Consumption of sugar-sweetened beverages may cause excessive weight gain. We aimed to assess the effect on weight gain of an intervention that included the provision of noncaloric beverages at home ...for overweight and obese adolescents.
We randomly assigned 224 overweight and obese adolescents who regularly consumed sugar-sweetened beverages to experimental and control groups. The experimental group received a 1-year intervention designed to decrease consumption of sugar-sweetened beverages, with follow-up for an additional year without intervention. We hypothesized that the experimental group would gain weight at a slower rate than the control group.
Retention rates were 97% at 1 year and 93% at 2 years. Reported consumption of sugar-sweetened beverages was similar at baseline in the experimental and control groups (1.7 servings per day), declined to nearly 0 in the experimental group at 1 year, and remained lower in the experimental group than in the control group at 2 years. The primary outcome, the change in mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) at 2 years, did not differ significantly between the two groups (change in experimental group minus change in control group, -0.3; P=0.46). At 1 year, however, there were significant between-group differences for changes in BMI (-0.57, P=0.045) and weight (-1.9 kg, P=0.04). We found evidence of effect modification according to ethnic group at 1 year (P=0.04) and 2 years (P=0.01). In a prespecified analysis according to ethnic group, among Hispanic participants (27 in the experimental group and 19 in the control group), there was a significant between-group difference in the change in BMI at 1 year (-1.79, P=0.007) and 2 years (-2.35, P=0.01), but not among non-Hispanic participants (P>0.35 at years 1 and 2). The change in body fat as a percentage of total weight did not differ significantly between groups at 2 years (-0.5%, P=0.40). There were no adverse events related to study participation.
Among overweight and obese adolescents, the increase in BMI was smaller in the experimental group than in the control group after a 1-year intervention designed to reduce consumption of sugar-sweetened beverages, but not at the 2-year follow-up (the prespecified primary outcome). (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT00381160.).
To determine the effects of diets varying in carbohydrate to fat ratio on total energy expenditure.
Randomized trial.
Multicenter collaboration at US two sites, August 2014 to May 2017.
164 adults ...aged 18-65 years with a body mass index of 25 or more.
After 12% (within 2%) weight loss on a run-in diet, participants were randomly assigned to one of three test diets according to carbohydrate content (high, 60%, n=54; moderate, 40%, n=53; or low, 20%, n=57) for 20 weeks. Test diets were controlled for protein and were energy adjusted to maintain weight loss within 2 kg. To test for effect modification predicted by the carbohydrate-insulin model, the sample was divided into thirds of pre-weight loss insulin secretion (insulin concentration 30 minutes after oral glucose).
The primary outcome was total energy expenditure, measured with doubly labeled water, by intention-to-treat analysis. Per protocol analysis included participants who maintained target weight loss, potentially providing a more precise effect estimate. Secondary outcomes were resting energy expenditure, measures of physical activity, and levels of the metabolic hormones leptin and ghrelin.
Total energy expenditure differed by diet in the intention-to-treat analysis (n=162, P=0.002), with a linear trend of 52 kcal/d (95% confidence interval 23 to 82) for every 10% decrease in the contribution of carbohydrate to total energy intake (1 kcal=4.18 kJ=0.00418 MJ). Change in total energy expenditure was 91 kcal/d (95% confidence interval -29 to 210) greater in participants assigned to the moderate carbohydrate diet and 209 kcal/d (91 to 326) greater in those assigned to the low carbohydrate diet compared with the high carbohydrate diet. In the per protocol analysis (n=120, P<0.001), the respective differences were 131 kcal/d (-6 to 267) and 278 kcal/d (144 to 411). Among participants in the highest third of pre-weight loss insulin secretion, the difference between the low and high carbohydrate diet was 308 kcal/d in the intention-to-treat analysis and 478 kcal/d in the per protocol analysis (P<0.004). Ghrelin was significantly lower in participants assigned to the low carbohydrate diet compared with those assigned to the high carbohydrate diet (both analyses). Leptin was also significantly lower in participants assigned to the low carbohydrate diet (per protocol).
Consistent with the carbohydrate-insulin model, lowering dietary carbohydrate increased energy expenditure during weight loss maintenance. This metabolic effect may improve the success of obesity treatment, especially among those with high insulin secretion.
ClinicalTrials.gov NCT02068885.
Reduced energy expenditure following weight loss is thought to contribute to weight gain. However, the effect of dietary composition on energy expenditure during weight-loss maintenance has not been ...studied.
To examine the effects of 3 diets differing widely in macronutrient composition and glycemic load on energy expenditure following weight loss.
A controlled 3-way crossover design involving 21 overweight and obese young adults conducted at Children's Hospital Boston and Brigham and Women's Hospital, Boston, Massachusetts, between June 16, 2006, and June 21, 2010, with recruitment by newspaper advertisements and postings.
After achieving 10% to 15% weight loss while consuming a run-in diet, participants consumed an isocaloric low-fat diet (60% of energy from carbohydrate, 20% from fat, 20% from protein; high glycemic load), low-glycemic index diet (40% from carbohydrate, 40% from fat, and 20% from protein; moderate glycemic load), and very low-carbohydrate diet (10% from carbohydrate, 60% from fat, and 30% from protein; low glycemic load) in random order, each for 4 weeks.
Primary outcome was resting energy expenditure (REE), with secondary outcomes of total energy expenditure (TEE), hormone levels, and metabolic syndrome components.
Compared with the pre-weight-loss baseline, the decrease in REE was greatest with the low-fat diet (mean 95% CI, -205 -265 to -144 kcal/d), intermediate with the low-glycemic index diet (-166 -227 to -106 kcal/d), and least with the very low-carbohydrate diet (-138 -198 to -77 kcal/d; overall P = .03; P for trend by glycemic load = .009). The decrease in TEE showed a similar pattern (mean 95% CI, -423 -606 to -239 kcal/d; -297 -479 to -115 kcal/d; and -97 -281 to 86 kcal/d, respectively; overall P = .003; P for trend by glycemic load < .001). Hormone levels and metabolic syndrome components also varied during weight maintenance by diet (leptin, P < .001; 24-hour urinary cortisol, P = .005; indexes of peripheral P = .02 and hepatic P = .03 insulin sensitivity; high-density lipoprotein HDL cholesterol, P < .001; non-HDL cholesterol, P < .001; triglycerides, P < .001; plasminogen activator inhibitor 1, P for trend = .04; and C-reactive protein, P for trend = .05), but no consistent favorable pattern emerged.
Among overweight and obese young adults compared with pre-weight-loss energy expenditure, isocaloric feeding following 10% to 15% weight loss resulted in decreases in REE and TEE that were greatest with the low-fat diet, intermediate with the low-glycemic index diet, and least with the very low-carbohydrate diet.
clinicaltrials.gov Identifier: NCT00315354.
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and ...PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.
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•Chronic IFNG promotes epigenomic and transcriptomic features of resistant tumors•IFN-driven PDL1-independent resistance comprises multiple inhibitory pathways•Targeting IFN-driven resistance improves function of distinct exhausted T cell subsets•Blocking tumor IFN signaling can bypass need for combination checkpoint blockade
Prolonged interferon signaling in tumor cells increases resistance to immune checkpoint blockade through multiple inhibitory pathways, and inhibiting this response can bypass the need for multi-agent blockade.
Background Few studies have investigated the effectiveness of enhanced recovery pathways (ERP) for lung resection. This study estimates the impact of an ERP for lobectomy on duration of stay, ...complications, and readmissions. Methods Patients undergoing open lobectomy were identified from an OR database between 2011 and 2013. Beginning September 2012, all patients were managed according to a 4-day multidisciplinary ERP with written daily patient education treatment plans, multimodal analgesia, early diet, structured mobilization and standardized drain management. Pre-pathway (PRE) and post-pathway (POST) patients were compared in terms of duration of stay, complications, and readmissions. Results We identified 234 patients (PRE, 127; POST, 107). Groups were similar with respect to age, gender, American Society of Anesthesiologists score, and baseline pulmonary function. Compared with the PRE group, the POST group had decreased duration of stay (median, 6 interquartile range (IQR), 5–7 vs 7 6–10 days; P < .05), total complications (40 37% vs 64 50%; P < .05), urinary tract infections (3 3% vs 15 12%; P < .05), and chest tube duration (median, 4 IQR, 3–6 vs 5 4–7 days; P < .05), with no difference in readmissions (7 7% vs 6 5%; P < .05) or chest tube reinsertion (4 4% vs 6 5%; P < .05). Decreased duration of stay was driven by patients without complications (median, 5 IQR, 4–6 vs 6 5–7 days; P < .05). Conclusion Implementation of a multimodal ERP for lobectomy was associated with decreased duration of stay and complications with no difference in readmissions.
Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging ...research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the "A/T/N" system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. "A" refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); "T," the value of a tau biomarker (CSF phospho tau, or tau PET); and "N," biomarkers of neurodegeneration or neuronal injury ((18)F-fluorodeoxyglucose-PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N-, or A+/T-/N-, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.
Hunger evokes stereotypic behaviors that favor the discovery of nutrients. The neural pathways that coordinate internal and external cues to motivate foraging behaviors are only partly known. ...Drosophila that are food deprived increase locomotor activity, are more efficient in locating a discrete source of nutrition, and are willing to overcome adversity to obtain food. We developed a simple open field assay that allows flies to freely perform multiple steps of the foraging sequence, and we show that two distinct dopaminergic neural circuits regulate measures of foraging behaviors. One group, the PAM neurons, functions in food deprived flies while the other functions in well fed flies, and both promote foraging. These satiation state-dependent circuits converge on dopamine D1 receptor-expressing Kenyon cells of the mushroom body, where neural activity promotes foraging independent of satiation state. These findings provide evidence for active foraging in well-fed flies that is separable from hunger-driven foraging.
Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion ...of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
► Noncoding repeat expansion in C9ORF72 causes FTD and ALS linked to chromosome 9p ► C9ORF72 repeat expansion forms nuclear RNA foci in brain and spinal cord ► Repeat expansion results in loss of one alternatively spliced C9ORF72 transcript ► Repeat expansion in C9ORF72 is a major cause of both FTD and ALS
The role of sugar-sweetened beverages (SSBs) in promoting obesity is controversial. Observational data link SSB consumption with excessive weight gain; however, randomized, controlled trials are ...lacking and necessary to resolve the debate. We conducted a pilot study to examine the effect of decreasing SSB consumption on body weight.
We randomly assigned 103 adolescents aged 13 to 18 years who regularly consumed SSBs to intervention and control groups. The intervention, 25 weeks in duration, relied largely on home deliveries of noncaloric beverages to displace SSBs and thereby decrease consumption. Change in SSB consumption was the main process measure, and change in body mass index (BMI) was the primary end point.
All of the randomly assigned subjects completed the study. Consumption of SSBs decreased by 82% in the intervention group and did not change in the control group. Change in BMI, adjusted for gender and age, was 0.07 +/- 0.14 kg/m2 (mean +/- SE) for the intervention group and 0.21 +/- 0.15 kg/m2 for the control group. The net difference, -0.14 +/- 0.21 kg/m2, was not significant overall. However, baseline BMI was a significant effect modifier. Among the subjects in the upper baseline-BMI tertile, BMI change differed significantly between the intervention (-0.63 +/- 0.23 kg/m2) and control (+0.12 +/- 0.26 kg/m2) groups, a net effect of -0.75 +/- 0.34 kg/m2. The interaction between weight change and baseline BMI was not attributable to baseline consumption of SSBs.
A simple environmental intervention almost completely eliminated SSB consumption in a diverse group of adolescents. The beneficial effect on body weight of reducing SSB consumption increased with increasing baseline body weight, offering additional support for American Academy of Pediatrics guidelines to limit SSB consumption.
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