Targeting the endothelium by combining endothelin-1 antagonism and SGLT-2 inhibition: better together?

Endothelin A and B receptors, together with sodium-glucose cotransporter-2 (SGLT-2) channels are important targets in improving endothelial function and intervention with inhibitors has been the subject of multiple mechanistic and clinical outcome trials over recent years. Notable successes include the treatment of pulmonary hypertension with endothelin receptor antagonists, and the treatment of heart failure and chronic kidney disease with SGLT-2 inhibitors. With distinct and complementary mechanisms, in this review, we explore the logic of combination therapy for a number of diseases which have endothelial dysfunction at their heart.

The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan.

BACKGROUND: Endothelin A receptor antagonists (ETARA) slow chronic kidney disease (CKD) progression but their use is limited due to fluid retention and associated clinical risks. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) cause osmotic diuresis and improve clinical outcomes in CKD and heart failure. We hypothesized that co-administration of the SGLT2i dapagliflozin with the ETARA zibotentan would mitigate the fluid retention risk using hematocrit (Hct) and bodyweight as proxies for fluid retention. METHODS: Experiments were performed in 4% salt fed WKY rats. First, we determined the effect of zibotentan (30, 100 or 300 mg/kg/day) on Hct and bodyweight. Second, we assessed the effect of zibotentan (30 or 100 mg/kg/day) alone or in combination with dapagliflozin (3 mg/kg/day) on Hct and bodyweight. RESULTS: Hct at Day 7 was lower in zibotentan versus vehicle groups [zibotentan 30 mg/kg/day, 43% (standard error 1); 100 mg/kg/day, 42% (1); and 300 mg/kg/day, 42% (1); vs vehicle, 46% (1); P < .05], while bodyweight was numerically higher in all zibotentan groups compared with vehicle. Combining zibotentan with dapagliflozin for 7 days prevented the change in Hct [zibotentan 100 mg/kg/day and dapagliflozin, 45% (1); vs vehicle 46% (1); P = .44] and prevented the zibotentan-driven increase in bodyweight (zibotentan 100 mg/kg/day + dapagliflozin 3 mg/kg/day = -3.65 g baseline corrected bodyweight change; P = .15). CONCLUSIONS: Combining ETARA with SGLT2i prevents ETARA-induced fluid retention, supporting clinical studies to assess the efficacy and safety of combining zibotentan and dapagliflozin in individuals with CKD.

The role of chronic disease in the disparity of influenza incidence and severity between indigenous and non-indigenous Australian peoples during the 2009 influenza pandemic.

BACKGROUND: The 2009 H1N1 influenza pandemic (influenza A(H1N1)pdm09) disproportionately impacted Indigenous peoples. Indigenous Australians are also affected by a health gap in chronic disease prevalence. We hypothesised that the disparity in influenza incidence and severity was accounted for by higher chronic disease prevalence. METHODS: We analysed influenza data from Western Australia, South Australia, the Northern Territory, and Queensland. We calculated population prevalence of chronic diseases in Indigenous and non-Indigenous Australian populations using nationally-collected health survey data. We compared influenza case notifications, hospitalisations, intensive care admissions, and deaths reported amongst the total population of Indigenous and non-Indigenous Australians ≥ 15 years. We accessed age-specific influenza data reported to the Australian Department of Health during the 2009 'swine flu' pandemic, stratified by Indigenous status and the presence of one of five chronic conditions: chronic lower respiratory conditions, diabetes mellitus, obesity, renal disease, and cardiac disease. We calculated age-standardised Indigenous: non-Indigenous rate ratios and confidence intervals. FINDINGS: Chronic diseases were more prevalent in Indigenous Australians. Rates of influenza diagnoses were higher in Indigenous Australians and more frequent across all indices of severity. In those with chronic conditions, Indigenous: non-Indigenous influenza notification rate ratios were no lower than in the total population; in many instances they were higher. Rate ratios remained above 1·0 at all levels of severity. However, once infected (reflected in notifications), there was no evidence of a further increase in risk of severe outcomes (hospitalisations, ICU admissions, deaths) amongst Indigenous Australians compared to non-Indigenous Australians with a chronic disease. INTERPRETATION: Higher rates of influenza infection was observed amongst those Indigenous compared to non-Indigenous Australians, and this difference was preserved amongst those with a chronic condition. However, there was no further increase in prevalence of more severe influenza outcomes amongst Indigenous Australians with a chronic condition. This suggests that the prevalence of chronic disease, rather than Indigenous status, affected influenza severity. Other factors may be important, including presence of multiple morbidities, as well as social and cultural determinants of health.

Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction.

We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.

Assessment of Temporary Crown Extensions to Correct Linguoverted Mandibular Canine Teeth in 72 Client-Owned Dogs (2012-2016).

A search of the medical and dental records at Evidensia Lørenskog Dyreklinikk, in Lørenskog, Norway, was conducted to identify dogs that received temporary crown extensions (TCEs) to correct linguoverted mandibular canine (LMC) teeth over a 54-month investigation period (2012-2016). Criteria for inclusion into the study were the presence of complete medical and dental records, pre- and postoperative clinical photographs and intraoral radiographs of the affected canine teeth, adequate information pertaining to the procedures performed, and at least 1 follow-up >3 months after appliance removal. Seventy-two dogs with LMC teeth were treated with TCE. Thirty-nine breeds were represented in this study. Mean age at the time of appliance installation was 6.4 (range, 4.7-13.4 months [median, 5.9 months] months). Fifty-three (73.6%) dogs presented with class I malocclusion, 14 (19.5%) dogs with class II malocclusion, and 5 (6.9%) dogs with class III malocclusion. Twenty-five (34.7%) dogs were considered to have mild, 32 (44.4%) dogs to have moderate, and 15 (20.8%) dogs to have severe mandibular canine malocclusion. The TCE was combined with other treatment modalities (active orthodontics, extraction of nonstrategic teeth, gingivectomy, and inclined bite plane and ball therapy) to correct mandibular canine tooth malocclusions in 19 (26.4%) dogs. Fractured or detached crown extensions were seen in 9 (12.5%) dogs. Soft tissue ulceration or inflammation was seen in 7 (9.7%) dogs. The mandibular canine teeth occlusion resolved completely with self-retaining, functional, nontraumatic occlusion in 56 (77.8%) dogs. Fifteen dogs (20.8%) resolved with functional, nontraumatic occlusion, but the mandibular canine teeth were too short to be perfectly self-retained, thus left with 1- to 2-mm crown extensions for permanent retention. In 1 (1.4%) dog, both mandibular canine teeth relapsed almost back to original position. The results show that TCE is a viable treatment option to correct LMC teeth in young dogs.

Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension.

BACKGROUND: The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss-of-function mutations in the gene encoding 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2), allowing inappropriate activation of the mineralocorticoid receptor by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron, but 11ßHSD2 is also expressed in the brain. However, the central contribution to Apparent Mineralocorticoid Excess and other hypertensive states is often overlooked and is unresolved. We therefore used a Cre-Lox strategy to generate 11ßHSD2 brain-specific knockout (Hsd11b2.BKO) mice, measuring blood pressure and salt appetite in adults. METHODS AND RESULTS: Basal blood pressure, electrolytes, and circulating corticosteroids were unaffected in Hsd11b2.BKO mice. When offered saline to drink, Hsd11b2.BKO mice consumed 3 times more sodium than controls and became hypertensive. Salt appetite was inhibited by spironolactone. Control mice fed the same daily sodium intake remained normotensive, showing the intrinsic salt resistance of the background strain. Dexamethasone suppressed endogenous glucocorticoid and abolished the salt-induced blood pressure differential between genotypes. Salt sensitivity in Hsd11b2.BKO mice was not caused by impaired renal sodium excretion or volume expansion; pressor responses to phenylephrine were enhanced and baroreflexes impaired in these animals. CONCLUSIONS: Reduced 11ßHSD2 activity in the brain does not intrinsically cause hypertension, but it promotes a hunger for salt and a transition from salt resistance to salt sensitivity. Our data suggest that 11ßHSD2-positive neurons integrate salt appetite and the blood pressure response to dietary sodium through a mineralocorticoid receptor-dependent pathway. Therefore, central mineralocorticoid receptor antagonism could increase compliance to low-sodium regimens and help blood pressure management in cardiovascular disease.

Purinergic signaling in kidney disease.

Nucleotides are key subunits for nucleic acids and provide energy for intracellular metabolism. They can also be released from cells to act physiologically as extracellular messengers or pathologically as danger signals. Extracellular nucleotides stimulate membrane receptors in the P2 and P1 family. P2X are ATP-activated cation channels; P2Y and P1 are G-protein coupled receptors activated by ATP, ADP, UTP, and UDP in the case of P2 or adenosine for P1. Renal P2 receptors influence both vascular contractility and tubular function. Renal cells also express ectonucleotidases that rapidly hydrolyze extracellular nucleotides. These enzymes integrate this multireceptor purinergic-signaling complex by determining the nucleotide milieu to titrate receptor activation. Purinergic signaling also regulates immune cell function by modulating the synthesis and release of various cytokines such as IL1-ß and IL-18 as part of inflammasome activation. Abnormal or excessive stimulation of this intricate paracrine system can be pro- or anti-inflammatory, and is also linked to necrosis and apoptosis. Kidney tissue injury causes a localized increase in ATP concentration, and sustained activation of P2 receptors can lead to renal glomerular, tubular, and vascular cell damage. Purinergic receptors also regulate the activity and proliferation of fibroblasts, promoting both inflammation and fibrosis in chronic disease. In this short review we summarize some of the recent findings related to purinergic signaling in the kidney. We focus predominantly on the P2X7 receptor, discussing why antagonists have so far disappointed in clinical trials and how advances in our understanding of purinergic signaling might help to reposition these compounds as potential treatments for renal disease.

Determining the contribution of Streptococcus pneumoniae to community-acquired pneumonia in Australia.

OBJECTIVE: To evaluate trends in the proportion and severity of community-acquired pneumonia (CAP) attributable to Streptococcus pneumoniae (pneumococcus) in Australians aged 18 years and over. STUDY DESIGN: Systematic review with unpublished data from the largest study. DATA SOURCES: Multiple key bibliographic databases to June 2016. STUDY SELECTION: Australian studies on the aetiology of CAP in adults. DATA SYNTHESIS: In the 12 studies identified, pneumococcus was the most common cause of CAP. Four studies were assessed as being of good quality. Participants in two studies were predominantly non-Indigenous (n = 991); the proportion of pneumococcal CAP cases declined from 26.4% in 1987-88 to 13.9% in 2004-06, and the proportion with bacteraemia decreased from 7.8% to 3.8%. In two studies with predominantly Indigenous participants (n = 252), the proportion with pneumococcal bacteraemia declined from 6.8% in 1999-2000 to 4.2% in 2006-07. In the largest study (n = 885; 2004-06), 50.8% (60/118) of pneumococcal CAP occurred in people who were ≥ 65 years old. Among patients aged ≥ 65 years, intensive care unit admission and death were more common in patients who were ≥ 85 years old compared with younger patients (12.5% v 6.8%; 18.8% v 6.8% respectively), and also more common in the 19 patients with bacteraemia than in those without it (15.8% v 2.6%; 10.5% v 7.9% respectively). Of 17 cases of bacteraemia serotyped, 12 were due to 13-valent pneumococcal conjugate vaccine (13vPCV) serotypes and three to additional serotypes in 23-valent pneumococcal polysaccharide vaccine (23vPPV). CONCLUSIONS: Available data suggest that the proportion of CAP attributable to pneumococcus (both bacteraemic and non-bacteraemic) has been declining in Australian adults. Should 13vPCV replace the 23vPPV currently funded by the National Immunisation Program for persons aged ≥ 65 years, surveillance to track non-bacteraemic pneumococcal CAP will be essential to evaluate the impact.

Twelve-Month Follow-up of a Randomized Clinical Trial Comparing Intradiscal Biacuplasty to Conventional Medical Management for Discogenic Lumbar Back Pain.

Objective: This report conveys 12-month outcomes of subjects treated with intradiscal biacuplasty (IDB) and conservative medical management (CMM) for chronic low back pain of discogenic origin, and results for subjects who elected to receive IDB + CMM 6 months after CMM-alone. Methods: Sixty-three subjects were originally randomized to the IDB + CMM group (N = 29) or CMM-alone (N = 34). Six months following continuous CMM-alone treatment, participants in this study group were permitted to "cross-over" to IDB + CMM (N = 25), and followed for an additional 6 months. The original IDB + CMM study subjects were followed for a total of 12 months (N = 22). Results: Pain reduction at 12 months was statistically significant and clinically meaningful in the original IDB + CMM group compared to baseline. Functional and disability outcomes were also improved statistically and clinically. Fifty-five percent of the IDB + CMM patients responded to treatment with a mean VAS reduction of 2.2 points at 12 months. Furthermore, 50% and 64% of subjects reported clinically significant improvements in SF36-PF and in ODI, respectively. There was a 1.7-point reduction (improvement) on a 7-point PGIC scale, and a 0.13-point increase (improvement) in the EQ-5D Health Index. Fifty-percent of cross-over subjects responded to IDB + CMM intervention. Mean outcome scores for cross-over subjects were similar to those of the originally-treated subjects, and functional and disability endpoints were improved statistically and clinically compared to respective baseline values. Conclusions: The study demonstrated long-term clinical effectiveness of IDB + CMM for treating chronic lumbar discogenic pain. Furthermore, the cross-over study subjects experienced similar improvements in pain, function, disability, and satisfaction.

Feasibility study of a space-based high pulse energy 2 µm CO2 IPDA lidar.

Sustained high-quality column carbon dioxide (CO2) atmospheric measurements from space are required to improve estimates of regional and continental-scale sources and sinks of CO2. Modeling of a space-based 2 µm, high pulse energy, triple-pulse, direct detection integrated path differential absorption (IPDA) lidar was conducted to demonstrate CO2 measurement capability and to evaluate random and systematic errors. Parameters based on recent technology developments in the 2 µm laser and state-of-the-art HgCdTe (MCT) electron-initiated avalanche photodiode (e-APD) detection system were incorporated in this model. Strong absorption features of CO2 in the 2 µm region, which allows optimum lower tropospheric and near surface measurements, were used to project simultaneous measurements using two independent altitude-dependent weighting functions with the triple-pulse IPDA. Analysis of measurements over a variety of atmospheric and aerosol models using a variety of Earth's surface target and aerosol loading conditions were conducted. Water vapor (H2O) influences on CO2 measurements were assessed, including molecular interference, dry-air estimate, and line broadening. Projected performance shows a <0.35 ppm precision and a <0.3 ppm bias in low-tropospheric weighted measurements related to column CO2 optical depth for the space-based IPDA using 10 s signal averaging over the Railroad Valley (RRV) reference surface under clear and thin cloud conditions.

Trends in genital warts by socioeconomic status after the introduction of the national HPV vaccination program in Australia: analysis of national hospital data.

BACKGROUND: Human papillomavirus (HPV) vaccination targeting females 12-13 years commenced in Australia in 2007, with catch-up of females 13-26 years until the end of 2009. No analyses of HPV vaccination program impact by either socioeconomic or geographic factors have been reported for Australia. METHODS: Hospital admissions between July 2004-June 2011 involving a diagnosis of genital warts were obtained from a comprehensive national database. We compared sex- and age-specific admission rates in July 2006-June 2007 (pre-vaccination period) and July 2010-June 2011 (post-vaccination period) according to Index of Relative Socio-economic Disadvantage, nationally and stratified by remoteness area relating to the individual's area of residence, using Poisson/ negative binomial models. RESULTS: Admission rates per 100,000 population in females aged 10-19 years (predominantly vaccinated at school), reduced from 42.2 to 6.0 (rate reduction 86.7 %; 95 % CI:82.2-90.0 %) in more disadvantaged areas and from 26.8 to 4.0 (85.0 %; 95 % CI:79.7-88.9 %) in less disadvantaged areas. In females aged 20-29 years (predominantly vaccinated in the community), the decreases were from 73.9 to 26.4 (66.0 %; 95 % CI:57.7-72.6 %) and from 61.9 to 23.8 (61.6 %; 95 % CI:52.9-68.7 %) in more and less disadvantaged areas, respectively. The reductions were similar in more vs less disadvantaged areas both inside major cities (88.6 %; 95 % CI: 82.2-92.7 % vs 87.9 %; 95 % CI:82.6-91.6 % in females aged 10-19 years; 64.0 %; 95 % CI:57.0-69.9 % vs 63.8 %; 95 % CI:52.9-72.1 % for females aged 20-29 years) and outside major cities (88.8 %; 95 % CI: 83.7-92.3 % vs 85.8 %; 95 % CI:73.5-92.4 % in females aged 10-19 years; 71.1 %; 95 % CI:58.8-79.7 % vs 67.6 %; 95 % CI:48.2-79.8 % for females aged 20-29 years). Admission rates in males aged 20-29 years also reduced, by 23.0 % (95 % CI:4.8-37.8 %) and 39.4 % (95 % CI:28.9-48.3 %) in more versus less disadvantaged areas respectively. CONCLUSIONS: The relative reduction in genital warts appears similar in young females across different levels of disadvantage, including within and outside major cities, both for females predominantly vaccinated at school and in the community.

Influenza and pneumococcal vaccination in Australian adults: a systematic review of coverage and factors associated with uptake.

BACKGROUND: In the absence of an adult vaccination register, coverage estimates for influenza and pneumococcal vaccination come from surveys and other data sources. METHODS: Systematic review and meta-analysis of studies examining vaccination coverage in Australian adults from 1990 to 2015, focusing on groups funded under the National Immunisation Program, and intervals prior to and following the introduction of universal funding. RESULTS: Twenty-two studies met the inclusion criteria; 18 used self-report to determine vaccination status. There were 130 unique estimates of coverage extracted. Among adults aged ≥65y, during the period of universal funding (1999-onwards), the summary estimate of annual influenza vaccination coverage from 27 point estimates was 74.8 % (95 % CI 73.4-76.2 %; range 63.9-82.4 %); prior to this period (1992-1998) from 10 point estimates it was 61.3 % (95 % CI 58.0-64.6 %; range 44.3-71.3 %). For the period of universal funding for pneumococcal vaccination (2005-onwards) the summary estimate for coverage was 56.0 % (95 % CI 53.2-58.8 %; range 51.2-72.8 %, 10 point estimates); prior to 2005 it was 35.4 % (95 % CI 18.8-52.0 %; range 15.4-45.2 %). Coverage for both vaccines was significantly higher following the introduction of universal funding. Influenza vaccination coverage in those aged 18-65 years with a medical indication was lower but data were not combined. Seven studies reported on Aboriginal Australians with three studies reporting five coverage estimates for influenza vaccination in adults ≥65 years (range 71 % - 89 %). CONCLUSIONS: Adult influenza and pneumococcal vaccination coverage has increased since the introduction of universal funding, but remains sub-optimal, with pneumococcal coverage lower than influenza. IMPLICATIONS: This review highlights the need for more coverage data overall and in high risk groups, to support public health programs to improve coverage.

Lidar reflectance from snow at 2.05 µm wavelength as measured by the JPL Airborne Laser Absorption Spectrometer.

We report airborne measurements of lidar directional reflectance (backscatter) from land surfaces at a wavelength in the 2.05 µm CO2 absorption band, with emphasis on snow-covered surfaces in various natural environments. Lidar backscatter measurements using this instrument provide insight into the capabilities of lidar for both airborne and future global-scale CO2 measurements from low Earth orbit pertinent to the NASA Active Sensing of CO2 Emissions over Nights, Days, and Seasons mission. Lidar measurement capability is particularly useful when the use of solar scattering spectroscopy is not feasible for high-accuracy atmospheric CO2 measurements. Consequently, performance in high-latitude and winter season environments is an emphasis. Snow-covered surfaces are known to be dark in the CO2 band spectral regions. The quantitative backscatter data from these field measurements help to elucidate the range of backscatter values that can be expected in natural environments.

A wearable wound moisture sensor as an indicator for wound dressing change: an observational study of wound moisture and status.

Wound moisture is known to be a key parameter to ensure optimum healing conditions in wound care. This study tests the moisture content of wounds in normal practice in order to observe the moisture condition of the wound at the point of dressing change. This study is also the first large-scale observational study that investigates wound moisture status at dressing change. The WoundSense sensor is a commercially available moisture sensor which sits directly on the wound in order to find the moisture status of the wound without disturbing or removing the dressing. The results show that of the 588 dressing changes recorded, 44·9% were made when the moisture reading was in the optimum moisture zone. Of the 30 patients recruited for this study, 11 patients had an optimum moisture reading for at least 50% of the measurements before dressing change. These results suggest that a large number of unnecessary dressing changes are being made. This is a significant finding of the study as it suggests that the protocols currently followed can be modified to allow fewer dressing changes and less disturbance of the healing wound bed.

Fall in genital warts diagnoses in the general and indigenous Australian population following implementation of a national human papillomavirus vaccination program: analysis of routinely collected national hospital data.

BACKGROUND: Human papillomavirus (HPV) vaccination targeting females aged 12-13 years commenced in Australia in 2007, with catch-up vaccination of females aged 13-26 years continuing to 2009. Whole-population analyses, including effects on the Indigenous population, have not previously been reported. METHODS: All hospital admissions between 1999-2011 involving a diagnosis of genital warts were obtained from a comprehensive national database. We compared the age-specific rates before to those after implementation of the vaccination program, according to sex and other characteristics. RESULTS: Admission rates decreased from mid-2007 in females aged 12-17 years (annual decline, 44.1% [95% confidence interval {CI}, 35.4%-51.6%]) and from mid-2008 in females and males aged 18-26 years (annual declines, 31.8% [95% CI, 28.4%-35.2%] and 14.0% [95% CI, 5.1%-22.1%], respectively). The overall reductions from 2006-2007 to 2010-2011 were 89.9% (95% CI, 84.4%-93.4%) for females aged 12-17 years, 72.7% (95% CI, 67.0%-77.5%) for females aged 18-26 years, and 38.3% (95% CI, 27.7%-47.2%) for males aged 18-26 years. Compared with the average annual number before program implementation, about 1000 fewer hospital admissions involved a warts diagnosis during 2010-2011. Reductions after program implementation were similar for Indigenous (86.7% [95% CI, 76.0-92.7]) and non-Indigenous (76.1% [95% CI, 71.6%-79.9%]) females aged 15-24 years (P(heterogeneity) = .08). CONCLUSIONS: National population-based hospital data confirm previous clinic-based reports of a marked decline in genital warts diagnoses among young people in Australia after program implementation, including indirect benefits to males. The impact of HPV vaccination appears to be similar in young Indigenous and non-Indigenous females.

Pneumonia in Elderly Australians: Reduction in Presumptive Pneumococcal Hospitalizations but No Change in All-Cause Pneumonia Hospitalizations Following 7-Valent Pneumococcal Conjugate Vaccination.

BACKGROUND: Studies evaluating long-term trends in hospitalizations coded as pneumonia following introduction of the 7-valent pneumococcal vaccine (PCV7) are sparse, especially in adults. We extended our previous analysis to 6.5 years after the "3 + 0" PCV7 schedule was introduced in Australia in 2005. METHODS: We estimated vaccine impact on hospitalizations coded as pneumonia (pneumococcal/lobar, other specified, unspecified, and all-cause) using a multivariate negative binomial regression model of monthly hospitalization rates by age group for the pre-PCV7 (July 1998 to December 2004) and post-PCV7 (January 2005 to June 2011) periods, adjusting for vaccination coverage. Changes in pneumonia hospitalizations were measured as incidence rate ratios. RESULTS: A total of 791 000 hospitalizations coded as pneumonia were identified; unspecified causes accounted for >85%. Reductions in pneumonia coded as pneumococcal/lobar were statistically significant in all age groups and greatest in children. Significant reductions in all-cause pneumonia were seen only in children aged <2 years (32%; 95% confidence interval [CI], 28%-37%) and 2-4 years (20%; 95% CI, 14%-27%), with no significant changes in other age groups, including adults aged 65-74 (4%; 95% CI, -3% to 10%), 75-84 (2%; 95% CI, -4% to 9%), and ≥85 years (3%; 95% CI, -3% to 10%). CONCLUSIONS: We could not replicate reductions of 23% in all-cause pneumonia 7-9 years post-PCV7 introduction reported for adults aged ≥85 years in the United States. This could be attributable to vaccine program factors, differing proportions of pneumonia due to pneumococci, or data limitations. More data from countries with differing PCV schedules and from the PCV13 era are needed to inform vaccination strategies for elderly adults.

Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats.

Chronic activation of the renin-angiotensin system promotes hypertension, renal microvascular dysfunction, tissue hypoxia, and inflammation. Despite similar hypertension, an injurious response to excess angiotensin II is greater in F344 than in Lewis rats; the latter displaying renoprotection. Here we studied whether p2rx7, encoding the P2X7 receptor (P2X7R), is a candidate gene for the differential susceptibility to vascular dysfunction under high angiotensin II tone. A 14-day infusion of angiotensin II into F344 rats increased blood pressure by about 15 mm Hg without inducing fibrosis or albuminuria. In vivo pressure natriuresis was suppressed, medullary perfusion reduced by half, and the corticomedullary oxygenation gradient disrupted. Selective P2X7R antagonism restored pressure natriuresis, promoting a significant leftward shift in the intercept and increasing the slope. Sodium excretion was increased sixfold and blood pressure normalized. The specific P2X7R antagonist AZ11657312 increased renal medullary perfusion, but only in angiotensin II-treated rats. Tissue oxygenation was improved by P2X7R blockade, particularly in poorly oxygenated regions of the kidney. Thus, activation of P2X7R induces microvascular dysfunction and regional hypoxia when angiotensin II is elevated and these effects may contribute to progression of renal injury induced by chronic angiotensin II.

Estimating vaccine coverage from serial trivariate serologic data in the presence of waning immunity.

INTRODUCTION: Vaccine coverage data are typically collected through vaccine registers and retrospective surveys. Alternatively, cross-sectional serosurveys enable direct estimation of vaccine coverage from antibody prevalence by exploiting correlated seropositivity for multi-antigen vaccines. Here, we extend previous methods by accounting for temporal antibody decline in estimating vaccine coverage for measles-mumps-rubella vaccine using serial serosurvey data. METHODS: We introduce a Markovian cohort model of antibody waning and boosting applied to dichotomous seropositivity data for measles, mumps, and rubella. Simulation studies are used to test model identifiability and to explore bias induced by previous methods that ignore waning. The cohort model is then fitted to three Australian serosurveys, entailing estimates of vaccine coverage from routine and catch-up vaccination as well as waning rates for each antigen. RESULTS: The simulation results show that the cohort model is identifiable and qualitatively captures the decline in seropositivity observed in older children. When fitted to all three Australian surveys, the estimated seroconversion and waning parameters are similar to estimates based on recent meta-analyses, whereas the coverage estimates appear consistent with previous Australian survey-based estimates. DISCUSSION: We show that previous methods of estimating coverage from serological data can be improved by fitting a cohort model with waning and boosting processes to serial serosurvey data, furthermore yielding estimates of more parameters of interest such as rates of waning. In settings where serial serosurvey data is available, our method could be duplicated or applied to related questions such as coverage in routine two-dose schedules or from other combination vaccines.

Sensor-Based Interactive Balance Training with Visual Joint Movement Feedback for Improving Postural Stability in Diabetics with Peripheral Neuropathy: A Randomized Controlled Trial.

BACKGROUND: Individuals with diabetic peripheral neuropathy (DPN) have deficits in sensory and motor skills leading to inadequate proprioceptive feedback, impaired postural balance and higher fall risk. OBJECTIVE: This study investigated the effect of sensor-based interactive balance training on postural stability and daily physical activity in older adults with diabetes. METHODS: Thirty-nine older adults with DPN were enrolled (age 63.7 ± 8.2 years, BMI 30.6 ± 6, 54% females) and randomized to either an intervention (IG) or a control (CG) group. The IG received sensor-based interactive exercise training tailored for people with diabetes (twice a week for 4 weeks). The exercises focused on shifting weight and crossing virtual obstacles. Body-worn sensors were implemented to acquire kinematic data and provide real-time joint visual feedback during the training. Outcome measurements included changes in center of mass (CoM) sway, ankle and hip joint sway measured during a balance test while the eyes were open and closed at baseline and after the intervention. Daily physical activities were also measured during a 48-hour period at baseline and at follow-up. Analysis of covariance was performed for the post-training outcome comparison. RESULTS: Compared with the CG, the patients in the IG showed a significantly reduced CoM sway (58.31%; p = 0.009), ankle sway (62.7%; p = 0.008) and hip joint sway (72.4%; p = 0.017) during the balance test with open eyes. The ankle sway was also significantly reduced in the IG group (58.8%; p = 0.037) during measurements while the eyes were closed. The number of steps walked showed a substantial but nonsignificant increase (+27.68%; p = 0.064) in the IG following training. CONCLUSION: The results of this randomized controlled trial demonstrate that people with DPN can significantly improve their postural balance with diabetes-specific, tailored, sensor-based exercise training. The results promote the use of wearable technology in exercise training; however, future studies comparing this technology with commercially available systems are required to evaluate the benefit of interactive visual joint movement feedback.