Search

The liver abscess is the most frequent visceral abscess caused by a parasite or bacterial infection in low and middle-income countries. A liver abscess can cause fever, chills, night sweats, malaise, nausea or vomiting, right shoulder ache, right upper quadrant pain, cough, dyspnea, anorexia, etc. A 20 years old male patient presented with symptoms of fever, chills, malaise, right shoulder pain, and right upper quadrantpain.The patient was treated with Virechan Karma (therapeutic purgation) followed by oral Ayurvedic medicines such as Varunadi Kwatha, Kanchanar Guggulu, and Aarogyavardhini Vati. Pathyaapathy (wholesome-unwholesome diet) based on Ayurveda perspectives was also advised to the patient. The total duration of the treatment was four months, and follow-up was done for one month. Improvement was assessed based on relief in the symptoms and abdomen USG. Complete relief in all symptoms was noted after completion of the treatment. The USG findings revealed a reduction in hypoechoic lesion to size 5.1*5.1 cm with calcified margins in the right lobe segment VIII of the liver. Any complications or adverse events due to treatment were not observed during the treatment period. This case report demonstrates the effectiveness of Ayurvedic approaches in managing Liver abscesses.

ObjectiveTo assess the demographic, clinical, and survival profile of people living with HIV.MethodsA retrospective cohort study was conducted among patients enrolled at a single antiretroviral therapy center in North Karnataka. A total of 11,099 were recruited from April 2007 to January 2020, out of which 3,676 were excluded and the final 7,423 entries were subjected to analysis. The outcome of interest was the time to death in months of people living with HIV on antiretroviral therapy (ART). The clinical and demographic characteristics were examined as potential risk factors for survival analysis. To investigate the factors that influence the mortality of patients using ART, univariate and multivariate Cox regression were performed. Hazard ratio (HR), 95% confidence interval (CI), and p-values were presented to show the significance. The log-rank test was used to determine the significance of the Kaplan–Meier survival curve.ResultsOut of 7,423 HIV-positive people, majority were female (51.4%), heterosexual typology (89.2%), and in the age group 31–45 years (45.5%). The risk of death in male patients was 1.24 times higher (95% CI: 1.14–1.35) than female patients. Patients with age >45 were 1.67 times more likely to die than patients ≤30 (95% CI: 1.50–1.91). In the multivariable analysis, the hazards of mortality increased by 3.11 times (95% CI: 2.09–2.79) in patients with baseline CD4 count ≤50 as compared to those who had baseline CD4 count >200. The risk of death in patients who were diagnosed with TB was 1.30 times more (95% CI: 1.19–1.42) than in those who did not have TB. The survival probabilities at 3 and 90 months were more in female patients (93%, 70%) compared with male patients (89, 54%), respectively.ConclusionThis study proved that age, sex, baseline CD4 count, and tuberculosis (TB) status act as risk factors for mortality among people with HIV. Prevention strategies, control measures, and program planning should be done based on the sociodemographic determinants of mortality.

While Mek1/2 and Gsk3β inhibition (“2i”) supports the maintenance of murine embryonic stem cells (ESCs) in a homogenous naïve state, prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential. Additionally, 2i fails to support derivation and culture of fully potent female ESCs. Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin (AlbuMAX) undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture. Mechanistically, lipids in AlbuMAX impact intracellular metabolism including nucleotide biosynthesis, lipid biogenesis, and TCA cycle intermediates, with enhanced expression of DNMT3s that prevent DNA hypomethylation. Lipids induce a formative-like pluripotent state through direct stimulation of Erk2 phosphorylation, which also alleviates X chromosome loss in female ESCs. Importantly, both male and female “all-ESC” mice can be generated from de novo derived ESCs using AlbuMAX-based media. Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.

Objective This study aims to identify and codify the facilitators and barriers to help implementing partners institutionalize health technology assessment (HTA) successfully and navigate complex systems for health-related policy making. Methods We searched for peer-reviewed and gray literature articles examining HTA programs globally using six databases. Keywords used as a guide for capturing articles included “health technology assessment,” “barrier,” and “facilitator” and their synonyms. Search results were scrutinized for duplicates and screened through a review of titles and abstracts. A full-text review was conducted exploring articles’ coverage of twenty-seven evaluation criteria across four primary areas of interest: barriers/facilitators, motivations, guidelines, and institutional frameworks. Results A total of 18,599 records were identified for duplication check, title, and abstract review. A total of 1,594 articles underwent full-text review, leading to a final synthesis of 262 studies. We found that ninety-seven articles discussed barriers/facilitators, with fifty-three of those discussing local capacity and unavailable human resources. Out of the sixty-six articles discussing motivations, forty-two cited the interest in supporting the decision-making process for, and promoting, appropriate resource allocation. Of the sixty-one articles that discussed guidelines and institutional framework, twenty-one articles described HTA as an independent national unit, and sixteen described their HTA unit as a unit within the Ministry of Health (MOH). Conclusions This systematic review unpacks the dynamic and relevant contexts for understanding the HTA institutionalization process to help policy makers and practitioners achieve tangible progress in confronting the most critical issues facing priority setting and HTA institutionalization.

The world has taken proactive measures to combat the pandemic since the coronavirus disease 2019 (COVID-19) outbreak, which was caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). These measures range from increasing the production of personal protective equipment (PPE) and highlighting the value of social distancing to the emergency use authorization (EUA) of therapeutic drugs or antibodies and their appropriate use; nonetheless, the disease is still spreading quickly and is ruining people’s social lives, the economy, and public health. As a result, effective vaccines are critical for bringing the pandemic to an end and restoring normalcy in society. Several potential COVID-19 vaccines are now being researched, developed, tested, and reviewed. Since the end of June 2022, several vaccines have been provisionally approved, whereas others are about to be approved. In the upcoming years, a large number of new medications that are presently undergoing clinical testing are anticipated to hit the market. To illustrate the advantages and disadvantages of their technique, to emphasize the additives and delivery methods used in their creation, and to project potential future growth, this study explores these vaccines and the related research endeavors, including conventional and prospective approaches.

Lipids play vital roles in cellular homeostasis and regulate pluripotency of human stem cells. However, the impact of lipids on murine pluripotent stem cells is unclear. While Mek1/2 and Gsk3β inhibition (“2i”) supports the maintenance of murine embryonic stem cells (ESCs) in a homogenous naïve state, prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential. Additionally, 2i fails to support derivation and culture of fully potent female ESCs. Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin (AlbuMAX) undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture. Mechanistically, lipids in AlbuMAX impact intracellular metabolism including nucleotide biosynthesis, lipid biogenesis, and TCA cycle intermediates, with enhanced expression of ZCAN4 and DNMT3s that prevent telomere shortening and DNA hypomethylation. In concert with 2i, lipids induce a formative-like pluripotent state through direct stimulation of Mek-mediated Erk2 phosphorylation, which also alleviates X chromosome loss in female ESCs. Importantly, both male and female “all-ESC” mice can be generated from de novo derived ESCs using AlbuMAX-based media. Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.

PurposeE-government quality (e-GovQual) and e-government user value (e-GUV) are multidimensional concepts. While previous studies have identified apparent factors influencing e-government satisfaction (e-GovSat) and e-government adoption intention (e-GovAI), such as e-GovQual and e-GUV, but they have neglected to explain the influence of the dimensions of these two concepts. The purpose of this research is to study e-government service value chain (e-GSVC) one-GovQual dimensions, e-GUV dimensions, e-GovSat and e-GovAI.Design/methodology/approachThe study employs a quantitative method to test the hypotheses and validate the proposed model. Data are collected from 378 e-government users across different parts of India comprising of different demographic characteristics. The model is analyzed using structural equation modeling.FindingsThe findings highlight the impact of the dimensions of e-GovQual (efficiency, trust, reliability and citizen support) on the dimensions of e-GUV (functional, economic, social and emotional value) as e-GUV dimensions affect e-GovSat, which in turn influences e-GovAI. The results validate the e-GSVC and also stress the partial mediating role of the dimensions of e-GUV on the relationship between the dimensions of e-GovQual and e-GovSat.Research limitations/implicationsThe sample size of 378 may not be a proper representation of a country like India, which has huge diversity within its vast population.Practical implicationsThe study offers practitioners a clear picture and a useful guide to better understand the drivers of value, satisfaction and adoption in the case of e-government users.Originality/valueThis study is probably the first attempt toward demonstrating the process influencing e-GovSat via e-GUV dimensions originating from excellent e-GovQual dimensions to ultimately trigger e-GovAI.

Objective To provide an update on the use of health technology assessment (HTA) in Asia and lessons for countries seeking to advance HTA. Methods Build upon the research by Chootipongchaivat and the World Health Organization identifying eighteen “factors conducive to the development of HTA in Asia.” These factors were used to create a balanced scorecard to assess the progress of HTA, measuring progress against each factor in China, India, Indonesia, Malaysia, Philippines, South Korea, Taiwan, Thailand, and Vietnam. A scoring system was used wherein: 1, No progress; 2, milestone at early stages, ad hoc HTA use; 3, progress on milestone but limited impact; 4, significant progress but limited remit; and 5, significant progress on milestone, routine HTA informs decisions. Total scores indicated progress of HTA while milestone scores provided contextual insights within countries. Literature reviews and expert interviews were used to complete scorecards. Results South Korea and Thailand scored highest with seventy-three and seventy-one points, respectively, while Vietnam scored lowest at 28.5. Advanced HTA programs have independent HTA agencies with a broad remit, explicit process and methods, network of researchers, and routine use of HTA. Taiwan and Malaysia fall in a middle tier, with established HTA programs with limited remit. The final tier with China, India, Indonesia, Philippines, and Vietnam, emerging HTA processes. Conclusions Universal Health Coverage goals have catalyzed expansion of HTA. Political will, technical expertise, and sustained financing remain challenges for sustainable HTA programs. Legislation supporting HTA is helpful but political will is key. Recommendations for regional collaboration are provided.

The objective of this study is to assess the frequency and severity of adverse events following immunization (AEFI) in Indian children aged 5–17 years who received the Pfizer-BioNTech mRNA COVID-19 vaccine, as well as to investigate for predictors of AEFI. To examine AEFI following the first and second doses of Pfizer’s vaccine, semi-structured questionnaires were distributed as Google forms at Indian schools in Saudi Arabia. The 385 responses included 48.1% male and 51.9% female children, with 136 responses of children aged 5–11 years (group A) and 249 responses from children aged 12–17 years (group B). Overall, 84.4% of children had two shots. The frequency of AEFI was reported to be higher after the first dose than after the second (OR = 2.12, 95% CI = 1.57–2.86). The reported AEFIs included myalgia, rhinitis, local reaction with fever, a temperature of 102 °F or higher, and mild to moderate injection site reactions. While group B frequently reported multiple AEFIs, group A typically reported just one. Local reaction with low grade fever was more frequently reported in group B after the first dose (24.1%) and second dose (15.4%), while local reaction without low grade fever was most frequently observed in group A after the first (36.8%) and second dose (30%). Only prior COVID-19 infection (OR = 2.98, 95% CI = 1.44–6.2) was associated with AEFI after the second dose in the study sample, whereas male gender (OR = 1.71, 95% CI = 1.13–2.6) and prior COVID-19 infection (OR = 2.95, 95% CI = 1.38–6.3) were predictors of AEFI after the first dose. Non-serious myocarditis was reported by only one child. According to the analysis conducted, the Pfizer’s mRNA COVID-19 vaccination was found to be safe in Indian children.

Sphingosine‐1‐phosphate (S1P) is a bioactive lipid molecule regulating organogenesis, angiogenesis, cell proliferation, and apoptosis. S1P is generated by sphingosine kinases (SPHK1 and SPHK2) through the phosphorylation of ceramide‐derived sphingosine. Phenotypes caused by manipulating S1P metabolic enzymes and receptors suggested several possible functions for S1P in embryonic stem cells (ESCs), yet the mechanisms by which S1P and related sphingolipids act in ESCs are controversial. We designed a rigorous test to evaluate the requirement of S1P in murine ESCs by knocking out both Sphk1 and Sphk2 to create cells incapable of generating S1P. To accomplish this, we created lines mutant for Sphk2 and conditionally mutant (floxed) for Sphk1, allowing evaluation of ESCs that transition to double‐null state. The Sphk1/2‐null ESCs lack S1P and accumulate the precursor sphingosine. The double‐mutant cells fail to grow due to a marked cell cycle arrest at G2/M. Mutant cells activate expression of telomere elongation factor genes Zscan4, Tcstv1, and Tcstv3 and display longer telomeric repeats. Adding exogenous S1P to the medium had no impact, but the cell cycle arrest is partially alleviated by the expression of a ceramide synthase 2, which converts excess sphingosine into ceramide. The results indicate that sphingosine kinase activity is essential in mouse ESCs for limiting the accumulation of sphingosine that otherwise drives cell cycle arrest., To test the function of the S1P signaling pathway in ESCs, conditional sphingosine kinase null mouse embryonic stem cell (mESC) lines were created. Sphk1 fl/fl ; Sphk2 −/− mice were crossed, and embryonic blastocysts used to derive mESC lines. Expression of Cre recombinase allows for excision of Sphk1 and produces sphingosine kinase null cells, which become blocked at G2/M due to excessive sphingosine.

Screen identifies demethylation regulator DNA methylation was one of the first epigenetic mechanisms discovered, but there is a limited understanding of its regulation and dysregulation in the context of development and disease. Dixon et al. performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to identify DNA methylation regulators (see the Perspective by Gu and Goodell). A top screen hit, QSER1, proved to be essential for maintaining low methylation at DNA methylation valleys, which overlap with developmental genes and broad H3K27me3 and EZH2 peaks. Mechanistic examination revealed that QSER1 and the demethylating enzyme TET1 cooperate to safeguard developmental programs from de novo methylation by the enzyme DNMT3. Science , this issue p. eabd0875 ; see also p. 128

Purpose The purpose of this study is to explore the factors that enable citizens to adopt e-government services in India. Design/methodology/approach The study uses a qualitative approach by conducting semi-structured interviews. Findings The study reveals novel e-government adoption factors, namely, auxiliary facilities, corruption avoidance, transparency and fairness in process, customer support, connectedness and forced adoption, previously unexplored in e-government adoption literature. In addition, the results highlight 17 e-government adoption factors that strengthen the findings from previous literature. Research limitations/implications This study was qualitative in nature, and rather than generalization, the focus was explicitly on obtaining an in-depth understanding. The sample used was sufficient for the purpose of this study and allowed reasonable conclusions to be drawn; however, it cannot be considered representative of a vast country like India. Academicians and information systems researchers can use these findings for further research. Practical implications The findings of this study provide useful insights into the decision-making process of e-government services users in India and similar emerging economies. These findings can be important for government officials tasked with providing e-government services. Originality/value Previous studies in the context of e-government adoption, so far, have tried to integrate adoption factors from previous technology adoption models. Hence, these studies have not been able to capture the complete essence of e-government characteristics. In addition, there are limited studies in e-government adoption in the Indian context.

Purpose A government website is considered as an electronic government service delivery system (eGSDS). The authors look at this eGSDS from its process point of view. This study aims to expand the existing knowledge of e-government adoption, and to identify the significance of eGSDS process to user satisfaction. Design/methodology/approach This study uses a quantitative technique using data collected from 197 respondents. Structure equation modeling has been used to test the model and the proposed hypotheses. Findings The findings indicate that as the eGSDS process improves, a user’s perception of the government website’s ease of use increases, leading to increased perceived usefulness, which increases user satisfaction. The findings also indicate that eGSDS process has a significant impact on perceived usefulness and user satisfaction. This study provides evidence that the technological capabilities embedded in the government website processes are an important factor in determining e-government service quality and ultimately e-government user satisfaction. Research limitations/implications The sample used was sufficient for this study and allowed reasonable conclusions to be drawn, but cannot be considered representative of all e-government users in India. Further research may help to validate the findings and generalize the results to a wider population. This study extends the current literature that looks at e-government adoption. Academicians and information systems researchers may use these findings for further research. Practical implications The research provides evidence that the technological capabilities embedded in the eGSDS process are critical in adopting e-government services. Government or concerned agencies may consider eGSDS process attributes (e.g. navigation, searching and transacting) while designing e-government service to give improved experience to its user. Originality/value E-government websites have become an important point of contact with citizens for many public services. However, more study is needed to understand how Web-based technological capabilities of e-government services affect user satisfaction. This study is an attempt to explore the impact of the eGSDS process on e-government user satisfaction.

Introduction Polymorphic ventricular tachycardia (PMVT) can occur in patients with structurally normal hearts and in 8% of cases can lead to sudden cardiac death, typically exercise-induced. The role of the cardiac type 2 ryanodine receptor (RyR2) in pathogenesis of PMVT presenting at rest is unclear. Objective We aimed here at modelling PMVT observed in a patient harboring the RyR2-H29D mutation by comparing the molecular and functional properties of RyR2-H29D hiPSC-derived cardiomyocytes (hiPSC-CMs) with their isogenic control counterparts with a particular focus on the RyR2 properties. Methods We collected blood samples from the patient and generated several clones of RyR2-H29D hiPSC, in addition to generating an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. We used fluorescent confocal microscopy, patch-clamp and video-image-based analysis to investigate the molecular and functional consequences of the RyR2-H29D mutation. Results We first hypothesized that PMVT hiPSC-CMs expressing the RyR2-H29D mutation would exhibit abnormal Ca2+ homeostasis. Thus, we measured and analyzed the intracellular Ca2+ variation. We found that the RyR2-H29D hiPSC-CMs exhibit clone-independent aberrant properties including intracellular sarcoplasmic reticulum (SR) Ca2+ leak through RyR2 under physiological pacing. The contribution of inositol 1,4,5-trisphosphate receptors to excitation-contraction coupling (ECC) exacerbate the abnormal intracellular Ca2+ release in the RyR2-H29D hiPSC-CMs. Moreover, the RyR2-H29D hiPSC-CMs exhibit RyR2 post-translational remodeling, shorter action potentials, delayed afterdepolarizations, arrhythmias and aberrant contractile properties compared to isogenic controls. These abnormalities are fully reversed with isogenic control. Conclusions Our results suggest that RyR2-mediated Ca2+ leak induces an impairment of Ca2+ homeostasis and provide support to decipher the molecular mechanisms of short-coupled PMVT at rest.

This study identifies the impact of Internet banking service delivery system (IBSDS) process on consumer behaviour; the mediating effect of customer satisfaction on the relationship between IBSDS process and behavioural intention; and the moderating effect of the customer’s perceived value. The study uses a quantitative method using the data collected from 416 respondents. Mediated regression is used to examine the mediating effect of customer satisfaction. SPSS Process v2.16.3 is employed to analyse the moderating effect of the perceived value. The results indicate that IBSDS process impacts customer satisfaction and behavioural intention. Further, customer satisfaction plays a partial mediating role between the association of IBSDS process and behavioural intention. This study provides evidence that the technological capabilities embedded in the bank website processes are an important factor in determining customer satisfaction and ultimately behavioural intention. The study also reveals that perceived value moderates the relationship between IBSDS process and customer satisfaction, and between customer satisfaction, and, behavioural intention. It also adds to the existing knowledge on the adoption of Internet banking literature. Academicians and information systems researchers may use these findings for further research. Financial service providers or related agencies may consider the attributes of the IBSDS process (e.g., navigation, searching, transacting, etc.) while designing their Internet banking services to provide enhanced customer experiences. The paper also highlights the research limitations and scope for future research.

Infant and child mortality rates are considered to be sensitive indicators of socio-economic and health conditions prevailing in a community. They are often used to reflect the state of public health, environmental sanitation, socio-economic development, and the people’s attitude towards the value of human life itself in a country. For demographic and statistical purposes, all children under one year of age are considered infants, and so, the term ‘infant mortality’ refers to mortality among children of less than one year of age. After infancy, childhood is the most crucial period for survival over the entire lifespan. Decreases in the risk of mortality in succeeding age periods during infancy continue beyond the first birthday.

Well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors with varying metastatic potential. The underlying molecular basis for metastasis by GEP-NETs remains undefined. Quantitative PCR and immunohistochemistry (IHC) staining for ubiquitin carboxyl-terminal esterase L1 (UCHL1) gene and protein expression was performed on a group of localized and metastatic well-differentiated GEP-NET samples acquired from a prospectively maintained tissue bank. The ability of extent of UCHL1 IHC staining to differentiate localized and metastatic tumors was compared with Ki-67 index. Among 46 total samples, UCHL1 expression at both the gene and protein level was significantly greater among localized GEP-NETs compared with metastatic tumors and metastases (p

Harm reduction packages for people who inject illicit drugs, including those infected with human immunodeficiency virus (HIV), are cost-effective but have not been scaled up globally. In the north-eastern Indian states of Manipur and Nagaland, the epidemic of HIV infection is driven by the injection of illicit drugs, especially opioids. These states needed to scale up harm reduction programmes but faced difficulty doing so.In 2004, the BillMelinda Gates Foundation funded Project ORCHID to scale up a harm reduction programme in Manipur and Nagaland.In 2003, an estimated 10 000 and 16 000 people were injecting drugs in Manipur and Nagaland, respectively. The prevalence of HIV infection among people injecting drugs was 24.5% in Manipur and 8.4% in Nagaland.By 2012, the harm reduction programme had been scaled up to an average of 9011 monthly contacts outside clinics (80% of target); an average of 1709 monthly clinic visits (15% of target, well above the 5% monthly goal) and an average monthly distribution of needles and syringes of 16 each per programme participant. Opioid agonist maintenance treatment coverage was 13.7% and retention 6 months after enrolment was 63%. Antiretroviral treatment coverage for HIV-positive participants was 81%.A harm reduction model consisting of community-owned, locally relevant innovations and business approaches can result in good harm reduction programme scale-up and influence harm reduction policy. Project ORCHID has influenced national harm reduction policy in India and contributed to the development of harm reduction guidelines.Les kits de réduction des risques pour les personnes qui s'injectent des drogues illicites, y compris celles qui sont infectées par le virus de l'immunodéficience humaine (VIH), sont rentables, mais n'ont pas été généralisés. Dans les États du Nord-est indien de Manipur et de Nagaland, l'épidémie d'infection au VIH est induite par l'injection de drogues illicites, en particulier les opioïdes. Ces États avaient besoin d'intensifier les programmes de réduction des risques, mais ils étaient confrontés à des difficultés pour le faire.En 2004, la Fondation Bill-et-Melinda-Gates a financé le projet ORCHID pour intensifier un programme de réduction des risques dans le Manipur et le Nagaland.En 2003, on estimait que 10 000 à 16 000 personnes s'injectaient de la drogue dans le Manipur et le Nagaland, respectivement. La prévalence de l'infection par le VIH chez les personnes s'injectant des drogues était de 24,5% dans le Manipur et de 8,4% dans le Nagaland.En 2012, le programme de réduction des risques a été étendu à une moyenne de 9 011 contacts par mois en dehors des cliniques (80% de la cible), pour une moyenne de 1 709 visites cliniques mensuelles (15% de l'objectif, bien au-dessus de l'objectif de 5% par mois) et pour une distribution mensuelle moyenne d'aiguilles et de seringues de 16 pour chaque participant au programme. La couverture du traitement d'entretien par agoniste opioïde était de 13,7% et la rétention 6 mois après l'inscription était de 63%. La couverture du traitement antirétroviral pour les participants séropositifs était de 81%.Un modèle de réduction des risques, constitué d'innovations pertinentes au niveau local et appartenant à la collectivité, ainsi que d'approches commerciales, peut entraîner une extension satisfaisante du programme de réduction des risques et influencer la politique de réduction des risques. Le projet ORCHID a influencé la politique nationale de réduction des risques en Inde et a contribué à l'élaboration de recommandations en matière de réduction des risques.Los paquetes de medidas para reducir los daños que se producen entre las personas que se inyectan drogas ilegales, incluidas aquellas infectadas por el virus de la inmunodeficiencia humana (VIH), si bien eficaces en relación con el costo, no se han ampliado a nivel global. En los estados de Manipur y Nagaland, situados en el noreste de India, la epidemia de infecciones por el VIH se debe a la inyección de drogas ilegales, en especial de opiáceos. Estos estados tuvieron que ampliar sus programas de reducción de daños pero, al hacerlo, se enfrentaron a diversas dificultades.En el año 2004, la BillMelinda Foundation fundó el Proyecto ORCHID con objeto de ampliar un programa de reducción de daños en Manipur y Nagaland.En el año 2003, se estimó que 10 000 y 16 000 personas se inyectaban drogas en Manipur y Nagaland, respectivamente. La prevalencia de la infección por el VIH entre los consumidores de drogas inyectables fue del 24,5% en Manipur y del 8,4% en Nagaland.Hasta el año 2012, el programa de reducción de daños se amplió hasta una media de 9011 contactos mensuales fuera de clínicas (80% del objetivo); una media de 1709 visitas clínicas (15% del objetivo, muy por encima del 5% de la meta mensual) y una distribución mensual media de 16 agujas y jeringuillas por participante en el programa. La cobertura del tratamiento de mantenimiento con opioides agonistas fue del 13,7% y la permanencia 6 meses después de la inscripción, del 63%. La cobertura del tratamiento con antirretrovirales para los participantes seropositivos fue del 81%.Un modelo de reducción de daños consistente en innovaciones basadas en la comunidad y relevantes a nivel local y en enfoques comerciales puede resultar en una ampliación positiva del programa de reducción de daños e influir en la política de reducción de daños. El proyecto ORCHID ha influido en la política nacional de reducción de daños en India y ha contribuido al desarrollo de directrices para la reducción de daños.تعتبر حزم الحد من الأضرار للأشخاص الذين يتعاطون العقاقير غير المشروعة عن طريق الحقن، بما فيهم المصابين بعدوى فيروس العوز المناعي البشري (HIV) عالية المردود غير أنه لم يتم تعزيزها على الصعيد العالمي. وفي ولاياتي مانيبور وناغالاند في شمال شرق الهند، ينتج وباء عدوى فيروس العوز المناعي البشري عن تعاطي العقاقير غير المشروعة عن طريق الحقن، ولاسيما المواد الأفيونية المفعول. واحتاجت هاتان الولايتان إلى تعزيز برامج الحد من الأضرار ولكنهما واجهتا صعوبة في القيام بهذا.في عام 2004، مولت مؤسسة بيل وميليندا غيتس مشروع ORCHID لتعزيز برنامج الحد من الأضرار في مانيبور وناغالاند.في عام 2003، قُدّر عدد الأشخاص الذين يتعاطون الأدوية عن طريق الحقن في مانيبور وناغالاند بعدد 10000 و16000 شخصاً على التوالي. وبلغ معدل انتشار عدوى فيروس العوز المناعي البشري بين الأشخاص الذين يتعاطون الأدوية عن طريق الحقن 24.5 % في مانيبور و8.4 % في ناغالاند.بحلول عام 2012، تم تعزيز برنامج الحد من الأضرار حتى وصل إلى متوسط 9011 نقطة اتصال شهرية خارج العيادات (80 % من المستهدف)؛ ومتوسط 1709 زيارة شهرية إلى العيادات (15 % من المستهدف، وهو أعلى بدرجة كبيرة من الهدف الشهري البالغ نسبته 5 %) وتوزيع شهري للإبر والمحاقن بلغ في المتوسط 16 إبرة ومحقن لكل مشارك في البرنامج. وبلغت تغطية العلاج الصياني بناهض المواد الأفيونية المفعول 13.7 % وبلغ إبقاء العلاج بعد التسجيل بستة أشهر 63 %. وبلغت تغطية العلاج بمضادات الفيروسات القهقرية للمشاركين الإيجابيين لفيروس العوز المناعي البشري 81 %.يتمتع نموذج للحد من الأضرار يتألف من ابتكارات وأساليب عمل مملوكة للمجتمع المحلي وملائمة للظروف المحلية بالقدرة على تحسين تعزيز برنامج الحد من الأضرار والتأثير على سياسة الحد من الأضرار. وأثر مشروع ORCHID على السياسة الوطنية للحد من الأضرار في الهند وأسهم في وضع المبادئ التوجيهية للحد من الأضرار.针对注射违禁药物的人群的一整套减害措施具有成本效益，这套措施同样适用于感染艾滋病毒（HIV）的注射人群，但是还没有在全球范围内推广。在印度东北地区的曼尼普尔邦和那加兰邦，注射非法药物，尤其是阿片类药物加剧了艾滋病毒感染的流行。这些邦需要推广减害计划，但实施起来面临困难。2004 年，由比尔和梅林达·盖茨基金会资助的项目ORCHID在曼尼普尔邦和那加兰邦扩大减害计划规模。据估计，2003 年曼尼普尔邦和那加兰邦分别有1 万和1.6 万人注射毒品。注射毒品人群的艾滋病毒感染率在曼尼普尔邦为24.5%，在那加兰邦为 8.4%。2012 年，减害计划已扩大为每月平均9011 个诊所外联系人（目标人数的80%）；每月平均1709 人就诊（目标人数的15%，远高于5%的每月目标），每个计划参与者每月平均各发放16 个针头和注射器。阿片受体激动剂维持治疗覆盖率为13.7%，参加治疗之后6 个月的保持率是63%。艾滋病毒阳性参与者的抗逆转录病毒治疗的覆盖率是81%。由社区拥有、因地制宜的创新和商业途径组成的减害模型可以很好地推广减害计划，并影响减害政策。ORCHID项目已经对印度的国家减害政策产生了影响，对减害指导方针的发展作出了贡献。Комплексы мер по сокращению вреда для людей, употребляющих запрещенные инъекционные наркотики, в том числе, инфицированных вирусом иммунодефицита человека (ВИЧ), оправдывают затраты, но не применяются в глобальном масштабе. Основной причиной ВИЧ-инфекции в северо-восточных индийских штатах Манипур и Нагаленд является употребление запрещенных инъекционных наркотиков, особенно опиатов. В этих штатах потребовалось более масштабное применение программ по сокращению вреда, которое, однако, столкнулось с трудностями.В 2004 г. Фонд Билла и Мелинды Гейтсов профинансировал проект ORCHID по более масштабному применению программ сокращения вреда в штатах Манипур и Нагаленд.В 2003 г. количество человек, употребляющих инъекционные наркотики в штатах Манипур и Нагаленд, оценивалось, соответственно, на уровне 10 000 и 16 000 человек. Уровень распространения ВИЧ-инфекции среди людей, употребляющих инъекционные наркотики, составил 24,5% в Манипуре и 8,4% в Нагаленде.В 2012 г. было осуществлено более масштабное развертывание программы сокращения вреда в среднем до 9011 контактов за пределами клиник в месяц (80% от целевого показателя), до в среднем 1709 посещений клиники в месяц (15% от целевого показателя, на 5% выше месячной цели), а среднее количество выданных каждому участнику программы игл и шприцов составило 16 штук. Охват поддерживающей терапией с использованием агонистов опиоидных рецепторов составил 13,7%, а показатель удержания в программе через 6 месяцев после регистрации составлял 63%. Охват антиретровирусной терапией для ВИЧ-положительных участников составил 81%.Результатом использования модели снижения вреда, включающей принадлежащие местному сообществу, актуальные для местных условий инновации и бизнес-подходы, может стать значительное расширение масштабов применения программы сокращения вреда и влияние на политику сокращения вреда. Проект ORCHID повлиял на национальную политику сокращения вреда в Индии и внес свой вклад в разработку руководящих принципов сокращения вреда.

Highlights • 8 factors predict the viability of vaccine manufacturers in developing countries. • These factors have evolved as the vaccine landscape has changed over 2 decades. • A new analysis updates a framework first published in 1997 to assess viability. • The updated framework is useful for assessing investments in vaccine manufacturers., In 1997, Milstien, Batson, and Meaney published “A Systematic Method for Evaluating the Potential Viability of Local Vaccine Producers.” The paper identified characteristics of successful vaccine manufacturers and developed a viability framework to evaluate their performance. This paper revisits the original study after two decades to determine the ability of the framework to predict manufacturer success. By reconstructing much of the original dataset and conducting in-depth interviews, the authors developed informed views on the continued viability of manufacturers in low- and middle-income country markets. Considering the marked changes in the market and technology landscape since 1997, the authors find the viability framework to be predictive and a useful lens through which to evaluate manufacturer success or failure. Of particular interest is how incumbent and potentially new developing-country vaccine manufacturers enter and sustain production in competitive international markets and how they integrate (or fail to integrate) new technology into the production process. Ultimately, most manufacturers will need to meet global quality standards to be viable. As governments and donors consider investments in vaccine producers, the updated viability factors will be a useful tool in evaluating the prospects of manufacturers over the mid to long term. The paper emphasizes that while up-front investments are important, other critical factors—including investments in a national regulatory authority, manufacturer independence, and ability to adapt and adopt new technology—are necessary to ensure viability.

We present the design, development and testing of an electronics module to harvest, regulate and store vibrational energy. The module includes a flexible rechargeable battery to store the harvested vibrational energy generated from normal human physical motion. The proposed regenerative power source is examined by integrating with a Galvanic Skin Response (GSR) sensor suitable for continuous long term measurement of stress and fatigue levels of personnel working in physically demanding and extreme work conditions.

B cells, the Ab-producing cells of the immune system, develop from hematopoietic stem cells (HSCs) through well-defined stages during which Ig genes are rearranged to generate a clonal BCR. Signaling through the BCR plays a role in the subsequent cell fate decisions leading to the generation of three distinct types of B cells: B1, marginal zone, and follicular B cells. Common lymphoid progenitors (CLPs) are descended from HSCs, and although recent observations suggest that CLPs may not be physiological T cell precursors, it is generally accepted that CLPs are obligate progenitors for B cells. In addition, a CLP-like progenitor of unknown significance that lacks expression of c-kit (kit−CLP) was recently identified in the mouse model. In this study, we show that CLPs, kit−CLPs and a population within the lin−Sca1+kit+flt3− HSC compartment generate mature B cell types in different proportions: CLPs and kit−CLPs show a stronger marginal zone /follicular ratio than lin−Sca1+kit+flt3− cells, whereas kit−CLPs show a stronger B1 bias than any other progenitor population. Furthermore, expression of Sca1 on B cells depends on their progenitor origin as B cells derived from CLPs and kit−CLPs express more Sca1 than those derived from lin−Sca1+kit+flt3− cells. These observations indicate a role for progenitor origin in B cell fate choices and suggest the existence of CLP-independent B cell development.

The significance of a population in mouse bone marrow of lineage-negative (Lin(-)), Sca1-positive, c-kit-negative (LSK(-)) cells, which is reported to be devoid of long-term repopulation capacity or myeloid potential, is unknown. In this study, we show that the LSK(-) population is composed of several subsets defined by the expression of flt3, CD25, and IL-7Ralpha. The first subset was CD25(-) and more than 90% expressed either flt3, IL-7Ralpha, or both. The CD25(-)LSK(-) population had T cell, B cell, and NK cell potential in vivo, and most of this activity was localized in the flt3(+) subset, irrespective of the expression of IL-7Ralpha. Although lymphoid potential of flt3(+)LSK(-) cells in vivo was 3-fold lower than that of lin(-)Sca1(low)kit(low)IL7Ralpha(+) common lymphoid progenitors (CLPs), their cloning efficiency in vitro was 10-fold lower than that of CLPs. Furthermore, although the myeloid potential of flt3(+)LSK(-) cells was 10-fold lower than that of CLPs in the absence of M-CSF, the relative myeloid potential of both populations was similar in its presence. These observations suggest differential growth factor requirements of both populations. The second subset of LSK(-) cells was homogeneously CD25(+)flt3(-)IL7Ralpha(+) and could be generated from both CD25(-)LSK(-) cells and from CLPs, but did not engraft in immunodeficient Rag1(-/-) or Rag1(-/-)gamma(c)(-/-) hosts. This population, of which the significance is unclear, was increased in Rag1(-/-) mice and in old mice. Thus, the LSK(-) population is phenotypically and functionally heterogeneous and contains early lymphoid-committed precursors. Our findings imply that the early stages of lymphoid commitment are more complex than was thus far assumed.

Control of Epigenetic Memory and Pluripotency by DNA Methylation The DNA sequence of most differentiated cells is the same, so that epigenetic mechanisms must provide the means for cells to remember their fate, and maintain a stable and restricted phenotype. DNA methylation is a reversible epigenetic modification that provides one of the major strategies to mark genes to generate cellular memory. In vertebrates, most methyl marks are applied to the 5-position of cytidine at CpG residues, and the role of de novo and maintenance methyltransferases in generating memory is well understood. Less clear has been how methyl marks can be removed, to erase memory and allow cell fate to change.

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings. Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0896-8) contains supplementary material, which is available to authorized users.

Background Mycobacterium avium complex (MAC) is a ubiquitous pathogen, widely distributed in the environment including water, soil and animals. It is an uncommonly encountered clinical pathogen; primarily causing pulmonary infections in patients with underlying lung disease or disseminated disease in immunocompromised hosts. Sporadically, extra-pulmonary infections have been documented including involvement of the liver, spleen, skin, soft tissue and lymph nodes. Central nervous system (CNS) infections due to MAC are exceedingly rare and carry a poor prognosis. Additionally, such infections are largely reported in patients infected with HIV. Herein we report the first case of intracranial abscess due to MAC in an immunocompetent man with a normal CD4 count and negative HIV status. Case presentation A previously healthy 40-year-old male presented to us with progressively worsening CNS symptoms. The patient’s presentation was uncharacteristic of MAC infection in immunocompetent hosts, as he developed subacute, progressive symptoms that included severe frontal headaches, left eyelid swelling, blurry vision, and diplopia, without any pulmonary or systemic manifestations. Neuroimaging revealed multiple ring-enhancing lesions, which required neurosurgical intervention. MAC was the only pathogen that grew from intraoperative tissue cultures. The patient was subsequently treated with a 12-month regimen consisting of Clarithromycin, Ethambutol, and Rifampin, with successful clinical resolution. Conclusion Our findings indicate that it is important to consider rare infections such as MAC in immunocompetent patients, regardless of atypical symptoms. Despite the severity of this infection, with timely diagnosis effective treatment is available.

What is the preparedness of the Indian insurance industry to deal with the growing frequency and severity of natural disasters? We examine this question and argue that the continuation of present p...

Oxalate plays a crucial role in the formation of most renal stones. Oxalate is a common constituent of most diets and a byproduct of metabolism, and if it is not sufficiently degraded, it may accumulate. In humans, gut bacteria degrade 70 to 100 mg of oxalate per day. Oxalobacter formigenes is a gram-negative, obligately anaerobic, rod-shaped bacterium with an absolute requirement for oxalate. Although not present in the gut at birth, it quickly colonizes most children, and there is epidemiologic evidence that its absence is a risk factor in calcium oxalate stone formation. We review the metabolism, genetics, and identification of this organism and its possible therapeutic role in recurrent stone-forming patients.

OBJECTIVE: Though prior authorization (PA) programs are widely used in the managed care pharmacy environment, some stakeholders question whether these programs are effective. The objective of this article is to critically examine the effect of PA programs on health-related outcomes. DATA SOURCES: A computer-aided search of the literature was conducted using several online databases to find studies that have evaluated PA programs. Other sources of information used were reference lists, authors of previous studies, and meeting abstracts. STUDY SELECTION: In order for a study to be included in our analysis, it had to (1) appear in the peer-reviewed literature and (2) investigate the effects of a PA program on specified drugs. We excluded papers that studied the effectiveness of formulary systems, of which PA may be a component. DATA EXTRACTION: From each study evaluated, we extracted data related to the study design and to the effect of the PA program on economic, clinical, and humanistic outcomes. DATA SYNT...

This paper describes the innovations required from companies, local authorities and national governments to make manufacturing industry contribute to sustainable development in cities. It argues that the urban dimension has often been overlooked in discussions on industry and sustainable development, with most attention focusing on the roles of the individual firm and/or national policy in achieving change. The paper then presents a series of examples to demonstrate how industry will need to become responsible not only for the social and environmental performance of its own production activities but also for the sourcing of raw material inputs “upstream” and for the emissions and wastes that its products generate “downstream”.

Chryseobacterium meningosepticum is a Gram-negative bacillus historically associated with meningitis and sepsis in premature neonates. Clinicians should suspect this organism when Gram-negative bacilli are seen on Gram-stain and culture, particularly in immunocompromised patients, and in cases of disrupted host tissue integrity. We report the first case of septic arthritis due to this organism.

The activation-induced cytidine deaminase (AID; also known as AICDA) enzyme is required for somatic hypermutation and class switch recombination at the immunoglobulin locus. In germinal-centre B cells, AID is highly expressed, and has an inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine in concert with base-excision repair to exchange cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, different studies have suggested either a requirement or a lack of function for AID in promoting pluripotency in somatic nuclei after fusion with embryonic stem cells. Here we tested directly whether AID regulates epigenetic memory by comparing the relative ability of cells lacking AID to reprogram from a differentiated murine cell type to an induced pluripotent stem cell. We show that Aid-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize in the pluripotent state. The genome of Aid-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably upregulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status, and implicated a secondary set of pluripotency network components. AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state.

Gastrointestinal bleeding is a common complaint encountered in the emergency department and frequent cause of hospitalization. Important diagnostic factors that increase morbidity and mortality include advanced age, serious comorbid conditions, hemodynamic instability, esophageal varices, significant hematemesis or melena, and marked anemia. Because gastrointestinal bleeding carries a 10% overall mortality rate, emergency physicians must perform timely diagnosis, aggressive resuscitation, risk stratification, and early consultation for these patients.

In amniotes, mesoderm and endoderm arise during gastrulation, the process that derives the three primary germ layers and establishes the basic body plan of the embryo. However, in recent years there has been a new appreciation for a very early stage of development, when some blastomeres are bipotential and may still contribute to either mesoderm or endoderm (but not ectoderm). This tissue has been termed “mesendoderm” (or sometimes “endomesoderm”, but we will use the more common term). Specifically, experiments in nematodes, sea urchins, frogs, or zebrafish showed that when certain single cells were marked at the mid-blastula stage, the labeled cell can contribute to both mesoderm (e.g. blood, heart, muscle) and endoderm (e.g. gut, liver, pancreas) derivatives. Remarkably, the signaling molecules and genetic programs appear to be well conserved across these species (reviewed in Rodaway and Patient, 2001; Wardle and Smith, 2006). Most prominently this involves the nodal signaling pathway (Schier, 2003) and several families of regulatory proteins, including those encoding T-box and GATA transcription factors (Fig. 1). Since zebrafish and frogs are vertebrates, it seems likely that the same developmental programs should function in other vertebrates, including mouse and man. In the mouse, the three germ layers are derived from the epiblast through gastrulation beginning at approximately day 6.5 of gestation. After implantation, the blastocyst, comprising the inner cell mass inside the trophectoderm, develops into an elongated structure composed of the ectoplacental cone, the extraembryonic ectoderm, the visceral endoderm and the epiblast. Gastrulation begins with the formation of a transient structure known as the primitive streak (PS) in the presumptive posterior end of the embryo through which uncommitted epiblast cells mobilize and egress to form the mesoderm and the endoderm (Tam et al., 2007). On the basis of developmental potential and gene expression patterns, the PS can be divided into anterior, mid and posterior regions, with mesoderm developing from the posterior region and the endoderm developing from the most anterior domain. While the close developmental association between endoderm and mesoderm supports the notion that mesendoderm also generates these two germ layers in mammals, the concept is most strongly supported by studies in the embryonic stem cell system (Tada et al., 2005). Mouse embryonic stem (ES) cells generated from the blastocyst inner cell mass can be maintained and expanded as a pure undifferentiated population of cells when grown on mouse feeder cells in media containing leukemia inhibitory factor (LIF) and serum (Evans

We discovered a novel population of gammadelta T cells in the mouse that accumulates with age in hematopoietic organs, but not in epithelia. These cells are CD25low (an unusual phenotype for gammadelta T cells in the mouse); express higher levels of TCRgammadelta and CD44 than do CD25- gammadelta T cells; mainly express Vgamma2, Vgamma3, and Vgamma4 chains; and are largely quiescent. A very similar cell population appears in the late stages of fetal thymus organ cultures, suggesting that the accumulation of CD44 + CD25lowTCRgammadelta + cells is a response to stress induced by aging in vivo or by culture in vitro. The precursors of CD44 + CD25lowTCRgammadelta + cells are generated during fetal or very young adult life, as this population was undetectable in aged recipients of bone marrow from old or young donors. CD44 + CD25lowTCRgammadelta + cells may be a biomarker of aging, but could also play a role in the inflammatory changes that accompany aging.

Oxalobacter formigenes is a bacterium residing in the human gastrointestinal tract that degrades oxalate and reduces its availability for absorption. This bacterium is assumed to be antibiotic sensitive, and repeated antibiotic therapies could eradicate it. The aim of the present study was to determine the differences in the colonization by O. formigenes of individuals who had been on antibiotics for at least 5 days at the time of sample collection and individuals who had not taken antibiotics for at least 3 months.Stool samples were collected from 80 individuals without stone disease (35 with and 45 without antibiotic consumption) and 100 patients with stone disease (20 with and 80 without antibiotic consumption). Oxalobacter formigenes was detected by a polymerase chain reaction-based method, and the presence/absence of O. formigenes was correlated with urinary oxalate concentrations.Lower percentages of individuals without stone disease and with stone disease who were consuming antibiotics had O. formigenes colonization than individuals without antibiotic consumption. Urinary oxalate concentrations were higher in the individuals without O. formigenes than in colonized individuals.Our observations confirm a direct association between antibiotic consumption and absence of O. formigenes. Absence of intestinal O. formigenes could represent a pathogenic factor in calcium oxalate urolithiasis when antibiotics are prescribed generously.

This paper examines the rising demand for Koshala state in Orissa and looks for factors responsible for it. It found that the issue of underdevelopment and state apathy-cum-failures in addressing the same has been the single most important factor contributed for the demand for Koshala state. The study prescribes suitable policies for Orissa government to adopt to contain the demand for this new state.

Objective: To examine stone composition, metabolic evaluation and colonization of Oxalobacter formigenes as risk factors for renal stone formation. Subjects and Methods: Eighty patients with renal stones and 70 healthy controls were enrolled in the study. Of the 80 patients, 48 were first-time stone formers (FSF) and 32 were ‘recurrent’ stone formers (RSF), recurrent indicating 2 or more episodes of stone formation. Stone analysis by X-ray crystallography, 24-hour urine metabolic profile and detection of O. formigenes-specific DNA by PCR were performed for each patient. Detection of O. formigenes was also performed on 45 and urinary metabolic profile on an additional 25 controls. Results: Calcium oxalate monohydrate was the major component of stones, hyperoxaluria and hypocitraturia were the most common urinary abnormalities in the 80 patients, 46% of RSF patients had hypercalciuria. Urinary abnormalities were far less frequent in the controls, with the exception of hypocitraturia (40%). Of the urinary metabolites, only calcium levels were significantly different (p < 0.05) between FSF (6.50 ± 4.08 mmol/24 h) and RSF (8.21 ± 5.26 mmol/24 h) patients. Colonization of O. formigenes was higher in controls (62.2%) than in FSF (33.3%) or RSF (28%) patients, it was least in patients with more than 4 episodes (7%) of stone formation. Conclusion: The findings indicate that lack of colonization of O. formigenes may be an important risk factor for recurrence of stone formation (calcium oxalate monohydrate).

Background: Today's uncertain HIV funding landscape threatens to slow progress towards treatment goals. Understanding the costs of antiretroviral therapy (ART) will be essential for governments to make informed policy decisions about the pace of scale-up under the 2013 WHO HIV Treatment Guidelines, which increase the number of people eligible for treatment from 17.6 million to 28.6 million. The study presented here is one of the largest of its kind and the first to describe the facility-level cost of ART in a random sample of facilities in Ethiopia, Malawi, Rwanda, South Africa and Zambia.Methods and Findings: In 2010-2011, comprehensive data on one year of facility-level ART costs and patient outcomes were collected from 161 facilities, selected using stratified random sampling. Overall, facility-level ART costs were significantly lower than expected in four of the five countries, with a simple average of $208 per patient-year (ppy) across Ethiopia, Malawi, Rwanda and Zambia. Costs were higher in South Africa, at $682 ppy. This included medications, laboratory services, direct and indirect personnel, patient support, equipment and administrative services. Facilities demonstrated the ability to retain patients alive and on treatment at these costs, although outcomes for established patients (2-8% annual loss to follow-up or death) were better than outcomes for new patients in their first year of ART (77-95% alive and on treatment).Conclusions: This study illustrated that the facility-level costs of ART are lower than previously understood in these five countries. While limitations must be considered, and costs will vary across countries, this suggests that expanded treatment coverage may be affordable. Further research is needed to understand investment costs of treatment scale-up, non-facility costs and opportunities for more efficient resource allocation.

Activation-induced Cytidine Deaminase (AID) is an essential regulator of B cell diversification, but its full range of action has until recently been an enigma. Based on homology, it was originally proposed to be an RNA-editing enzyme, but so far, no RNA substrates are known. Rather, it functions by deaminating cytidine, and in this manner, coupled with base-excision repair or mismatch repair machinery, it is a natural mutator. This allows it to play a central role in adaptive immunity, whereby it initiates the processes of class switch recombination and somatic hypermutation to help generate a diverse and high-affinity repertoire of immunoglobulin isotypes. More recently, it has been appreciated that methylated cytidine, already known as a key epigenetic mark on DNA controlling gene expression, can also be a target for AID modification. Coupled with repair machinery, this can facilitate the active removal of methylated DNA. This activity can impact the process of cellular reprogramming, including transition of a somatic cell to pluripotency, which requires major reshuffling of epigenetic memory. Thus, seemingly disparate roles for AID in controlling immune diversity and epigenetic memory have a common mechanistic basis. However, the very activity that is so useful for B cell diversity and cellular reprogramming is dangerous for the integrity of the genome. Thus, AID expression and activity is tightly regulated, and deregulation is associated with diseases including cancer. Here, we review the range of AID functions with a focus on its mechanisms of action and regulation. Major questions remain to be answered concerning how and when AID is targeted to specific loci and how this impacts development and disease.

The management of environment infrastructure has become critical for all countries, developing and developed, due to the increasing scarcity of environmental resources and assets, and, the consequent need for an efficient and just allocation of these resources. Two principal mechanisms to achieve efficient resource allocation are the state and the market. The state authorities have done this through the use of command and control measures and direct control of quantities (rationing). The market attempts to do this through prices that equate demand and supply. For either system to achieve its objective, a number of prerequisites are needed. These include for example, the existence of sufficient information on resource endowments, consumer preferences and technologies in the case of state planning, and, well defined and transferable property rights in the case of efficient market allocation of resources. Since neither of these sets of conditions is always met in full measure, there is a strong case for devising the right mix of polices including both regulatory and market based instruments to manage environmental resources and mitigate the negative environmental consequences of economic activity.

During B-cell development rearrangement of immunoglobulin heavy and light chain genes occurs sequentially, separated by a pre-BCR checkpoint where the quality of the heavy chains is tested by pairing with a surrogate light chain (SLC). Here we demonstrate the existence of a second B-cell development pathway, that is characterized by a high expression of Sca1 and LFA1, is less dependent on SLC expression and does not have a late pre-B stage. This pathway becomes predominant with age and in conditions of lymphopenia, and is biased towards marginal zone B cells. However, cell fate switches occur between marginal zone and follicular B cells, likely to maintain marginal zone homeostasis. FO B cells derived directly from MZ B cells are distinguished by a higher expression of Sca1. Thus, an alternative, and perhaps ancestral, B-cell development pathway exists that is biased toward to the generation of MZ B cells.