Increasing doses of fiber do not influence short-term satiety or food intake and are inconsistently linked to gut hormone levels

Background: People who eat more fiber often have a lower body weight than people who eat less fiber. The mechanism for this relationship has been explained, in part, by increased satiety, which may occur as a result of changes in appetite-suppressing gut hormone levels, and decreases in food intake at subsequent meals. Objective: We hypothesized that increasing doses of mixed fiber, consumed in muffins for breakfast, would proportionally influence satiety, gut hormone levels, and subsequent food intake. Design: This was a randomized, double-blind, crossover study. Healthy men (n=10) and women (n=10) with a BMI of 24±2 (mean±SEM) participated in this study. Fasting subjects consumed a muffin with 0, 4, 8, or 12 g of mixed fibers and approximately 500 kcal. Visual analog scales rated hunger and satiety for 3 h; blood was drawn to measure ghrelin, glucagon-like peptide-1 (GLP-1), and peptide YY3–36 (PYY3–36) at various intervals; and food intake was measured at an ad libitum lunch. Results: Responses to satiety-related questions did not differ among treatments. However, despite lack of differences in satiety, gut hormone levels differed among treatments. Ghrelin was higher after the 12 g fiber dose than after the 4 and 8 g fiber doses. GLP-1 was higher after the 0 g fiber dose than after the 12 and 4 g fiber doses, and PYY3–36 did not differ among fiber doses. Food intake was also indistinguishable among doses. Conclusion: Satiety, gut hormone response, and food intake did not change in a dose-dependent manner after subjects consumed 0, 4, 8, and 12 g of mixed fiber in muffins for breakfast

Evidence synthesis for constructing directed acyclic graphs (ESC-DAGs): a novel and systematic method for building directed acyclic graphs

Background: Directed acyclic graphs (DAGs) are popular tools for identifying appropriate adjustment strategies for epidemiological analysis. However, a lack of direction on how to build them is problematic. As a solution, we propose using a combination of evidence synthesis strategies and causal inference principles to integrate the DAG-building exercise within the review stages of research projects. We demonstrate this idea by introducing a novel protocol: ‘Evidence Synthesis for Constructing Directed Acyclic Graphs’ (ESC-DAGs)’.\ud Methods: ESC-DAGs operates on empirical studies identified by a literature search, ideally a novel systematic review or review of systematic reviews. It involves three key stages: (i) the conclusions of each study are ‘mapped’ into a DAG; (ii) the causal structures in these DAGs are systematically assessed using several causal inference principles and are corrected accordingly; (iii) the resulting DAGs are then synthesised into one or more ‘integrated DAGs’. This demonstration article didactically applies ESC-DAGs to the literature on parental influences on offspring alcohol use during adolescence. Conclusions: ESC-DAGs is a practical, systematic and transparent approach for developing DAGs from background knowledge. These DAGs can then direct primary data analysis and DAG-based sensitivity analysis. ESC-DAGs has a modular design to allow researchers who are experienced DAG users to both use and improve upon the approach. It is also accessible to researchers with limited experience of DAGs or evidence synthesis

Trace-element abundances in the shallow lithospheric mantle of the North Atlantic Craton margin: implications for melting and metasomatism beneath Northern Scotland

Bulk rock geochemistry and major- and trace-element compositions of clinopyroxene have been determined for three suites of peridotitic mantle xenoliths from the North Atlantic Craton (NAC) in northern Scotland, to establish the magmatic and metasomatic history of subcontinental lithospheric mantle (SCLM) below this region. Spinel lherzolites from the southernmost locality (Streap Com'laidh) have non-NAC mantle compositions, while the two northern xenolith suites (Loch Roag and Rinibar) are derived from the thinned NAC marginal keel. Clinopyroxene compositions have characteristic trace-element signatures which show both 'primary' and 'metasomatic' origins. We use Zr and Hf abundances to identify ancient cryptic refertilization in 'primary' clinopyroxenes. We suggest that Loch Roag and Rinibar peridotite xenoliths represent an ancient Archaean-Palaeoproterozoic SCLM with original depleted cratonic signatures which were overprinted by metasomatism around the time of intrusion of the Scourie Dyke Swarm (∼2.4 Ga). This SCLM keel was preserved during Caledonian orogenesis, although some addition of material and/or metasomatism probably also occurred, as recorded by Rinibar xenoliths. Rinibar and Streap xenoliths were entrained in Permo-Carboniferous magmas and thus were isolated from the SCLM ∼200 Ma before Loch Roag xenoliths (in an Eocene dyke). Crucially, despite their geographical location, lithospheric mantle peridotite samples from Loch Roag show no evidence of recent melting or refertilization during the Palaeogene opening of the Atlantic

Tazarotene 0.045% Lotion for Moderate-to-Severe Acne in Male and Female Participants: A Phase II Post-hoc Analysis

BACKGROUND: In a Phase II study, tazarotene 0.045% lotion was statistically superior to vehicle and comparable to tazarotene 0.1% cream in reducing acne lesions, with fewer treatment-related adverse events (TEAEs) than the cream. OBJECTIVE: We analyzed data from the aforementioned study post-hoc to evaluate the effects of sex on treatment outcomes. METHODS: Participants aged 12 years or older with moderate-to-severe acne were randomized to tazarotene (0.045% lotion or 0.1% cream) or vehicle (lotion or cream) for 12 weeks of double-blind treatment. Outcomes analyzed in male and female subgroups included changes from baseline in inflammatory/noninflammatory lesions and TEAEs. RESULTS: In the intent-to-treat population (94 males and 116 females), reductions in lesion count were greater with tazarotene (lotion or cream) than with vehicle. In participants receiving tazarotene 0.045% lotion, the least-squares mean percent changes from baseline to Week 12 were greater in females than males, but the differences were not statistically significant (inflammatory [-70.3% vs. -56.2%]; noninflammatory [-60.0% vs. -53.2%]). In both females and males, the TEAE incidence was lower with tazarotene 0.045% lotion than 0.1% cream. CONCLUSION: Tazarotene 0.045% lotion substantially reduced acne lesions in both female and male participants. This newest tazarotene formulation might benefit patients who cannot tolerate older formulations or other topical retinoids. Given the relatively small size of this study, however, the results of this post-hoc analysis are intended to be exploratory in nature

DDX3X and specific initiation factors modulate FMR1 repeat‐associated non‐AUG‐initiated translation

A CGG trinucleotide repeat expansion in the 5′ UTR of FMR1 causes the neurodegenerative disorder Fragile X‐associated tremor/ataxia syndrome (FXTAS). This repeat supports a non‐canonical mode of protein synthesis known as repeat‐associated, non‐AUG (RAN) translation. The mechanism underlying RAN translation at CGG repeats remains unclear. To identify modifiers of RAN translation and potential therapeutic targets, we performed a candidate‐based screen of eukaryotic initiation factors and RNA helicases in cell‐based assays and a Drosophila melanogaster model of FXTAS. We identified multiple modifiers of toxicity and RAN translation from an expanded CGG repeat in the context of the FMR1 5′UTR. These include the DEAD‐box RNA helicase belle/DDX3X, the helicase accessory factors EIF4B/4H, and the start codon selectivity factors EIF1 and EIF5. Disrupting belle/DDX3X selectively inhibited FMR1 RAN translation in Drosophila in vivo and cultured human cells, and mitigated repeat‐induced toxicity in Drosophila and primary rodent neurons. These findings implicate RNA secondary structure and start codon fidelity as critical elements mediating FMR1 RAN translation and identify potential targets for treating repeat‐associated neurodegeneration.SynopsisFragile X‐associated tremor/ataxia syndrome is caused by CGG repeat‐associated non‐AUG (RAN) translation that initiates within the 5′UTR of FMR1. A candidate‐based screen identified several initiation factors—DDX3X/Belle, eIF4B, eIF4H, eIF1, and eIF5—critical for FMR1 RAN translation.Knockdown of the RNA helicase DDX3X selectively suppresses FMR1 RAN translation in Drosophila melanogaster, cultured HeLa cells, and in vitro translation assays.DDX3X knockdown reduces CGG repeat‐associated toxicity in Drosophila and mammalian neurons.Eukaryotic initiation factors that modulate RNA‐RNA secondary structure (DDX3X, EIF4B, EIF4H) or start codon fidelity (EIF1, EIF5) impact FMR1 RAN translation.FXTAS is caused by CGG repeat‐associated non‐AUG (RAN) translation that initiates within the 5′UTR of FMR1. A candidate‐based screen identified several initiation factors—DDX3X/Belle, eIF4B, eIF4H, eIF1, and eIF5—critical for FMR1 RAN translation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151325/1/embr201847498.reviewer_comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151325/2/embr201847498-sup-0001-Appendix.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151325/3/embr201847498_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151325/4/embr201847498.pd

Abuse and Diversion of Buprenorphine Sublingual Tablets and Film

Buprenorphine abuse is common worldwide. Rates of abuse and diversion of three sublingual buprenorphine formulations (single ingredient tablets; naloxone combination tablets and film) were compared. Data were obtained from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Poison Center, Drug Diversion, Opioid Treatment (OTP), Survey of Key Informants\u27 Patients (SKIP), and College Survey Programs through December 2012. To control for drug availability, event ratios (rates) were calculated quarterly, based on the number of patients filling prescriptions for each formulation ( unique recipients of a dispensed drug, URDD) and averaged and compared using negative binomial regression. Abuse rates in the OTP, SKIP, and College Survey Programs were greatest for single ingredient tablets, and abuse rates in the Poison Center Program and illicit diversion rates were greatest for the combination tablets. Combination film rates were significantly less than rates for either tablet formulation in all programs. No geographic pattern could be discerned

The power of practice: simulation training improving the quality of neonatal resuscitation skills in Bihar, India.

BACKGROUND: Globally, neonatal mortality accounts for nearly half of under-five mortality, and intrapartum related events are a leading cause. Despite the rise in neonatal resuscitation (NR) training programs in low- and middle-income countries, their impact on the quality of NR skills amongst providers with limited formal medical education, particularly those working in rural primary health centers (PHCs), remains incompletely understood. METHODS: This study evaluates the impact of PRONTO International simulation training on the quality of NR skills in simulated resuscitations and live deliveries in rural PHCs throughout Bihar, India. Further, it explores barriers to performance of key NR skills. PRONTO training was conducted within CARE India's AMANAT intervention, a maternal and child health quality improvement project. Performance in simulations was evaluated using video-recorded assessment simulations at weeks 4 and 8 of training. Performance in live deliveries was evaluated in real time using a mobile-phone application. Barriers were explored through semi-structured interviews with simulation facilitators. RESULTS: In total, 1342 nurses participated in PRONTO training and 226 NR assessment simulations were matched by PHC and evaluated. From week 4 to 8 of training, proper neck extension, positive pressure ventilation (PPV) with chest rise, and assessment of heart rate increased by 14%, 19%, and 12% respectively (all p ≤ 0.01). No difference was noted in stimulation, suction, proper PPV rate, or time to completion of key steps. In 252 live deliveries, identification of non-vigorous neonates, use of suction, and use of PPV increased by 21%, 25%, and 23% respectively (all p < 0.01) between weeks 1-3 and 4-8. Eighteen interviews revealed individual, logistical, and cultural barriers to key NR skills. CONCLUSION: PRONTO simulation training had a positive impact on the quality of key skills in simulated and live resuscitations throughout Bihar. Nevertheless, there is need for ongoing improvement that will likely require both further clinical training and addressing barriers that go beyond the scope of such training. In settings where clinical outcome data is unreliable, data triangulation, the process of synthesizing multiple data sources to generate a better-informed evaluation, offers a powerful tool for guiding this process

Targeting lysyl oxidase reduces peritoneal fibrosis

Abdominal surgery and disease cause persistent abdominal adhesions, pelvic pain, infertility and occasionally, bowel obstruction. Current treatments are ineffective and the aetiology is unclear, although excessive collagen deposition is a consistent feature. Lysyl oxidase (Lox) is a key enzyme required for crosslinking and deposition of insoluble collagen, so we investigated whether targeting Lox might be an approach to reduce abdominal adhesions.Female C57Bl/6 mice were treated intraperitoneally with multiwalled carbon nanotubes (NT) to induce fibrosis, together with chemical (ß-aminoproprionitrile-BAPN) or miRNA Lox inhibitors, progesterone or dexamethasone. Fibrotic lesions on the diaphragm, and expression of fibrosis-related genes in abdominal wall peritoneal mesothelial cells (PMC) were measured. Effects of BAPN and dexamethasone on collagen fibre alignment were observed by TEM. Isolated PMC were cultured with interleukin-1 alpha (IL-1α) and progesterone to determine effects on Lox mRNA in vitro.NT-induced fibrosis and collagen deposition on the diaphragm was ameliorated by BAPN, Lox miRNA, or steroids. BAPN and dexamethasone disrupted collagen fibres. NT increased PMC Lox, Col1a1, Col3a1 and Bmp1 mRNA, which was inhibited by steroids. Progesterone significantly inhibited IL-1α induced Lox expression by PMC in vitro.Our results provide proof-of-concept that targeting peritoneal Lox could be an effective approach in ameliorating fibrosis and adhesion development