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

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Fatores relacionados à Duração do Tratamento Ortodôntico no Programa de Graduação em Ortodontia

Introduction: To establish the relationship between orthodontic treatment time with educational/administrative/clinical factors, in patients treated and finished, at the orthodontics program clinic of an University. Methods: Data were obtained from clinical records, panoramic radiographs and final dental cast from 40 treated patients (21 women and 19 men), 15.97 ± 5.79 years old. The administrative variables included:  number of accomplished appointments, number of appointments per year of treatment, total number of missed appointments, total months of treatment, number of effective months of treatment, number of residents and instructors attending the patients and percentage of treatment planning for next appointment. Clinical variables included: malocclusion complexity, quality of finalization, teeth extractions, age and number of orthodontic appliance issues/breakages. Results: The average ± SD treatment duration was 55.5 ± 22.2 months. In patients with dental extractions, treatment time was significantly higher (p=0.0231). A model of multiple linear regression explained 59% of the variability, identifying four significant variables, two related to administration (number of missed appointments and number of instructors) and two clinical variables (number of orthodontic appliance issues/breakages and quality of finalization). Conclusion: Significant clinical and administrative issues were detected and it was observed that excessive time for treatment may deteriorate the static clinical results achieved.Introducción: Este estudio observacional de corte transversal fue  realizado con el fin de determinar el tiempo de tratamiento y los factores que pueden afectarlo en los pacientes finalizados en el programa de posgrado de ortodoncia de la Universidad de Antioquia. Métodos: Los datos fueron obtenidos de las historias clínicas, radiografías panorámicas y modelos finales de 40 pacientes (21 mujeres y 19 hombres) con edad promedio de  15.97 años (± 5.79), que cumplieron los criterios de selección. Se estudiaron variables administrativas como  número de citas cumplidas en total, numero de citas cumplidas por año de tratamiento, numero de citas incumplidas en total,  numero de meses  totales de tratamiento, numero de meses efectivos de tratamiento, número de docentes, número de residentes que atendieron a los pacientes y porcentaje de planeación de cita y variables clínicas como edad, complejidad de la maloclusión, calidad de la finalización del tratamiento, exodoncias y numero de reparaciones. Resultados: Se encontró un  tiempo promedio de tratamiento de 55.5 meses (± 22.2). El tiempo de tratamiento en los pacientes con exodoncias fue significativamente mayor (p=0.0231) comparado con los que no se les realizaron exodoncias. Un modelo de regresión lineal múltiple explico el 59% de la variabilidad e identifico cuatro variables significativas, dos administrativas (número de citas incumplidas y número de docentes) y dos clínicas (número de reparaciones y calidad de finalización). Conclusiones: Algunos factores administrativos y clínicos afectan el tiempo de tratamiento de manera significativa y el alargar excesivamente el tiempo de tratamiento, puede empeorar los resultados clínicos estáticos obtenidos.Introdução: Estabelecer a relação entre a duração do tratamento ortodôntico e osfatores educacionais/administrativos/clínicos em pacientes tratados e finalizados na clínicade ortodontia da universidade. Métodos: Dados foram obtidos a partir de registros clínicos,radiografias panorâmicas e modelagens dentárias finais de 40 pacientes tratados (21mulheres e 19 homens), de 15,97 ± 5,79 anos. Variáveis administrativas incluíram númerode consultas atendidas, número de consultas por ano de tratamento, número total de consultas perdidas, total de meses de tratamento, número de meses efetivos de tratamento, número de residentes e instrutores atendendo aos pacientes e percentual de planejamento de tratamento para a próxima consulta. Variáveis clínicas incluíram a complexidade da maloclusão, a qualidade da finalização, extrações dentárias, idade e número de problemas e quebras de aplicações ortodônticas. Resultados: A média de duração do tratamento era de 55,5 ± 22,2 meses. Em pacientes com extrações dentárias, a duração do tratamento era significativamente mais longa (p=0,0231). Um modelo de regressão linear múltipla explicou 59% da variabilidade, identificando quatro variáveis significativas, duas relacionadas à administração (número de consultas perdidas e números de instrutores) e duas variáveis clínicas (número de problemas e quebras de aplicações ortodônticas e qualidade da finalização). Conclusão: Questões clínicas e administrativas significativas foram detectadas efoi observado que o tempo excessivo de tratamento pode deteriorar os resultados clínicosestáticos alcançados

Fatores relacionados à Duração do Tratamento Ortodôntico no Programa de Graduação em Ortodontia

Introduction: To establish the relationship between orthodontic treatment time with educational/administrative/clinical factors, in patients treated and finished, at the orthodontics program clinic of an University. Methods: Data were obtained from clinical records, panoramic radiographs and final dental cast from 40 treated patients (21 women and 19 men), 15.97 ± 5.79 years old. The administrative variables included:  number of accomplished appointments, number of appointments per year of treatment, total number of missed appointments, total months of treatment, number of effective months of treatment, number of residents and instructors attending the patients and percentage of treatment planning for next appointment. Clinical variables included: malocclusion complexity, quality of finalization, teeth extractions, age and number of orthodontic appliance issues/breakages. Results: The average ± SD treatment duration was 55.5 ± 22.2 months. In patients with dental extractions, treatment time was significantly higher (p=0.0231). A model of multiple linear regression explained 59% of the variability, identifying four significant variables, two related to administration (number of missed appointments and number of instructors) and two clinical variables (number of orthodontic appliance issues/breakages and quality of finalization). Conclusion: Significant clinical and administrative issues were detected and it was observed that excessive time for treatment may deteriorate the static clinical results achieved.Introducción: Este estudio observacional de corte transversal fue  realizado con el fin de determinar el tiempo de tratamiento y los factores que pueden afectarlo en los pacientes finalizados en el programa de posgrado de ortodoncia de la Universidad de Antioquia. Métodos: Los datos fueron obtenidos de las historias clínicas, radiografías panorámicas y modelos finales de 40 pacientes (21 mujeres y 19 hombres) con edad promedio de  15.97 años (± 5.79), que cumplieron los criterios de selección. Se estudiaron variables administrativas como  número de citas cumplidas en total, numero de citas cumplidas por año de tratamiento, numero de citas incumplidas en total,  numero de meses  totales de tratamiento, numero de meses efectivos de tratamiento, número de docentes, número de residentes que atendieron a los pacientes y porcentaje de planeación de cita y variables clínicas como edad, complejidad de la maloclusión, calidad de la finalización del tratamiento, exodoncias y numero de reparaciones. Resultados: Se encontró un  tiempo promedio de tratamiento de 55.5 meses (± 22.2). El tiempo de tratamiento en los pacientes con exodoncias fue significativamente mayor (p=0.0231) comparado con los que no se les realizaron exodoncias. Un modelo de regresión lineal múltiple explico el 59% de la variabilidad e identifico cuatro variables significativas, dos administrativas (número de citas incumplidas y número de docentes) y dos clínicas (número de reparaciones y calidad de finalización). Conclusiones: Algunos factores administrativos y clínicos afectan el tiempo de tratamiento de manera significativa y el alargar excesivamente el tiempo de tratamiento, puede empeorar los resultados clínicos estáticos obtenidos.Introdução: Estabelecer a relação entre a duração do tratamento ortodôntico e osfatores educacionais/administrativos/clínicos em pacientes tratados e finalizados na clínicade ortodontia da universidade. Métodos: Dados foram obtidos a partir de registros clínicos,radiografias panorâmicas e modelagens dentárias finais de 40 pacientes tratados (21mulheres e 19 homens), de 15,97 ± 5,79 anos. Variáveis administrativas incluíram númerode consultas atendidas, número de consultas por ano de tratamento, número total de consultas perdidas, total de meses de tratamento, número de meses efetivos de tratamento, número de residentes e instrutores atendendo aos pacientes e percentual de planejamento de tratamento para a próxima consulta. Variáveis clínicas incluíram a complexidade da maloclusão, a qualidade da finalização, extrações dentárias, idade e número de problemas e quebras de aplicações ortodônticas. Resultados: A média de duração do tratamento era de 55,5 ± 22,2 meses. Em pacientes com extrações dentárias, a duração do tratamento era significativamente mais longa (p=0,0231). Um modelo de regressão linear múltipla explicou 59% da variabilidade, identificando quatro variáveis significativas, duas relacionadas à administração (número de consultas perdidas e números de instrutores) e duas variáveis clínicas (número de problemas e quebras de aplicações ortodônticas e qualidade da finalização). Conclusão: Questões clínicas e administrativas significativas foram detectadas efoi observado que o tempo excessivo de tratamento pode deteriorar os resultados clínicosestáticos alcançados

Re-Emergence of a West Nile Virus (WNV) Variant in South Spain with Rapid Spread Capacity

West Nile Virus (WNV) is a mosquito vector-borne zoonosis with an increasing incidence in Europe that has become a public health concern. In Spain, although local circulation has been known for decades, until 2020, when a large outbreak occurred, West Nile Virus cases were scarce and mostly occurred in southern Spain. Since then, there have been new cases every year and the pathogen has spread to new regions. Thus, monitoring of circulating variants and lineages plays a fundamental role in understanding WNV evolution, spread and dynamics. In this study, we sequenced WNV consensus genomes from mosquito pools captured in 2022 as part of a newly implemented surveillance program in southern Spain and compared it to other European, African and Spanish sequences. Characterization of WNV genomes in mosquitoes captured in 2022 reveals the co-circulation of two WNV lineage 1 variants, the one that caused the outbreak in 2020 and another variant that is closely related to variants reported in Spain in 2012, France in 2015, Italy in 2021-2022 and Senegal in 2012-2018. The geographic distribution of these variants indicates that WNV L1 dynamics in southern Europe include an alternating dominance of variants in some territories.This work was funded by Junta de Andalucía contract “63/22“, the Agencia Estatal de Investigación (project PID2020-118921RJ-100/AEI/10.13039/501100011033) and INIA-MAPA agreements EG17-141 and AEG21-198, INIA grant E-RTA2015-00002-C02-00 and the Instituto de Salud Carlos III Project PI19CIII/00014 and the European Commission-NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global+).S

Comparison of 1-year outcome in patients with severe aorta stenosis treated conservatively or by aortic valve replacement or by percutaneous transcatheter aortic valve implantation (data from a multicenter Spanish registry)

The factors that influence decision making in severe aortic stenosis (AS) are unknown. Our aim was to assess, in patients with severe AS, the determinants of management and prognosis in a multicenter registry that enrolled all consecutive adults with severe AS during a 1-month period. One-year follow-up was obtained in all patients and included vital status and aortic valve intervention (aortic valve replacement [AVR] and transcatheter aortic valve implantation [TAVI]). A total of 726 patients were included, mean age was 77.3 ± 10.6 years, and 377 were women (51.8%). The most common management was conservative therapy in 468 (64.5%) followed by AVR in 199 (27.4%) and TAVI in 59 (8.1%). The strongest association with aortic valve intervention was patient management in a tertiary hospital with cardiac surgery (odds ratio 2.7, 95% confidence interval 1.8 to 4.1, p <0.001). The 2 main reasons to choose conservative management were the absence of significant symptoms (136% to 29.1%) and the presence of co-morbidity (128% to 27.4%). During 1-year follow-up, 132 patients died (18.2%). The main causes of death were heart failure (60% to 45.5%) and noncardiac diseases (46% to 34.9%). One-year survival for patients treated conservatively, with TAVI, and with AVR was 76.3%, 94.9%, and 92.5%, respectively, p <0.001. One-year survival of patients treated conservatively in the absence of significant symptoms was 97.1%. In conclusion, most patients with severe AS are treated conservatively. The outcome in asymptomatic patients managed conservatively was acceptable. Management in tertiary hospitals is associated with valve intervention. One-year survival was similar with both interventional strategies

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (&lt;45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale &amp; Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting &amp; Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (&lt;60, 60-69, and &gt;_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 &amp; PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages &lt;60, 60-69, and &gt;_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791