Cell cycle regulators and bone: development and regeneration.

Cell cycle regulators act as inhibitors or activators to prevent cancerogenesis. It has also been established that they can play an active role in differentiation, apoptosis, senescence, and other cell processes. Emerging evidence has demonstrated a role for cell cycle regulators in bone healing/development cascade. We demonstrated that deletion of p21, a cell cycle regulator acting at the G1/S transition enhanced bone repair capacity after a burr-hole injury in the proximal tibia of mice. Similarly, another study has shown that inhibition of p27 can increase bone mineral density and bone formation. Here, we provide a concise review of cell cycle regulators that influence cells like osteoblasts, osteoclasts, and chondrocytes, during development and/or healing of bone. It is imperative to understand the regulatory processes that govern cell cycle during bone healing and development as this will pave the way to develop novel therapies to improve bone healing after injury in instances of aged or osteoporotic fractures.

Determination of albuterol and montelukast post-expiry drug strength by HPLC.

Background: Knowing the level of active ingredients in an expired drug is a matter of concern irrespective of its final disposition. This is also a matter of national security and defense as it has important implications on the nation's stockpile of prescription medications. Current literature has limited information about the strength of expired medications and any relevant trends. Objective: To utilize high performance liquid chromatography (HPLC) to determine the strength of selected drugs for asthma and chronic obstructive pulmonary disease (COPD) as a class of therapeutic agents commonly used in free clinics. Methods: Samples from expired lots of montelukast and albuterol pharmaceutical products were analyzed for their levels of their respective active ingredients. Two HPLC methods were developed, validated, and applied to achieve this goal. Quantitative analysis of each drug was performed using two different reversed phase C18 columns with a linear gradient of acetonitrile in 0.1% aqueous formic acid at a flow rate of 1 mL/min for both methods. Detection wavelength for montelukast and albuterol was 280 and 277 nm, respectively. Results: Expiry dates of analyzed batches ranged from 2003 to 2019. Despite the extended time range beyond expiry dates, levels of both drugs were relatively consistent and exceeded 90% of the listed strength in most analyzed lots. Conclusions: Our results introduce a new perspective towards reducing the financial burden resulting from disposal of expired medications with retained strength. They also offer supporting evidence to extend the use of out-of-date montelukast and albuterol preparations at home and in free clinics.

Estimating under-reporting of COVID-19 cases in Indian states: an approach using a delay-adjusted case fatality ratio.

OBJECTIVES: The COVID-19 pandemic has spread to all states in India. Due to limitations in testing coverage, the true extent of the spread may not be fully reflected in the reported cases. In this study, we obtain time-varying estimates of the fraction of COVID-19 infections reported in the different states. METHODS: Following a methodology developed in prior work, we use a delay-adjusted case fatality ratio to estimate the true fraction of cases reported in different states. We also develop a delay adjusted test positivity estimation method and study the relationship between the estimated test positivity rate for each state and the estimated fraction of cases reported. SETTING: We apply this method of analysis to all Indian states reporting at least 100 deaths as of 10 October 2020. RESULTS: Our analysis suggests that delay-adjusted case fatality ratios observed in different states range from 0.47% to 3.55%. The estimated fraction of cases reported in different states ranges from 39% to 100% for an assumed baseline case fatality ratio of 1.38%, from 18.6% to 100% for an assumed baseline case fatality ratio of 0.66%, and from 2.8% to 19.7% for an assumed baseline case fatality ratio of 0.1%. We also demonstrate a statistically significant negative relationship between the fraction of cases reported in each state and the testing positivity rate. CONCLUSIONS: The estimates provide a means to quantify and compare the trends of reporting and the true level of current infections in different states. This information may be used to guide policies for prioritising testing in different states, and also to analyse the time-varying effects of different quarantine measures adopted in different states.

Astrocytes influence medulloblastoma phenotypes and CD133 surface expression.

The medulloblastoma (MB) microenvironment is diverse, and cell-cell interactions within this milieu is of prime importance. Astrocytes, a major component of the microenvironment, have been shown to impact primary tumor cell phenotypes and metastasis. Based on proximity of MB cells and astrocytes in the brain microenvironment, we investigated whether astrocytes may influence MB cell phenotypes directly. Astrocyte conditioned media (ACM) increased Daoy MB cell invasion, adhesion, and in vivo cellular protrusion formation. ACM conditioning of MB cells also increased CD133 surface expression, a key cancer stem cell marker of MB. Additional neural stem cell markers, Nestin and Oct-4A, were also increased by ACM conditioning, as well as neurosphere formation. By knocking down CD133 using short interfering RNA (siRNA), we showed that ACM upregulated CD133 expression in MB plays an important role in invasion, adhesion and neurosphere formation. Collectively, our data suggests that astrocytes influence MB cell phenotypes by regulating CD133 expression, a key protein with defined roles in MB tumorgenicity and survival.

Discovery and Characterization of Halogenated Xanthene Inhibitors of DUSP5 as Potential Photodynamic Therapeutics.

Dual specific phosphatases (DUSPs) are an important class of mitogen-activated protein kinase (MAPK) regulators, and are drug targets for treating vascular diseases. Previously we had shown that DUSP5 plays a role in embryonic vertebrate vascular patterning. Herein, we screened a library of FDA-approved drugs and related compounds, using a para-nitrophenylphosphate substrate (pNPP)-based assay. This assay identified merbromin (also known as mercurochrome) as targeting DUSP5; and, we subsequently identified xanthene-ring based merbromin analogs eosin Y, erythrosin B, and rose bengal, all of which inhibit DUSP5 in vitro. Inhibition was time-dependent for merbromin, eosin Y, 2',7'-dibromofluorescein, and 2',7'-dichlorofluorescein, with enzyme inhibition increasing over time. Reaction progress curve data fit best to a slow-binding model of irreversible enzyme inactivation. Potency of the time-dependent compounds, except for 2',7'-dichlorofluorescein, was diminished when dithiothreitol (DTT) was present, suggesting thiol reactivity. Two additional merbromin analogs, erythrosin B and rose bengal also inhibit DUSP5, but have the therapeutic advantage of being less sensitive to DTT and exhibiting little time dependence for inhibition. Inhibition potency is correlated with the xanthene dye's LUMO energy, which affects ability to form light-activated radical anions, a likely active inhibitor form. Consistent with this hypothesis, rose bengal inhibition is light-dependent and demonstrates the expected red shifted spectrum upon binding to DUSP5, with a Kd of 690 nM. These studies provide a mechanistic foundation for further development of xanthene dyes for treating vascular diseases that respond to DUSP5 inhibition, with the following relative potencies: rose bengal > merbromin > erythrosin B > eosin Y.

Prevalence of risk factors of non-communicable diseases in Kerala, India: results of a cross-sectional study.

OBJECTIVE: To estimate the prevalence of non-communicable disease (NCD) risk factors in Kerala. DESIGN: A community-based, cross-sectional survey. PARTICIPANTS: In 2016-2017 a multistage, cluster sample of 12 012 (aged 18-69 years) participants from all 14 districts of Kerala were studied. MAIN OUTCOME MEASURES: NCD risk factors as stipulated in the WHO's approach to NCD risk factors surveillance were studied. Parameters that were studied included physical activity score, anthropometry, blood pressure (BP), and fasting blood glucose (FBG) and morning urine sample to estimate dietary intake of salt. RESULTS: The mean age was 42.5 years (SD=14.8). Abdominal obesity was higher in women (72.6%; 95% CI 70.7 to 74.5) compared with men (39.1%; 95% CI 36.6 to 41.7), and also higher among urban (67.4%; 95% CI 65.0 to 69.7) compared with rural (58.6%; 95% CI 56.6 to 60.5) residents. Current use of tobacco and alcohol in men was 20.3% (95% CI 18.6 to 22.1) and 28.9% (95% CI 26.5 to 31.4), respectively. The estimated daily salt intake was 6.7 g/day. The overall prevalence of raised BP was 30.4% (95% CI 29.1 to 31.7) and raised FBG was 19.2% (95% CI 18.1 to 20.3). Raised BP was higher in men (34.6%; 95% CI 32.6 to 36.7) compared with women (28%; 95% CI 26.4 to 29.4), but was not different between urban (33.1%; 95% CI 31.3 to 34.9) and rural (29.8%; 95% CI 28.3 to 31.3) residents. Only 12.4% of individuals with hypertension and 15.3% of individuals with diabetes were found to have these conditions under control. Only 13.8% of urban and 18.4% of rural residents did not have any of the seven NCD risk factors studied. CONCLUSION: Majority of the participants had more than one NCD risk factor. There was no rural-urban difference in terms of raised BP or raised FBG prevalence in Kerala. The higher rates of NCD risk factors and lower rates of hypertension and diabetes control call for concerted primary and secondary prevention strategies to address the future burden of NCDs.

Availability and affordability of blood pressure-lowering medicines and the effect on blood pressure control in high-income, middle-income, and low-income countries: an analysis of the PURE study data.

BACKGROUND: Hypertension is considered the most important risk factor for cardiovascular diseases, but its control is poor worldwide. We aimed to assess the availability and affordability of blood pressure-lowering medicines, and the association with use of these medicines and blood pressure control in countries at varying levels of economic development. METHODS: We analysed the availability, costs, and affordability of blood pressure-lowering medicines with data recorded from 626 communities in 20 countries participating in the Prospective Urban Rural Epidemiological (PURE) study. Medicines were considered available if they were present in the local pharmacy when surveyed, and affordable if their combined cost was less than 20% of the households' capacity to pay. We related information about availability and affordability to use of these medicines and blood pressure control with multilevel mixed-effects logistic regression models, and compared results for high-income, upper-middle-income, lower-middle-income, and low-income countries. Data for India are presented separately because it has a large generic pharmaceutical industry and a higher availability of medicines than other countries at the same economic level. FINDINGS: The availability of two or more classes of blood pressure-lowering drugs was lower in low-income and middle-income countries (except for India) than in high-income countries. The proportion of communities with four drug classes available was 94% in high-income countries (108 of 115 communities), 76% in India (68 of 90), 71% in upper-middle-income countries (90 of 126), 47% in lower-middle-income countries (107 of 227), and 13% in low-income countries (nine of 68). The proportion of households unable to afford two blood pressure-lowering medicines was 31% in low-income countries (1069 of 3479 households), 9% in middle-income countries (5602 of 65 471), and less than 1% in high-income countries (44 of 10 880). Participants with known hypertension in communities that had all four drug classes available were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio [OR] 2·23, 95% CI 1·59-3·12); p<0·0001), combination therapy (1·53, 1·13-2·07; p=0·054), and have their blood pressure controlled (2·06, 1·69-2·50; p<0·0001) than were those in communities where blood pressure-lowering medicines were not available. Participants with known hypertension from households able to afford four blood pressure-lowering drug classes were more likely to use at least one blood pressure-lowering medicine (adjusted OR 1·42, 95% CI 1·25-1·62; p<0·0001), combination therapy (1·26, 1·08-1·47; p=0·0038), and have their blood pressure controlled (1·13, 1·00-1·28; p=0·0562) than were those unable to afford the medicines. INTERPRETATION: A large proportion of communities in low-income and middle-income countries do not have access to more than one blood pressure-lowering medicine and, when available, they are often not affordable. These factors are associated with poor blood pressure control. Ensuring access to affordable blood pressure-lowering medicines is essential for control of hypertension in low-income and middle-income countries. FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research Strategy for Patient Oriented Research through the Ontario SPOR Support Unit, the Ontario Ministry of Health and Long-Term Care, pharmaceutical companies (with major contributions from AstraZeneca [Canada], Sanofi Aventis [France and Canada], Boehringer Ingelheim [Germany amd Canada], Servier, and GlaxoSmithKline), Novartis and King Pharma, and national or local organisations in participating countries.

Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study.

BACKGROUND: The relation between dietary nutrients and cardiovascular disease risk markers in many regions worldwide is unknown. In this study, we investigated the effect of dietary nutrients on blood lipids and blood pressure, two of the most important risk factors for cardiovascular disease, in low-income, middle-income, and high-income countries. METHODS: We studied 125 287 participants from 18 countries in North America, South America, Europe, Africa, and Asia in the Prospective Urban Rural Epidemiology (PURE) study. Habitual food intake was measured with validated food frequency questionnaires. We assessed the associations between nutrients (total fats, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, carbohydrates, protein, and dietary cholesterol) and cardiovascular disease risk markers using multilevel modelling. The effect of isocaloric replacement of saturated fatty acids with other fats and carbohydrates was determined overall and by levels of intakes by use of nutrient density models. We did simulation modelling in which we assumed that the effects of saturated fatty acids on cardiovascular disease events was solely related to their association through an individual risk marker, and then compared these simulated risk marker-based estimates with directly observed associations of saturated fatty acids with cardiovascular disease events. FINDINGS: Participants were enrolled into the study from Jan 1, 2003, to March 31, 2013. Intake of total fat and each type of fat was associated with higher concentrations of total cholesterol and LDL cholesterol, but also with higher HDL cholesterol and apolipoprotein A1 (ApoA1), and lower triglycerides, ratio of total cholesterol to HDL cholesterol, ratio of triglycerides to HDL cholesterol, and ratio of apolipoprotein B (ApoB) to ApoA1 (all ptrend<0·0001). Higher carbohydrate intake was associated with lower total cholesterol, LDL cholesterol, and ApoB, but also with lower HDL cholesterol and ApoA1, and higher triglycerides, ratio of total cholesterol to HDL cholesterol, ratio of triglycerides to HDL cholesterol, and ApoB-to-ApoA1 ratio (all ptrend<0·0001, apart from ApoB [ptrend=0·0014]). Higher intakes of total fat, saturated fatty acids, and carbohydrates were associated with higher blood pressure, whereas higher protein intake was associated with lower blood pressure. Replacement of saturated fatty acids with carbohydrates was associated with the most adverse effects on lipids, whereas replacement of saturated fatty acids with unsaturated fats improved some risk markers (LDL cholesterol and blood pressure), but seemed to worsen others (HDL cholesterol and triglycerides). The observed associations between saturated fatty acids and cardiovascular disease events were approximated by the simulated associations mediated through the effects on the ApoB-to-ApoA1 ratio, but not with other lipid markers including LDL cholesterol. INTERPRETATION: Our data are at odds with current recommendations to reduce total fat and saturated fats. Reducing saturated fatty acid intake and replacing it with carbohydrate has an adverse effect on blood lipids. Substituting saturated fatty acids with unsaturated fats might improve some risk markers, but might worsen others. Simulations suggest that ApoB-to-ApoA1 ratio probably provides the best overall indication of the effect of saturated fatty acids on cardiovascular disease risk among the markers tested. Focusing on a single lipid marker such as LDL cholesterol alone does not capture the net clinical effects of nutrients on cardiovascular risk. FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments).

Dual Specificity Phosphatase 5-Substrate Interaction: A Mechanistic Perspective.

The mammalian genome contains approximately 200 phosphatases that are responsible for catalytically removing phosphate groups from proteins. In this review, we discuss dual specificity phosphatase 5 (DUSP5). DUSP5 belongs to the dual specificity phosphatase (DUSP) family, so named after the family members' abilities to remove phosphate groups from serine/threonine and tyrosine residues. We provide a comparison of DUSP5's structure to other DUSPs and, using molecular modeling studies, provide an explanation for DUSP5's mechanistic interaction and specificity toward phospho-extracellular regulated kinase, its only known substrate. We also discuss new insights from molecular modeling studies that will influence our current thinking of mitogen-activated protein kinase signaling. Finally, we discuss the lessons learned from identifying small molecules that target DUSP5, which might benefit targeting efforts for other phosphatases. © 2017 American Physiological Society. Compr Physiol 7:1449-1461, 2017.

Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study

BACKGROUND: The relation between dietary nutrients and cardiovascular disease risk markers in many regions worldwide is unknown. In this study, we investigated the effect of dietary nutrients on blood lipids and blood pressure, two of the most important risk factors for cardiovascular disease, in low-income, middle-income, and high-income countries.METHODS: We studied 125 287 participants from 18 countries in North America, South America, Europe, Africa, and Asia in the Prospective Urban Rural Epidemiology (PURE) study. Habitual food intake was measured with validated food frequency questionnaires. We assessed the associations between nutrients (total fats, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, carbohydrates, protein, and dietary cholesterol) and cardiovascular disease risk markers using multilevel modelling. The effect of isocaloric replacement of saturated fatty acids with other fats and carbohydrates was determined overall and by levels of intakes by use of nutrient density models. We did simulation modelling in which we assumed that the effects of saturated fatty acids on cardiovascular disease events was solely related to their association through an individual risk marker, and then compared these simulated risk marker-based estimates with directly observed associations of saturated fatty acids with cardiovascular disease events.

Availability and affordability of blood pressure-lowering medicines and the effect on blood pressure control in high-income, middle-income, and low-income countries: an analysis of the PURE study data

Hypertension is considered the most important risk factor for cardiovascular diseases, but its control is poor worldwide. We aimed to assess the availability and affordability of blood pressure-lowering medicines, and the association with use of these medicines and blood pressure control in countries at varying levels of economic development. We analysed the availability, costs, and affordability of blood pressure-lowering medicines with data recorded from 626 communities in 20 countries participating in the Prospective Urban Rural Epidemiological (PURE) study. Medicines were considered available if they were present in the local pharmacy when surveyed, and affordable if their combined cost was less than 20% of the households' capacity to pay. We related information about availability and affordability to use of these medicines and blood pressure control with multilevel mixed-effects logistic regression models, and compared results for high-income, upper-middle-income, lower-middle-income, and low-income countries. Data for India are presented separately because it has a large generic pharmaceutical industry and a higher availability of medicines than other countries at the same economic level...

Dual Specificity Phosphatase 5 Is Essential for T Cell Survival.

The mitogen-activated protein kinase (MAPK) pathway regulates many key cellular processes such as differentiation, apoptosis, and survival. The final proteins in this pathway, ERK1/2, are regulated by dual specificity phosphatase 5 (DUSP5). DUSP5 is a nuclear, inducible phosphatase with high affinity and fidelity for ERK1/2. By regulating the final step in the MAPK signaling cascade, DUSP5 exerts strong regulatory control over a central cellular pathway. Like other DUSPs, DUSP5 plays an important role in immune function. In this study, we have utilized new knockout mouse reagents to explore its function further. We demonstrate that global loss of DUSP5 does not result in any gross phenotypic changes. However, loss of DUSP5 affects memory/effector CD8+ T cell populations in response to acute viral infection. Specifically, Dusp5-/- mice have decreased proportions of short-lived effector cells (SLECs) and increased proportions of memory precursor effector cells (MPECs) in response to infection. Further, we show that this phenotype is T cell intrinsic; a bone marrow chimera model restricting loss of DUSP5 to the CD8+ T cell compartment displays a similar phenotype. Dusp5-/- T cells also display increased proliferation, increased apoptosis, and altered metabolic profiles, suggesting that DUSP5 is a pro-survival protein in T cells.

Identification of inhibitors that target dual-specificity phosphatase 5 provide new insights into the binding requirements for the two phosphate pockets.

BACKGROUND: Dual-specificity phosphatase-5 (DUSP5) plays a central role in vascular development and disease. We present a p-nitrophenol phosphate (pNPP) based enzymatic assay to screen for inhibitors of the phosphatase domain of DUSP5. METHODS: pNPP is a mimic of the phosphorylated tyrosine on the ERK2 substrate (pERK2) and binds the DUSP5 phosphatase domain with a Km of 7.6 ± 0.4 mM. Docking followed by inhibitor verification using the pNPP assay identified a series of polysulfonated aromatic inhibitors that occupy the DUSP5 active site in the region that is likely occupied by the dual-phosphorylated ERK2 substrate tripeptide (pThr-Glu-pTyr). Secondary assays were performed with full length DUSP5 with ERK2 as substrate. RESULTS: The most potent inhibitor has a naphthalene trisulfonate (NTS) core. A search for similar compounds in a drug database identified suramin, a dimerized form of NTS. While suramin appears to be a potent and competitive inhibitor (25 ± 5 µM), binding to the DUSP5 phosphatase domain more tightly than the monomeric ligands of which it is comprised, it also aggregates. Further ligand-based screening, based on a pharmacophore derived from the 7 Å separation of sulfonates on inhibitors and on sulfates present in the DUSP5 crystal structure, identified a disulfonated and phenolic naphthalene inhibitor (CSD (3) _2320) with IC50 of 33 µM that is similar to NTS and does not aggregate. CONCLUSIONS: The new DUSP5 inhibitors we identify in this study typically have sulfonates 7 Å apart, likely positioning them where the two phosphates of the substrate peptide (pThr-Glu-pTyr) bind, with one inhibitor also positioning a phenolic hydroxyl where the water nucleophile may reside. Polysulfonated aromatic compounds do not commonly appear in drugs and have a tendency to aggregate. One FDA-approved polysulfonated drug, suramin, inhibits DUSP5 and also aggregates. Docking and modeling studies presented herein identify polysulfonated aromatic inhibitors that do not aggregate, and provide insights to guide future design of mimics of the dual-phosphate loops of the ERK substrates for DUSPs.

Protein expression, characterization and activity comparisons of wild type and mutant DUSP5 proteins.

BACKGROUND: The mitogen-activated protein kinases (MAPKs) pathway is critical for cellular signaling, and proteins such as phosphatases that regulate this pathway are important for normal tissue development. Based on our previous work on dual specificity phosphatase-5 (DUSP5), and its role in embryonic vascular development and disease, we hypothesized that mutations in DUSP5 will affect its function. RESULTS: In this study, we tested this hypothesis by generating full-length glutathione-S-transferase-tagged DUSP5 and serine 147 proline mutant (S147P) proteins from bacteria. Light scattering analysis, circular dichroism, enzymatic assays and molecular modeling approaches have been performed to extensively characterize the protein form and function. We demonstrate that both proteins are active and, interestingly, the S147P protein is hypoactive as compared to the DUSP5 WT protein in two distinct biochemical substrate assays. Furthermore, due to the novel positioning of the S147P mutation, we utilize computational modeling to reconstruct full-length DUSP5 and S147P to predict a possible mechanism for the reduced activity of S147P. CONCLUSION: Taken together, this is the first evidence of the generation and characterization of an active, full-length, mutant DUSP5 protein which will facilitate future structure-function and drug development-based studies.

Changing epidemiology of maternal mortality in rural India: time to reset strategies for MDG-5.

OBJECTIVE: To understand changes in epidemiology of maternal mortality in rural India in the context of increasing institutional deliveries and implementation of community-based interventions that can inform policies to reach MDG-5. METHODS: This study is a secondary analysis of prospectively collected community-based data of every pregnancy and its outcomes from 2002 to 2011 in a rural, tribal area of Gujarat, India as part of safe-motherhood programme implemented by voluntary organisation, SEWA Rural. The programme consisted of community-based interventions supported by a first referral unit, and promotion of institutional deliveries. For every maternal death, a verbal autopsy was conducted. The incidence rates for maternal mortality according to place, cause and timing of maternal deaths in relation to pregnancy were computed. Annual incidence rate ratios (IRR) and 95% confidence intervals, adjusted for caste and maternal education, were estimated using Poisson regression to test for linear trend in reduction in mortality during the study period. RESULTS: Thirty-two thousand eight hundred and ninety-three pregnancies, 29,817 live births and 80 maternal deaths were recorded. Maternal mortality ratio improved from 607 (19 deaths) in 2002-2003 to 161 (five deaths) in 2010-2011. The institutional delivery rate increased from 23% to 65%. The trend of falling maternal deaths was significant over time, with an annual reduction of 17% (adjusted IRR 0.83 CI 0.75-0.91, P-value <0.001). There were significant reductions in adjusted incidence rate of maternal deaths due to direct causes, during intrapartum and post-partum periods, and those which occurred at home. However, reductions in incidence of maternal deaths due to indirect causes, at hospital and during antepartum period were not statistically significant. Most maternal deaths are now occurring at hospitals and due to indirect causes. CONCLUSION: Gains in institutional deliveries and community-based interventions resulting in fewer maternal deaths due to direct causes should be maintained. However, it would be essential to now prioritize management of indirect causes of maternal mortality during pregnancy at community and hospitals for further reduction in maternal deaths to achieve MDG-5.

Risk factors of post-traumatic stress disorder in tsunami survivors of Kanyakumari District, Tamil Nadu, India.

CONTEXT: In this study, we assessed the relation of possible risk factors with post-traumatic stress disorder (PTSD) in the survivors of December 2004 tsunami in Kanyakumari district. MATERIALS AND METHODS: We identified cases (n=158) and controls (n=141) by screening a random sample of 485 tsunami survivors from June 2005 to October 2005 using a validated tool, "Impact of events scale-revised (IES-R)," for symptoms suggestive of PTSD. Subjects whose score was equal to or above the 70(th) percentile (total score 48) were cases and those who had score below or equal to 30(th) percentile (total score 33) were controls. Analysis was done using statistical package for the social sciences to find the risk factors of PTSD among various pre-disaster, within-disaster and post-disaster factors. RESULTS: Multivariate analysis showed that PTSD was related to female gender [odds ratio (OR) 6.35, 95% confidence interval (CI) 3.26-12.39], age 40 years and above (OR 2.38, 95% CI 1.23-4.63), injury to self (OR 2.97, 95% CI 1.55-5.67), injury to family members (OR 2.09, 95% CI 1.05-4.15), residence in urban area (area of maximum destruction) (OR 3.37, 95% CI 1.35-8.41) and death of close relatives (OR 3.83, 95% CI 1.91-7.68). Absence of fear of recurrence of tsunami (OR 0.32, 95% CI 0.17-0.60), satisfaction of services received (OR 0.57, 95% CI 0.36-0.92) and counseling services received more than three times (OR 0.45, 95% CI 0.26-0.78) had protective effect against PTSD. CONCLUSIONS: There is an association of pre-disaster, within-disaster and post-disaster factors with PTSD, which demands specific interventions at all phases of disaster, with a special focus on vulnerable groups.

Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey.

BACKGROUND: Although most cardiovascular disease occurs in low-income and middle-income countries, little is known about the use of effective secondary prevention medications in these communities. We aimed to assess use of proven effective secondary preventive drugs (antiplatelet drugs, ß blockers, angiotensin-converting-enzyme [ACE] inhibitors or angiotensin-receptor blockers [ARBs], and statins) in individuals with a history of coronary heart disease or stroke. METHODS: In the Prospective Urban Rural Epidemiological (PURE) study, we recruited individuals aged 35-70 years from rural and urban communities in countries at various stages of economic development. We assessed rates of previous cardiovascular disease (coronary heart disease or stroke) and use of proven effective secondary preventive drugs and blood-pressure-lowering drugs with standardised questionnaires, which were completed by telephone interviews, household visits, or on patient's presentation to clinics. We report estimates of drug use at national, community, and individual levels. FINDINGS: We enrolled 153,996 adults from 628 urban and rural communities in countries with incomes classified as high (three countries), upper-middle (seven), lower-middle (three), or low (four) between January, 2003, and December, 2009. 5650 participants had a self-reported coronary heart disease event (median 5·0 years previously [IQR 2·0-10·0]) and 2292 had stroke (4·0 years previously [2·0-8·0]). Overall, few individuals with cardiovascular disease took antiplatelet drugs (25·3%), ß blockers (17·4%), ACE inhibitors or ARBs (19·5%), or statins (14·6%). Use was highest in high-income countries (antiplatelet drugs 62·0%, ß blockers 40·0%, ACE inhibitors or ARBs 49·8%, and statins 66·5%), lowest in low-income countries (8·8%, 9·7%, 5·2%, and 3·3%, respectively), and decreased in line with reduction of country economic status (p(trend)<0·0001 for every drug type). Fewest patients received no drugs in high-income countries (11·2%), compared with 45·1% in upper middle-income countries, 69·3% in lower middle-income countries, and 80·2% in low-income countries. Drug use was higher in urban than rural areas (antiplatelet drugs 28·7% urban vs 21·3% rural, ß blockers 23·5%vs 15·6%, ACE inhibitors or ARBs 22·8%vs 15·5%, and statins 19·9%vs 11·6%; all p<0·0001), with greatest variation in poorest countries (p(interaction)<0·0001 for urban vs rural differences by country economic status). Country-level factors (eg, economic status) affected rates of drug use more than did individual-level factors (eg, age, sex, education, smoking status, body-mass index, and hypertension and diabetes statuses). INTERPRETATION: Because use of secondary prevention medications is low worldwide-especially in low-income countries and rural areas-systematic approaches are needed to improve the long-term use of basic, inexpensive, and effective drugs. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, andlow-income countries (the PURE Study): a prospective epidemiological survey

Background Although most cardiovascular disease occurs in low-income and middle-income countries, little is known about the use of effective secondary prevention medications in these communities. We aimed to assess use of proven effective secondary preventive drugs (antiplatelet drugs, â blockers, angiotensin-converting-enzyme [ACE] inhibitors or angiotensin-receptor blockers [ARBs], and statins) in individuals with a history of coronary heart disease or stroke.MethodsIn the Prospective Urban Rural Epidemiological (PURE) study, we recruited individuals aged 35—70 years from rural and urban communities in countries at various stages of economic development. We assessed rates of previous cardiovascular disease (coronary heart disease or stroke) and use of proven effective secondary preventive drugs and blood-pressure-lowering drugs with standardised questionnaires, which were completed by telephone interviews, household visits, or on patient's presentation to clinics. We report estimates of drug use at national, community, and individual levels.FindingsWe enrolled 153 996 adults from 628 urban and rural communities in countries with incomes classified as high (three countries), upper-middle (seven), lower-middle (three), or low (four) between January, 2003, and December, 2009. 5650 participants had a self-reported coronary heart disease event (median 5·0 years previously [IQR 2·0—10·0]) and 2292 had stroke (4·0 years previously [2·0—8·0]). Overall, few individuals with cardiovascular disease took antiplatelet drugs (25·3%), â blockers (17·4%), ACE inhibitors or ARBs (19·5%), or statins (14·6%). Use was highest in high-income countries (antiplatelet drugs 62·0%, â blockers 40·0%, ACE inhibitors or ARBs 49·8%, and statins 66·5%), lowest in low-income countries (8·8%, 9·7%, 5·2%, and 3·3%, respectively), and decreased in line with reduction of country economic status (ptrend<0·0001 for every drug type)...