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Rationale Short‐term weight loss is possible in a variety of settings. However, long‐term, free‐living weight loss maintenance following structured weight loss interventions remains elusive. Objective The purpose was to study body weight trajectories over 2 years of intensive lifestyle intervention (ILI) and up to 4 years of follow‐up versus usual care (UC). Methods Data were obtained from electronic medical records (EMRs) from participating clinics. Baseline (Day 0) was established as the EMR data point closest but prior to the baseline date of the trial. The sample included 111 ILI and 196 UC patients. The primary statistical analysis focused on differentiating weight loss trajectories between ILI and UC. Results The ILI group experienced significantly greater weight loss compared with the UC group from Day 100 to Day 700, beyond which there were no significant differences. Intensive lifestyle intervention patients who maintained ≥5% and ≥10% weight loss at 24 months demonstrated significantly greater weight loss (p < 0.001) across the active intervention and follow‐up. Conclusions Following 24 months of active intervention, patients with ILI regained weight toward their baseline to the point where ILI versus UC differences were no longer statistically or clinically significant. However, patients in the ILI who experienced ≥5% or ≥10% weight loss at the cessation of the active intervention maintained greater weight loss at the end of the follow‐up phase. Clinical Trial Registration ClinicalTrials.gov: NCT02561221. Following 24 months of active intervention, patients in an intensive lifestyle intervention regained weight toward their baseline to the point where differences between the intervention and usual care groups were no longer statistically or clinically significant during the 4‐year follow‐up phase. Patients in the intervention who experienced ≥5% or ≥10% weight loss at the end of the active intervention maintained greater weight loss at the end of the 4‐year follow‐up phase.

Background/objectivesPragmatic trials are increasingly used to study the implementation of weight loss interventions in real-world settings. This study compared researcher-measured body weights versus electronic medical record (EMR)-derived body weights from a pragmatic trial conducted in an underserved patient population.Subjects/methodsThe PROPEL trial randomly allocated 18 clinics to usual care (UC) or to an intensive lifestyle intervention (ILI) designed to promote weight loss. Weight was measured by trained technicians at baseline and at 6, 12, 18, and 24 months. A total of 11 clinics (6 UC/5 ILI) with 577 enrolled patients also provided EMR data (n = 561), which included available body weights over the period of the trial.ResultsThe total number of assessments were 2638 and 2048 for the researcher-measured and EMR-derived body weight values, respectively. The correlation between researcher-measured and EMR-derived body weights was 0.988 (n = 1 939; p < 0.0001). The mean difference between the EMR and researcher weights (EMR-researcher) was 0.63 (2.65 SD) kg, and a Bland-Altman graph showed good agreement between the two data collection methods; the upper and lower boundaries of the 95% limits of agreement are −4.65 kg and +5.91 kg, and 71 (3.7%) of the values were outside the limits of agreement. However, at 6 months, percent weight loss in the ILI compared to the UC group was 7.3% using researcher-measured data versus 5.5% using EMR-derived data. At 24 months, the weight loss maintenance was 4.6% using the technician-measured data versus 3.5% using EMR-derived data.ConclusionAt the group level, body weight data derived from researcher assessments and an EMR showed good agreement; however, the weight loss difference between ILI and UC was blunted when using EMR data. This suggests that weight loss studies that rely on EMR data may require larger sample sizes to detect significant effects.Clinical trial registrationClinicalTrials.gov number NCT02561221.

The potential clinical application of gadolinium-neutron capture therapy (Gd-NCT) for glioblastoma multiforme (GBM) treatment has been compromised by the fast clearance and nonspecific biodistribution of gadolinium-based agents. We have developed a stem cell–nanoparticle system (SNS) to actively target GBM for advanced Gd-NCT by magnetizing umbilical cord mesenchymal stem cells (UMSCs) using gadodiamide-concealed magnetic nanoparticles (Gd-FPFNP). Nanoformulated gadodiamide shielded by a dense surface composed of fucoidan and polyvinyl alcohol demonstrates enhanced cellular association and biocompatibility in UMSCs. The SNS preserves the ability of UMSCs to actively penetrate the blood brain barrier and home to GBM and, when magnetically navigates by an external magnetic field, an 8-fold increase in tumor-to-blood ratio is achieved compared with clinical data. In an orthotopic GBM-bearing rat model, using a single dose of irradiation and an ultra-low gadolinium dose (200 μg kg −1 ), SNS significantly attenuates GBM progression without inducing safety issues, prolonging median survival 2.5-fold compared to free gadodiamide. The SNS is a cell-based delivery system that integrates the strengths of cell therapy and nanotechnology, which provides an alternative strategy for the treatment of brain diseases. Gadolinium-neutron capture therapy (Gd-NCT) in glioblastoma shows promise but is limited by toxicity and short-half life in the brain. Here, the authors present a magnetised stem cell-nanoparticle system to facilitate brain penetrance of Gd-NCT and demonstrate its utility in an orthotopic rat glioblastoma model.

Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca 2+ influx via PreNMDARs. Small conductance Ca 2+ -activated K + (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization. Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. Here, the authors show that also presynaptic NMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner.

Krebs von den Lungen-6 (KL-6) is expressed on regenerating type II pneumocytes and has been recognized as biomarkers in interstitial lung disease (ILD). We aim to identify the role of the serum KL-6 level in patients with newly diagnosed Sjögren syndrome (SS), as well as the correlation between the immunoassays. Patients with newly diagnosed SS and receiving HRCT for clinical reason during follow-up were included. Baseline KL-6 level was measured via enzyme-linked immunosorbent assay (ELISA) and latex particle-enhanced turbidimetric immunoassay (LETIA). Of the 39 patients, 21 (53.85%) developed interstitial lung disease (ILD) by the conclusion of the follow-up period. The median time to diagnosis of ILD was 2.24 years (IQR 1.15-4.34) in the ILD group. The median serum KL-6 level, measured using ELISA, was 1232 U/mL (IQR 937-2242) and 764.5 U/mL (IQR 503.25-1035.75) in the ILD group and the non-ILD group, respectively (p = 0.001). The median LETIA for serum KL-6 was 329 U/mL (IQR 235-619) and 245 U/mL (IQR 215.25-291) in the ILD group and the non-ILD group, respectively (p = 0.074). Serum KL-6 levels were higher in newly diagnosed SS patients with ILD diagnosis during follow-up. Thus, the serum KL-6 level can serve as a valuable biomarker to identify hidden ILD in patients with newly diagnosed SS patients. However, the immunoassay procedure may influence the efficacy of the prediction and its clinical association.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation. Idiopathic pulmonary fibrosis is associated with myofibroblast activation in the lungs and metabolic alterations. Here, the authors show that the antidiabetic drug metformin has antifibrotic effects in human-derived samples and mouse models, by modulating a number of metabolic pathways to induce lipogenic transdifferentiation of myofibroblasts.

To evaluate the prevalence of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in the illicit male ketamine abusers (KA). The male street KAs caught by policemen and patients visiting urologic clinics were invited to answer a structured questionnaire including demographic data, illicit drug use related details (duration, frequency, dosage and abstinence status), international prostate symptoms score (IPSS), interstitial cystitis symptoms and problem index (ICSI and ICPI) and International index of erectile function (IIEF-5). Erectile dysfunction was defined as IIEF-5 ≦21. Finally, we included 1056 participants (993 street, 63 hospital KAs) with a mean age of 27.4 ±6.2 years. ED presented in 30.8% of all KAs. and Hospital KAs were more subject to having ED than street KAs (69.6% vs. 28.0%, p<0.01). Multi-variate analysis revealed that risk factor for male ED were age ≧30 years (OR = 1.765). Subgroup analysis on male street KAs disclosed that abstinence ≧3 months is a protective factor for ED. Lower urinary tract symptoms (ICSI+ICPI ≧12) was prevalent in KAs and multivariate analysis disclosed that significant risk factors for LUTS (ICSI+ICPI ≧12) were age ≧30 years, duration ≧24 months and co-use of other illicit drugs. Male ED and LUTS were frequently observed in the ketamine abusers. We suggested that street ketamine abuse should be considered in young men presented with ED and LUTS in the clinics.

To assess the role of human disturbances in species’ extinction requires an understanding of the species population history before human impact. The passenger pigeon was once the most abundant bird in the world, with a population size estimated at 3–5 billion in the 1800s; its abrupt extinction in 1914 raises the question of how such an abundant bird could have been driven to extinction in mere decades. Although human exploitation is often blamed, the role of natural population dynamics in the passenger pigeon’s extinction remains unexplored. Applying high-throughput sequencing technologies to obtain sequences from most of the genome, we calculated that the passenger pigeon’s effective population size throughout the last million years was persistently about 1/10,000 of the 1800’s estimated number of individuals, a ratio 1,000-times lower than typically found. This result suggests that the passenger pigeon was not always super abundant but experienced dramatic population fluctuations, resembling those of an “outbreak” species. Ecological niche models supported inference of drastic changes in the extent of its breeding range over the last glacial–interglacial cycle. An estimate of acorn-based carrying capacity during the past 21,000 y showed great year-to-year variations. Based on our results, we hypothesize that ecological conditions that dramatically reduced population size under natural conditions could have interacted with human exploitation in causing the passenger pigeon’s rapid demise. Our study illustrates that even species as abundant as the passenger pigeon can be vulnerable to human threats if they are subject to dramatic population fluctuations, and provides a new perspective on the greatest human-caused extinction in recorded history.

Background Insomnia is a common sleep disturbance in older adults and is associated with many poor health outcomes. This study aimed to explore factors associated with insomnia in older adult outpatient clinics, and to further analyze the influence of gender on factors associated with insomnia. Methods This cross-sectional study was conducted in the outpatient clinics of a tertiary hospital in Southern Taiwan from July to September 2018. A total of 400 consecutive subjects aged 60 years or older were recruited. Insomnia was defined as a score of ≥ 6 points on the Athens Insomnia Scale (AIS). Socio-demographics, health behaviors and clinical data were collected by face-to-face interview. Multivariable logistic regression was adopted for statistical analysis of the entire sample and stratified by gender. Results Participants’ mean age was 74.74 ± 8.54 years, and the majority (93%) had more than one chronic disease. The prevalence of insomnia accounted for 30% (120/400) of all subjects, with males 22.9% (46/201) and females 37.2% (74/199). Gender, appetite, exercise, depressive symptoms, and sleep-related conditions such as short sleep duration, sleeping pills usage, medium-high risk of obstructive sleep apnea (OSA) and restless leg syndrome (RLS) were factors associated with insomnia in older adults. Exercise, sleeping pills usage, and RLS were independently associated with insomnia only in men, while appetite and medium-high risk of OSA were associated with insomnia in women only. In addition, after further adjusting for covariates, prevalence of the insomnia-related symptoms such as sleep induction, total sleep duration, sleep quality and sleepiness during the day was significantly higher in females than in males. Conclusions Insomnia symptoms are highly prevalent among older adults, predominantly females. Significant differences are found between genders in factors associated with insomnia and insomnia-related symptoms. Understanding gender differences may help clinicians to modify associated factors when managing older adults with insomnia.

No large trials have been done to investigate the efficacy of an intervention combining a specific compound and several lifestyle interventions compared with placebo for the prevention of cognitive decline. We tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on cognitive decline. The Multidomain Alzheimer Preventive Trial was a 3-year, multicentre, randomised, placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco. Participants were non-demented, aged 70 years or older, and community-dwelling, and had either relayed a spontaneous memory complaint to their physician, limitations in one instrumental activity of daily living, or slow gait speed. They were randomly assigned (1:1:1:1) to either the multidomain intervention (43 group sessions integrating cognitive training, physical activity, and nutrition, and three preventive consultations) plus omega 3 polyunsaturated fatty acids (ie, two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid), the multidomain intervention plus placebo, omega 3 polyunsaturated fatty acids alone, or placebo alone. A computer-generated randomisation procedure was used to stratify patients by centre. All participants and study staff were blinded to polyunsaturated fatty acid or placebo assignment, but were unblinded to the multidomain intervention component. Assessment of cognitive outcomes was done by independent neuropsychologists blinded to group assignment. The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini-Mental State Examination orientation items, Digit Symbol Substitution Test, and Category Naming Test) in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT00672685). 1680 participants were enrolled and randomly allocated between May 30, 2008, and Feb 24, 2011. In the modified intention-to-treat population (n=1525), there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group. Between-group differences compared with placebo were 0·093 (95% CI 0·001 to 0·184; adjusted p=0·142) for the combined intervention group, 0·079 (−0·012 to 0·170; 0·179) for the multidomain intervention plus placebo group, and 0·011 (−0·081 to 0·103; 0·812) for the omega 3 polyunsaturated fatty acids group. 146 (36%) participants in the multidomain plus polyunsaturated fatty acids group, 142 (34%) in the multidomain plus placebo group, 134 (33%) in the polyunsaturated fatty acids group, and 133 (32%) in the placebo group had at least one serious emerging adverse event. Four treatment-related deaths were recorded (two in the multidomain plus placebo group and two in the placebo group). The interventions did not raise any safety concerns and there were no differences between groups in serious or other adverse events. The multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline over 3 years in elderly people with memory complaints. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remain to be determined, particularly in real-world settings. French Ministry of Health, Pierre Fabre Research Institute, Gerontopole, Exhonit Therapeutics, Avid Radiopharmaceuticals.