Elevation of CD56brightCD16- lymphocytes in MDR pulmonary tuberculosis

Background: Protective immune responses induced in the majority of people infected with Mycobacterium tuberculosis enable them to control TB infection. Objective: The aim of this study was to investigate CD56 and CD16 positive peripheral blood mononuclear cells (PBMCs) and leukocyte subsets from multi-drug resistant pulmonary tuberculosis (MDR-TB), and compare them with nonresistant (NR) TB patients and healthy controls. Methods: 13 MDR-tuberculosis patients, 20 NR-TB individuals and 40 healthy subjects were included. Peripheral blood mononuclear cells were double stained with fluorochrome conjugated antibodies against CD56 and CD16 cell surface markers. The phenotype of positive cells was then analyzed by flow cytometry and the percent- ages of CD56+ CD16+, CD56- CD16+, CD56dimCD16+/-, and CD56brightCD16+/- subsets were calculated. Results: There was a significant decline in the percentage of CD56+CD16+ lymphocytes in both MDR and NR-TB patients compared with healthy controls. We also observed lower proportions of CD56dim/brightCD16+ in addition to higher percentages of CD56dim/brightCD16- subsets in all TB patients (p�0.05). In MDR- TB, our findings demonstrated a distinct phenotypic feature with increased levels of CD56brightCD16- in comparison with both NR-TB and healthy subjects. Conclusion: Considering the function of CD56/CD16 expressing cells in TB, we suggest that pheno- typic characteristics of PBMCs in MDR-TB may correlate with their status of drug re- sistance and probably with their high mortality rates

Geographical and socioeconomic inequalities in women and children’s nutritional status in Pakistan in 2011: an analysis of data from a nationally representative survey

Background Pakistan has one of the highest levels of child and maternal undernutrition worldwide, but little information about geographical and socioeconomic inequalities is available. We aimed to analyse anthropometric indicators for childhood and maternal nutrition at a district level in Pakistan and assess the association of nutritional status with food security and maternal and household socioeconomic factors. Methods We used data from the 2011 Pakistan National Nutrition Survey, which included anthropometric measurements for 33 638 children younger than 5 years and 24 826 women of childbearing age. We estimated the prevalences of stunting, wasting, and underweight among children and of underweight, overweight, and obesity in women for all 143 districts of Pakistan using a Bayesian spatial technique. We used a mixed-eff ect linear model to analyse the association of nutritional status with individual and household sociodemographic factors and food security. Findings Stunting prevalence in Pakistan’s districts ranged between 22% (95% credible interval 19–26) and 76% (69–83); the lowest fi gures for wasting and underweight were both less than 2·5% and the highest were 42% (34–50) for wasting and 54% (49–59) for underweight. In 106 districts, more women were overweight than were underweight; in 49 of these districts more women were obese than were underweight. Children were better nourished if their mothers were taller or had higher weight, if they lived in wealthier households, and if their mothers had 10 or more years of education. Severe food insecurity was associated with worse nutritional outcomes for both children and women. Interpretation We noted large social and geographical inequalities in child and maternal nutrition in Pakistan, masked by national and provincial averages. Pakistan is also beginning to face the concurrent challenge of high burden of childhood undernutrition and overweight and obesity among women of reproductive age. Planning, implementation, and evaluation of programmes for food and nutrition should be based on district-level needs and outcomes

Transcriptomic profiling of tumor-infiltrating CD4 + TIM-3 + T Cells reveals their suppressive, exhausted, and metastatic characteristics in colorectal cancer patients

T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients

Network information and connected correlations

Entropy and information provide natural measures of correlation among elements in a network. We construct here the information theoretic analog of connected correlation functions: irreducible $N$--point correlation is measured by a decrease in entropy for the joint distribution of $N$ variables relative to the maximum entropy allowed by all the observed $N-1$ variable distributions. We calculate the ``connected information'' terms for several examples, and show that it also enables the decomposition of the information that is carried by a population of elements about an outside source.Comment: 4 pages, 3 figure

A systematic review of community-to-facility neonatal referral completion rates in Africa and Asia

Background An estimated 2.8 million neonatal deaths occur annually worldwide. The vulnerability of newborns makes the timeliness of seeking and receiving care critical for neonatal survival and prevention of long-term sequelae. To better understand the role active referrals by community health workers play in neonatal careseeking, we synthesize data on referral completion rates for neonates with danger signs predictive of mortality or major morbidity in low- and middle-income countries. Methods A systematic review was conducted in May 2014 of the following databases: Medline-PubMed, Embase, and WHO databases. We also searched grey literature. In addition, an investigator group was established to identify unpublished data on newborn referral and completion rates. Inquiries were made to the network of research groups supported by Save the Children’s Saving Newborn Lives project and other relevant research groups. Results Three Sub-Saharan African and five South Asian studies reported data on community-to-facility referral completion rates. The studies varied on factors such as referral rates, the assessed danger signs, frequency of home visits in the neonatal period, and what was done to facilitate referrals. Neonatal referral completion rates ranged from 34 to 97 %, with the median rate of 74 %. Four studies reported data on the early neonatal period; early neonatal completion rates ranged from 46 to 97 %, with a median of 70 %. The definition of referral completion differed by studies, in aspects such as where the newborns were referred to and what was considered timely completion. Conclusions Existing literature reports a wide range of neonatal referral completion rates in Sub-Saharan Africa and South Asia following active illness surveillance. Interpreting these referral completion rates is challenging due to the great variation in study design and context. Often, what qualifies as referral and/or referral completion is poorly defined, which makes it difficult to aggregate existing data to draw appropriate conclusions that can inform programs. Further research is necessary to continue highlighting ways for programs, governments, and policymakers to best aid families in low-resource settings in protecting their newborns from major health consequences

Modelling stunting in LiST: the effect of applying smoothing to linear growth data

Background: The Lives Saved Tool (LiST) is a widely used resource for evidence-based decision-making regarding health program scale-up in low- and middle-income countries. LiST estimates the impact of specified changes in intervention coverage on mortality and stunting among children under 5 years of age. We aimed to improve the estimates of the parameters in LiST that determine the rate at which the effects of interventions to prevent stunting attenuate as children get older.Methods: We identified datasets with serial measurements of children\u27s lengths or heights and used random effects models and restricted cubic splines to model the growth trajectories of children with at least six serial length/height measurements. We applied WHO growth standards to both measured and modelled (smoothed) lengths/heights to determine children\u27s stunting status at multiple ages (1, 6, 12, 24 months). We then calculated the odds ratios for the association of stunting at one age point with stunting at the next ( stunting-to-stunting ORs ) using both measured and smoothed data points. We ran analyses in LiST to compare the impact on intervention effect attenuation of using smoothed rather than measured stunting-to-stunting ORs.Results: A total of 21,786 children with 178,786 length/height measurements between them contributed to our analysis. The odds of stunting at a given age were strongly related to whether a child is stunted at an earlier age, using both measured and smoothed lengths/heights, although the relationship was stronger for smoothed than measured lengths/heights. Using smoothed lengths/heights, we estimated that children stunted at 1 month have 45 times the odds of being stunted at 6 months, with corresponding odds ratios of 362 for the period 6 to 12 months and 175 for the period 12 to 24 months. Using the odds ratios derived from the smoothed data in LiST resulted in a somewhat slower attenuation of intervention effects over time, but substantial attenuation was still observed in the LiST outputs. For example, in Mali the effect of effectively eliminating SGA births reduced prevalence of stunting at age 59 months from 44.4% to 43.7% when using odds ratios derived from measured lengths/heights and from 44.4% to 41.9% when using odds ratios derived from smoothed lengths/heights.Conclusions: Smoothing of children\u27s measured lengths/heights increased the strength of the association between stunting at a given age and stunting at an earlier age. Using odds ratios based on smoothed lengths/heights in LiST resulted in a small reduction in the attenuation of intervention effects with age and thus some increase in the estimated benefits, and may better reflect the true benefits of early nutritional interventions

Direct maternal morbidity and the risk of pregnancy-related deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa: A population-based prospective cohort study in 8 countries

Background: Maternal morbidity occurs several times more frequently than mortality, yet data on morbidity burden and its effect on maternal, foetal, and newborn outcomes are limited in low- and middle-income countries. We aimed to generate prospective, reliable population-based data on the burden of major direct maternal morbidities in the antenatal, intrapartum, and postnatal periods and its association with maternal, foetal, and neonatal death in South Asia and sub-Saharan Africa.Methods and findings: This is a prospective cohort study, conducted in 9 research sites in 8 countries of South Asia and sub-Saharan Africa. We conducted population-based surveillance of women of reproductive age (15 to 49 years) to identify pregnancies. Pregnant women who gave consent were include in the study and followed up to birth and 42 days postpartum from 2012 to 2015. We used standard operating procedures, data collection tools, and training to harmonise study implementation across sites. Three home visits during pregnancy and 2 home visits after birth were conducted to collect maternal morbidity information and maternal, foetal, and newborn outcomes. We measured blood pressure and proteinuria to define hypertensive disorders of pregnancy and woman\u27s self-report to identify obstetric haemorrhage, pregnancy-related infection, and prolonged or obstructed labour. Enrolled women whose pregnancy lasted at least 28 weeks or those who died during pregnancy were included in the analysis. We used meta-analysis to combine site-specific estimates of burden, and regression analysis combining all data from all sites to examine associations between the maternal morbidities and adverse outcomes. Among approximately 735,000 women of reproductive age in the study population, and 133,238 pregnancies during the study period, only 1.6% refused consent. Of these, 114,927 pregnancies had morbidity data collected at least once in both antenatal and in postnatal period, and 114,050 of them were included in the analysis. Overall, 32.7% of included pregnancies had at least one major direct maternal morbidity; South Asia had almost double the burden compared to sub-Saharan Africa (43.9%, 95% CI 27.8% to 60.0% in South Asia; 23.7%, 95% CI 19.8% to 27.6% in sub-Saharan Africa). Antepartum haemorrhage was reported in 2.2% (95% CI 1.5% to 2.9%) pregnancies and severe postpartum in 1.7% (95% CI 1.2% to 2.2%) pregnancies. Preeclampsia or eclampsia was reported in 1.4% (95% CI 0.9% to 2.0%) pregnancies, and gestational hypertension alone was reported in 7.4% (95% CI 4.6% to 10.1%) pregnancies. Prolonged or obstructed labour was reported in about 11.1% (95% CI 5.4% to 16.8%) pregnancies. Clinical features of late third trimester antepartum infection were present in 9.1% (95% CI 5.6% to 12.6%) pregnancies and those of postpartum infection in 8.6% (95% CI 4.4% to 12.8%) pregnancies. There were 187 pregnancy-related deaths per 100,000 births, 27 stillbirths per 1,000 births, and 28 neonatal deaths per 1,000 live births with variation by country and region. Direct maternal morbidities were associated with each of these outcomes.Conclusions: Our findings imply that health programmes in sub-Saharan Africa and South Asia must intensify their efforts to identify and treat maternal morbidities, which affected about one-third of all pregnancies and to prevent associated maternal and neonatal deaths and stillbirths.Trial registration: The study is not a clinical trial

Validation of verbal autopsy tool for ascertaining the causes of stillbirth

Objective: To assess performance of the WHO revised verbal autopsy tool for ascertaining the causes of still birth in comparison with reference standard cause of death ascertained by standardized clinical and supportive data.Methods: All stillbirths at a tertiary hospital in Karachi, Pakistan were prospectively recruited into study from August 2006- February 2008. The reference standard cause of death was established by two senior obstetricians within 48 hours using the ICD coding system. Verbal autopsy interviews using modified WHO tool were conducted by trained health workers within 2- 6 weeks of still birth and the cause of death was assigned by second panel of obstetricians. The performance was assessed in terms of sensitivity, specificity and Kappa.Results: There were 204 still births. Of these, 80.8% of antepartum and 50.5% of intrapartum deaths were correctly diagnosed by verbal autopsy. Sensitivity of verbal autopsy was highest 68.4%, (95%CI: 46-84.6) for congenital malformation followed by obstetric complication 57.6%, (95%CI: 25-84.2). The specificity for all major causes was greater than 90%. The level of agreement was high (kappa=0.72) for anomalies and moderate (k=0.4) for all major causes of still birth, except asphyxia.Conclusion: Our results suggest that verbal autopsy has reasonable validity in identifying and discriminating between causes of stillbirth in Pakistan. On the basis of these findings, we feel it has a place in resource constrained areas to inform strategic planning and mobilization of resources to attain Millennium Development Goal

Use of antibiotics in children younger than two years in eight countries: A prospective cohort study

Objective: To describe the frequency and factors associated with antibiotic use in early childhood, and estimate the proportion of diarrhoea and respiratory illnesses episodes treated with antibiotics.Methods: Between 2009 and 2014, we followed 2134 children from eight sites in Bangladesh, Brazil, India, Nepal, Pakistan, Peru, South Africa and the United Republic of Tanzania, enrolled in the MAL-ED birth cohort study. We documented all antibiotic use from mothers’ reports at twice-weekly visits over the children’s first two years of life. We estimated the incidence of antibiotic use and the associations of antibiotic use with child and household characteristics. We described treatment patterns for diarrhoea and respiratory illnesses, and identified factors associated with treatment and antibiotic class.Findings: Over 1 346 388 total days of observation, 16 913 courses of antibiotics were recorded (an incidence of 4.9 courses per child per year), with the highest use in South Asia. Antibiotic treatment was given for 375/499 (75.2%) episodes of bloody diarrhoea and for 4274/9661 (44.2%) episodes of diarrhoea without bloody stools. Antibiotics were used in 2384/3943 (60.5%) episodes of fieldworker-confirmed acute lower respiratory tract illness as well as in 6608/16742 (39.5%) episodes of upper respiratory illness. Penicillins were used most frequently for respiratory illness, while antibiotic classes for diarrhoea treatment varied within and between sites.Conclusion: Repeated antibiotic exposure was common early in life, and treatment of non-bloody diarrhoea and non-specific respiratory illnesses was not consistent with international recommendations. Rational antibiotic use programmes may have the most impact in South Asia, where antibiotic use was highest