Concurrent infections by all four dengue virus serotypes during an outbreak of dengue in 2006 in Delhi, India

<p>Abstract</p> <p>Background</p> <p>Co-circulation of multiple dengue virus serotypes has been reported from many parts of the world including India, however concurrent infection with more than one serotype of dengue viruses in the same individual is rarely documented. An outbreak of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) occurred in and around Delhi in 2006. This is the first report from India with high percentage of concurrent infections with different dengue virus serotypes circulating during one outbreak.</p> <p>Results</p> <p>Acute phase sera from patients were tested for the presence of dengue virus RNA by RT-PCR assay. Of the 69 samples tested for dengue virus RNA, 48 (69.5%) were found to be positive. All the four dengue virus serotypes were found to be co-circulating in this outbreak with DENV-3 being the predominant serotype. In addition in 9 of 48 (19%) dengue virus positive samples, concurrent infection with more than one dengue virus serotype were identified.</p> <p>Conclusion</p> <p>This is the first report in which concurrent infections with different dengue virus serotypes is being reported during an outbreak from India. Delhi is now truly hyperendemic for dengue.</p

miR-22 regulates expression of oncogenic neuro-epithelial transforming gene 1, NET1

MicroRNAs control cellular processes by regulating expression of their target genes. Here we report that neuro-epithelial transforming gene 1 (NET1) is a target of tumor suppressor microRNA 22 (miR-22). miR-22 is downregulated in peripheral blood mononuclear cells derived from chronic myeloid leukemia (CML) patients and in CML cell line K562. NET1 was identified as one of the targets of miR-22 using both in vitro and in vivo experiments. Either mutations or naturally occurring single-nucleotide polymorphisms in NET1 3′-UTR that map at the miR-22 binding site were found to affect binding of miR-22 to NET1 mRNA. Over expression of NET1 in K562 cells resulted in increased proliferation. However decreased proliferation and alteration in cell cycle were observed on either overexpression of miR-22 or knockdown of NET1 expression respectively. We also found that overexpression of miR-22 or NET1 knockdown inhibits actin fiber formation, probably by downregulation of NET1 as NET1 knockdown also resulted in depletion of actin fiber formation. We suggest that the oncogenic properties of CML cells are probably due to deregulated expression of NET1 as a result of altered expression of miR-22

Diatom teratologies as biomarkers of contamination: Are all deformities ecologically meaningful?

Contaminant-related stress on aquatic biota is difficult to assess when lethal impacts are not observed. Diatoms, by displaying deformities (teratologies) in their valves, have the potential to reflect sub-lethal responses to environmental stressors such as metals and organic compounds. For this reason, there is great interest in using diatom morphological aberrations in biomonitoring. However, the detection and mostly the quantification of teratologies is still a challenge; not all studies have succeeded in showing a relationship between the proportion of abnormal valves and contamination level along a gradient of exposure. This limitation in part reflects the loss of ecological information from diatom teratologies during analyses when all deformities are considered. The type of deformity, the severity of aberration, species proneness to deformity formation, and propagation of deformities throughout the population are key components and constraints in quantifying teratologies. Before a metric based on diatom deformities can be used as an indicator of contamination, it is important to better understand the “ecological signal” provided by this biomarker. Using the overall abundance of teratologies has proved to be an excellent tool for identifying contaminated and non-contaminated environments (presence/absence), but refining this biomonitoring approach may bring additional insights allowing for a better assessment of contamination level along a gradient. The dilemma: are all teratologies significant, equal and/or meaningful in assessing changing levels of contamination? This viewpoint article examines numerous interrogatives relative to the use of diatom teratologies in water quality monitoring, provides selected examples of differential responses to contamination, and proposes solutions that may refine our understanding and quantification of the stress. This paper highlights the logistical problems associated with accurately evaluating and interpreting teratologies and stimulates more discussion and research on the subject to enhance the sensitivity of this metric in bioassessments

Reappraisal of the toxicity test method using the green alga Ulva pertusa Kjellman (Chlorophyta),

This study was aimed to develop an objective way of quantifying the reproductive status of the green macroalga, Ulva pertusa using a vital stain and programmed automated analysis (by Image J program). The EC50 values (with 95% CI), the concentrations of toxicants inducing a reduction of 50% in sporulation after 96 h exposure, from the newly developed method were similar to those obtained by the conventional method: 0.651 (0.598-0.705) mg l(-1) for Cd, 0.144 (0.110-0.162) mg l(-1) for Cu, 0.180 (0.165-0.195) mg l(-1) for atrazine, 0.076 (0.049-0.094) mg l(-1) for diuron and 30.6 (26.5-34.4) ml l(-1) for DMSO, respectively. When the EC50 values from this study were compared to that those from literatures, the sensitivity for some toxicants was similar or higher than that of U. fasciata (1.930 mg l(-1) for germination for Cd), U. armoricana (0.250 mg l(-1) for Fv/Fm for Cu), U. reticulata (0.126-1.585 mg l(-1) for growth for Cu), and U. intestinalis (0.650 mg l(-1) for Fv/Fm for atrazine). The subjective views of the experimental performers can be eliminated using the newly developed method. The Ulva method gave consistent responses to Cu and Cd of internationally allowable ranges for effluents, implying that the method is a useful tool for monitoring industrial wastewaters containing these metals

Hydrochloride Salt of the GABAkine KRM-II-81

Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABAA receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1H NMR and 13C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation

Mapping of variations in child stunting, wasting and underweight within the states of India: the Global Burden of Disease Study 2000–2017

Background To inform actions at the district level under the National Nutrition Mission (NNM), we assessed the prevalence trends of child growth failure (CGF) indicators for all districts in India and inequality between districts within the states. Methods We assessed the trends of CGF indicators (stunting, wasting and underweight) from 2000 to 2017 across the districts of India, aggregated from 5 × 5 km grid estimates, using all accessible data from various surveys with subnational geographical information. The states were categorised into three groups using their Socio-demographic Index (SDI) levels calculated as part of the Global Burden of Disease Study based on per capita income, mean education and fertility rate in women younger than 25 years. Inequality between districts within the states was assessed using coefficient of variation (CV). We projected the prevalence of CGF indicators for the districts up to 2030 based on the trends from 2000 to 2017 to compare with the NNM 2022 targets for stunting and underweight, and the WHO/UNICEF 2030 targets for stunting and wasting. We assessed Pearson correlation coefficient between two major national surveys for district-level estimates of CGF indicators in the states. Findings The prevalence of stunting ranged 3.8-fold from 16.4% (95% UI 15.2–17.8) to 62.8% (95% UI 61.5–64.0) among the 723 districts of India in 2017, wasting ranged 5.4-fold from 5.5% (95% UI 5.1–6.1) to 30.0% (95% UI 28.2–31.8), and underweight ranged 4.6-fold from 11.0% (95% UI 10.5–11.9) to 51.0% (95% UI 49.9–52.1). 36.1% of the districts in India had stunting prevalence 40% or more, with 67.0% districts in the low SDI states group and only 1.1% districts in the high SDI states with this level of stunting. The prevalence of stunting declined significantly from 2010 to 2017 in 98.5% of the districts with a maximum decline of 41.2% (95% UI 40.3–42.5), wasting in 61.3% with a maximum decline of 44.0% (95% UI 42.3–46.7), and underweight in 95.0% with a maximum decline of 53.9% (95% UI 52.8–55.4). The CV varied 7.4-fold for stunting, 12.2-fold for wasting, and 8.6-fold for underweight between the states in 2017; the CV increased for stunting in 28 out of 31 states, for wasting in 16 states, and for underweight in 20 states from 2000 to 2017. In order to reach the NNM 2022 targets for stunting and underweight individually, 82.6% and 98.5% of the districts in India would need a rate of improvement higher than they had up to 2017, respectively. To achieve the WHO/UNICEF 2030 target for wasting, all districts in India would need a rate of improvement higher than they had up to 2017. The correlation between the two national surveys for district-level estimates was poor, with Pearson correlation coefficient of 0.7 only in Odisha and four small north-eastern states out of the 27 states covered by these surveys. Interpretation CGF indicators have improved in India, but there are substantial variations between the districts in their magnitude and rate of decline, and the inequality between districts has increased in a large proportion of the states. The poor correlation between the national surveys for CGF estimates highlights the need to standardise collection of anthropometric data in India. The district-level trends in this report provide a useful reference for targeting the efforts under NNM to reduce CGF across India and meet the Indian and global targets. Keywords Child growth failureDistrict-levelGeospatial mappingInequalityNational Nutrition MissionPrevalenceStuntingTime trendsUnder-fiveUndernutritionUnderweightWastingWHO/UNICEF target

Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021

Background Osteoarthritis is the most common form of arthritis in adults, characterised by chronic pain and loss of mobility. Osteoarthritis most frequently occurs after age 40 years and prevalence increases steeply with age. WHO has designated 2021–30 the decade of healthy ageing, which highlights the need to address diseases such as osteoarthritis, which strongly affect functional ability and quality of life. Osteoarthritis can coexist with, and negatively effect, other chronic conditions. Here we estimate the burden of hand, hip, knee, and other sites of osteoarthritis across geographies, age, sex, and time, with forecasts of prevalence to 2050. Methods In this systematic analysis for the Global Burden of Disease Study, osteoarthritis prevalence in 204 countries and territories from 1990 to 2020 was estimated using data from population-based surveys from 26 countries for knee osteoarthritis, 23 countries for hip osteoarthritis, 42 countries for hand osteoarthritis, and US insurance claims for all of the osteoarthritis sites, including the other types of osteoarthritis category. The reference case definition was symptomatic, radiographically confirmed osteoarthritis. Studies using alternative definitions from the reference case definition (for example self-reported osteoarthritis) were adjusted to reference using regression models. Osteoarthritis severity distribution was obtained from a pooled meta-analysis of sources using the Western Ontario and McMaster Universities Arthritis Index. Final prevalence estimates were multiplied by disability weights to calculate years lived with disability (YLDs). Prevalence was forecast to 2050 using a mixed-effects model. Findings Globally, 595 million (95% uncertainty interval 535–656) people had osteoarthritis in 2020, equal to 7·6% (95% UI 6·8–8·4) of the global population, and an increase of 132·2% (130·3–134·1) in total cases since 1990. Compared with 2020, cases of osteoarthritis are projected to increase 74·9% (59·4–89·9) for knee, 48·6% (35·9–67·1) for hand, 78·6% (57·7–105·3) for hip, and 95·1% (68·1–135·0) for other types of osteoarthritis by 2050. The global age-standardised rate of YLDs for total osteoarthritis was 255·0 YLDs (119·7–557·2) per 100 000 in 2020, a 9·5% (8·6–10·1) increase from 1990 (233·0 YLDs per 100 000, 109·3–510·8). For adults aged 70 years and older, osteoarthritis was the seventh ranked cause of YLDs. Age-standardised prevalence in 2020 was more than 5·5% in all world regions, ranging from 5677·4 (5029·8–6318·1) per 100 000 in southeast Asia to 8632·7 (7852·0–9469·1) per 100 000 in high-income Asia Pacific. Knee was the most common site for osteoarthritis. High BMI contributed to 20·4% (95% UI –1·7 to 36·6) of osteoarthritis. Potentially modifiable risk factors for osteoarthritis such as recreational injury prevention and occupational hazards have not yet been explored in GBD modelling. Interpretation Age-standardised YLDs attributable to osteoarthritis are continuing to rise and will lead to substantial increases in case numbers because of population growth and ageing, and because there is no effective cure for osteoarthritis. The demand on health systems for care of patients with osteoarthritis, including joint replacements, which are highly effective for late stage osteoarthritis in hips and knees, will rise in all regions, but might be out of reach and lead to further health inequity for individuals and countries unable to afford them. Much more can and should be done to prevent people getting to that late stage

The unfinished agenda of communicable diseases among children and adolescents before the COVID-19 pandemic, 1990-2019: a systematic analysis of the Global Burden of Disease Study 2019

BACKGROUND: Communicable disease control has long been a focus of global health policy. There have been substantial reductions in the burden and mortality of communicable diseases among children younger than 5 years, but we know less about this burden in older children and adolescents, and it is unclear whether current programmes and policies remain aligned with targets for intervention. This knowledge is especially important for policy and programmes in the context of the COVID-19 pandemic. We aimed to use the Global Burden of Disease (GBD) Study 2019 to systematically characterise the burden of communicable diseases across childhood and adolescence. METHODS: In this systematic analysis of the GBD study from 1990 to 2019, all communicable diseases and their manifestations as modelled within GBD 2019 were included, categorised as 16 subgroups of common diseases or presentations. Data were reported for absolute count, prevalence, and incidence across measures of cause-specific mortality (deaths and years of life lost), disability (years lived with disability [YLDs]), and disease burden (disability-adjusted life-years [DALYs]) for children and adolescents aged 0-24 years. Data were reported across the Socio-demographic Index (SDI) and across time (1990-2019), and for 204 countries and territories. For HIV, we reported the mortality-to-incidence ratio (MIR) as a measure of health system performance. FINDINGS: In 2019, there were 3·0 million deaths and 30·0 million years of healthy life lost to disability (as measured by YLDs), corresponding to 288·4 million DALYs from communicable diseases among children and adolescents globally (57·3% of total communicable disease burden across all ages). Over time, there has been a shift in communicable disease burden from young children to older children and adolescents (largely driven by the considerable reductions in children younger than 5 years and slower progress elsewhere), although children younger than 5 years still accounted for most of the communicable disease burden in 2019. Disease burden and mortality were predominantly in low-SDI settings, with high and high-middle SDI settings also having an appreciable burden of communicable disease morbidity (4·0 million YLDs in 2019 alone). Three cause groups (enteric infections, lower-respiratory-tract infections, and malaria) accounted for 59·8% of the global communicable disease burden in children and adolescents, with tuberculosis and HIV both emerging as important causes during adolescence. HIV was the only cause for which disease burden increased over time, particularly in children and adolescents older than 5 years, and especially in females. Excess MIRs for HIV were observed for males aged 15-19 years in low-SDI settings. INTERPRETATION: Our analysis supports continued policy focus on enteric infections and lower-respiratory-tract infections, with orientation to children younger than 5 years in settings of low socioeconomic development. However, efforts should also be targeted to other conditions, particularly HIV, given its increased burden in older children and adolescents. Older children and adolescents also experience a large burden of communicable disease, further highlighting the need for efforts to extend beyond the first 5 years of life. Our analysis also identified substantial morbidity caused by communicable diseases affecting child and adolescent health across the world. FUNDING: The Australian National Health and Medical Research Council Centre for Research Excellence for Driving Investment in Global Adolescent Health and the Bill & Melinda Gates Foundation

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Mapping child growth failure across low- and middle-income countries

Child growth failure (CGF), manifested as stunting, wasting, and underweight, is associated with high 5 mortality and increased risks of cognitive, physical, and metabolic impairments. Children in low- and middle-income countries (LMICs) face the highest levels of CGF globally. Here we illustrate national and subnational variation of under-5 CGF indicators across LMICs, providing 2000–2017 annual estimates mapped at a high spatial resolution and aggregated to policy-relevant administrative units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the World Health 10 Organization’s ambitious Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and rates of progress exist across regions, countries, and within countries; our maps identify areas where high prevalence persists even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where subnational disparities exist and the highest-need populations reside, these geospatial estimates can support policy-makers in planning locally 15 tailored interventions and efficient directing of resources to accelerate progress in reducing CGF and its health implications