Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

24 h Holter ECG Monitoring of Patients with Rheumatoid Arthritis—A Potential Role for a Precise Evaluation of QT Interval Duration and Associated Arrhythmic Complications

Background: Patients with rheumatoid arthritis (RA) have increased systemic inflammatory burden associated with elevated cardiovascular mortality. Prolonged ventricular repolarisation evaluated by QT interval duration is a risk factor for cardiovascular and total mortality. In RA, mortality risk is correlated with dynamics and cumulative incidence of QTc prolongation rather than QTc value. The aim is to evaluate if QT parameters evaluated with 24 h Holter ECG are a better option to complete the cardiovascular profile of RA patients than parameters from short ECG recordings. Materials and methods: A total of 58 patients (22 males, 36 females) with RA were submitted to short ECG recordings at admission and to 24 h Holter ECG. QT interval parameters and ventricular ectopy generated from both types of recordings were analyzed. Results: QTc interval values obtained from Holter ECG were significantly higher than the values from short term ECG and were correlated with severity of inflammatory process. The number of QRS complexes with QTc > 450 ms recorded during 24 h Holter was strongly correlated with the number of ventricular events and severity of the inflammatory process. Conclusions: In patients with RA, the Holter ECG recordings could realize a more precise evaluation of the extent and dynamics of QTc interval duration and of ventricular ectopic events with potential risk of sudden death

Overview of the Success of In Vitro Culture for Ex Situ Conservation and Sustainable Utilization of Endemic and Subendemic Native Plants of Romania

Romania has a relatively high diversity of plant species, including 3829 vascular and 979 non-vascular spontaneous plant taxa (species and subspecies). Due to uncontrolled harvesting as well as other causes, including climate change and ecological collapse, the speed of species extinction and the narrowing of the genetic base of plant resources has been reported as a critical issue. Therefore, the national Red List of Romanian flora includes 1453 threatened taxa, of which 95 are endemic and 90 subendemic. Many of these have high ornamental, medicinal–cosmetic, and/or aromatic properties. The high extinction risk of these valuable plants has stimulated both the reconsideration of their vital importance as genetic resources and interest in finding effective methods for conservation. Cultivating these phytogenetic resources in a human-controlled environment is of high importance for effective ex situ conservation, which can further serve sustainable exploitation needs and may facilitate in situ conservation actions. In vitro culture is a powerful tool for producing elite plants for cultivation for different purposes. This review summarizes the current knowledge on in vitro multiplication of 22 endemic and subendemic native plants of Romania, examining the materials used, the treatments applied, and the results obtained in each stage of the micropropagation protocol (culture initiation, proliferation, rooting, and acclimatization). The findings from the reviewed studies are presented in a comparative way, and the potential of plant tissue culture in conservation and sustainable exploitation of these Romanian species is outlined

Nailfold Videocapillaroscopy in Patients with Rheumatoid Arthritis and Psoriatic Arthropathy on ANTI-TNF-ALPHA Therapy

Videocapillaroscopy is a simple, non-invasive investigation that allows the “in vivo” study of the nailfold capillaries. This method is inexpensive, easily accepted by patients and the results can be easily interpreted. It is mainly used in patients with Raynaud’s phenomenon and systemic sclerosis, but this examination can also be performed on patients who are suspected of having microcirculation alterations, such as rheumatoid arthritis and psoriatic arthritis. It may aid in the diagnosis, evaluation and prognosis of other rheumatic diseases, besides systemic sclerosis. The aim of this study is to identify the nailfold videocapillaroscopic abnormalities in rheumatoid arthritis and psoriatic arthritis patients and analyze the correlation between their evolution and 12 months of anti-TNF-α therapy. The abnormal capillaroscopic findings comprised widened, dilated or giant capillaries and the distortion of the normal nailfold architecture, avascular areas, hemorrhages and neoangiogenesis. Overall, capillary density, dilated capillaries, giant capillaries, elongated capillaries and angiogenesis significantly improved after 12 months. Moreover, no avascular areas were found after 12 months of anti-TNF treatment

ULTRASONOGRAPHIC SALIVARY GLAND RESPONSE TO RITUXIMAB IN SECONDARY SJÖ GREN’S SYNDROME

B cell hyper-reactivity implied in the pathogenesis of Sjö gren’s syndrome (SS) justifies the therapy that involves B cell depletion. Ultrasound of salivary glands demonstrated alterations during disease progression. Objective. To evaluate changes in salivary gland parenchyma with ultrasound after rituximab treatment in patients’ with secondary SS (sSS). Methods. 7 patients evaluated at baseline (under treatment with rituximab) and after 6 months, underwent ultrasonography of major salivary gland (submandibular and parotid). Clinical data as dryness, pain and diseases activity evaluated with ESSDAI were registered. Salivary gland ultrasound (SGUS) was performed to asses echogenity (using a semiquantitative score from 0-4, with improvement defined as an at least 1 point decrease), size of gland and glandular borders. Results. Of 7 patients, 14% had clinically detectable bilateral parotid tumefaction at baseline. 6 patients (85.71%) showed ultrasonographic alterations at baseline. Parotid parenchyma echostructure improved in 42.85% of patients versus 14.28% in control group (p=0.05). At the submandibular glands, both submandibular glands showed changes in 28.57% of patients, while control group showed no changes. 42.85% patients showed parotid tumefaction which changed in 66.6% of patients at 6 months. Conclusion. Ultrasonography showed improvement in salivary gland echostructure in secondary Sjogren Syndrome with rituximab

THE ROLE OF NAILFOLD CAPILLAROSCOPY IN MONITORING LUNG INVOLVEMENT IN SYSTEMIC SCLEROSIS

The usefulness of capillaroscopy in the follow-up of scleroderma patients and the possible prognostic role for the appearance of visceral involvement is suggested by many authors but still under debate.The aim of this study was to assess the role of monitoring capillaroscopic abnormalities (qualitative and semiquantitative) in relation with parameters of interstitial lung involvement and pulmonary arterial hypertension(PAH). A strong correlation was identified between initial capillaroscopy scores and FVC (r=-.47, p=0.002), DLCO (r=- .51, p< 0.001) and sPAP (r=0.34, p<0.001). Active and late capillaroscopic pattern were correlated with diagnosis of lung fibrosis (χ2=14, p=0.007) and PAH at follow-up examinations (χ2=14,2, p=0.007). Progression of capillaroscopic pattern at follow-up evaluations was not correlated with significant worsening of lung volumes, DLCO, sPAP. Instead, progression of microangiopathy evolution score (>1) was asociated with worsening of FVC (r=0.32,p<0.001), DLCO(r=0.21,p=0.02) and new diagnosis of lung fibrosis on HRCT (r=0,19,p=0.035). Semiquantitative scoring, rather then qualitative capillaroscopic assessment can have a predictive role for new involvement or worsening of previous lung involvement (especially interstitial lung disease) in scleroderma patients, confirming the putative role of capillaroscopy as biomarker in SSc

GENERAL CHARACTERISTICS AND FAMILIAL AGGREGATION IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies, which deposit within tissues and fix complement leading to systemic inflammation (1). Is a heterogeneous disease with a continuum of disease activity. Some patients can have predominant skin and joint involvement, whereas others can present with organ-threatening diseases such as nephritis, cardiac involvement or even neurologic manifestations. Relatives of patients with SLE appear to be at higher risk of SLE and other autoimmune diseases, but estimates of individual familial risks are largely unavailable or unreliable (2,3)

EVIDENCE FOR FAMILIAL AGGREGATION IN SIBLINGS WITH AUTOIMMUNE RHEUMATIC DISEASES

Autoimmune rheumatic disorders have a multifactorial determinism, caused by various environmental factors acting on the individual’s genetic susceptibility, destabilizing the systems which regulate the immune response. Epidemiological and genetic investigations are very important to demonstrate the contribution of genetic factors to the development of these autoimmune diseases. The contribution of genetic factors in causing autoimmune diseases has been demonstrated by familial aggregation. Moreover, it was also quantified by determining heritability, expressing the proportion of genetic factors in the etiology. It is now clear that common genes underlie multiple autoimmune disorders