Objectively-assessed physical activity and weight change in young adults: a randomized controlled trial

Abstract Background Reductions in physical activity (PA) are common throughout young adulthood and low PA is associated with weight gain. The SNAP Trial previously reported that two self-regulation approaches to weight gain prevention reduced weight gain over a 2-year period in 18–35 year olds. Presented here are secondary analyses examining changes in PA and the relationship between PA and weight change over 2 years. Methods 599 young adults (age: 27.4 ± 4.4 yrs.; BMI: 25.4 ± 2.6 kg/m2) were randomly assigned to 1 of 3 treatment arms: Small Changes (reduce calorie intake by 100 kcals/day & add 2000 steps/day), Large Changes (lose 2.3–4.5 kg initially & increase PA to ≥250 min/wk), or Self-guided (control condition). Small and Large Changes received 10, face-to-face group sessions (months 1–4), and two 4-week refresher courses each subsequent year. Body weight and PA were objectively-measured at baseline, 4 months, 1 and 2 years. Daily steps and bout-related moderate-to-vigorous intensity PA (MVPA: ≥3 METs, ≥10-min bouts) was calculated. Results Changes in bout-related MVPA and daily steps did not differ among treatment groups over the 2-year period (p’s > 0.16). Collapsed across groups, participants gaining >1 lb. (n = 187; 39.6%) had smaller changes in bout-related MVPA at 4 months, 1 and 2 years relative to those maintaining or losing weight (≤1 lb. weight gain; n = 282, 60.4%, p’s 1 lb. did not differ on daily steps (p’s > 0.10). Among participants engaging in ≥250 min/wk. of MVPA at 2 years (n = 181), 30% gained >1 lb. from baseline to 2 years, which was not different from those engaging in 150–250 min/wk. (n = 87; 36%; p = 0.40), but this percentage was significantly lower when compared to those engaging in 150 min/week of MVPA is needed for weight gain prevention and that increasing MVPA, rather than steps, should be targeted. Trial registration www.clinicaltrials.gov (NCT01183689). Registered Aug 13, 2010

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. Methods: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. Results: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs

Detecting Foci of Malaria Transmission with School Surveys: A Pilot Study in the Gambia.

BACKGROUND: In areas of declining malaria transmission such as in The Gambia, the identification of malaria infected individuals becomes increasingly harder. School surveys may be used to identify foci of malaria transmission in the community. METHODS: The survey was carried out in May-June 2011, before the beginning of the malaria transmission season. Thirty two schools in the Upper River Region of The Gambia were selected with probability proportional to size; in each school approximately 100 children were randomly chosen for inclusion in the study. Each child had a finger prick blood sample collected for the determination of antimalarial antibodies by ELISA, malaria infection by microscopy and PCR, and for haemoglobin measurement. In addition, a simple questionnaire on socio-demographic variables and the use of insecticide-treated bed nets was completed. The cut-off for positivity for antimalarial antibodies was obtained using finite mixture models. The clustered nature of the data was taken into account in the analyses. RESULTS: A total of 3,277 children were included in the survey. The mean age was 10 years (SD = 2.7) [range 4-21], with males and females evenly distributed. The prevalence of malaria infection as determined by PCR was 13.6% (426/3124) [95% CI = 12.2-16.3] with marked variation between schools (range 3-25%, p<0.001), while the seroprevalence was 7.8% (234/2994) [95%CI = 6.4-9.8] for MSP119, 11.6% (364/2997) [95%CI = 9.4-14.5] for MSP2, and 20.0% (593/2973) [95% CI = 16.5-23.2) for AMA1. The prevalence of all the three antimalarial antibodies positive was 2.7% (79/2920). CONCLUSIONS: This survey shows that malaria prevalence and seroprevalence before the transmission season were highly heterogeneous

Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine (PC)-containing secreted product, ES-62

Filarial nematodes, parasites of vertebrates, including humans, secrete immunomodulatory molecules into the host environment. We have previously demonstrated that one such molecule, the phosphorylcholine-containing glycoprotein ES-62, acts to bias the immune response toward an anti-inflammatory/Th2 phenotype that is conducive to both worm survival and host health. For example, although ES-62 initially induces macrophages to produce low levels of IL-12 and TNF-{alpha}, exposure to the parasite product ultimately renders the cells unable to produce these cytokines in response to classic stimulators such as LPS/IFN-{gamma}. We have investigated the possibility that a TLR is involved in the recognition of ES-62 by target cells, because phosphorylcholine, a common pathogen-associated molecular pattern, appears to be responsible for many of the immunomodulatory properties of ES-62. We now demonstrate that ES-62-mediated, low level IL-12 and TNF-{alpha} production by macrophages and dendritic cells is abrogated in MyD88 and TLR4, but not TLR2, knockout, mice implicating TLR4 in the recognition of ES-62 by these cells and MyD88 in the transduction of the resulting intracellular signals. We also show that ES-62 inhibits IL-12 induction by TLR ligands other than LPS, bacterial lipopeptide (TLR2) and CpG (TLR9), via this TLR4-dependent pathway. Surprisingly, macrophages and dendritic cells from LPS-unresponsive, TLR4-mutant C3H/HeJ mice respond normally to ES-62. This is the first report to demonstrate that modulation of cytokine responses by a pathogen product can be abrogated in cells derived from TLR4 knockout, but not C3H/HeJ mice, suggesting the existence of a novel mechanism of TLR4-mediated immunomodulation

Metabolic and hormonal signatures in pre-manifest and manifest Huntington's disease patients

Huntington's disease (HD) is an inherited neurodegenerative disorder typified by involuntary body movements, and psychiatric and cognitive abnormalities. Many HD patients also exhibit metabolic changes including progressive weight loss and appetite dysfunction. Here we have investigated metabolic function in pre-manifest and manifest HD subjects to establish an HD subject metabolic hormonal plasma signature. Individuals at risk for HD who have had predictive genetic testing showing the cytosine-adenine-guanine (CAG) expansion causative of HD, but who do not yet present signs and symptoms sufficient for the diagnosis of manifest HD are said to be pre-manifest. Pre-manifest and manifest HD patients, as well as both familial and non-familial controls, were evaluated for multiple peripheral metabolism signals including circulating levels of hormones, growth factors, lipids and cytokines. Both pre-manifest and manifest HD subjects exhibited significantly reduced levels of circulating growth factors, including growth hormone and prolactin. HD-related changes in the levels of metabolic hormones such as ghrelin, glucagon and amylin were also observed. Total cholesterol, HDL-C and LDL-C were significantly decreased in HD subjects. C-reactive protein was significantly elevated in pre-manifest HD subjects. The observation of metabolic alterations, even in subjects considered to be in the pre-manifest stage of HD, suggests that in addition, and prior, to overt neuronal damage, HD affects metabolic hormone secretion and energy regulation, which may shed light on pathogenesis, and provide opportunities for biomarker development

Metabolic and hormonal signatures in pre-manifest and manifest Huntington's disease patients

Huntington's disease (HD) is an inherited neurodegenerative disorder typified by involuntary body movements, and psychiatric and cognitive abnormalities. Many HD patients also exhibit metabolic changes including progressive weight loss and appetite dysfunction. Here we have investigated metabolic function in pre-manifest and manifest HD subjects to establish an HD subject metabolic hormonal plasma signature. Individuals at risk for HD who have had predictive genetic testing showing the cytosine-adenine-guanine (CAG) expansion causative of HD, but who do not yet present signs and symptoms sufficient for the diagnosis of manifest HD are said to be pre-manifest. Pre-manifest and manifest HD patients, as well as both familial and non-familial controls, were evaluated for multiple peripheral metabolism signals including circulating levels of hormones, growth factors, lipids and cytokines. Both pre-manifest and manifest HD subjects exhibited significantly reduced levels of circulating growth factors, including growth hormone and prolactin. HD-related changes in the levels of metabolic hormones such as ghrelin, glucagon and amylin were also observed. Total cholesterol, HDL-C and LDL-C were significantly decreased in HD subjects. C-reactive protein was significantly elevated in pre-manifest HD subjects. The observation of metabolic alterations, even in subjects considered to be in the pre-manifest stage of HD, suggests that in addition, and prior, to overt neuronal damage, HD affects metabolic hormone secretion and energy regulation, which may shed light on pathogenesis, and provide opportunities for biomarker development

Objectively-assessed physical activity and weight change in young adults: a randomized controlled trial

Abstract Background Reductions in physical activity (PA) are common throughout young adulthood and low PA is associated with weight gain. The SNAP Trial previously reported that two self-regulation approaches to weight gain prevention reduced weight gain over a 2-year period in 18–35 year olds. Presented here are secondary analyses examining changes in PA and the relationship between PA and weight change over 2 years. Methods 599 young adults (age: 27.4 ± 4.4 yrs.; BMI: 25.4 ± 2.6 kg/m2) were randomly assigned to 1 of 3 treatment arms: Small Changes (reduce calorie intake by 100 kcals/day & add 2000 steps/day), Large Changes (lose 2.3–4.5 kg initially & increase PA to ≥250 min/wk), or Self-guided (control condition). Small and Large Changes received 10, face-to-face group sessions (months 1–4), and two 4-week refresher courses each subsequent year. Body weight and PA were objectively-measured at baseline, 4 months, 1 and 2 years. Daily steps and bout-related moderate-to-vigorous intensity PA (MVPA: ≥3 METs, ≥10-min bouts) was calculated. Results Changes in bout-related MVPA and daily steps did not differ among treatment groups over the 2-year period (p’s > 0.16). Collapsed across groups, participants gaining >1 lb. (n = 187; 39.6%) had smaller changes in bout-related MVPA at 4 months, 1 and 2 years relative to those maintaining or losing weight (≤1 lb. weight gain; n = 282, 60.4%, p’s 1 lb. did not differ on daily steps (p’s > 0.10). Among participants engaging in ≥250 min/wk. of MVPA at 2 years (n = 181), 30% gained >1 lb. from baseline to 2 years, which was not different from those engaging in 150–250 min/wk. (n = 87; 36%; p = 0.40), but this percentage was significantly lower when compared to those engaging in 150 min/week of MVPA is needed for weight gain prevention and that increasing MVPA, rather than steps, should be targeted. Trial registration www.clinicaltrials.gov (NCT01183689). Registered Aug 13, 2010

The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis

In countries where parasitic infections are endemic, autoimmune disease is relatively rare, leading to the hypothesis that parasite-derived immunomodulators may protect against its development. Consistent with this, we have previously demonstrated that ES-62, a 62 kDa phosphorylcholine (PC)-containing glycoprotein that is secreted by filarial nematodes, can exert anti-inflammatory action in the murine collagen-induced arthritis (CIA) model and human rheumatoid arthritis-derived synovial tissue cultures. As a first step to developing ES-62-based drugs, the aim of this study was to determine whether the PC-moiety of ES-62 was responsible for its anti-inflammatory actions. We compared the anti-inflammatory activity of a PC-free form of recombinant ES-62 (rES-62) and a synthetic PC-ovalbumin conjugate (OVA-PC) with that of native ES-62 in the CIA model and synovial tissues from patients with rheumatoid arthritis. Results: The anti-inflammatory actions of ES-62 in CIA appear to be dependent on the PC moiety as indicated by the reduction in severity of disease and also suppression of collagen-specific T helper 1 cytokine production observed when testing OVA-PC, but not rES-62. Interestingly, the anti-inflammatory activity of PC did not correlate with a reduction in anti-collagen IgG2a levels. Also, the ES-62-mediated suppression of interferon- from human patient tissues could be mimicked by OVA-PC but not rES-62 or ovalbumin. In countries where filariasis is endemic the reduced detection of inflammatory diseases, such as rheumatoid arthritis may be because of the anti-inflammatory action of the PC moieties of ES-62. PC may thus provide the starting point for the development of novel, safe immunomodulatory therapies