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Background Government of India and the World Health Organization have guidelines for outpatient management of young infants 0–59 days with signs of Possible Serious Bacterial Infection (PSBI), when referral is not feasible. Implementation research was conducted to identify facilitators and barriers to operationalizing these guidelines. Methods Himachal Pradesh government implemented the guidelines in program settings supported by Centre for Health Research and Development, Society for Applied Studies. The strategy included community sensitization, skill enhancement of Accredited Social Health Activists (ASHA), Auxiliary Nurse Midwives (ANMs) and Medical Officers (MOs) to identify PSBI and treat when referral was not feasible. The research team collected information on facilitators and barriers. A technical support unit provided training and oversight. Findings Among 1997 live births from June 2017 to January 2019, we identified 160 cases of PSBI in young infants resulting in a coverage of 80%, assuming an incidence of 10%. Of these,29(18.1%) had signs of critical illness (CI), 92 (57.5%) had clinical severe infection (CSI), 5 (3.1%)had severe pneumonia (only fast breathing in young infants 0–6 days), while 34 (21%) had pneumonia (only fast breathing in young infants 7–59 days). Hospital referral was accepted by 48/160 (30%), whereas 112/160 (70%) were treated with the simplified treatment regimens at primary level facilities. Of the 29 infants with CI, 18 (62%) accepted referral; 26 (90%) recovered while 3 (10%) who had accepted referral, died. Of the 92 infants who had CSI, 86 (93%) recovered, 65 (71%) received simplified treatment and one infant who had accepted referral, died. All the five infants who had severe pneumonia, recovered; 3 (60%) had received simplified treatment. Of the 34 pneumonia cases, 33 received simplified treatment of which 5 (15%) failed treatment; two out of these 5 died. Overall, 6/160 infants died (case-fatality-rate 3.4%); 2 in the simplified treatment (case-fatality-rate 1.8%) and 4 in the hospital group (case-fatality-rate 8.3%). Delayed identification and care-seeking by families and health system weaknesses like manpower gaps and interrupted supplies were challenges in implementation. Conclusions Implementation of the guidelines in program settings is possible and acceptable. Scaling up would require creating community awareness, early identification and appropriate care-seeking, strengthening ASHA home-visitation program, building skills and confidence of MOs and ANMs, uninterrupted supplies and a dependable referral system.

BackgroundThere is a growing interest in the life course approach for the prevention, early detection and subsequent management of morbidity in women of reproductive age to ensure optimal health and nutrition when they enter pregnancy. Reliable estimates of such morbidities are lacking. We report the prevalence of health or nutrition-related morbidities, specifically, anemia, undernutrition, overweight and obesity, sexually transmitted infections (STIs) or reproductive tract infections (RTIs), diabetes or prediabetes, hypothyroidism, hypertension, and depressive symptoms, during the preconception period among women aged 18 to 30 years.MethodsA cross-sectional study was conducted among 2000 nonpregnant married women aged 18 to 30 years with no or one child who wished to have more children in two low- to middle-income urban neighborhoods in Delhi, India, in the context of a randomized controlled trial. STIs and RTIs were measured by symptoms and signs, blood pressure by a digital device, height by stadiometer and weight by a digital weighing scale. A blood specimen was taken to screen for anemia, diabetes, thyroid disorders and syphilis. Maternal depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). Multivariable logistic regression analysis was performed to identify sociodemographic factors associated with individual morbidity.ResultsOverall, 58.7% of women were anemic; 16.5%, undernourished; 26%, overweight or obese; 13.2%, hypothyroid; and 10.5% with both symptoms and signs of STIs/RTIs. There was an increased risk of RTI/STI symptoms and signs in undernourished women and an increased risk of diabetes or prediabetes in overweight or obese women. An increased risk of undernutrition was also observed in women from lower categories of wealth quintiles. A decreased risk of moderate to severe anemia was seen in overweight women and those who completed at least secondary education.ConclusionsOur findings show a high burden of undernutrition, anemia, RTIs, hypothyroidism and prediabetes among women in the study. This information will aid policymakers in planning special programs for women of reproductive age.

Background Childhood diarrhea deaths have declined more than 80% from 1980 to 2015, in spite of an increase in the number of children in low- and middle-income countries (LMIC). Possible drivers of this remarkable accomplishment can guide the further reduction of the half million annual child deaths from diarrhea that still occur. Methods We used the Lives Saved Tool, which models effects on mortality due to changes in coverage of preventive or therapeutic interventions or risk factors, for 50 LMIC to determine the proximal drivers of the diarrhea mortality reduction. Results Diarrhea treatment (oral rehydration solution [ORS], zinc, antibiotics for dysentery and management of persistent diarrhea) and use of rotavirus vaccine accounted for 49.7% of the diarrhea mortality reduction from 1980 to 2015. Improvements in nutrition (stunting, wasting, breastfeeding practices, vitamin A) accounted for 38.8% and improvements in water, sanitation and handwashing for 11.5%. The contribution of ORS was greater from 1980 to 2000 (58.0% of the reduction) than from 2000 to 2015 (30.7%); coverage of ORS increased from zero in 1980 to 29.5% in 2000 and more slowly to 44.1% by 2015. To eliminate the remaining childhood diarrhea deaths globally, all these interventions will be needed. Scaling up diarrhea treatment and rotavirus vaccine, to 90% coverage could reduce global child diarrhea mortality by 74.1% from 2015 levels by 2030. Adding improved nutrition could increase that to 89.1%. Finally, adding increased use of improved water sources, sanitation and handwashing could result in a 92.8% reduction from the 2015 level. Conclusions Employing the interventions that have resulted in such a large reduction in diarrhea mortality in the last 35 years can virtually eliminate remaining childhood diarrhea deaths by 2030.

Background India has achieved 86% reduction in the number of under-five diarrheal deaths from 1980 to 2015. Nonetheless diarrhea is still among the leading causes of under-five deaths. The aim of this analysis was to study the contribution of factors that led to decline in diarrheal deaths in the country and the effect of scaling up of intervention packages to address the remaining diarrheal deaths. Methods We assessed the attribution of different factors and intervention packages such as direct diarrhea case management interventions, nutritional factors and WASH interventions which contributed to diarrhea specific under-five mortality reduction (DSMR) during 1980 to 2015 using the Lives Saved Tool (LiST). The potential impact of scaling up different packages of interventions to achieve universal coverage levels by year 2030 on reducing the number of remaining diarrheal deaths were estimated. Results The major factors associated with DSMR reduction in under-fives during 1980 to 2015, were increase in ORS use, reduction in stunting prevalence, improved sanitation, changes in age appropriate breastfeeding practices, increase in the vitamin-A supplementation and persistent diarrhea treatment. ORS use and reduction in stunting were the two key interventions, each accounting for around 32% of the lives saved during this period. Scaling up the direct diarrhea case management interventions from the current coverage levels in 2015 to achieve universal coverage levels by 2030 can save around 82 000 additional lives. If the universal targets for nutritional factors and WASH interventions can be achieved, an additional 23 675 lives can potentially be saved. Conclusions While it is crucial to improve the coverage and equity in ORS use, an integrated approach to promote nutrition, WASH and direct diarrhea interventions is likely to yield the highest impact on reducing the remaining diarrheal deaths in under-five children.

Executive summaryDespite dramatic improvements in survival, nutrition, and education over recent decades, today’s children face an uncertain future. Climate change, ecological degradation, migrating populations, conflict, pervasive inequalities, and predatory commercial practices threaten the health and future of children in every country. In 2015, the world’s countries agreed on the Sustainable Development Goals (SDGs), yet nearly 5 years later, few countries have recorded much progress towards achieving them. This Commission presents the case for placing children, aged 0–18 years, at the centre of the SDGs: at the heart of the concept of sustainability and our shared human endeavour. Governments must harness coalitions across sectors to overcome ecological and commercial pressures to ensure children receive their rights and entitlements now and a liveable planet in the years to come.

Aim The aim of this study was to determine the immunologic effects and safety of oral anti-CD3 in patients with ulcerative colitis (UC). Methods An open-label pilot study of orally delivered anti-CD3 was performed in patients with moderate-to-severe UC. The primary end points were changes in immunologic parameters and evaluation for safety. Results Six subjects received oral OKT3. Biologic effects of oral anti-CD3 included significantly increased proliferation in response to anti-CD3 and anti-inflammatory gene expression profile in peripheral blood mononuclear cells. No serious treatment-related adverse events occurred. Conclusion Orally delivered anti-CD3 resulted in immunologic changes in patients with UC., There remains an unmet need for drugs given as pills that can treat the inflammation of ulcerative colitis (UC). In addition to developing new drugs, a parallel approach is to evaluate existing drugs that have been FDA approved for other diseases (repurposing). Muromunab (OKT3) is a drug that was approved in 1985 to treat acute rejection after organ transplantation. It works by binding to CD3, a protein on some immune cells, and then prevents those cells from causing inflammation. In this pilot study, the researchers gave OKT3 to patients with active UC to assess whether it would suppress the inflammation in their colon. They also measured side effects and the impact of OKT3 on their immune cells. After 3 weeks, 3 of 6 patients had improved symptoms, and 1 of 6 had improvement in the inflammation in their colon. One mild, and one moderate, side effect were recorded. At the cell level, OKT3 led to modest changes in cell proliferation and expression of genes associated with inflammation. This small study suggests that local blockade of CD3 could be a target for treatment in UC.

Burden and risk factors for wasting in the first 6 months of life among Indian children are not well documented. We used data from India's National Family Health Survey 4 to estimate the prevalence of severe wasting (weight for length < -3 SD) among 18,898 infants under 6 months of age. We also examined the association of severe wasting with household, maternal, and child-related factors using multivariable logistic regression analysis. Prevalence of severe wasting among infants less than 6 months of age was 14.8%, ranging from 3.5 to 21% across states. Low birth weight (

Rashidian et al. show that 89Zr-PEGylated single-domain antibodies that target CD8+ T cells can be used to monitor and evaluate the response to immunotherapy as a predictive tool., Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non–small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno–positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8+ T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade. A 89Zr-labeled PEGylated anti-CD8 VHH detected thymus and secondary lymphoid structures as well as intratumoral CD8 T cells. Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the anti-CD8 PET signal throughout the tumor, whereas more heterogeneous infiltration of CD8 T cells correlated with faster tumor growth and worse responses. To support the validity of these observations, we used two different transplantable breast cancer models, yielding results that conformed with predictions based on the antimelanoma response. It may thus be possible to use immuno-PET and monitor antitumor immune responses as a prognostic tool to predict patient responses to checkpoint therapies.

Summary - Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5–61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum (ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis., Leona M. and Harry B. Helmsley Charitable Trust (2014PG-IBD016), Crohn's and Colitis Foundation of America, National Institutes of Health (U.S.) (grant DK043351), National Institutes of Health (U.S.) (grant DK097485)

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

MEMS based accelerometers have already penetrated defense programs including navigation control in addition to their usual deployment in automotive, consumer and industrial markets because of their improved reliability, accuracy and excellent price performance. This paper discussed about the fabrication and testing of single axis capacitive accelerometer structures based on change in area (comb-type) and change in gap (Crab type) sensing principles. The accelerometers are designed for ±30 g acceleration range. A common fabrication process flow is designed for the fabrication of both types of accelerometers that are fabricated by using a three mask dissolved wafer process (DWP). Both the accelerometers showed a scale factor sensitivity of >60 mV/g at ±1 g flip test. Vibration and sensitivity testing at higher frequency was conducted on shaker table using a half sine wave shock (HSWS) of 2 ms. Using HSWS test, a sensitivity in the range of ~60 mV/g was obtained for both comb or crab type structures in the 0-30 g range. It can be further tuned upto 100 mV/g by increasing the gain of the capacitance Read Out Integrated Circuit (ROIC). However, performance of the comb type of accelerometers gets affected in – 30 g to – 0 g range due to deep boron diffusion induced residual stress. The crab accelerometers showed almost linear (nonlinearity

// Burcu Yigit 1 , Peter J. Halibozek 1 , Shih-Shih Chen 2 , Michael S. O’Keeffe 1 , Jon Arnason 3 , David Avigan 3 , Valter Gattei 4 , Atul Bhan 5 , Osman Cen 6 , Richard Longnecker 6 , Nicholas Chiorazzi 2 , Ninghai Wang 1 , Pablo Engel 7 , Cox Terhorst 1 1 Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 2 Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA 3 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 4 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy 5 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 6 Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 7 Immunology Unit, Department of Cell Biology, Immunology and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain Correspondence to: Burcu Yigit, email: byigit@bidmc.harvard.edu Cox Terhorst, email: cterhors@bidmc.harvard.edu Keywords: CLL, TCL1-192, SLAMF6, BCR, ibrutinib Received: January 29, 2016 Accepted: March 07, 2016 Published: March 25, 2016 ABSTRACT The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220 + CD5 + Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo , we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors.

Background South Asia contributes substantially to global low birth weight population (i.e. those with birth weight

Objectives We examined the utilisation, equity and determinants of full antenatal care (ANC), defined as 4 or more antenatal visits, at least one tetanus toxoid (TT) injection and consumption of iron folic acid (IFA) for a minimum of 100 days, in India. Methods We analysed a sample of 190,898 women from India’s National Family Health Survey 4. Concentration curves and concentration index were used to assess equity in full ANC utilisation. Multivariable logistic regression model was used to examine the factors associated with full ANC utilisation. Results In India, 21% of pregnant women utilised full ANC, ranging from 2.3–65.9% across states. Overall, 51.6% had 4 or more ANC visits, 30.8% consumed IFA for atleast 100 days, and 91.1% had one or more doses of tetanus toxoid. Full ANC utilisation was inequitable across place of residence, caste and maternal education. Registration of pregnancy, utilisation of government’s Integrated Child Development Services (ICDS) and health insurance coverage were associated with higher odds of full ANC utilisation. Lower maternal education, lower wealth quintile(s), lack of father’s participation during antenatal visits, higher birth order, teenage and unintended pregnancy were associated with lower odds of full ANC utilisation. Conclusions Full ANC utilisation in India was inadequate and inequitable. Although half of the women did not receive the minimum recommended ANC visits, the utilisation of TT immunisation was almost universal. The positive association of full ANC with ICDS utilisation and child’s father involvement may be leveraged for increasing the uptake of full ANC. Strategies to address the socio-demographic factors associated with low and inequitable utilisation of full ANC are imperative for strengthening India’s maternal health program. Electronic supplementary material The online version of this article (10.1186/s12884-019-2473-6) contains supplementary material, which is available to authorized users.

Background Understanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS. Results Here we show that gut microbiome mediates the preventive effect of estrogen (17β-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17β-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17β-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17β-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters. Conclusions In summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women. Electronic supplementary material The online version of this article (10.1186/s40168-018-0587-0) contains supplementary material, which is available to authorized users.

This study validates a non-invasive, quantitative technique to diagnose steatosis within tissue. The proposed method is based on two fundamental concepts: (i) the speed of sound in a fatty liver is lower than that in a healthy liver and (ii) the quality of an ultrasound image is maximized when the beamformer's speed of sound matches the speed in the medium under examination. The method uses image brightness and sharpness as quantitative image-quality metrics to predict the true sound speed and capture the effects of fat infiltration, while accounting for the transmission through subcutaneous fat. Ex vivo testing on sheep liver, mouse livers and tissue-mimicking phantoms indicated the technique's ability to predict the true speed of sound with errors less than 0.5% and to quantify the inverse correlation between fat content and speed of sound.

The tumor microenvironment in leukemia and solid tumors induces a shift of activated CD8

Objectives Low birth weight (LBW) is a risk factor for neonatal mortality and morbidity. It is important to examine whether this risk persists beyond neonatal period. The current secondary data analysis aimed to examine association of birth weight with mortality, hospitalisation and breast feeding practices during infancy. Design Data from a large randomised controlled trial of neonatal vitamin A supplementation (Neovita) trial were used. Log binomial model was applied to assess association between birth weight and mortality, hospitalisation and breast feeding practices. Setting Rural Haryana, North India. Participants Newborns recruited in the primary intervention trial that aimed to evaluate the effect of single-dose oral vitamin A supplementation on mortality in the first 6 months of life. Results We recruited a total of 44 984 infants, of which 10 658 (23.7%) were born LBW, that is, birth weight less than 2500 g. In the neonatal period, LBW babies had four times higher risk of mortality (relative risk (RR) 3.92; 95% CI 3.33 to 4.66) compared with normal birthweight babies. In the postneonatal period, the risk was two times higher (RR 1.92; 95% CI 1.71 to 2.15); even higher in those with birth weight

A simple experimental method based on capacitance voltage (CV) measurements is presented to extract the spring constants (k) different actuation voltages and gaps, in crab type capacitive MEMS accelerometer sensors. It is shown that in addition to main spring action provided by the legs of the structure, the additional spring constants related to the interaction of main spring-proof mass joint and corner region of the proof mass also contribute to change in capacitance. The proposed approach is used in resolving and measuring these model parameters simultaneously because all of them can be extracted from the just one CV measurement. It is found that this additional k varies by more than a factor of 10 across the 6-inch wafer. Furthermore, zero bias capacitance C0, zero bias gap g0, main spring constant k and initial pull down voltage Vpd1 vary by factors of 2.4, 2.38, 30 and 3 respectively. The method also allows us to extract different values of pull down and spring constants associated with different regions of crab structure. The experimental results agree well with the theoretical predictions and reported trends in literatures. The method is routinely applied while fabricating the actual prototype sensors fabricated in our laboratory.

Amyloidosis is extremely rare, with an estimated 2225 new US cases reported annually. Signs and symptoms of the disease are subtle and imaging findings are not pathognomonic. Currently, diagnosis requires biopsy to demonstrate the deposition of amyloid. Elastography is a new imaging modality that evaluates tissue elasticity. It has shown to have efficacy in characterizing thyroid nodules, detecting prostate cancer, and staging liver fibrosis. We present a case of hepatic amyloidosis in a 51-year-old male that demonstrates significantly increased stiffness with a median value of 99.1 kPa (range 25.7-188.9 kPa) on shear-wave elastography (SWE) imaging, which is significantly higher than the cut-off range reported for cirrhosis on SWE (10.4-11.5 kPa). This finding raises the possibility that elastographic imaging may be sensitive to tissue mechanical changes induced by amyloid deposition.

A simple experimental method and improved analytical approach based on tilt measurements (output versus angle) is presented to determine the misalignment error in sensing axis direction of single, two or three-axis accelerometer sensors. The approach is advantageous in resolving and measuring the error because the accuracy is enhanced by using identification that is based on differential and reciprocal differential data of the tilt measurements. Furthermore, the method does not require three accelerometers and there is no need for determination of matrix coefficients as is the practice presently followed in the literature. The method is validated on actual prototype sensors fabricated in our laboratory. The experimental results agree well with the theoretical predictions. The estimates obtained from the proposed method compares well with conventional analytical fit method that requires prior knowledge of sensitivity parameter.

AIM To conduct implementation research in integrated community case management (ICCM) of childhood pneumonia, diarrhoea and fever by promoting accredited social health activists as treatment providers and generate lessons for upscaling this approach. METHODS In this one-sample study, 49 Accredited Social Health Activists were trained in ICCM. Community awareness and demand generation activities undertaken included announcements, pamphlets and posters. Supplies of medicines and supervision of activists were maintained throughout the 10-month implementation period. Three cross-sectional surveys were conducted in households with children aged 2-59 months for documenting two-week prevalence of illnesses and care-seeking practices. Focus group discussions and in-depth interviews were carried out with mothers/grandmothers and activists for documenting perceptions about health activists as treatment providers. RESULTS One third of pneumonia (113/334) and one quarter of diarrhoea (102/408) cases at end-line were treated by Accredited Social Health Activists. Proportion of households seeking care from private providers (mostly unqualified) reduced significantly from baseline to endline (81-56% for diarrhoea, p

OBJECTIVES—: To assess performance of shear wave elastography for evaluation of fibrosis and the histologic stage in patients with autoimmune liver disease (ALD) and to validate previously established advanced fibrosis cutoff values in this cohort. METHODS—: Shear wave elastography was performed on patients with ALD with an Aixplorer ultrasound system (SuperSonic Imagine, Aix-en-Provence, France) using an SC6–1 transducer. The median estimated tissue Young modulus was calculated from sets of 8 to 10 elastograms. A blinded, subspecialty-trained pathologist reviewed biopsy specimens. The METAVIR classification was used to stage liver fibrosis and necroinflammation. Steatosis was graded from 0 to 4+. The Kendall τ-b correlation test was performed to identify the correlation between the estimated tissue Young modulus and fibrosis, steatosis, and the necroinflammatory score. The Spearman correlation test was performed to identify the correlation between the estimated tissue Young modulus and clinical data. The diagnostic performance of shear wave elastography for differentiating METAVIR stage F2 or higher from F0 and F1 fibrosis was evaluated by a receiver operating characteristic (ROC) curve analysis. RESULTS—: Fifty-one patients with ALD were analyzed. The estimated tissue Young modulus was positively correlated with the fibrosis stage and necroinflammation score (r = 0.386; P < .001; r = 0.338; P = .002, respectively) but not steatosis (r = −0.091; P = .527). Serum aspartate aminotransferase, alanine aminotransferase, and total bilirubin values were positively correlated with the estimated tissue Young modulus (r = 0.501; P < .001; r = 0.44; P = .001; r = 0.291; P = .038). The serum albumin value was negatively correlated (r = −0.309; P = .033). The area under the ROC curve was 0.781 (95% confidence interval, 0.641–0.921) for distinguishing F2 or greater fibrosis from F0 and F1 fibrosis. Based on the ROC curve, an optimal cutoff value of 9.15 kPa was identified (sensitivity, 83.3%; specificity, 72.7%). CONCLUSIONS—: Shear wave elastography is a novel noninvasive adjunct to liver biopsy in evaluation and staging of patients with ALD, showing the potential for serial evaluations of disease progression and treatment responses.

Background Low birth weight (LBW) infants constitute a vulnerable subset of infants with impaired immunity in early life. In India, there is scarcity of studies that focus on immunization practices in such infants. This analysis aimed to examine immunization practices in LBW infants with the intention to identify areas requiring intervention. Methods Data on immunization status of LBW infants enrolled in an individually randomized, double-masked, placebo-controlled trial of neonatal vitamin A supplementation were analysed. Study outcomes were full immunization by one year of age and delayed vaccination with DPT1 and DPT3. Multivariable logistic regression was performed to identify factors associated with the outcome(s). Findings Out of 10 644 LBW infants enrolled in trial, immunization data were available for 10 517 (98.8%). Less than one-third (29.7%) were fully immunized by one year of age. Lowest wealth quintile (adjusted odds ratio (AOR) 0.39, 95% confidence interval (CI) 0.32-0.47), Muslim religion (AOR 0.41, 95% CI 0.35-0.48) and age of mother

A phase III randomized double-blind placebo-controlled trial was conducted in the urban neighborhoods of Delhi to assess whether Oral Rotavirus Vaccine ROTAVAC® interferes with the immune response to childhood vaccines when coadministered. Infants aged 6 weeks were randomized to receive three doses of either ROTAVAC® or placebo along with childhood vaccines: Oral Polio Vaccine and vaccines against Diphtheria, Pertussis, Tetanus, Hepatitis B and Haemophilus influenza type b given as Pentavalent at 6, 10, 14 weeks of age. Blood specimens were collected from all infants at baseline and 4 weeks post dose 3 to assess the immune response to antigens in Oral Polio Vaccine, Pentavalent and ROTAVAC® vaccines. Non-inferiority of immune response to all vaccine components of the childhood vaccines when ROTAVAC® was administered concurrently was demonstrated. Non-inferior immune responses to childhood vaccines were evaluated based on the seroprotective levels of antibodies against polio types 1, 2, and 3, Diphtheria toxoid, Tetanus toxoid, Haemophilus influenza type b anti- polyribosyl ribitol phosphate antibodies and Hepatitis B antibodies; and the Geometric Mean Concentration for Pertussis. The proportion of infants who seroconverted (≥4 fold rise) was 38.6% in the ROTAVAC® group and 12.2% in the placebo group. The frequency and severity of immediate adverse events, adverse events and serious adverse events were similar in both groups. None of the five reported deaths were considered to be related to the ROTAVAC® and no case of intussusception meeting Brighton Diagnostic Certainty Level I criteria was reported. This study demonstrated that ROTAVAC® can be safely administered with childhood vaccines without interfering with the immune response to the antigens contained in these vaccines.

Rotavirus is the leading cause of severe gastroenteritis in young children worldwide and is responsible for around 100,000 deaths in India annually. Vaccination against rotavirus (RV) is a high priority: ‘ROTAVAC’ an indigenous vaccine will soon be licensed in India. Surveillance to determine the impact of vaccines on emerging RV strains is required. In this study we compared the pattern of RV strains circulating in Delhi over a 5 year period with the strains over the past 12 years. The most commonly detected G genotypes were G1 (22.4%), G2 (17.2%), and G9 (25.2%) with P[4] (25.5%), P[6] (20%) and P[8] (16.9%) specificity. G12 genotype was found to be the fourth common G-type with 14.8% prevalence. Among the G–P combinations; G1P[8], G2P[4], G9P[8] and G12P[6] were detected at 7.2%, 7.2%, 5.2% and 10%, respectively. Of note, G9P[4] and G2P[6] that were rarely detected during 2000–2007 in Delhi, were observed quite frequently with prevalence of 6.5% and 3.4%, respectively. In total, 16 different G–P combinations were detected in the present study demonstrating the rich diversity of rotavirus strains in Delhi. Our data from the 12 year period indicate wide circulation of G1 and G9 genotypes in combination with P[8], G2 with P[4] and G12 with P[6] with high frequency of RV strains having rare G–P combinations in Delhi. Since the indigenous vaccine ‘ROTAVAC’ has a monovalent formulation, the impact of vaccines on strains and the effect of strain diversity on the efficacy of the vaccine should be monitored.

Summary Background Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. Methods We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6–7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6–7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry–India (CTRI/2010/091/000102) and ClinicalTrials.gov (NCT01305109). Findings 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0–66·9; p=0·0013) and 56·4% (36·6–70·1; p Interpretation Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. Funding Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.

A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the mechanisms by which single disease-associated polymorphisms contribute to pathogenesis have been difficult to dissect given that environmental factors likely influence disease initiation in these patients. Here we introduce a knock-in mouse model expressing the Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do not develop spontaneous intestinal inflammation, but exhibit morphological defects in Paneth and goblet cells. Selective autophagy is reduced in multiple cell types from T300A knock-in mice compared with WT mice. The T300A polymorphism significantly increases caspase 3- and caspase 7-mediated cleavage of Atg16L1, resulting in lower levels of full-length Atg16Ll T300A protein. Moreover, Atg16L1 T300A is associated with decreased antibacterial autophagy and increased IL-1β production in primary cells and in vivo. Quantitative proteomics for protein interactors of ATG16L1 identified previously unknown nonoverlapping sets of proteins involved in ATG16L1-dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell type- and pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease.

To determine the efficacy of oral supplementation of the gut enzyme intestinal alkaline phosphatase (IAP) in preventing antibiotic-associated infections from Salmonella enterica serovar Typhimurium (S. Typhimurium) and Clostridium difficile.The intestinal microbiota plays a pivotal role in human health and well-being. Antibiotics inherently cause dysbiosis, an imbalance in the number and composition of intestinal commensal bacteria, which leads to susceptibility to opportunistic bacterial infections. Previously, we have shown that IAP preserves the normal homeostasis of intestinal microbiota and that oral supplementation with calf IAP (cIAP) rapidly restores the normal gut flora. We hypothesized that oral IAP supplementation would protect against antibiotic-associated bacterial infections.C57BL/6 mice were treated with antibiotic(s) ± cIAP in the drinking water, followed by oral gavage of S. Typhimurium or C. difficile. Mice were observed for clinical conditions and mortality. After a defined period of time, mice were killed and investigated for hematological, inflammatory, and histological changes.We observed that oral supplementation with cIAP during antibiotic treatment protects mice from infections with S. Typhimurium as well as with C. difficile. Animals given IAP maintained their weight, had reduced clinical severity and gut inflammation, and showed improved survival.Oral IAP supplementation protected mice from antibiotic-associated bacterial infections. We postulate that oral IAP supplementation could represent a novel therapy to protect against antibiotic-associated diarrhea (AAD), C. difficile-associated disease (CDAD), and other enteric infections in humans.

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

A 6.5-month-old boy was admitted to the hospital because of thrombocytopenia. Anti-D immune globulin was administered intravenously, with improvement, but thrombocytopenia recurred, with anemia and neutropenia, and food allergies developed. Diagnostic tests were performed.

Patients with hormone receptor–positive early breast cancer have a continuous yearly rate of recurrence extending out to 15 years after having received adjuvant endocrine therapy with tamoxifen for 5 years (1). More than half of the recurrences and about two-thirds of breast cancer deaths in this group will occur beyond 5 years from diagnosis (ie, late recurrences and death) (1). The National Cancer Institute of Canada (NCIC) Clinical Trials Group MA.17 trial was a randomized, placebo-controlled trial demonstrating that extended endocrine therapy with letrozole improves disease-free survival (DFS) (2), distant DFS (DDFS), and overall survival (OS) in disease-free postmenopausal patients with hormonal receptor–positive breast cancer after 5 years of tamoxifen (3). Although extended antihormonal therapy has become standard practice and is endorsed by international clinical practice guidelines (4,5), understanding which patients will actually benefit from longer treatment is paramount to individualized therapy. The status of primary tumor estrogen receptor (ER) and progesterone receptor (PR) expression has been suggested, but not confirmed, as a way to identify patients who have increased benefit from extended letrozole (5). Patients with ER+ and PR+ tumors have been shown to have improved DFS (P = .02) when compared with patients with ER+ and PR− tumors (6). Currently, however, there are no guideline-accepted biomarkers to stratify hormonal receptor–positive patients for prediction of benefit beyond the 5 years of adjuvant endocrine therapy. In addition, standard clinico-pathological factors and clinically available genomic signatures, including the 21-gene (Recurrence Score) assay (7) and the 70-gene assay (8), have greatest prognostic performance for recurrence risk within the first 5 years of adjuvant therapy. Identification of additional biomarkers to further stratify hormone receptor–positive tumors to predict those at risk of late recurrence and those who may or may not benefit from extended endocrine therapy would be of substantial clinical utility (9). We have previously demonstrated that the two-gene expression ratio, HOXB13/IL17BR (H/I), is a prognostic biomarker in both untreated and tamoxifen-treated early-stage ER+ breast cancer patients (10–13). However, potential assessment of H/I as a predictive biomarker for endocrine therapy has been limited by the analysis of retrospective/observational cohorts or by the use of single treatment arm cohorts from randomized trials (11–13). Herein, we have conducted a prospective–retrospective (14), nested case-control study in a subset of patients from NCIC Clinical Trials Group MA.17 trial to evaluate the performance of H/I for 1) prognostication of late disease recurrence and 2) prediction of treatment benefit from extended adjuvant letrozole therapy in patients with hormone receptor–positive early breast cancer.

Tumour necrosis factor (TNF)-α secreted by macrophages and dendritic cells (DCs) plays a predominant role in arthritis. Our previous studies suggest that a small peptide, RVG-9R (29-aa peptide derived from the rabies virus glycoprotein, fused to 9R residues), can deliver small interfering RNA (siRNA) to macrophages and DCs. We therefore tested whether knockdown of TNF-α expression in macrophages and DCs by RVG-9R/bound siRNA targeting TNF-α reduces the severity of collagen antibody-induced arthritis (CAIA) in mice.Arthritis was induced in mice by injecting a combination of antibodies to collagen followed by lipopolysaccharide (LPS) treatment. Mice were also injected with TNF-α siRNA complexed with RVG-9R peptide or an irrelevant peptide RVMAT-9R on days 1, 3, 5, and 7. As a positive control, dexamethasone was injected intravenously. Paw thickness was measured every 2 days and the mice were killed on day 10 for testing synovial TNF-α levels and histological analysis of joints.In control mice, arthritis developed on day 4 and reached its peak between day 7 and day 9. Treatment with siTNF-α bound to RVG-9R, but not to RVMAT-9R, resulted in reducing paw thickness scores to the same level as dexamethasone treatment, associated with reduced TNF-α level in synovial fluid. Histological analysis of joints in the control RVMAT-9R/TNF-α siRNA-treated mice showed marked pannus formation and destruction of cartilage and subchondrial bone, as well as severe infiltration of inflammatory cells into the synovium. By contrast, the joint pathology was markedly reduced in RVG-9R/TNF-α siRNA-treated mice resembling the dexamethasone-treated mice.Suppression of TNF-α expression in macrophages and DCs by RVG-9R-mediated siRNA delivery could potentially be a clinically viable strategy for treatment of arthritis.

Low‐birthweight (LBW) infants are at an increased risk of stunting and poor linear growth. The risk might be additionally higher in these infants when born to short mothers. However, this hypothesis has been less explored. The objective of this secondary data analysis was to determine the risk of linear growth faltering and difference in linear growth velocity in LBW infants born to short mothers (

Background Vitamin-D deficiency has been linked with impaired development in animal studies; however, the evidence from human studies is scanty. Evidence as to whether vitamin-D deficiency during early childhood affects growth is also limited and conflicting. We examined the extent to which vitamin-D deficiency (

B cells are an important component of mucosal immune responses in normal and diseased states. Whether B cells play a regulatory or pathogenic role in inflammatory bowel disease (IBD) has not been determined. The pathogenic role of antibodies has been suggested by the frequent presence of circulating antibodies to self- and microbial antigens in IBD. Antibodies could also regulate inflammation through Fc receptors of IgG. Although most studies performed in the experimental models of IBD suggest that B cells suppress mucosal inflammation either by secreting cytokines or by interacting with T cells, a pathogenic role of B cells has been raised in a model of ileitis. An inducible B-cell subset, termed Breg, develops in gut-associated lymphoid tissues under intestinal inflammatory conditions and causes attenuation of colitis through production of a regulatory cytokine IL-10 and by regulating T-cell expansion. An IL-12p70 producing B-cell subset capable of inhibiting colitis has also been identified. Future human studies including functional characterization of mucosal lymphocytes in normal and diseased states are needed to determine whether B cells regulate human intestinal inflammation as shown in the experimental models.

Summary Circulatory antigens transit through the small intestine via the fenestrated capillaries in the lamina propria prior to entering into the draining lymphatics. But whether or how this process controls mucosal immune responses remains unknown. Here we demonstrate that dendritic cells (DCs) of the lamina propria can sample and process both circulatory and luminal antigens. Surprisingly, antigen cross-presentation by resident CX3CR1 + DCs induced differentiation of precursor cells into CD8 + T cells that expressed interleukin-10 (IL-10), IL-13, and IL-9 and could migrate into adjacent compartments. We conclude that lamina propria CX3CR1 + DCs facilitate the surveillance of circulatory antigens and act as a conduit for the processing of self- and intestinally absorbed antigens, leading to the induction of CD8 + T cells, that partake in the control of T cell activation during mucosal immune responses.

Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.

Background Recent studies have demonstrated a relationship between poor vitamin D status and respiratory infections and diarrhea among young children. Acute lower respiratory infections (ALRI) and diarrhea are among the two most important causes of death in under-5 children. In this paper, we examined the extent to which vitamin-D deficiency (

Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria-induced colitis. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria and accumulation of aberrant lysosomes. Similarly, IBD patient cells and epithelial cells expressing an IBD-associated missense variant, GPR65 I231L, displayed aberrant lysosomal pH resulting in lysosomal dysfunction, impaired bacterial restriction, and altered lipid droplet formation. The GPR65 I231L polymorphism was sufficient to confer decreased GPR65 signaling. Collectively, these data establish a role for GPR65 in IBD susceptibility and identify lysosomal dysfunction as a potentially causative element in IBD pathogenesis with effects on cellular homeostasis and defense. Gene mapping efforts have identified numerous disease-associated genes, but understanding how these genes influence disease has proved challenging. Xavier and colleagues identify a role for GPR65 in lysosomal homeostasis and demonstrate that the IBD-associated risk variant GPR65 I231L confers lysosomal dysfunction with effects on autophagy, pathogen clearance, and intestinal homeostasis.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor, often metastatic at presentation, for which current chemotherapeutic regimens are largely ineffective. As its pathogenesis is still unknown, we hypothesized that deregulation of signaling pathways commonly activated in cancer may contribute to MCC tumorigenesis and may provide insights into targeted therapy approaches for this malignancy. Experimental Design: We retrospectively profiled 60 primary MCC samples using a SNaPshot-based tumor genotyping assay to screen for common mutations in 13 cancer genes. Results: We identified mutations in 9 (15%) MCC primary tumors, including mutations in TP53 (3 of 60) and activating mutations in the PIK3CA gene (6 of 60). Sanger sequencing of the primary MCC tumors detected one additional PIK3CA mutation (R19K) that had not been previously described in cancer. Merkel cell polyoma virus (MCPyV) was detected in 38 (66%) MCC cases and patients with MCPyV-positive cancers showed a trend toward better survival. With one exception, the presence of MCPyV and activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling through the PI3K/pAKT pathway was active in one MCPyV-positive and in all MCPyV-negative MCC cell lines, as evidenced by AKT phosphorylation. Importantly, the presence of a PIK3CA-activating mutation was associated with sensitivity to treatment with ZST474, a specific phosphoinositide 3-kinase (PI3K) inhibitor, and to NVP-BEZ235, a dual PI3K/mTOR inhibitor, targeted agents under active clinical development. Conclusions: PI3K pathway activation may drive tumorigenesis in a subset of MCC and screening these tumors for PIK3CA mutations could help identify patients who may respond to treatment with PI3K pathway inhibitors. Clin Cancer Res; 18(5); 1227–36. ©2012 AACR.

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.

Vaccines against important enteric pathogens such as rotavirus and poliovirus have shown lower efficacy in some populations. The application of new technologies and diverse scientific disciplines are needed to realize the promise of truly universal and effective solutions to combat those and other enteric diseases.

In the present investigation we molecularly characterized nontypeable rotavirus strains previously identified during surveillance in New Delhi, India. The majority of strains were demonstrated to belong to genotype G1 (54.5%) or P[8] (77.8%) on the basis of nucleotide sequencing of fragments from their VP7 and VP4 genes. The other genotypes detected included G2, G8, G9, G12, and P[4]. A G8P[6] strain, strain DS108, was detected for the first time in northern India. The VP7 gene of DS108 was most homologous with the VP7 gene of a bovine G8 strain, strain A5 (98.9%), indicating its bovine parentage. In contrast, the VP4 gene had a high degree of nucleotide sequence homology (92.9% to 99.1%) with the VP4 genes of human P[6] strains. The VP6 gene and nonstructural genes (NSP1 to NSP3 and NSP5) were most homologous with the VP6 gene and nonstructural genes of human rotaviruses belonging to the DS1 genogroup. Interestingly, the NSP4 gene of DS108 clustered within genotype E6 that until now had only two representative strains, both with G12P[6] specificity (strains RV176-00 and N26-02). Together, these results indicate that G8 strain DS108 belongs to the DS1 genogroup and could be the result of the acquisition of the VP7, VP4, and NSP4 genes by a human G2P[4] strain from more than one donor, similar to the evolution of G12P[6] strain RV176-00. The present study highlights the importance of characterizing multiple genes of nontypeable rotavirus strains to detect novel strains and get a more complete picture of rotavirus evolution.