Safety of two-year caloric restriction in non-obese healthy individuals

BACKGROUND: The extent to which sustained caloric restriction (CR) in healthy non-obese adults is safe has not been previously investigated. OBJECTIVE: Assess the safety and tolerability of sustained two-year CR intervention in healthy, non-obese adults. DESIGN: A multi-center, randomized controlled trial. Participants were randomized using a 2:1 allocation in favor of 25% CR vs. Ad-Libitum intake (AL). Adverse and serious adverse events (AE, SAE), safety laboratory tests, and other safety parameters were closely monitored. RESULTS: Three participants were withdrawn from the CR intervention because of the safety concerns. No deaths and one SAE was reported by participants in the CR group. Although the difference in AE between AL and CR groups was not significant, within the CR group, the incidence of nervous system (p = 0.02), musculoskeletal (p = 0.02) and reproductive system (p = 0.002) disorders was significantly higher in the normal-weight than in the overweight participants. At months 12 and 24, bone mineral densities at the lumbar spine, total hip, and femoral neck of participants in the CR group were significantly lower than in those in the AL group. CONCLUSIONS: Two-years of CR at levels achieved in CALERIE was safe and well tolerated. Close monitoring for excessive bone loss and anemia is important

Poor Reporting of Scientific Leadership Information in Clinical Trial Registers

BACKGROUND: In September 2004, the International Committee of Medical Journal Editors (ICMJE) issued a Statement requiring that all clinical trials be registered at inception in a public register in order to be considered for publication. The World Health Organization (WHO) and ICMJE have identified 20 items that should be provided before a trial is considered registered, including contact information. Identifying those scientifically responsible for trial conduct increases accountability. The objective is to examine the proportion of registered clinical trials providing valid scientific leadership information. METHODOLOGY/PRINCIPAL FINDINGS: We reviewed clinical trial entries listing Canadian investigators in the two largest international and public trial registers, the International Standard Randomized Controlled Trial Number (ISRCTN) register, and ClinicalTrials.gov. The main outcome measures were the proportion of clinical trials reporting valid contact information for the trials' Principal Investigator (PI)/Co-ordinating Investigator/Study Chair/Site PI, and trial e-mail contact address, stratified by funding source, recruiting status, and register. A total of 1388 entries (142 from ISRCTN and 1246 from ClinicalTrials.gov) comprised our sample. We found non-compliance with mandatory registration requirements regarding scientific leadership and trial contact information. Non-industry and partial industry funded trials were significantly more likely to identify the individual responsible for scientific leadership (OR = 259, 95% CI: 95-701) and to provide a contact e-mail address (OR = 9.6, 95% CI: 6.6-14) than were solely industry funded trials. CONCLUSIONS/SIGNIFICANCE: Despite the requirements set by WHO and ICMJE, data on scientific leadership and contact e-mail addresses are frequently omitted from clinical trials registered in the two leading public clinical trial registers. To promote accountability and transparency in clinical trials research, public clinical trials registers should ensure adequate monitoring of trial registration to ensure completion of mandatory contact information fields identifying scientific leadership

Clinical and Histopathologic Features of Fluoroquinolone-Induced Liver Injury

Fluoroquinolone-induced liver injury is rare; no prospective studies of well-characterized case series have been published. We studied patients with fluoroquinolone-induced hepatoxicity, using data from the Drug-Induced Liver Injury Network (DILIN) to characterize injury patterns, outcomes, and associated features

Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: A randomized clinical trial

Young-onset calorie restriction (CR) in rodents decreases serum IGF-1 concentration and increases serum corticosterone levels, which have been hypothesized to play major roles in mediating its anticancer and anti-aging effects. However, little is known on the effects of CR on the IGF-1 system and cortisol in humans. To test the sustained effects of CR on these key hormonal adaptations, we performed a multicenter randomized trial of a 2-year 25% CR intervention in 218 nonobese (body mass index between 22 and 27.8 kg m(-2) ) young and middle-aged (20-50 years age range) men and women. Average CR during the first 6 months was 19.5 ± 0.8% and 9.1 ± 0.7% over the next 18 months of the study. Weight loss averaged 7.6 ± 0.3 kg over the 2-years period of which 71% was fat mass loss (P < 0.0001). Average CR during the CR caused a significant 21% increase in serum IGFBP-1 and a 42% reduction in IGF-1:IGFBP-1 ratio at 2 years (P < 0.008), but did not change IGF-1 and IGF-1:IGFBP-3 ratio levels. Serum cortisol concentrations were slightly but significantly increased by CR at 1 year only (P = 0.003). Calorie restriction had no effect on serum concentrations of PDGF-AB and TGFβ-1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF-1 concentration or with a sustained and biological relevant increase in serum cortisol. However, long-term CR in humans significantly and persistently increases serum IGFBP-1 concentration

Drug-Induced Liver Injury Network (DILIN) Prospective Study: Rationale, Design and Conduct

Drug-induced liver injury (DILI) is an uncommon adverse drug reaction of increasing importance to the medical community, pharmaceutical industry, regulatory agencies and the general public

Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States

Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled

Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury

The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean ± standard deviation age at protocol-defined onset was 44.8 ± 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from −7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally

Digital wound monitoring with artificial intelligence to prioritise surgcial wounds in cardiac surgery: protocol for a randomised feasibility trial (WISDOM)

Introduction: Digital surgical wound monitoring for patients at home is becoming an increasingly common method of wound follow-up. This regular monitoring improves patient outcomes by detecting wound complications early and enabling treatment to start before complications worsen. However, reviewing the digital data creates a new and additional workload for staff. The aim of this study is to assess a surgical wound monitoring platform that uses artificial intelligence to assist clinicians to review patients’ wound images by prioritising concerning images for urgent review. This will manage staff time more effectively.Methods and analysis: This is a feasibility study for a new artificial intelligence module with 120 cardiac surgery patients at two centres serving a range of patient ethnicities and urban, rural and coastal locations. Each patient will be randomly allocated using a 1:1 ratio with mixed block sizes to receive the platform with the new detection and prioritising module (for up to 30 days after surgery) plus standard postoperative wound care or standard postoperative wound care only. Assessment is through surveys, interviews, phone calls and platform review at 30 days and through medical notes review and patient phone calls at 60 days. Outcomes will assess safety, acceptability, feasibility and health economic endpoints. The decision to proceed to a definitive trial will be based on prespecified progression criteria.Ethics and dissemination: Permission to conduct the study was granted by the North of Scotland Research Ethics Committee 1 (24/NS0005) and the MHRA (CI/2024/0004/GB). The results of this Wound Imaging Software Digital platfOrM (WISDOM) study will be reported in peer-reviewed open-access journals and shared with participants and stakeholders

Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States

Background and Aims Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled. Methods Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded. Results DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%. Conclusions DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related