The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction.
Renal function is frequently impaired in patients ...with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin–angiotensin system.
In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR.
At screening, the eGFR was 70 ± 20 ml/min/1.73 m2 and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range IQR: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (−1.61 ml/min/1.73 m2/year; 95% confidence interval: −1.77 to −1.44 ml/min/1.73 m2/year vs. −2.04 ml/min/1.73 m2/year 95% CI: −2.21 to −1.88 ml/min/1.73 m2/year ; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol 95% CI: 1.04 to 1.36 mg/mmol vs. 0.90 mg/mmol 95% CI: 0.77 to 1.03 mg/mmol; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38).
Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.
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Civil Islam Hefner, Robert W; Hefner, Robert W
2011., 20110521, 2011, 2000, 2000-01-01, Letnik:
9
eBook
Civil Islam tells the story of Islam and democratization in Indonesia, the world's largest Muslim nation. Challenging stereotypes of Islam as antagonistic to democracy, this study of courage and ...reformation in the face of state terror suggests possibilities for democracy in the Muslim world and beyond.
CONTEXT Rates of obesity and other childhood chronic conditions have increased over recent decades. Patterns of how conditions change over time have not been widely examined. OBJECTIVE To evaluate ...change in prevalence of obesity and other chronic conditions in US children, including incidence, remission, and prevalence. DESIGN, SETTING, AND PARTICIPANTS Prospective study using the National Longitudinal Survey of Youth–Child Cohort (1988-2006) of 3 nationally representative cohorts of children. Children were aged 2 through 8 years at the beginning of each study period, and cohorts were followed up for 6 years, from 1988 to 1994 (cohort 1, n = 2337), 1994 to 2000 (cohort 2, n = 1759), and 2000 to 2006 (n = 905). MAIN OUTCOME MEASURES Parent report of a child having a health condition that limited activities or schooling or required medicine, special equipment, or specialized health services and that lasted at least 12 months. Obesity was defined as a body mass index at or above the 95th percentile for age. Chronic conditions were grouped into 4 categories: obesity, asthma, other physical conditions, and behavior/learning problems. RESULTS The end-study prevalence of any chronic health condition was 12.8% (95% confidence interval CI, 11.2%-14.5%) for cohort 1 in 1994, 25.1% (95% CI, 22.7%-27.6%) for cohort 2 in 2000, and 26.6% (95% CI, 23.5%-29.9%) for cohort 3 in 2006. There was substantial turnover in chronic conditions: 7.4% (95% CI, 6.5%-8.3%) of participants in all cohorts had a chronic condition at the beginning of the study that persisted to the end, 9.3% (95% CI, 8.3%-10.3%) reported conditions at the beginning that resolved within 6 years, and 13.4% (95% CI, 12.3%-14.6%) had new conditions that arose during the 6-year study period. The prevalence of having a chronic condition during any part of the 6-year study period was highest for cohort 3 (51.5%; 95% CI, 47.3%-55.0%), and there were higher rates among male (adjusted odds ratio AOR, 1.24; 95% CI, 1.07-1.42), Hispanic (AOR, 1.36; 95% CI, 1.11-1.67), and black (AOR, 1.60; 95% CI, 1.35-1.90) youth. CONCLUSIONS Prevalence of chronic conditions among children and youth increased from 1988 to 2006. However, presence of these conditions was dynamic over each 6-year cohort.
Didattiche orientate all'intercomprensione tra lingue romanze dimostrano che, incoraggiando specifiche pragmatiche traduttive, è possibile raggiungere un obiettivo: in un circuito di parlanti lingue ...romanze, ogni discente può arrivare a parlare la propria lingua sapendo di essere compreso dagli interlocutori, soprattutto su argomenti di interesse comune. Ispirandoci a queste teorie che valorizzano concetti noti da secoli, riflettiamo su quali pragmatiche, a un tempo traduttive e politico-culturali, Raízes do Brasil abbia incoraggiato nel 1936 prendendo come asse il bilinguismo luso-ispano-americano, per favorire l'intercomprensione su una condividenda idea di América Latina. Altre quattro edizioni di Raízes do Brasil continueranno, con dati aggiornati, a ‘parlare in portoghese’ fino al 1969 sia con lusofoni/ispanofoni sia con una serie di altri teorici interlocutori fra i quali, dagli argomenti evidenziati sin dall'editio princeps, si riconosce l’italofono. Si enunciano pertanto alcuni nuclei di una ricerca sui riscontri che documentano la varietà dei processi inferenziali riconoscibili in due profili di lettori, i lusofoni/ispanofoni e quelli di altri background: lettori invitati a cooperare in quel processo di risemantizzazione del frame América Latina onde evitare che venisse inquinato da ideologie dittatoriali provenienti dall'Europa. Continuando a ‘parlare’ contro le dittature – in un portoghese classico che qualsiasi ispanoamericano e italofono poteva deverbalizzare direttamente nell'atto lettorio – la storia redazionale/editoriale del saggio coinciderà con un tempo sufficientemente lungo affinché la risemantizzazione del frame América Latina basata sui portati culturali veicolati dal bilinguismo luso/ispano-americano si affermasse. Di quell’incessante reframing di América Latina si avrà riscontro nella Constituição del 1988 che restituirà al Brasile la democrazia, ponendo al contempo le basi per il MercoSul/Sur le cui lingue ufficiali saranno ovviamente il portoghese e lo spagnolo.
Inflammation has been implicated in the pathogenesis of Parkinson's disease (PD). We here investigate levels of inflammatory biomarkers in cerebrospinal fluid (CSF) in PD and atypical parkinsonian ...disorders (APD) compared with neurologically healthy controls. We included 131 patients with PD and 27 PD with dementia (PDD), 24 with multiple system atrophy (MSA), 14 with progressive supranuclear palsy (PSP) and 50 controls, all part of the Swedish BioFINDER study. CSF was analyzed for CRP, SAA, IL-6, IL-8, YKL-40 and MCP-1 (CCL2) as well as α-synuclein (α-syn), tau, tau phosphorylated at Thr181 (P-tau), Aβ
and NfL. In this exploratory study, we found higher levels of the inflammatory biomarker SAA in PDD and MSA compared with controls and PD and higher levels of CRP in PDD and MSA compared with PD. YKL-40 was lower in PD compared with controls. There were multiple positive correlations between the inflammatory markers, α-syn and markers of neuroaxonal injury (NfL and tau). In PD, higher levels of inflammatory biomarkers correlated with worse motor function and cognitive impairment. Thus, inflammatory biomarkers were increased in PDD and MSA. Furthermore, inflammatory biomarkers correlated with more severe disease regarding motor symptoms and cognitive impairment in PD, indicating an association between inflammation and more aggressive disease course. However, the results need confirmation in follow-up studies.
We provide the first detailed analysis of the carbonaceous chondrite Dhofar (Dho) 1988. This meteorite find was recovered in 2011 from the Zufar desert region of Oman and initially classified as a C2 ...ungrouped chondrite. Dho 1988 is a monomict breccia composed of millimetre-sized clasts, between which large (∼50–250 µm) intermixed sulphide-Ca-carbonate veins formed. It has high sulphide abundances (∼14 vol%), medium-sized chondrules (avg. 530 µm, N = 33), relatively low chondrule/CAI abundances (<20 area%), a heavy bulk O-isotope composition (δ17O = 9.12‰, δ18O = 19.46‰) and an aqueously altered and then dehydrated alteration history. These characteristics are consistent with the newly defined Yamato-type (CY) carbonaceous chondrite group, suggesting this meteorite should be reclassified as a CY chondrite.
Dho 1988 experienced advanced aqueous alteration petrologic subtype 1.3 in the scheme of Howard et al. (2015). Alteration style and extent are similar to the CM chondrite group, with the matrix having been replaced by tochilinite-cronstedtite intergrowths and chondrules progressively pseudomorphed by phyllosilicates, sulphides and in one instance Ca-carbonates. However, departures from CM-like alteration include the replacement of chondrule cores with Al-rich, Na-saponite and upon which Cr-spinel and Mg-ilmenite grains precipitated. These late-stage aqueous alteration features are common among the CY chondrites. Fractures in Dho 1988 that are infilled by phyllosilicates, sulphides and carbonates attest to post-brecciation aqueous alteration. However, whether aqueous alteration was also active prior to brecciation remains unclear. Veins are polymineralic with a layered structure, allowing their relative chronology to be reconstructed: intermixed phyllosilicate-sulphide growth transitioned to sulphide-carbonate deposition. We estimate temperatures during aqueous alteration to have been between 110 °C < T < 160 °C, based on the co-formation of Na-saponite and tochilinite.
Dho 1988 was later overprinted by thermal metamorphism. Peak temperatures are estimated between 700 °C and 770 °C, based on the thermal decomposition of phyllosilicates (both serpentine and saponite) combined with the survival of calcite. As temperatures rose during metamorphism the thermal decomposition of pyrrhotite produced troilite. Sulphur gas was liberated in this reaction and flowed through the chondrite reacting with magnetite (previously formed during aqueous alteration) to form a second generation of troilite grains. The presence of both troilite and Ni-rich metal in Dho 1988 (and other CY chondrites) demonstrate that conditions were constrained at the iron-troilite buffer.
Summary Background National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective ...medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015. Methods We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure–the Healthcare Quality and Access (HAQ) Index–on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r=0·88), an index of 11 universal health coverage interventions ( r =0·83), and human resources for health per 1000 ( r =0·77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time. Findings Between 1990 and 2015, nearly all countries and territories saw their HAQ Index values improve; nonetheless, the difference between the highest and lowest observed HAQ Index was larger in 2015 than in 1990, ranging from 28·6 to 94·6. Of 195 geographies, 167 had statistically significant increases in HAQ Index levels since 1990, with South Korea, Turkey, Peru, China, and the Maldives recording among the largest gains by 2015. Performance on the HAQ Index and individual causes showed distinct patterns by region and level of development, yet substantial heterogeneities emerged for several causes, including cancers in highest-SDI countries; chronic kidney disease, diabetes, diarrhoeal diseases, and lower respiratory infections among middle-SDI countries; and measles and tetanus among lowest-SDI countries. While the global HAQ Index average rose from 40·7 (95% uncertainty interval, 39·0–42·8) in 1990 to 53·7 (52·2–55·4) in 2015, far less progress occurred in narrowing the gap between observed HAQ Index values and maximum levels achieved; at the global level, the difference between the observed and frontier HAQ Index only decreased from 21·2 in 1990 to 20·1 in 2015. If every country and territory had achieved the highest observed HAQ Index by their corresponding level of SDI, the global average would have been 73·8 in 2015. Several countries, particularly in eastern and western sub-Saharan Africa, reached HAQ Index values similar to or beyond their development levels, whereas others, namely in southern sub-Saharan Africa, the Middle East, and south Asia, lagged behind what geographies of similar development attained between 1990 and 2015. Interpretation This novel extension of the GBD Study shows the untapped potential for personal health-care access and quality improvement across the development spectrum. Amid substantive advances in personal health care at the national level, heterogeneous patterns for individual causes in given countries or territories suggest that few places have consistently achieved optimal health-care access and quality across health-system functions and therapeutic areas. This is especially evident in middle-SDI countries, many of which have recently undergone or are currently experiencing epidemiological transitions. The HAQ Index, if paired with other measures of health-system characteristics such as intervention coverage, could provide a robust avenue for tracking progress on universal health coverage and identifying local priorities for strengthening personal health-care quality and access throughout the world. Funding Bill & Melinda Gates Foundation.
Hypoglycaemia (low plasma glucose) is a serious and potentially fatal complication of insulin-treated diabetes. In healthy individuals, hypoglycaemia triggers glucagon secretion, which restores ...normal plasma glucose levels by stimulation of hepatic glucose production. This counterregulatory mechanism is impaired in diabetes. Here we show in mice that therapeutic concentrations of insulin inhibit glucagon secretion by an indirect (paracrine) mechanism mediated by stimulation of intra-islet somatostatin release. Insulin's capacity to inhibit glucagon secretion is lost following genetic ablation of insulin receptors in the somatostatin-secreting δ-cells, when insulin-induced somatostatin secretion is suppressed by dapagliflozin (an inhibitor of sodium-glucose co-tranporter-2; SGLT2) or when the action of secreted somatostatin is prevented by somatostatin receptor (SSTR) antagonists. Administration of these compounds in vivo antagonises insulin's hypoglycaemic effect. We extend these data to isolated human islets. We propose that SSTR or SGLT2 antagonists should be considered as adjuncts to insulin in diabetes therapy.
•Natural experiment of post-fire understory successional development over ~30 years.•Study examined effects of soil moisture regime and developing tree canopies.•Early understory composition ...reflected differences in soil moisture regime.•After three decades, understory composition was related more to canopy closure.•Limited tree canopy development may expose seral understories to climate warming.
Subalpine coniferous forests are adapted to cycles of fire and successional development, but increasing fire frequency and severity are altering historical stand structure, composition, and plant diversity. For instance, conifer regeneration has become increasingly variable as a result of prolonged aridity following fire, but the potential cascading effects on understory community development remain virtually unexplored. We used a natural experiment to investigate the relationships among understory plant succession, soil moisture regime, and variable tree canopy development over 30 years following the 1988 fires in the Greater Yellowstone Ecosystem, U.S.A. In 1990, at each of two study areas, plots were established in different site types defined by burn status (burned or unburned) and soil moisture regime (mesic or xeric), determined using biophysical indicators. We asked: (1) Are differences in soil moisture regime associated with differences in understory community composition (species richness, diversity, and functional group representation) during the first three decades after fire? (2) Does the relationship between soil moisture regime and community composition change over time as subcanopy (height >137 cm) tree densities increase? We confirmed our original designations of soil moisture regime using in situ measurements of soil moisture. Over the first decade of succession, species richness and diversity were lower in xeric-burned than in mesic-burned plots. Nearly 30 years after fire at the south-aspect study area, where subcanopy tree densities were low, seral understories diverged by soil moisture regime. There, graminoid cover was 23-fold higher, and forb cover was 3-fold lower, in xeric-burned than in mesic-burned plots. In contrast, in the mixed aspect study area, subcanopy tree densities were markedly higher. There, the understory did not vary by soil moisture regime, converging successionally and becoming more similar to unburned forest communities. Our results suggest that site-specific soil moisture regimes structure the early trajectory of post-fire understory recovery, but the relationship diminishes as tree canopies develop over time. However, under a warming climate, variable tree canopy development may compound increasing aridity, particularly on xeric sites, resulting in decreases in plant diversity and forb cover, increases in graminoid cover, and the potential for altered successional dynamics.
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