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The New England Journal of Medicine Jun 2019Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors... (Randomized Controlled Trial)
Randomized Controlled Trial
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 m 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 m), 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. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).
Topics: Aged; Canagliflozin; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 30990260
DOI: 10.1056/NEJMoa1811744 -
The New England Journal of Medicine Jul 2021In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.
METHODS
In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).
RESULTS
Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.
CONCLUSIONS
In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).
Topics: Administration, Oral; Adult; Celiac Disease; Dose-Response Relationship, Drug; Double-Blind Method; Duodenum; Female; GTP-Binding Proteins; Glutens; Humans; Imidazoles; Intestinal Mucosa; Lymphocyte Count; Male; Middle Aged; Proof of Concept Study; Protein Glutamine gamma Glutamyltransferase 2; Pyridines; Quality of Life; Severity of Illness Index; Transglutaminases
PubMed: 34192430
DOI: 10.1056/NEJMoa2032441 -
The American Journal of Sports Medicine Jul 2019Previous studies have shown that changing acutely from shod to barefoot running induces several changes to running biomechanics, such as altered ankle kinematics,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Previous studies have shown that changing acutely from shod to barefoot running induces several changes to running biomechanics, such as altered ankle kinematics, reduced ground-reaction forces, and reduced loading rates. However, uncertainty exists whether these effects still exist after a short period of barefoot running habituation.
PURPOSE/HYPOTHESIS
The purpose was to investigate the effects of a habituation to barefoot versus shod running on running biomechanics. It was hypothesized that a habituation to barefoot running would induce different adaptations of running kinetics and kinematics as compared with a habituation to cushioned footwear running or no habituation.
STUDY DESIGN
Controlled laboratory study.
METHODS
Young, physically active adults without experience in barefoot running were randomly allocated to a barefoot habituation group, a cushioned footwear group, or a passive control group. The 8-week intervention in the barefoot and footwear groups consisted of 15 minutes of treadmill running at 70% of VO max (maximal oxygen consumption) velocity per weekly session in the allocated footwear. Before and after the intervention period, a 3-dimensional biomechanical analysis for barefoot and shod running was conducted on an instrumented treadmill. The passive control group did not receive any intervention but was also tested prior to and after 8 weeks. Pre- to posttest changes in kinematics, kinetics, and spatiotemporal parameters were then analyzed with a mixed effects model.
RESULTS
Of the 60 included participants (51.7% female; mean ± SD age, 25.4 ± 3.3 years; body mass index, 22.6 ± 2.1 kg·m), 53 completed the study (19 in the barefoot habituation group, 18 in the shod habituation group, and 16 in the passive control group). Acutely, running barefoot versus shod influenced foot strike index and ankle, foot, and knee angles at ground contact ( < .001), as well as vertical average loading rate ( = .003), peak force ( < .001), contact time ( < .001), flight time ( < .001), step length ( < .001), and cadence ( < .001). No differences were found for average force ( = .391). After the barefoot habituation period, participants exhibited more anterior foot placement ( = .006) when running barefoot, while no changes were observed in the footwear condition. Furthermore, barefoot habituation increased the vertical average loading rates in both conditions (barefoot, = .01; shod, = .003) and average vertical ground-reaction forces for shod running ( = .039). All other outcomes (ankle, foot, and knee angles at ground contact and flight time, contact time, cadence, and peak forces) did not change significantly after the 8-week habituation.
CONCLUSION
Changing acutely from shod to barefoot running in a habitually shod population increased the foot strike index and reduced ground-reaction force and loading rates. After the habituation to barefoot running, the foot strike index was further increased, while the force and average loading rates also as compared with the acute barefoot running situation. The increased average loading rate is contradictory to other studies on acute adaptations of barefoot running.
CLINICAL RELEVANCE
A habituation to barefoot running led to increased vertical average loading rates. This finding was unexpected and questions the generalizability of acute adaptations to long-term barefoot running. Sports medicine professionals should consider these adaptations in their recommendations regarding barefoot running as a possible measure for running injury prevention.
REGISTRATION
DRKS00011073 (German Clinical Trial Register).
Topics: Adult; Ankle Joint; Biomechanical Phenomena; Body Mass Index; Exercise Test; Female; Foot; Gait; Humans; Kinetics; Knee Joint; Male; Prospective Studies; Running; Shoes; Single-Blind Method; Young Adult
PubMed: 31166116
DOI: 10.1177/0363546519849920 -
The Lancet. Oncology Dec 2020Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+).
METHODS
Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464.
FINDINGS
7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine.
INTERPRETATION
The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable.
FUNDING
US National Cancer Institute.
Topics: Adolescent; Adult; Costa Rica; Double-Blind Method; Female; Human papillomavirus 16; Human papillomavirus 18; Humans; Immunization; Neoplasm Grading; Papillomavirus Infections; Papillomavirus Vaccines; Time Factors; Treatment Outcome; Uterine Cervical Neoplasms; Vaccines, Combined; Young Adult; Uterine Cervical Dysplasia
PubMed: 33271093
DOI: 10.1016/S1470-2045(20)30524-6 -
Cells Jan 2022Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation,... (Review)
Review
Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation, autophagy, lysosomal exocytosis, and endocytosis. Diseases comprise lysosomal storage disorders (LSDs) and neurodegenerative diseases, metabolic diseases, pigmentation defects, cancer, immune disorders, autophagy related diseases, infectious diseases and many more. Involvement in lung diseases has not been a focus of attention so far but recent developments in the field suggest critical functions in lung physiology and pathophysiology. Thus, loss of TRPML3 was discovered to exacerbate emphysema formation and cigarette smoke induced COPD due to dysregulated matrix metalloproteinase 12 (MMP-12) levels in the extracellular matrix of the lung, a known risk factor for emphysema/COPD. While direct lung function measurements with the exception of TRPML3 are missing for other endolysosomal cation channels or channels expressed in lysosome related organelles (LRO) in the lung, links between those channels and important roles in lung physiology have been established such as the role of P2X4 in surfactant release from alveolar epithelial Type II cells. Other channels with demonstrated functions and disease relevance in the lung such as TRPM2, TRPV2, or TRPA1 may mediate their effects due to plasma membrane expression but evidence accumulates that these channels might also be expressed in endolysosomes, suggesting additional and/or dual roles of these channels in cell and intracellular membranes. We will discuss here the current knowledge on cation channels residing in endolysosomes or LROs with respect to their emerging roles in lung disease.
Topics: Animals; Cations; Endosomes; Humans; Ion Channels; Lung Diseases; Lysosomes; Phagocytosis
PubMed: 35053420
DOI: 10.3390/cells11020304 -
Journal of Neurophysiology Nov 2022Research on embodied decision-making only recently started to examine whether and how concurrent actions influence value-based decisions. For instance, during walking...
Research on embodied decision-making only recently started to examine whether and how concurrent actions influence value-based decisions. For instance, during walking humans preferably make decisions that align with a turn toward the side of their current swing leg, sometimes resulting in unfavorable choices (e.g., less reward). It is suggested that concurrent movements influence decision-making by coincidental changes in motor costs. If this is true, systematic manipulations of motor costs should bias decisions. To test this, participants had to accumulate rewards (i.e., points) by walking and turning toward left and right targets displaying rewards across three experiments. In and , we manipulated the turning cost based on the current swing leg by applying different symmetric turning magnitudes (i.e., same angles for left and right targets). In , we manipulated the turning cost by administering asymmetric turning magnitudes (i.e., different angles for left and right targets). Finally, in , we increased the cost of walking by adding ankle weights. Altogether, the experiments support the claim that differences in motor costs influenced participants' decisions: and revealed that the swing leg effect and stepping behavior were moderated by turning magnitude. In , participants showed a preference for less costly, smaller turning magnitudes. replicated the swing leg effect when motor costs were increased by means of ankle weights. In conclusion, these findings provide further evidence that value-based decisions during ongoing actions seem to be influenced by dynamically changing motor costs, thereby supporting the concept of "embodied decision-making." Motor processes of concurrent movements have been shown to influence embodied decision-making. It is hypothesized that this is driven by coincidental changes in motor costs. We tested this claim by systematically manipulating motor costs of choice options during walking. In three experiments we show how variations in motor cost (e.g., turning angle or stepping constraints) bias decision-making, thereby supporting the concept of "embodied decision-making."
Topics: Humans; Walking; Reward; Movement
PubMed: 36197022
DOI: 10.1152/jn.00149.2022 -
Nature Metabolism Mar 2024Emerging evidence suggests that modulation of gut microbiota by dietary fibre may offer solutions for metabolic disorders. In a randomized placebo-controlled crossover... (Randomized Controlled Trial)
Randomized Controlled Trial
Emerging evidence suggests that modulation of gut microbiota by dietary fibre may offer solutions for metabolic disorders. In a randomized placebo-controlled crossover design trial (ChiCTR-TTRCC-13003333) in 37 participants with overweight or obesity, we test whether resistant starch (RS) as a dietary supplement influences obesity-related outcomes. Here, we show that RS supplementation for 8 weeks can help to achieve weight loss (mean -2.8 kg) and improve insulin resistance in individuals with excess body weight. The benefits of RS are associated with changes in gut microbiota composition. Supplementation with Bifidobacterium adolescentis, a species that is markedly associated with the alleviation of obesity in the study participants, protects male mice from diet-induced obesity. Mechanistically, the RS-induced changes in the gut microbiota alter the bile acid profile, reduce inflammation by restoring the intestinal barrier and inhibit lipid absorption. We demonstrate that RS can facilitate weight loss at least partially through B. adolescentis and that the gut microbiota is essential for the action of RS.
Topics: Animals; Humans; Male; Mice; Gastrointestinal Microbiome; Obesity; Overweight; Resistant Starch; Weight Gain; Weight Loss; Cross-Over Studies
PubMed: 38409604
DOI: 10.1038/s42255-024-00988-y -
Cells Mar 2022Idiopathic pulmonary fibrosis (IPF) is a fatal disease with incompletely understood aetiology and limited treatment options. Traditionally, IPF was believed to be mainly... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with incompletely understood aetiology and limited treatment options. Traditionally, IPF was believed to be mainly caused by repetitive injuries to the alveolar epithelium. Several recent lines of evidence, however, suggest that IPF equally involves an aberrant airway epithelial response, which contributes significantly to disease development and progression. In this review, based on recent clinical, high-resolution imaging, genetic, and single-cell RNA sequencing data, we summarize alterations in airway structure, function, and cell type composition in IPF. We furthermore give a comprehensive overview on the genetic and mechanistic evidence pointing towards an essential role of airway epithelial cells in IPF pathogenesis and describe potentially implicated aberrant epithelial signalling pathways and regulation mechanisms in this context. The collected evidence argues for the investigation of possible therapeutic avenues targeting these processes, which thus represent important future directions of research.
Topics: Epithelial Cells; Humans; Idiopathic Pulmonary Fibrosis; Respiratory Mucosa; Signal Transduction
PubMed: 35326501
DOI: 10.3390/cells11061050 -
PLoS Computational Biology Jan 2021Chemical graph generators are software packages to generate computer representations of chemical structures adhering to certain boundary conditions. Their development is...
Chemical graph generators are software packages to generate computer representations of chemical structures adhering to certain boundary conditions. Their development is a research topic of cheminformatics. Chemical graph generators are used in areas such as virtual library generation in drug design, in molecular design with specified properties, called inverse QSAR/QSPR, as well as in organic synthesis design, retrosynthesis or in systems for computer-assisted structure elucidation (CASE). CASE systems again have regained interest for the structure elucidation of unknowns in computational metabolomics, a current area of computational biology.
Topics: Algorithms; Cheminformatics; Computer Graphics; Metabolomics; Models, Molecular; Molecular Conformation; Software
PubMed: 33400699
DOI: 10.1371/journal.pcbi.1008504 -
Patterns (New York, N.Y.) Oct 2022Artificial intelligence (AI) and machine learning (ML) are expanding in popularity for broad applications to challenging tasks in chemistry and materials science.... (Review)
Review
Artificial intelligence (AI) and machine learning (ML) are expanding in popularity for broad applications to challenging tasks in chemistry and materials science. Examples include the prediction of properties, the discovery of new reaction pathways, or the design of new molecules. The machine needs to read and write fluently in a chemical language for each of these tasks. Strings are a common tool to represent molecular graphs, and the most popular molecular string representation, Smiles, has powered cheminformatics since the late 1980s. However, in the context of AI and ML in chemistry, Smiles has several shortcomings-most pertinently, most combinations of symbols lead to invalid results with no valid chemical interpretation. To overcome this issue, a new language for molecules was introduced in 2020 that guarantees 100% robustness: SELF-referencing embedded string (Selfies). Selfies has since simplified and enabled numerous new applications in chemistry. In this perspective, we look to the future and discuss molecular string representations, along with their respective opportunities and challenges. We propose 16 concrete future projects for robust molecular representations. These involve the extension toward new chemical domains, exciting questions at the interface of AI and robust languages, and interpretability for both humans and machines. We hope that these proposals will inspire several follow-up works exploiting the full potential of molecular string representations for the future of AI in chemistry and materials science.
PubMed: 36277819
DOI: 10.1016/j.patter.2022.100588