Using Drugs to Probe the Variability of Trans-Epithelial Airway Resistance

BACKGROUND:Precision medicine aims to combat the variability of the therapeutic response to a given medicine by delivering the right medicine to the right patient. However, the application of precision medicine is predicated on a prior quantitation of the variance of the reference range of normality. Airway pathophysiology provides a good example due to a very variable first line of defence against airborne assault. Humans differ in their susceptibility to inhaled pollutants and pathogens in part due to the magnitude of trans-epithelial resistance that determines the degree of epithelial penetration to the submucosal space. This initial 'set-point' may drive a sentinel event in airway disease pathogenesis. Epithelia differentiated in vitro from airway biopsies are commonly used to model trans-epithelial resistance but the 'reference range of normality' remains problematic. We investigated the range of electrophysiological characteristics of human airway epithelia grown at air-liquid interface in vitro from healthy volunteers focusing on the inter- and intra-subject variability both at baseline and after sequential exposure to drugs modulating ion transport. METHODOLOGY/PRINCIPAL FINDINGS:Brushed nasal airway epithelial cells were differentiated at air-liquid interface generating 137 pseudostratified ciliated epithelia from 18 donors. A positively-skewed baseline range exists for trans-epithelial resistance (Min/Max: 309/2963 Ω·cm2), trans-epithelial voltage (-62.3/-1.8 mV) and calculated equivalent current (-125.0/-3.2 μA/cm2; all non-normal, P<0.001). A minority of healthy humans manifest a dramatic amiloride sensitivity to voltage and trans-epithelial resistance that is further discriminated by prior modulation of cAMP-stimulated chloride transport. CONCLUSIONS/SIGNIFICANCE:Healthy epithelia show log-order differences in their ion transport characteristics, likely reflective of their initial set-points of basal trans-epithelial resistance and sodium transport. Our data may guide the choice of the background set point in subjects with airway diseases and frame the reference range for the future delivery of precision airway medicine

Priority knowledge needs for implementing nature-based solutions in the Mediterranean islands

Mediterranean islands face significant environmental challenges due to their high population density, reliance on imports, and water scarcity, exacerbated by increasing risks from climate change. Nature-based solutions (NbS) could address these challenges sustainably and with multiple benefits, but their uptake in policy and planning is limited, and stakeholder perspectives are conspicuously lacking from current research. Here, we report the results of a collaborative, multi-stakeholder exercise to identify priority knowledge needs (KNs) that could enhance the uptake of NbS in Mediterranean islands. We used a well-established iterative prioritisation method based on a modified Delphi process. This was conducted by the authors, environmental policy and practice stakeholders from across the Mediterranean islands, representing business, government, NGOs and research. We developed a long list of potential KNs through individual submissions, and prioritised them through voting, discussion and scoring. Excepting workshop discussion, all individual contributions were anonymous. We present the 47 resulting KNs in rank order, classified by whether they can be addressed by knowledge synthesis and further research, or demand action in policy and practice. The top priority KNs are i) a more precise definition of NbS, ii) which NbS are adapted to dry Mediterranean conditions? iii) how to increase the adoption and use of NbS in urban plans?, iv) how can buildings and built-up areas be modified to accommodate green infrastructure and v) cost-benefit analysis of urban green spaces. In collaboration with these stakeholders, our findings will determine future research strategies on NbS implementation in the Mediterranean islands

Test for CCR5 tropism and treatment with maraviroc in Sicily: an observational retrospective multicentre study

Purpose of the study: Maraviroc (MVC) is the first CCR5 inhibitor licensed for clinical use. A pre-treatment test is mandatory to identify R5 tropic patients. Aim of this study is to detect indications and results of tropism test and to evaluate efficacy and tolerability of MVC-based regimen. Methods: An observational retrospective multicentre study was performed in Sicily in 15 Infectious Diseases Units. Clinical records of 213 screened for tropism HIV+ subjects were reviewed for age, sex, risk, clinical stage (CDC, CD4 cell count, HIV RNA viral load), therapeutic line, indication and result of test for tropism; within subjects treated with MVC, HIV RNA, CD4 cell count and metabolic parameters trend and adverse events were analysed. Summary of results: Median age 44 (IQR 30&#x2013;50) years, 67.1% males; 46.3% heterosexuals, 28.6% MSMs, 21.4% IVDUs; 23.7% CDC A, 32.1% CDC B, 44.2% CDC C; median CD4 was 217 (IQR 121&#x2013;374) cells/&#x00B5;l and mean of HIV RNA was 4.72 (Cl 95% 4.07&#x2013;4.67) log10 copies/ml; median therapeutic line was 4 (IQR 2&#x2013;7). 80.8% were submitted to Trofile&#x2122; test, 19.2% to genotypic test, 75.5% after a therapeutic failure. 56.8% of subjects screened were R5, 7.5% X4, 21.6% DM, 14% undefined. All X4 patients were tested after a therapeutic failure; patients screened for toxicity were more frequently R5 (75%) (p&#60;0.01). 76 (35.7%) multi-experienced (at baseline 8% HIV RNA&#60;50 copies/ml, median CD4 cell count 219 (IQR 124&#x2013;345) cells/&#x00B5;l) subjects were treated with MVC plus an optimized background treatment: MVC was associated in 74% of cases with a protease inhibitors (56% darunavir/ritonavir), in 42% with raltegravir, in 56% with a NUC-sparing regimen. After 12 months of treatment 56.8% (ITT analysis) and 61.7% (AT) of patients had HIV RNA&#60;50 copies/ml; median CD4 cell count was 387 (IQR 222&#x2013;455) cells/&#x00B5;l. After 24 months 64.8% (ITT) 80% (AT) had HIV-RNA&#60;50 copies/ml. Median CD4 cell count was 381 (IQR 218.515) cells/&#x00B5;l with a median increase of 168 (IQR 54&#x2013;274) cells/&#x00B5;l. At 24 months median value of total and HDL cholesterol and triglycerides were within the normal range. 7 patients stopped the treatment: 2 died, 1 adverse event, 4 virological failure. Conclusions: Although the test has been proposed to patients with long treatment history and failure, only 3/5 of R5 tropic patients were treated with MVC. An high number of multi-experienced subjects treated with a MVC-based regimen obtained HIV RNA&#60;50 copies/ml and a satisfactory increase of CD4 cell count

Once versus twice daily administration of didanosine in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine. The Italian Pediatric Collaborative Study Group on Didanosine.

The objective of this study was to compare the safety, tolerability and clinical response of once- versus twice-daily administration of didanosine given at a dosage of 270 mg/m2/day in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine monotherapy. We carried out a randomized, open-label multicentre trial. Didanosine was supplied in buffered tablets, which could be chewed or dispersed in liquid. The children were recruited from 16 paediatric departments participating in the Italian Register for HIV Infection in Children. A total of 53 children (median age 5.5 years) started trial treatment; 26 were given didanosine twice daily and 27 once daily; 85% had AIDS and 98% had clinically deteriorated while on zidovudine therapy. Similar safety and tolerability results were demonstrated for the two schemes of therapy. A total of 11 children (20.7%) required discontinuation of didanosine for severe adverse events (five children (19.2%) in the twice-daily group; six children (22.2%) in the once-daily group, log-rank P = 0.81). Severe hepatic toxicity was uncommon (5.6%) while mild to moderate hepatic dysfunction was demonstrated in about 17% of the participants, without any difference between the two groups. Haematological toxicity was common (about 40% of the children, 11 in the twice- and 19 in the once-daily group) but never severe. Clinical pancreatitis and retinal lesions were never demonstrated. There was no significant difference in progression to death or to a new opportunistic infection between the two treatment regimens (log-rank P = 0.54). The modification of surrogate efficacy parameters during the study period was similar in the two groups. However, weight gain was poorer in children treated once daily. This study suggests that the safety and tolerability of 270 mg/m2/day of didanosine given once daily is substantially similar to that of the traditionally recommended schedule of two divided doses. Owing to the small sample and to the severity of the clinical condition of the children enrolled, no definite conclusions on the comparative efficacy of the two regimens can be drawn

Antonio Gramsci on religion

This article provides an introduction to Antonio Gramsci\u2019s understanding and analysis of religion. It shows that Gramsci\u2019s conceptual constellation and key terms \u2013 from hegemony to organic intellectuals, from moral and intellectual reform to common sense \u2013 were formulated precisely in his critique to religion, and specifically to Catholicism in Italy. Rejecting the determinism and reductionism of orthodox Marxism, Gramsci saw religion as an active mode of experiencing social and historical reality, and came to conceptualize Marxism (the philosophy of praxis) as a new secular religion. The article demonstrates how Gramsci subtly and deftly problematized the relationship between religion, power, and politics in society. It will in particular foreground his astute reading of religion in practices and in common sense. Gramsci\u2019s views on religion, this article argues, offer insightful theoretical tools that could be of considerable benefit for scholars (sociologists, anthropologists, and historians) examining religious phenomena in a global post-modern world

Disease outcomes after DAA-induced SVR: Data from the resist-HCV cohort

Background and aims: Large scale, real life data on the long term course of liver disease after HCV clearance obtained with DAAs are still scanty, and the separate effects on hepatic and non-hepatic causes of death still unclear. Method: We evaluated 4147 patients (mean age: 65.7 ± 11.5 years, 57.6% males) included in the prospective RESIST-HCV cohort who started DAAs treatment in 22 centres between March 2015 and April 2017. All patients were follow after SVR to register liver-related and unrelated outcomes. The primary endpoint was the evaluation of survival since starting DAAs. Cox regression analysis was used to assess the predictors of liver-related and unrelated death. Results: Patients were observed for a median of 50 weeks (range: 1–199), 934 (22.5%) had diagnosis of chronic hepatitis (F3 in &gt;90%), 2851 (68.7%) had Child A cirrhosis and 362 (8.7%) had Child B cirrhosis. Overall, 3766 patients (90.8%) achieved SVR while 381 patients (9.2%) were HCV-RNA positive at the last control. Fifty-five patients (1.3%) died during the observation: 25 of them died for liver related causes and 30 for unrelated causes (16: cardiovascular disease, 6: sepsis, 8: other). The lack of SVR was associated with an increased incidence of overall mortality in comparison to patients with SVR (hazard ratio [HR]; 28.9; 95% confidence interval [CI]: 16.5–50.8; p &lt; 0.001) and death from liver-related and unrelated causes (HR: 18.5, 95%CI: 8.2–41.3; p &lt; 0.001 and HR: 45.5; 95%CI: 19.3–107.4; p &lt; 0.001 respectively). By multivariate Cox regression analysis lack of SVR (HR: 14.9, 95%CI: 6.3–35.1; p &lt; 0.001) and Child B cirrhosis (HR: 29.4, 95%CI: 3.8–223.9; p &lt; 0.001) were independently related with liver mortality. Independent predictors of liver-unrelated mortality were no SVR (HR: 41.77, 95%CI: 17.30–100.87; p &lt; 0.001), Child B cirrhosis (HR: 3.00, 95%CI: 1.36–6.22; p = 0.006), BMI (HR: 0.89, 95%CI: 0.81–0.98, p = 0.023) and diabetes (HR: 2.38, 95%CI: 1.13–5.00, p = 0.022). Conclusion: In this real world setting using a variety of DAA regimens SVR reduced overall mortality and risk of liver-related and unrelated deaths at all stages of disease, nut mostly in Child A cirrhosis. The effect on cardiovascular deaths, which is evident also in the pre-cirrhotic stages deserves further follow up and investigation