Socioeconomic and behavioral factors associated with tuberculosis diagnostic delay in Lima, Peru

Early detection and diagnosis of tuberculosis (TB) is a global priority. Prolonged symptom duration prior to TB diagnosis is associated with increased morbidity, mortality and risk of transmission. We aimed to determine socioeconomic and behavioral factors associated with diagnostic delays among patients with TB. Data were collected from 105 patients with TB using a semi-structured interview guide in Lima, Peru. Factors associated with diagnostic delay were analyzed using negative binomial regression. The median delay from when symptoms commenced and the first positive diagnostic sample in public health facilities was 57 days (interquartile range (IQR): 28-126). In multivariable analysis, greater diagnostic delay was independently associated with patient older age; female sex; lower personal income prior to diagnosis; living with fewer people; and having more visits to professional health facilities prior to diagnosis (all p<0.05). Patients who first sought care at a private health facility had more visits overall to professional health facilities prior to diagnosis than those who first sought care from public or insured employee health facilities and had longer diagnostic delay in analysis adjusted for age and sex. Patients with TB were significantly more likely to first self-medicate than to visit professional health facilities prior to diagnosis (p=0.003). Thus, diagnostic delay was prolonged, greatest among older, low-income women and varied according to the type of care sought by individuals when their symptoms commenced. These findings suggest that TB case finding initiatives should target vulnerable groups in informal and private health facilities, where many patients with TB first seek healthcare

Physical and Aerodynamic Characterization of Particle Clusters at Sakurajima Volcano (Japan)

The process of particle aggregation significantly affects ash settling dynamics associated with volcanic explosive eruptions. Several experiments have been carried out to investigate the physics of ash aggregation and dedicated numerical schemes have been developed to produce more accurate forecasting of ash dispersal and sedimentation. However, numerical description of particle aggregation is complicated by the lack of complete datasets on natural samples required for model validation and calibration. Here we present a first comprehensive dataset for the internal structure, aerodynamical properties (e.g., size, density, terminal velocity) and grain size of constituting particles of a variety of aggregate types collected in the natural laboratory of Sakurajima Volcano (Japan). Even though the described particle clusters represent the most common types of aggregates associated with ash-rich fallouts, they are of difficult characterization due to the very low potential of preservation in tephra-fallout deposits. Properties were, therefore, derived based on a combination of high-resolution-high-speed videos of tephra fallout, scanning electron microscope analysis of aggregates collected on adhesive paper and analysis of tephra samples collected in dedicated trays. Three main types of particle clusters were recognized and quantitively characterized: cored clusters (PC3), coated particles (PC2), and ash clusters (PC1) (in order of abundance). A wide range of terminal velocities (0.5–4&nbsp;m/s) has been observed for these aggregates, with most values varying between 1 and 2&nbsp;m/s, while aggregate size varies between 200 and 1,200&nbsp;µm. PC1, PC2, and PC3 have densities between 250 and 500, 1,500 and 2,000, and 500 and 1,500&nbsp;kg/m3, respectively. The size of the aggregate core, where present, varies between 200 and 750&nbsp;µm and increases with aggregate size. Grain size of tephra samples was deconvoluted into a fine and a coarse Gaussian subpopulation, well correlated with the grain size of shells and of the internal cores of aggregates, respectively. This aspect, together with the revealed abundance of PC3 aggregates, reconciles the presence of a large amount of fine ash (aggregate shells) with coarse ash (aggregate cores) and better explains the grain size distribution bimodality, the high settling velocity with respect to typical PC1 velocities and the low settling velocities of large aggregates with respect to typical PC2 velocity. Furthermore, ash forming the aggregates was shown to be always finer than 45&nbsp;µm, confirming the key role played by aggregation processes in fine ash deposition at Sakurajima

Why wait? The social determinants underlying tuberculosis diagnostic delay.

BACKGROUND: Early detection and diagnosis of tuberculosis remain major global priorities for tuberculosis control. Few studies have used a qualitative approach to investigate the social determinants contributing to diagnostic delay and none have compared data collected from individual, community, and health-system levels. We aimed to characterize the social determinants that contribute to diagnostic delay among persons diagnosed with tuberculosis living in resource-constrained settings. METHODS/PRINCIPLE FINDINGS: Data were collected in public health facilities with high tuberculosis incidence in 19 districts of Lima, Peru. Semi-structured interviews with persons diagnosed with tuberculosis (n = 105) and their family members (n = 63) explored health-seeking behaviours, community perceptions of tuberculosis and socio-demographic circumstances. Focus groups (n = 6) were conducted with health personnel (n = 35) working in the National Tuberculosis Program. All interview data were transcribed and analysed using a grounded theory approach. The median delay between symptom onset and the public health facility visit that led to the first positive diagnostic sample was 57 days (interquartile range 28-126). The great majority of persons diagnosed with tuberculosis distrusted the public health system and sought care at public health facilities only after exhausting other options. It was universally agreed that persons diagnosed with tuberculosis faced discrimination by public and health personnel. Self-medication with medicines bought at local pharmacies was reported as the most common initial health-seeking behaviour due to the speed and low-cost of treatment in pharmacies. Most persons diagnosed with tuberculosis initially perceived their illness as a simple virus. CONCLUSIONS: Diagnostic delay was common and prolonged. When individuals reached a threshold of symptom severity, they addressed their health with the least time-consuming, most economically feasible, and well-known healthcare option available to them. In high-burden settings, more human and material resources are required to promote tuberculosis case-finding initiatives, reduce tuberculosis associated stigma and address the social determinants underlying diagnostic delay

Leachate Analyses of volcanic ashes from the 2010 Eyjafjallaj\uf6kull eruption

Volcanic processes which lead to eruptions can be investigated by monitoring a variety of parameters, including the composition of ash leachates. Fine-grained tephra erupted from active vents, and transported through volcanic plumes, can adsorb, and therefore rapidly scavenge, volatile elements such as sulphur, halogens, and metal species in the form of soluble salts adhering to ash surfaces. Analysis of such water-soluble surface materials is a suitable complement for the remote sensing of volcanic gases at inaccessible volcanoes. The April 2010 Eyjafjallaj\uf6kull eruption has been characterised by several distinct phases, with an initial effusion of alkali basalt on the volcano's northeast flank since March 20th, followed (since April 14th) by a complex summit, sustained, explosive to mixed activity, characterised by trachyandesitic magma The first phase of the summit eruption (14 to 18 April) was initially characterised by interaction between glacial meltwater from the icecap and erupting magma, and by three main pulses during which dark ash plumes were dispersed to the SE and S. Following a decrease in the intensity in explosive activity associated to the emission of a lava flow (from 19 April to 4 May), activity renewed in intensity on 5 May, when an ash-laden plume, up to 10 km in height, was continuously dispersed until May 18. Activity progressively declined and eruption closed on 9 June [1]. Here, we report on the chemical composition of leachates from volcanic ash samples deposited during the Eyjafjallaj\uf6kull explosive phase (from 14 April to 8 May). Twenty-eight freshly fallen volcanic ash samples were collected at various distances from the eruptive vent, and their leached solutions were analyzed for major and trace elements. We show that ash leachate solutions from Eyjafjallaj\uf6kull are dominated - among cations - by Na and Ca, while they display nearly equal S:Cl:F abundances (mean S/Cl and S/F molar ratios of 1.04 and 0.76 respectively), as characteristic of divergent-plate and within-plate volcanism. The good correlations between Ca and F (r2=0.8), Ca and SO4 (r2=0.7), and Na and Cl (r2=0.9) in ash leachates suggest that fluorite, anhydrite, and halite were the most likely soluble surface minerals formed in the plume (and therefore leached during our experiments). These correlations in the extracted solutions also indicate that either the sources of cations and anions in ash leachates were the same (e.g. direct condensation of NaCl(g) and CaSO4(g) from the plume) or, more probably, that the highest the condensation of plume acidic compounds (e.g., SO2(g), HCl(g), HF(g)) on ash, the largest the leaching of cations from silicate fragments. Indeed, our data bring evidence for that the extent of gas-ash reaction (likely, a proxy for ash residence time in the plume) was a key casual factor in determining ash leachate composition. Samples from the 4- 8th May eruptive period, showing the most acid pH values (4.5-5.5), consistently have the highest abundances for all elements, and especially Mg, S and F. Large variations in S and halogens proportions are observed in our dataset, with samples from the 4-8th May eruptive period showing the highest S/Cl and lowest Cl/F ratios. To interpret these variations, and particularly to verify whether they reflect changes in plume gas composition, in gas-ash reaction dynamics and rates,2]will require in-depth comparison with direct (FTIR) measurement of the Eyjafjallaj\uf6kull gas plume[2] . [1] Hoskuldsson, A., et al., 2011. Geophysical Research Abstracts Vol. 13, EGU2011-14165, 2011; [2] Allard, P., et al., 2010. Abstract V53F-07 presented at Fall Meeting, AGU, San Francisco, Calif. 13-17 Dec.

Impact of Age on the Effectiveness and Safety of Insulin Glargine 300 U/mL: Results from the REALI European Pooled Data Analysis

Introduction: Patients aged ≥ 65&nbsp;years continue to be underrepresented in clinical studies related to type 2 diabetes mellitus (T2DM). Accordingly, the REALI pooled analysis was performed to evaluate the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) across different age subgroups, using data from 14 interventional and non-interventional studies. Methods: Pooled efficacy and safety data were collected from 8106 European patients with uncontrolled T2DM who were initiated on or switched to Gla-300 injected once daily for 24&nbsp;weeks. Patients were categorised into five age subgroups: &lt; 50 (N = 727), 50–59 (N = 2030), 60–69 (N = 3054), 70–79 (N = 1847) and ≥ 80&nbsp;years (N = 448). Results: Mean baseline haemoglobin A1c (HbA1c) decreased linearly from the youngest (9.10%) to the oldest (8.46%) age subgroup. Following Gla-300 initiation, there were similar HbA1c reductions across age groups, with a least squares mean (95% confidence interval) change in HbA1c from baseline to week 24 of − 1.09% (− 1.18 to − 1.00), − 1.08% (− 1.14 to − 1.03), − 1.12% (− 1.17 to − 1.07), − 1.18% (− 1.24 to − 1.12) and − 1.11% (− 1.23 to − 0.99) in the &lt; 50, 50–59, 60–69, 70–79 and ≥ 80&nbsp;years subgroups, respectively. The incidences and event rates of reported hypoglycaemia were overall low. Compared to younger age subgroups, lower incidences of symptomatic hypoglycaemia occurring at any time of the day (5.9 vs. 7.6–9.4% for the younger subgroups) or during the night (0.5 vs. 1.6–2.5%) were recorded in patients aged ≥ 80&nbsp;years. By contrast, the highest incidence of severe hypoglycaemia occurring any time of the day was reported in the subgroup aged ≥ 80&nbsp;years (1.1 vs. 0.1–0.6% for the younger age subgroups). Conclusion: Gla-300 initiated in patients with uncontrolled T2DM provides glycaemic improvement with a favourable safety profile across a wide range of ages

Haplotypes of the genes (GCK and G6PC2) underlying the glucose/glucose-6-phosphate cycle are associated with pancreatic beta cell glucose sensitivity in patients with newly diagnosed type 2 diabetes from the VNDS study (VNDS 11)

Background: Elevated fasting plasma glucose has been associated with increased risk for development of type 2 diabetes (T2D). The balance between glucokinase (GCK) and glucose-6-phosphate catalytic subunit 2 (G6PC2) activity are involved in glucose homeostasis through glycolytic flux, and subsequent insulin secretion. Aim: In this study, we evaluated the association between the genetic variability of G6PC2 and GCK genes and T2D-related quantitative traits. Methods: In 794 drug-naïve, GADA-negative, newly diagnosed T2D patients (VNDS; NTC01526720) we performed: genotyping of 6 independent tag-SNPs within GCK gene and 5 tag-SNPs within G6PC2 gene; euglycaemic insulin clamp to assess insulin sensitivity; OGTT to estimate beta-cell function (derivative and proportional control; DC, PC) by mathematical modeling. Genetic association analysis has been conducted using Plink software. Results: Two SNPs within GCK gene (rs882019 and rs1303722) were associated to DC in opposite way (both p &lt; 0.004). Two G6PC2 variants (rs13387347 and rs560887) were associated to both parameters of insulin secretion (DC and PC) and to fasting C-peptide levels (all p &lt; 0.038). Moreover, subjects carrying the A allele of rs560887 showed higher values of 2h-plasma glucose (2hPG) (p = 0.033). Haplotype analysis revealed that GCK (AACAAA) haplotype was associated to decreased fasting C-peptide levels, whereas, the most frequent haplotype of G6PC2 (GGAAG) was associated with higher fasting C-peptide levels (p = 0.001), higher PC (β = 6.87, p = 0.022) and the lower 2hPG (p = 0.012). Conclusion: Our findings confirmed the role of GCK and G6PC2 in regulating the pulsatility in insulin secretion thereby influencing insulin-signaling and leading to a gradual modulation in glucose levels in Italian patients with newly diagnosed T2D

Glycaemic Control with Insulin Glargine 300 U/mL in Individuals with Type 2 Diabetes and Chronic Kidney Disease: A REALI European Pooled Data Analysis

Introduction: Management of type&nbsp;2 diabetes mellitus (T2DM) in patients with chronic kidney disease is complex. Using the REALI European pooled database, we determined the impact of baseline renal function on the effectiveness and safety of insulin glargine 300&nbsp;U/mL (Gla-300) initiated in adults with inadequately controlled T2DM. Methods: Data from 1712 patients with available estimated glomerular filtration rate (eGFR) at baseline were pooled from six 24-week prospective studies. Patients who received once-daily subcutaneous injections of Gla-300 were classified into four renal function subgroups, according to baseline eGFR: ≥ 90 (N = 599), 60–89 (N = 786), 45–59 (N = 219), and 15–44&nbsp;mL/min/1.73&nbsp;m2 (N = 108). Results: Compared to those with baseline eGFR ≥ 60&nbsp;mL/min/1.73&nbsp;m2, patients with lower eGFR values tended to be older, had a longer T2DM duration, and were more likely to present diabetic complications. After 24&nbsp;weeks of Gla-300 therapy, the least-squares mean (95% confidence interval) decrease in haemoglobin A1c (HbA1c) from baseline (−&nbsp;1.14% [−&nbsp;1.28 to −&nbsp;1.00], −&nbsp;1.21% [−&nbsp;1.34 to −&nbsp;1.08], −&nbsp;1.19% [−&nbsp;1.36 to −&nbsp;1.01], and −&nbsp;0.99% [−&nbsp;1.22 to −&nbsp;0.76]) and the proportion of patients achieving HbA1c &lt; 7.5% (53.3%, 51.3%, 49.5%, and 51.5%) were comparable in the ≥ 90, 60–89, 45–59, and 15–44&nbsp;mL/min/1.73&nbsp;m2 subgroups, respectively. Although the incidence of hypoglycaemia was overall low, more patients in the eGFR 15–44&nbsp;mL/min/1.73&nbsp;m2 subgroup experienced hypoglycaemia at night or at any time of the day compared with higher eGFR subgroups. There were no notable differences between the renal function subgroups in the changes in Gla-300 daily dose and body weight from baseline to week&nbsp;24. Conclusion: Although an eGFR of 15–44&nbsp;mL/min/1.73&nbsp;m2 was associated with a slightly increased risk of hypoglycaemia among patients with inadequately controlled T2DM, Gla-300 provided glycaemic improvement with an overall favourable safety profile regardless of baseline eGFR

Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: Potential relevance to prevention of cardiovascular events

Background: The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored. Method: MAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1-100 μM] to assess their effects on SA (100 μM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test. Results: NHE isoforms (1,5-9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 μM) significantly reduced SA-induced inflammation (IL1β, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 μM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT. Conclusions: EMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection

Similar glycaemic control and risk of hypoglycaemia with patient- versus physician-managed titration of insulin glargine 300 U/mL across subgroups of patients with T2DM: a post hoc analysis of ITAS

Aims: The Italian Titration Approach Study (ITAS) demonstrated comparable HbA1c reductions and similarly low hypoglycaemia risk at 6&nbsp;months in poorly controlled, insulin-naïve adults with T2DM who initiated self- or physician-titrated insulin glargine 300 U/mL (Gla-300) in the absence of sulphonylurea/glinide. The association of patient characteristics with glycaemic and hypoglycaemic outcomes was assessed. Methods: This post hoc analysis investigated whether baseline patient characteristics and previous antihyperglycaemic drugs were associated with HbA1c change and hypoglycaemia risk in patient- versus physician-managed Gla-300 titration. Results: HbA1c change, incidence of hypoglycaemia (any type) and nocturnal rates were comparable between patient- and physician-managed arms in all subgroups. Hypoglycaemia rates across subgroups (0.03 to 3.52 events per patient-year) were generally as low as observed in the full ITAS population. Small increases in rates of 00:00–pre-breakfast and anytime hypoglycaemia were observed in the ≤ 10-year diabetes duration subgroup in the patient- versus physician-managed arm (heterogeneity of effect; p &lt; 0.05). Conclusions: Comparably fair glycaemic control and similarly low hypoglycaemia risk were achieved in almost all patient subgroups with patient- versus physician-led Gla-300 titration. These results reinforce efficacy and safety of Gla-300 self-titration across a range of phenotypes of insulin-naïve people with T2DM. Clinical trial registration: EudraCT 2015-001167-3