Budesonide/formoterol combination in COPD: a US perspective

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents with progressive cough, sputum production, dyspnea, reduced exercise capacity, and diminished quality of life. Physiologically, it is characterized by the presence of partially reversible expiratory airflow limitation and hyperinflation. Pathologically, COPD is a multicomponent disease characterized by bronchial submucosal mucous gland hypertrophy, bronchiolar mucosal hyperplasia, increased luminal inflammatory mucus, airway wall inflammation and scarring, and alveolar wall damage and destruction. Management of COPD involves both pharmacological and nonpharmacological approaches. Bronchodilators and inhaled corticosteroids are recommended medications for management of COPD especially in more severe disease. Combination therapies containing these medications are now available for the chronic management of stable COPD. The US Food and Drug Administration, recently, approved the combination of budesonide/formoterol (160/4.5 μg; Symbicort™, AstraZeneca, Sweden) delivered via a pressurized meter dose inhaler for maintenance management of stable COPD. The combination also is delivered via dry powder inhaler (Symbicort™ and Turbuhaler™, AstraZeneca, Sweden) but is not approved for use in the United States. In this review, we evaluate available data of the efficacy and safety of this combination in patients with COPD

Effectiveness of oseltamivir prophylaxis in influenza outbreaks in residential aged care

Influenza outbreaks in Aged Care Facilities (ACFs) can lead to hospitalizations and deaths. Influenza can spread rapidly through ACFs if precautionary measures are not taken. Along with influenza vaccination and precautionary hygiene measures, Oseltamivir Prophylaxis (OP) may be effective in reducing the attack rate of influenza by preventing new cases. A cohort study was carried out to investigate the effectiveness of OP use during influenza outbreaks in ACFs located within South Western Sydney Local Health District from 1 January 2015 to 31 December 2018. The main outcome assessed was the rate of OP failure (new cases of influenza in patients treated with OP) among ACF residents. Subgroups and various predictors of OP failure were investigated including presence of a dementia ward, high care ward, and days to Public Health Unit (PHU) notification. The cohort consisted of 86 ACF outbreaks involving 10,064 residents. OP prevented 90% of influenza cases during influenza outbreaks [0.1 RR (95% confidence interval (CI): 0.08–0.12); P < 0.0001]. ACFs with dementia wards had a 44% (0.56 relative risk (RR) (95% CI: 0.34–0.93); P < 0.05) lower OP failure rate. ACFs with high level care had an 87% (0.13 RR (95% CI: 0.05–0.38); P < 0.05) lower OP failure rate. OP is highly effective in preventing new cases of influenza during outbreaks in ACFs, especially in ACFs with dementia or high care wards. Mandatory reporting of influenza outbreaks to PHUs would ensure that ACFs are supported throughout the outbreak, which will facilitate reductions in hospitalizations and mortality. © 2020 South Western Sydney Local Health District

Latitudinal variation and distribution of photoperiod and temperature sensitivity for flowering in the world collection of pearl millet germplasm at ICRISAT genebank

The ICRISAT genebank, Patancheru, India holds 22,211 pearl millet germplasm accessions from 50 countries, including 19,063 landraces. Among these, 15,904 landraces that were geo-referenced are either thermo-sensitive (52.5%), or photoperiod-sensitive (45.6%), or insensitive to both temperature and photoperiod (2%). Latitude ranges of 10–15°N with 39.6% and 15–20°S with 13.1% of total accessions are the important regions for pearl millet germplasm. A study on climate data of the germplasm collection sites revealed that most accessions from latitudes ranging from 10 to 20° on both sides of the equator were highly sensitive to longer photoperiod (>12.5 h) and/or lower temperature ( 20–35°) on both the hemispheres exhibited low sensitivity to both photoperiod and low temperature, as they were exposed to such climates during their evolution. The accessions that are insensitive to both photoperiod and temperature were few but they originated from locations spread across all latitudes, although the highest numbers were from mid-latitudes (15–20°) in both hemispheres. As germplasm accessions are sensitive to climatic variables such as temperature and photoperiod, recording of location-specific geo-reference data while collecting the germplasm, which can help to elucidate the sensitivity of accessions to temperature and photoperiod, is emphasized. Critical evaluation of photoperiod-sensitive accessions that are late flowering for forage production and the photoperiod-insensitive early-maturing accessions for grain production, multiple cropping and development of parental lines with synchronized flowering for the development of hybrids is suggested

In Vivo Delivery of Gremlin siRNA Plasmid Reveals Therapeutic Potential against Diabetic Nephropathy by Recovering Bone Morphogenetic Protein-7

Diabetic nephropathy is a complex and poorly understood disease process, and our current treatment options are limited. It remains critical, then, to identify novel therapeutic targets. Recently, a developmental protein and one of the bone morphogenetic protein antagonists, Gremlin, has emerged as a novel modulator of diabetic nephropathy. The high expression and strong co-localization with transforming growth factor- β1 in diabetic kidneys suggests a role for Gremlin in the pathogenesis of diabetic nephropathy. We have constructed a gremlin siRNA plasmid and have examined the effect of Gremlin inhibition on the progression of diabetic nephropathy in a mouse model. CD-1 mice underwent uninephrectomy and STZ treatment prior to receiving weekly injections of the plasmid. Inhibition of Gremlin alleviated proteinuria and renal collagen IV accumulation 12 weeks after the STZ injection and inhibited renal cell proliferation and apoptosis. In vitro experiments, using mouse mesangial cells, revealed that the transfect ion of gremlin siRNA plasmid reversed high glucose induced abnormalities, such as increased cell proliferation and apoptosis and increased collagen IV production. The decreased matrix metalloprotease level was partially normalized by transfection with gremlin siRNA plasmid. Additionally, we observed recovery of bone morphogenetic protein-7 signaling activity, evidenced by increases in phosphorylated Smad 5 protein levels. We conclude that inhibition of Gremlin exerts beneficial effects on the diabetic kidney mainly through maintenance of BMP-7 activity and that Gremlin may serve as a novel therapeutic target in the management of diabetic nephropathy

Geldanamycin Derivative Ameliorates High Fat Diet-Induced Renal Failure in Diabetes

Diabetic nephropathy is a serious complication of longstanding diabetes and its pathogenesis remains unclear. Oxidative stress may play a critical role in the pathogenesis and progression of diabetic nephropathy. Our previous studies have demonstrated that polyunsaturated fatty acids (PUFA) induce peroxynitrite generation in primary human kidney mesangial cells and heat shock protein 90β1 (hsp90β1) is indispensable for the PUFA action. Here we investigated the effects of high fat diet (HFD) on kidney function and structure of db/db mice, a widely used rodent model of type 2 diabetes. Our results indicated that HFD dramatically increased the 24 h-urine output and worsened albuminuria in db/db mice. Discontinuation of HFD reversed the exacerbated albuminuria but not the increased urine output. Prolonged HFD feeding resulted in early death of db/db mice, which was associated with oliguria and anuria. Treatment with the geldanamycin derivative, 17-(dimethylaminoehtylamino)-17-demethoxygeldanamycin (17-DMAG), an hsp90 inhibitor, preserved kidney function, and ameliorated glomerular and tubular damage by HFD. 17-DMAG also significantly extended survival of the animals and protected them from the high mortality associated with renal failure. The benefit effect of 17-DMAG on renal function and structure was associated with a decreased level of kidney nitrotyrosine and a diminished kidney mitochondrial Ca2+ efflux in HFD-fed db/db mice. These results suggest that hsp90β1 is a potential target for the treatment of nephropathy and renal failure in diabetes

Measuring subjective well-being from a multidimensional and temporal perspective: Italian adaptation of the I COPPE scale

Background: The objective of this study is to present the psychometric and cultural adaptation of the I COPPE scale to the Italian context. The original 21-item I COPPE was developed by Isaac Prilleltensky and colleagues to integrate a multidimensional and temporal perspective into the quantitative assessment of people’s subjective well-being. The scale comprises seven domains (Overall, Interpersonal, Community, Occupation, Psychological, Physical, and Economic well-being), which tap into past, present, and future self-appraisals of well-being. Methods: The Italian adapted version of the I COPPE scale underwent translation and backtranslation procedure. After a pilot study was conducted on a local sample of 683 university students, a national sample of 2432 Italian citizens responded to the final translated version of the I COPPE scale, 772 of whom re-completed the same survey after a period of four months. Respondents from both waves of the national sample were recruited partly through on-line social networks (i.e. Facebook, Twitter, and SurveyMonkey) and partly by university students who had been trained in Computer-Assisted Survey Information Collection. Results: Data were first screened for non-valid cases and tested for multivariate normality and missing data. The correlation matrix revealed highly significant correlation values, ranging from medium to high for nearly all congeneric variables of the I COPPE scale. Results from a series of nested and non-nested model comparisons supported the 7-factor correlated-traits model originally hypothesised, with factor loadings and inter-item reliability ranging from medium to high. In addition, they revealed that the I COPPE scale has strong internal reliability, with composite reliability always higher than .7, satisfactory construct validity, with average variance extracted nearly always higher than .5, and and full strict invariance across time. Conclusions: The Italian adaptation of the I COPPE scale presents appropriate psychometric properties in terms of both validity and reliability, and therefore can be applied to the Italian context. Some limitation and recommendations for future studies are discussed

Hypothalamic Neuroendocrine Functions in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome: Effects of Low-Frequency Electro-Acupuncture

Adult female rats continuously exposed to androgens from prepuberty have reproductive and metabolic features of polycystic ovary syndrome (PCOS). We investigated whether such exposure adversely affects estrous cyclicity and the expression and distribution of gonadotropin-releasing hormone (GnRH), GnRH receptors, and corticotrophin-releasing hormone (CRH) in the hypothalamus and whether the effects are mediated by the androgen receptor (AR). We also assessed the effect of low-frequency electro-acupuncture (EA) on those variables. At 21 days of age, rats were randomly divided into three groups (control, PCOS, and PCOS EA; n = 12/group) and implanted subcutaneously with 90-day continuous-release pellets containing vehicle or 5α-dihydrostestosterone (DHT). From age 70 days, PCOS EA rats received 2-Hz EA (evoking muscle twitches) five times/week for 4–5 weeks. Hypothalamic protein expression was measured by immunohistochemistry and western blot. DHT-treated rats were acyclic, but controls had regular estrous cycles. In PCOS rats, hypothalamic medial preoptic AR protein expression and the number of AR- and GnRH-immunoreactive cells were increased, but CRH was not affected; however, GnRH receptor expression was decreased in both the pituitary and hypothalamus. Low-frequency EA restored estrous cyclicity within 1 week and reduced the elevated hypothalamic GnRH and AR expression levels. EA did not affect GnRH receptor or CRH expression. Interestingly, nuclear AR co-localized with GnRH in the hypothalamus. Thus, rats with DHT-induced PCOS have disrupted estrous cyclicity and an increased number of hypothalamic cells expressing GnRH, most likely mediated by AR activation. Repeated low-frequency EA normalized estrous cyclicity and restored GnRH and AR protein expression. These results may help explain the beneficial neuroendocrine effects of low-frequency EA in women with PCOS

Non-AIDS complexity amongst patients living with HIV in Sydney: Risk factors and health outcomes

Objective: To assess the prevalence of non-AIDS co-morbidities (NACs) and predictors of adverse health outcomes amongst people living with HIV in order to identify health needs and potential gaps in patient management. Design: Retrospective, non-consecutive medical record audit of patients attending a publicly funded HIV clinic in metropolitan Sydney analysed for predictors of adverse health outcomes. We developed a scoring system based on the validated Charlson score method for NACs, mental health and social issues and confounders were selected using directed acyclic graph theory under the principles of causal inference. Results: 211 patient files were audited non-consecutively over 6 weeks. 89.5% were male; 41.8% culturally and linguistically diverse and 4.1% were of Aboriginal/Torres Strait Islander origin. Half of patients had no general practitioner and 25% were ineligible for Medicare subsidised care. The most common NACs were: cardiovascular disease (25%), hepatic disease (21%), and endocrinopathies (20%). One-third of patients had clinical anxiety, one-third major depression and almost half of patients had a lifetime history of tobacco smoking. Five predictors of poor health outcomes were identified: (1) co-morbidity score was associated with hospitalisation (odds ratio, OR 1.58; 95% CI 1.01-2.46; p = 0.044); (2) mental health score was associated with hospitalisation (OR 1.79; 95% CI 1.22-2.62; p = 0.003) and poor adherence to ART (OR 2.34; 95% CI 1.52-3.59; p = 0.001); (3) social issues score was associated with genotypic resistance (OR 2.61; 95% CI 1.48-4.59; p = 0.001), co-morbidity score (OR 1.69; 95% CI 1.24-2.3; p = 0.001) and hospitalisation (OR 1.72; 95% CI 1.1-2.7; p = 0.018); (4) body mass index < 20 was associated with genotypic resistance (OR 6.25; 95% CI 1.49-26.24; p = 0.012); and (5) Medicare eligibility was associated with co-morbidity score (OR 2.21; 95% CI 1.24-3.95; p = 0.007). Conclusion: Most HIV patients are healthy due to effective antiretroviral therapy; however, NACs and social/mental health issues are adding to patient complexity. The current findings underpin the need for multidisciplinary management beyond routine viral load and CD4 count monitoring