultrasound-confirmed pneumonia in 3-35 month-old children in the study area before and after PCV10 introduction; and 5) To determine the direct and indirect effects of vaccination status on nasopharyngeal colonization on VT pneumococci among children with pneumonia .  This paper presents the methodology. The study will allow us to conduct a comprehensive and robust assessment of the impact of national introduction of PCV10 on pneumococcal disease in Bangladesh.

Epidemiology of Otitis Media With Otorrhea Among Bangladeshi Children: Baseline Study for Future Assessment of Pneumococcal Conjugate Vaccine Impact.

BACKGROUND: Otitis media (OM) poses a high disease burden on Bangladeshi children, but little is known about its etiologies. We conducted a surveillance study in the largest pediatric hospital to characterize pathogens responsible for OM. METHODS: In the outpatient ear-nose-throat department of Dhaka Shishu Hospital, which serves 0 to 18-year-old children, we collected ear swabs from OM children with otorrhea from April 2014 to March 2015. We cultured all specimens for bacterial pathogens and assessed serotype and antimicrobial susceptibility of Streptococcus pneumoniae (Spn) and Haemophilus influenzae (Hi) isolates. RESULTS: We recorded 1111 OM episodes; 88% (981/1111) involved otorrhea, and we collected samples from 91% (891/981) of these children. Fifty-one percent (452/891) were culture positive (contaminants excluded), with Hi (21%, 187/891) and Spn (18%, 164/891) most commonly detected. Overall, 45 distinct single and mixed pathogens were revealed. Dominant pneumococcal serotypes were 19A, 19F, 3 and 14; 98% of Hi isolates were nontypeable. Pneumococcal conjugate vaccine (PCV)10 and PCV10 + 6A serotypes accounted for 8% and 9% of all OM and 46% and 49% of pneumococcus-positive cases, respectively, and were more likely to be nonsusceptible to at least 1 antibiotic (erythromycin and/or trimethoprim-sulfamethoxazole) than nonvaccine serotypes (91% vs. 77%). Staphylococcus aureus (9%, 83/891) and Pseudomonas aeruginosa (4%, 38/891) were also found. CONCLUSIONS: Nontypeable Hi (NTHi) and Spn are predominant causes of OM in Bangladesh. PCV10, introduced in March 2015, is likely to reduce pneumococcal and overall OM burden. Data collected post-PCV10 will provide comprehensive insight into the effects of this vaccine on these pathogens.

Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children: Why, What, and How to Undertake Estimates?

Improving maternal, newborn, and child health is central to Sustainable Development Goal targets for 2030, requiring acceleration especially to prevent 5.6 million deaths around the time of birth. Infections contribute to this burden, but etiological data are limited. Group B Streptococcus (GBS) is an important perinatal pathogen, although previously focus has been primarily on liveborn children, especially early-onset disease. In this first of an 11-article supplement, we discuss the following: (1) Why estimate the worldwide burden of GBS disease? (2) What outcomes of GBS in pregnancy should be included? (3) What data and epidemiological parameters are required? (4) What methods and models can be used to transparently estimate this burden of GBS? (5) What are the challenges with available data? and (6) How can estimates address data gaps to better inform GBS interventions including maternal immunization? We review all available GBS data worldwide, including maternal GBS colonization, risk of neonatal disease (with/without intrapartum antibiotic prophylaxis), maternal GBS disease, neonatal/infant GBS disease, and subsequent impairment, plus GBS-associated stillbirth, preterm birth, and neonatal encephalopathy. We summarize our methods for searches, meta-analyses, and modeling including a compartmental model. Our approach is consistent with the World Health Organization (WHO) Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER), published in The Lancet and the Public Library of Science (PLoS). We aim to address priority epidemiological gaps highlighted by WHO to inform potential maternal vaccination.

Estimates of the Burden of Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children.

BACKGROUND: We aimed to provide the first comprehensive estimates of the burden of group B Streptococcus (GBS), including invasive disease in pregnant and postpartum women, fetal infection/stillbirth, and infants. Intrapartum antibiotic prophylaxis is the current mainstay of prevention, reducing early-onset infant disease in high-income contexts. Maternal GBS vaccines are in development. METHODS: For 2015 live births, we used a compartmental model to estimate (1) exposure to maternal GBS colonization, (2) cases of infant invasive GBS disease, (3) deaths, and (4) disabilities. We applied incidence or prevalence data to estimate cases of maternal and fetal infection/stillbirth, and infants with invasive GBS disease presenting with neonatal encephalopathy. We applied risk ratios to estimate numbers of preterm births attributable to GBS. Uncertainty was also estimated. RESULTS: Worldwide in 2015, we estimated 205000 (uncertainty range [UR], 101000-327000) infants with early-onset disease and 114000 (UR, 44000-326000) with late-onset disease, of whom a minimum of 7000 (UR, 0-19000) presented with neonatal encephalopathy. There were 90000 (UR, 36000-169000) deaths in infants <3 months age, and, at least 10000 (UR, 3000-27000) children with disability each year. There were 33000 (UR, 13000-52000) cases of invasive GBS disease in pregnant or postpartum women, and 57000 (UR, 12000-104000) fetal infections/stillbirths. Up to 3.5 million preterm births may be attributable to GBS. Africa accounted for 54% of estimated cases and 65% of all fetal/infant deaths. A maternal vaccine with 80% efficacy and 90% coverage could prevent 107000 (UR, 20000-198000) stillbirths and infant deaths. CONCLUSIONS: Our conservative estimates suggest that GBS is a leading contributor to adverse maternal and newborn outcomes, with at least 409000 (UR, 144000-573000) maternal/fetal/infant cases and 147000 (UR, 47000-273000) stillbirths and infant deaths annually. An effective GBS vaccine could reduce disease in the mother, the fetus, and the infant.

Integration of enteric fever surveillance into the WHO-coordinated Invasive Bacterial-Vaccine Preventable Diseases (IB-VPD) platform: A low cost approach to track an increasingly important disease.

BACKGROUND: Lack of surveillance systems and accurate data impede evidence-based decisions on treatment and prevention of enteric fever, caused by Salmonella Typhi/Paratyphi. The WHO coordinates a global Invasive Bacterial-Vaccine Preventable Diseases (IB-VPD) surveillance network but does not monitor enteric fever. We evaluated the feasibility and sustainability of integrating enteric fever surveillance into the ongoing IB-VPD platform. METHODOLOGIES: The IB-VPD surveillance system uses WHO definitions to enroll 2-59 month children hospitalized with possible pneumonia, sepsis or meningitis. We expanded this surveillance system to additionally capture suspect enteric fever cases during 2012-2016, in two WHO sentinel hospitals of Bangladesh, by adding inclusion criteria of fever ≥102°F for ≥3 days, irrespective of other manifestations. Culture-positive enteric fever cases from in-patient departments (IPD) detected in the hospital laboratories but missed by the expanded surveillance, were also enrolled to assess completion. Costs for this integration were calculated for the additional personnel and resources required. PRINCIPAL FINDINGS: In the IB-VPD surveillance, 5,185 cases were enrolled; 3% (N = 171/5185) were positive for microbiological growth, of which 55% (94/171) were culture-confirmed cases of enteric fever (85 Typhi and 9 Paratyphi A). The added inclusion criteria for enteric fever enrolled an additional 1,699 cases; 22% (358/1699) were positive, of which 85% (349/358) were enteric fever cases (305 Typhi and 44 Paratyphi A). Laboratory surveillance of in-patients of all ages enrolled 311 additional enteric fever cases (263 Typhi and 48 Paratyphi A); 9% (28/311) were 2-59 m and 91% (283/311) >59 m. Altogether, 754 (94+349+311) culture-confirmed enteric fever cases were found, of which 471 were 2-59 m. Of these 471 cases, 94% (443/471) were identified through the hospital surveillances and 6% (28/471) through laboratory results. Twenty-three percent (170/754) of all cases were children <2 years. Additional cost for the integration was USD 44,974/year, a 27% increase to the IB-VPD annual expenditure. CONCLUSION: In a setting where enteric disease is a substantial public health problem, we could integrate enteric fever surveillance into the standard IB-VPD surveillance platform at a modest cost.

Detection of co-colonization with Streptococcus pneumoniae by algorithmic use of conventional and molecular methods.

Detection of pneumococcal carriage by multiple co-colonizing serotypes is important in assessing the benefits of pneumococcal conjugate vaccine (PCV). Various methods differing in sensitivity, cost and technical complexity have been employed to detect multiple serotypes of pneumococcus in respiratory specimens. We have developed an algorithmic method to detect all known serotypes that preserves the relative abundance of specific serotypes by using Quellung-guided molecular techniques. The method involves culturing respiratory swabs followed by serotyping of 100 colonies by either capsular (10 colonies) or PCR (90 colonies) reactions on 96-well plates. The method was evaluated using 102 nasal swabs from children carrying pneumococcus. Multiple serotypes were detected in 22% of carriers, compared to 3% by World Health Organization (WHO)-recommended morphology-based selection of 1 to 3 colonies. Our method, with a processing cost of $87, could detect subdominant strains making up as low as 1% of the population. The method is affordable, practical, and capable of detecting all known serotypes without false positive reactions or change in the native distribution of multiple serotypes.

Measuring coverage in MNCH: a prospective validation study in Pakistan and Bangladesh on measuring correct treatment of childhood pneumonia.

BACKGROUND: Antibiotic treatment for pneumonia as measured by Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) is a key indicator for tracking progress in achieving Millennium Development Goal 4. Concerns about the validity of this indicator led us to perform an evaluation in urban and rural settings in Pakistan and Bangladesh. METHODS AND FINDINGS: Caregivers of 950 children under 5 y with pneumonia and 980 with "no pneumonia" were identified in urban and rural settings and allocated for DHS/MICS questions 2 or 4 wk later. Study physicians assigned a diagnosis of pneumonia as reference standard; the predictive ability of DHS/MICS questions and additional measurement tools to identify pneumonia versus non-pneumonia cases was evaluated. Results at both sites showed suboptimal discriminative power, with no difference between 2- or 4-wk recall. Individual patterns of sensitivity and specificity varied substantially across study sites (sensitivity 66.9% and 45.5%, and specificity 68.8% and 69.5%, for DHS in Pakistan and Bangladesh, respectively). Prescribed antibiotics for pneumonia were correctly recalled by about two-thirds of caregivers using DHS questions, increasing to 72% and 82% in Pakistan and Bangladesh, respectively, using a drug chart and detailed enquiry. CONCLUSIONS: Monitoring antibiotic treatment of pneumonia is essential for national and global programs. Current (DHS/MICS questions) and proposed new (video and pneumonia score) methods of identifying pneumonia based on maternal recall discriminate poorly between pneumonia and children with cough. Furthermore, these methods have a low yield to identify children who have true pneumonia. Reported antibiotic treatment rates among these children are therefore not a valid proxy indicator of pneumonia treatment rates. These results have important implications for program monitoring and suggest that data in its current format from DHS/MICS surveys should not be used for the purpose of monitoring antibiotic treatment rates in children with pneumonia at the present time.

Assessment of aortic stiffness in marfan syndrome using two-dimensional and Doppler echocardiography.

BACKGROUND: Extracellular matrix remodeling in the aortic wall results in increased aortic stiffness (AoS) in Marfan syndrome (MFS). Pulsed-wave velocity (PWV) constitutes the best indirect AoS measurement. We aimed to assess PWV in MFS patients using two-dimensional (2D) and Doppler echocardiography. METHODS: Thirty-one MFS patients, (mean age 31 ± 14 years, 16 men) and 31 controls were examined. Blood flow was recorded in the aorta near the aortic valve and immediately after in the descending aorta with simultaneous electrocardiography. PWV was calculated by dividing the distance between the two sample volume positions (D) by the time difference (TD) between the intervals from the QRS start to the ascending and descending aortic flow onsets. B-stiffness was also measured. RESULTS: TD (described in "Methods" section) and, aortic arch length were significantly increased in MFS patients, P < 0.001. Thus, PWV values were significantly higher in patients when compared with controls, 7.20 m/s (5.12, 9.43) versus 4.64 m/s (3.37, 6.24), P < 0.001. B-stiffness was also significantly increased in MFS patients; 5.15 (3.69, 7.65) versus 2.44 (1.82, 3.66), P < 0.001. Multiple regression analysis showed a positive association with MFS diagnosis and age, (P = 0.002 and 0.009, respectively). Reproducibility of PWV measurements was <5%. CONCLUSIONS: AoS was significantly higher in MFS patients as expected. Our data demonstrated that PWV measurements can be performed, in the absence of serious musculoskeletal abnormalities in MFS adults, as part of a cardiac ultrasound scan. This technique can be helpful in diagnosis and management in MFS.