Alveolar progenitor differentiation and lactation depends on paracrine inhibition of notch via ROBO1/CTNNB1/JAG1.

In the mammary gland, how alveolar progenitor cells are recruited to fuel tissue growth with each estrus cycle and pregnancy remains poorly understood. Here, we identify a regulatory pathway that controls alveolar progenitor differentiation and lactation by governing Notch activation in mouse. Loss of Robo1 in the mammary gland epithelium activates Notch signaling, which expands the alveolar progenitor cell population at the expense of alveolar differentiation, resulting in compromised lactation. ROBO1 is expressed in both luminal and basal cells, but loss of Robo1 in basal cells results in the luminal differentiation defect. In the basal compartment, ROBO1 inhibits the expression of Notch ligand Jag1 by regulating ß-catenin (CTNNB1), which binds the Jag1 promoter. Together, our studies reveal how ROBO1/CTTNB1/JAG1 signaling in the basal compartment exerts paracrine control of Notch signaling in the luminal compartment to regulate alveolar differentiation during pregnancy.

Serum selenium and pancreatic cancer: a prospective study in the Prostate, Lung, Colorectal and Ovarian Cancer Trial cohort.

PURPOSE: Pancreatic cancer(PCa) is one of the most lethal cancers with few known consistent nutrition-related risk factors. Epidemiologic associations between the trace element selenium and PCa are inconsistent. This study examined the association of pre-diagnostic serum selenium with incident PCa. METHODS: We conducted a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Study (PLCO) cohort of men and women 55-70 years old at baseline (1993-2001). In total, 303 PCa cases developed during the 17-year follow-up period (1993-2009). We selected two controls (n = 606) for each case who were alive at the time the case was diagnosed who were matched on age, sex, race, and date of blood draw. We used conditional logistic regression analysis to calculate the odds ratio (OR) and 95% confidence intervals (CI) adjusting for smoking status and diabetes mellitus. RESULTS: Mean serum selenium concentrations were slightly lower in cases (mean, 95% CI: 139.0 ng/ml, 135.6-138.9) compared to controls (142.5 ng/ml, 140.4-142.4, p = 0.08). Overall, serum selenium was not associated with PCa risk (continuous OR: 0.66; 0.32-1.37). There was no significant interaction by sex, smoking, diabetes, or follow-up time (p > 0.05). CONCLUSION: Our results do not support the hypothesis that serum selenium is associated with PCa risk.

Transfer Time from the Intensive Care Unit and Patient Outcome: A Retrospective Analysis from a Tertiary Care Hospital in India.

BACKGROUND AND AIMS: Patients' outcome after ICU transfer reflect hospital's post-ICU care status. This study assessed association of after-hour ICU transfer on patient outcome. SUBJECTS AND METHODS: Single-centre, retrospective analysis of data between March 2016 and April 2017 was performed at a tertiary-care hospital in India. Patient data were collected on all consecutive ICU admissions during study period. Patients were categorized according to ICU transfer time into daytime (08:00-19:59 hours) and after-hour (20:00-07:59 hours). Patients transferred to other ICUs/hospitals, died in ICU, or discharged home from ICU were excluded. Only ?rst ICU admission was considered for outcome analysis. Primary outcome-hospital mortality; secondary outcomes-ICU readmission and hospital length of stay (LOS). All analysis were adjusted for illness severity. RESULTS: Of 1857 patients admitted during study period,1356 were eligible for study; out of which 53.9% were males and 383(28%) patients transferred during after-hour. Mean age of two groups (daytime vs. after-hour 65.7±15.2 vs. 66.3±16.2 years) was similar (p = 0.7). Mean APACHE IV score was comparable between daytime vs. after-hour transfers (45.6±20.4 vs 46.8±22; p = 0.05). Unadjusted hospital mortality rate of after-hour-transfers was significantly higher compared to daytime-transfers (7.1% vs. 4.1%; p = 0.02). After adjustment with illness severity, after-hour-transfers were associated with significantly higher hospital mortality compared to daytime-transfers(aOR1.7, 95%CI 1.1,2.8; p = 0.04). Median duration of hospital LOS and ICU readmission though higher for after-hour-transfers, was not statistically significant in adjusted analysis (aORhospitalLOS1.1, 95% CI 0.8, 1.4, p = 0.5; aORreadmission 1.6, 95% CI 0.9,2.7; p = 0.06, respectively). CONCLUSION: After-hour-transfers from ICU is associated with significantly higher hospital mortality. Hospital LOS and readmission rates are similar for daytime and after-hour -transfers. HOW TO CITE THIS ARTICLE: Chatterjee S, Sinha S et al., Transfer Time from the Intensive Care Unit and Patient Outcome: A Retrospective Analysis from a Tertiary Care Hospital in India. Indian J Crit Care Med 2019;23(3):115-121.

Epidemiology of Adult-population Sepsis in India: A Single Center 5 Year Experience.

BACKGROUND AND AIMS: Sepsis is a major worldwide cause of morbidity and mortality. Most sepsis epidemiologic data are from the Western literature. Sparse data from India describe the epidemiology of infection rather than sepsis which is a host response to infection. This study describes the epidemiology of sepsis in the Intensive Care Unit (ICU) of an Indian tertiary care hospital. SUBJECTS AND METHODS: A prospective study conducted between June 2006 and May 2011. All consecutively admitted patients during the 5 year study >=18 years of age were included and data obtained from hospital in-patient records. Variables measured were the incidence of severe sepsis, ICU, hospital, and 28-day mortality, the median length of ICU stay, median Acute Physiology and Chronic Health Evaluation II (APACHE II) score, infection site, and microbial profile. RESULTS: There were 4711 admissions during the study with 282 (6.2%, 95% confidence interval 2.3, 13.1) admissions with severe sepsis. ICU mortality, hospital mortality, and 28-day mortality were 56%, 63.6%, and 62.8%, respectively. Predominant infection site was respiratory tract. The most common organisms were Gram-negative microbes. The most common microbe was Acinetobacter baumanni. Median APACHE II score on admission was 22 (interquartile range 16-28) and median length of ICU stay was 8 days. Severe sepsis attributable mortality was 85%. CONCLUSION: Severe sepsis is common in Indian ICUs and is mainly due to Gram-negative organisms. ICU mortality is high in this group and care is resource intensive due to increased length of stay.

Congenital Heart Disease in the Pediatric Population in Eastern India: A Descriptive Study.

This cross-sectional study assessed distribution and pattern of echocardiography confirmed congenital heart disease, among 593 pediatric patients in outpatient departments of a tertiary care hospital in eastern India. Commonest defects were ventricular septal defect (43, 40.7%), atrial septal defect (241, 31.7%), and tetralogy of Fallot (125, 21%).

Gender differences in veterans health administration mental health service use: effects of age and psychiatric diagnosis.

PURPOSE: The objective of this study was to compare gender differences in mental health disease burden and outpatient mental health utilization among veterans utilizing Veterans Health Administration (VHA) mental health services in fiscal year 1999 (FY99), after the first Gulf War and significant restructuring of VHA services. METHODS: We used logistic regression to examine the relationships among gender, age, diagnostic groups, and utilization of mental health and specialty mental health services in a national sample of veterans. The sample included 782,789 veterans with at least 1 outpatient visit in the VHA in FY99 associated with a mental health or substance abuse (SA) diagnosis. Subgroup analyses were performed for 4 diagnostic categories: 1) posttraumatic stress disorder (PTSD), 2) SA disorders, 3) bipolar and psychotic disorders, and 4) mood and anxiety disorders. MAIN FINDINGS: Younger women veterans (<35 years old) were significantly less likely and older women (> or =35) more likely to use any mental health services in comparison with their male counterparts. Similar findings were observed for younger women diagnosed with SA or mood and anxiety disorders, but not among veterans with PTSD or bipolar and psychotic disorders, among whom no there were no gender or age differences. In the case of specialized services for SA or PTSD, women younger than 55 with SA or PTSD were significantly less likely to use services than men. CONCLUSION: Women veterans underutilized specialty mental health services in relation to men but receipt of mental health care overall in FY99 varied by age and diagnosis. Examining gender differences alone, without taking other factors into account, may not provide an adequate picture of women veterans' current mental health service needs.

Prevalence of chronic illness in pregnancy, access to care, and health care costs: implications for interconception care.

PURPOSE: Access to health care after pregnancy is especially important for pregnant women with chronic illness. The purpose of our study was to describe the prevalence of chronic illness in pregnant women and factors affecting the receipt of ongoing care. METHODS: We conducted a cross-sectional analysis of 6,294 women between 19 and 45 years of age from the Medical Expenditure Panel Survey (MEPS). Chronic illness was defined using aggregate clinical classification codes in the MEPS. Women were divided into 4 groups: pregnant and currently not pregnant, with and without chronic illness. We analyzed group differences in demographic variables, socioeconomic status, and access to health care. We also estimated inpatient, outpatient, emergency room, and pharmacy expenditures for the 4 study groups. All analyses accounted for the complex survey design of MEPS. MAIN FINDINGS: Overall, 27% of pregnant women and 39% of nonpregnant women reported a chronic illness. There were no differences in race/ethnicity, poverty, or health insurance status between pregnant women with and without chronic illness. Women with chronic illness were more likely to have a usual source of care. Among pregnant women, the presence of a chronic condition did increase out-of-pocket expenditures, but did not increase total average health care expenditures, even after adjusting for other characteristics. CONCLUSION: Pregnant women with chronic illness were similar to pregnant women without chronic illness in terms of access to care and total health care costs. Further research is needed to determine whether these similarities persist after delivery, given the relatively high prevalence of women with chronic illness who are of childbearing age.

Risk indicators for recurrent aphthous ulcers among adults in the US.

BACKGROUND AND AIMS: Recurrent aphthous ulcers (RAU) in the oral cavity are painful, causing substantial morbidity in the US and elsewhere in the world. Despite this, there is a lack of population-based studies representative of the US national adult population to describe the epidemiology, and estimate the true disease burden and association with independent risk factors. Although several studies have investigated the role of various factors in RAU etiology, the epidemiology and etiology of RAU remain unclear. This study aims to establish the prevalence and describe the epidemiology of RAU in adults. METHODS: Data from the Third National Health and Nutrition Examination Survey (NHANES III) were analyzed in SUDAAN using multivariable logistic regression, modeling RAU occurrences. RESULTS: Overall, for all Americans regardless of age, prevalence of RAU was 1030 per 100,000 people (95% CI 830-1220). The prevalence of RAU among adults was 850 per 100,000 (95% CI 630-1070). The lower vestibule was the most commonly involved site. Multivariable analyses suggested that adjusted odds of RAU were greatest for those 17-29 years of age (adjusted OR 2.7; 95% CI 1.4-5.5), for men (adjusted OR 1.7; 95% CI 0.9-2.8), and for those with low serum insulin levels (OR 2.0; 95% CI 0.9-4.4). Never smokers had greater risk of RAU (OR 9.2, 95% CI 2.8-30.1) compared with those who smoked more than 10 cigarettes per day. CONCLUSION: This study establishes the prevalence of RAU among adults in the US and demonstrates that whereas cigarette smoking is associated with lesser odds, low insulin levels might be independently associated with greater odds of RAU.

HPV and Cervical Cancer Epidemiology - Current Status of HPV Vaccination in India.

Cervical cancer (CaCx) is the second most fatal cancer contributing to 14% of cancers in Indian females, which account for 25.4% and 26.5% of the global burden of CaCx prevalence and mortality, respectively. Persistent infection with high-risk human papilloma virus (HPV- strains 16 and 18) is the most important risk factor for precursors of invasive CaCx. Comprehensive prevention strategies for CaCx should include screening and HPV vaccination. Three screening modalities for CaCx are cytology, visual inspection with acetic acid, and HPV testing. There is no Indian national policy on CaCx prevention, and screening of asymptomatic females against CaCx is practically non-existent. HPV vaccines can make a major breakthrough in the control of CaCx in India which has high disease load and no organized screening program. Despite the Indian Government's effort to introduce HPV vaccination in the National Immunization Program and bring down vaccine cost, challenges to implementing vaccination in India are strong such as: inadequate epidemiological evidence for disease prioritization, duration of vaccine use, parental attitudes, and vaccine acceptance. This paper reviews the current epidemiology of CaCx and HPV in India, and the current status of HPV vaccination in the country. This article stresses the need for more research in the Indian context, to evaluate interventions for CaCx and assess their applicability, success, scalability and sustainability within the constraints of the Indian health care system.

Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness.

Breast tumor progression is accompanied by changes in the surrounding extracellular matrix (ECM) that increase stiffness of the microenvironment. Mammary epithelial cells engage regulatory pathways that permit dynamic responses to mechanical cues from the ECM. Here, we identify a SLIT2/ROBO1 signaling circuit as a key regulatory mechanism by which cells sense and respond to ECM stiffness to preserve tensional homeostasis. We observed that Robo1 ablation in the developing mammary gland compromised actin stress fiber assembly and inhibited cell contractility to perturb tissue morphogenesis, whereas SLIT2 treatment stimulated Rac and increased focal adhesion kinase activity to enhance cell tension by maintaining cell shape and matrix adhesion. Further investigation revealed that a stiff ECM increased Robo1 levels by down-regulating miR-203. Consistently, patients whose tumor expressed a low miR-203/high Robo1 expression pattern exhibited a better overall survival prognosis. These studies show that cells subjected to stiffened environments up-regulate Robo1 as a protective mechanism that maintains cell shape and facilitates ECM adherence.

Cancer Registration in India - Current Scenario and Future Perspectives.

Cancer registration, an important component of cancer surveillance, is essential to a uni ed, scienti c and public health approach to cancer prevention and control. India has one of the highest cancer incidence and mortality rates in the world. A good surveillance system in the form of cancer registries is important for planning and evaluating cancer-control activities. Cancer registration in India was initiated in 1964 and expanded since 1982, through initiation of the National Cancer Registry Program (NCRP) by the Indian Council of Medical Research. NCRP currently has twenty-six population based registries and seven hospital based registries. Yet, Indian cancer registries, mostly in urban areas, cover less than 15% of the population. Other potential concerns about some Indian registries include accuracy and detail of information on cancer diagnosis, and timeliness in updating the registry databases. It is also important that necessary data collection related quality assurance measures be undertaken rigorously by the registries to ensure reliable and valid information availability. This paper reviews the current status of cancer registration in India and discusses some of the important pitfalls and issues related to cancer registration. Cancer registration in India should be complemented with a nationwide effort to foster systematic investigations of cancer patterns and trends by states, regions and sub populations and allow a continuous cycle of measurement, communication and action.

Between-ward disparities in colorectal cancer incidence and screening in Washington DC.

This study aims to investigate the incidence and determinants of colorectal cancer (CRC) and its screening in District of Columbia (DC), and identify modifiable risk factors. Data (2000-2009) from the DC Cancer Registry, Behavioral Risk Factor Surveillance System (BRFSS-DC) and Surveillance Epidemiology and End Results (SEER) were used to estimate CRC incidence in eight DC Wards. Risk factors and CRC screening were analyzed using uni-, bi-, and multivariable statistical methods with survey procedures in SAS (version 9.2) including binary, unconditional multivariable logistic regression analysis. Factors measured included stage of diagnosis, age, gender, race/ethnicity, smoking, alcohol, exercise, body weight, health insurance, education, employment, and income. Over the study time, CRC screening increased from 48.4% to 68.6%. Mean age at diagnosis was 67 years. CRC incidence is high in DC. Furthermore, CRC incidence rates in DC below 50 years' age were higher than the SEER18 average. Disparities exist between CRC incidence and screening among DC Wards. Identified risk factors for CRC are smoking, obesity, and low physical activity; screening was less prevalent among the uninsured and low socio-economic group. Local variations in CRC occurrence exist and may vary from average national experiences. Identification of local regions which vary from national trends in disease occurrence is important for comprehensive understanding of the disease in the community.

Exploring a clinically friendly web-based approach to clinical decision support linked to the electronic health record: design philosophy, prototype implementation, and framework for assessment.

BACKGROUND: Computer-based clinical decision support (CDS) is an important component of the electronic health record (EHR). As an increasing amount of CDS is implemented, it will be important that this be accomplished in a fashion that assists in clinical decision making without imposing unacceptable demands and burdens upon the provider's practice. OBJECTIVE: The objective of our study was to explore an approach that allows CDS to be clinician-friendly from a variety of perspectives, to build a prototype implementation that illustrates features of the approach, and to gain experience with a pilot framework for assessment. METHODS: The paper first discusses the project's design philosophy and goals. It then describes a prototype implementation (Neuropath/CDS) that explores the approach in the domain of neuropathic pain and in the context of the US Veterans Administration EHR. Finally, the paper discusses a framework for assessing the approach, illustrated by a pilot assessment of Neuropath/CDS. RESULTS: The paper describes the operation and technical design of Neuropath/CDS, as well as the results of the pilot assessment, which emphasize the four areas of focus, scope, content, and presentation. CONCLUSIONS: The work to date has allowed us to explore various design and implementation issues relating to the approach illustrated in Neuropath/CDS, as well as the development and pilot application of a framework for assessment.

Junctional adhesion molecule-A regulates vascular endothelial growth factor receptor-2 signaling-dependent mouse corneal wound healing.

Inflammation and angiogenesis are integral parts of wound healing. However, excessive and persistent wound-induced inflammation and angiogenesis in an avascular tissue such as the cornea may be associated with scarring and visual impairment. Junctional adhesion molecule A (Jam-A) is a tight junction protein that regulates leukocyte transmigration as well as fibroblast growth factor-2 (FGF-2)-induced angiogenesis. However its function in wound-induced inflammation and angiogenesis is still unknown. In this study, we report spontaneous corneal opacity in Jam-A deficient mice associated with inflammation, angiogenesis and the presence of myofibroblasts. Since wounds and/or corneal infections cause corneal opacities, we tested the role of Jam-A in wound-induced inflammation, angiogenesis and scarring by subjecting Jam-A deficient mice to full thickness corneal wounding. Analysis of these wounds demonstrated increased inflammation, angiogenesis, and increased number of myofibroblasts thereby indicating that Jam-A regulates the wound-healing response by controlling wound-induced inflammation, angiogenesis and scarring in the cornea. These effects were not due to inflammation alone since the inflammation-induced wound-healing response in Jam-A deficient mice was similar to wild type mice. In order to determine the molecular mechanism associated with the observed aberrant corneal wound healing in Jam-A deficient mice, we assessed the expression of the components of vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor- 2(VEGFR-2) signaling pathway. Interestingly, we observed increased levels of VEGF-A mRNA in Jam-A deficient eyes. We also observed nuclear localization of phosphorylated SMAD3 (pSMAD3) indicative of TGFß pathway activation in the Jam-A deficient eyes. Furthermore the increased wound-induced corneal inflammation, angiogenesis, and scarring in Jam-A deficient mice was attenuated by treatment with DC101, an anti-vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. Our results suggest that in the absence of Jam-A, the VEGF-A/VEGFR-2 pathway is upregulated, thereby augmenting wound induced corneal inflammation, angiogenesis, and myofibroblast accumulation leading to scarring.

Psoriasis in children: an insight.

Onset of psoriasis in childhood is quite common. Chronicity, inflammation and hyperproliferation are the cardinal features by which the condition establishes its uniqueness. Clearance of disease may be farfetched in most patients and relapse is frequent. Early recognition and management of psoriasis in children and adolescents is vital in therapy in children.

Improving risk adjustment of self-reported mental health outcomes.

Risk adjustment for mental health care is important for making meaningful comparisons of provider, program, and system performance. The purpose of this study was to compare the predictive value of three diagnosis-based risk-adjustment models for predicting self-reported mental health outcomes. Baseline and 3-month follow-up mental health assessments were obtained on 1,023 veterans in Veterans Health Administration mental health programs between 2004 and 2006. Least-squares regression models predicting mental health outcomes used the Behavior and Symptom Identification Scale-24, Veterans RAND-36, and Brief Symptom Inventory. Sequential models began with sociodemographics, added baseline self-reported mental health, and compared three psychiatric case mix schemes: two using six diagnostic categories and the other (psychiatric case mix system [PsyCMS]) using 46 categories. R (2) were lowest for sociodemographic models (0.010-0.074) and highest for models with the PsyCMS (0.187-0.425). The best predictive ability was obtained when baseline mental health and 1 year of psychiatric diagnoses were added to sociodemographic models; however, the "best" risk-adjustment model differed between inpatients and outpatients.