Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.

Restricted sugar and ketogenic diets can alter energy balance/metabolism, but decreased energy intake may be compensated by reduced expenditure. In healthy adults, randomization to restricting free sugars or overall carbohydrates (ketogenic diet) for 12 weeks reduces fat mass without changing energy expenditure versus control. Free-sugar restriction minimally affects metabolism or gut microbiome but decreases low-density lipoprotein cholesterol (LDL-C). In contrast, a ketogenic diet decreases glucose tolerance, increases skeletal muscle PDK4, and reduces AMPK and GLUT4 levels. By week 4, the ketogenic diet reduces fasting glucose and increases apolipoprotein B, C-reactive protein, and postprandial glycerol concentrations. However, despite sustained ketosis, these effects are no longer apparent by week 12, when gut microbial beta diversity is altered, possibly reflective of longer-term adjustments to the ketogenic diet and/or energy balance. These data demonstrate that restricting free sugars or overall carbohydrates reduces energy intake without altering physical activity, but with divergent effects on glucose tolerance, lipoprotein profiles, and gut microbiome.

Postprandial plasma amino acid and appetite responses with ingestion of a novel salmon-derived protein peptide in healthy young adults.

This study assessed postprandial plasma aminoacidemia, glycemia, insulinemia and appetite responses to ingestion of a novel salmon-derived protein peptide (Salmon PP) compared with milk protein isolate (Milk PI). In a randomised, participant-blind crossover design, eleven healthy adults (M = 5, F = 6; mean ± sd age: 22 ± 3 years; BMI: 24 ± 3 kg/m2) ingested 0·3 g/kg/body mass of Salmon PP or Milk PI. Arterialised blood samples were collected whilst fasted and over a 240-min postprandial period. Appetite sensations were measured via visual analogue scales. An ad libitum buffet-style test meal was administered after each trial. The incremental AUC (iAUC) plasma essential amino acid (EAA) response was similar between Salmon PP and Milk PI. The iAUC plasma leucine response was significantly greater following Milk PI ingestion (P < 0·001), whereas temporal and iAUC plasma total amino acid (P = 0·001), non-essential amino acid (P = 0·002), glycine (P = 0·0025) and hydroxyproline (P < 0·001) responses were greater following Salmon PP ingestion. Plasma insulin increased similarly above post-absorptive values following Salmon PP and Milk PI ingestion, whilst plasma glucose was largely unaltered. Indices of appetite were similarly altered following Salmon PP and Milk PI ingestion, and total energy and macronutrient intake during the ad libitum meal was similar between Salmon PP and Milk PI. The postprandial plasma EAA, glycine, proline and hydroxyproline response to Salmon PP ingestion suggest this novel protein source could support muscle and possibly connective tissue adaptive remodelling, which warrants further investigation, particularly as the plasma leucine response to Salmon PP ingestion was inferior to Milk PI.

SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry.

BACKGROUND: COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. METHODS: OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. FINDINGS: At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [50·7%] of 1902 patients with sex data were female and 938 [49·3%] were male). Overall, 317 (16·6%; 95% CI 14·8-18·5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the pre-vaccination phase (191 [19·1%; 95% CI 16·4-22·0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16·8%; 13·8-20·3] of 653 patients, p=0·24), but significantly lower in the omicron phase (16 [6·2%; 3·5-10·2] of 256 patients, p<0·0001). In the alpha-delta phase, 84 (18·3%; 95% CI 14·6-22·7) of 458 unvaccinated patients and three (9·4%; 1·9-27·3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7·4%; 95% CI 3·5-13·5] of 136 boosted patients, 18 [9·8%; 5·8-15·5] of 183 patients who had two vaccine doses vs 277 [18·5%; 16·5-20·9] of 1489 unvaccinated patients, p=0·0001), respiratory sequelae (six [4·4%; 1·6-9·6], 11 [6·0%; 3·0-10·7] vs 148 [9·9%; 8·4-11·6], p=0·030), and prolonged fatigue (three [2·2%; 0·1-6·4], ten [5·4%; 2·6-10·0] vs 115 [7·7%; 6·3-9·3], p=0·037). INTERPRETATION: Unvaccinated patients with cancer remain highly vulnerable to COVID-19 sequelae irrespective of viral strain. This study confirms the role of previous SARS-CoV-2 immunisation as an effective measure to protect patients from COVID-19 sequelae, disruption of therapy, and ensuing mortality. FUNDING: UK National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant outbreak among vaccinated and unvaccinated patients with cancer in Europe: results from the retrospective, multicentre, OnCovid registry study.

BACKGROUND: The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe. METHODS: In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing. FINDINGS: As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57-77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19-0·61) and 28 days (0·34 [0·16-0·79]), complications due to COVID-19 (0·26 [0·17-0·46]), and hospitalisation due to COVID-19 (0·17 [0·09-0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15-0·34]) and oxygen therapy (0·24 [0·14-0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase. INTERPRETATION: Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19. FUNDING: National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing.

Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear ribonucleoprotein (snRNP) splicing factor. Compounds that emerged from these studies had enhanced potency and selectivity for the target RNA relative to the initial hits, while also having significantly improved drug-like properties. The compounds are shown to directly target tau pre-mRNA in cells, via chemical cross-linking and isolation by pull-down target profiling, and to rescue disease-relevant splicing of tau pre-mRNA in a variety of cellular systems, including primary neurons. More broadly, this study shows that lead, structure-specific compounds can be designed from sequence and then further optimized for their physicochemical properties while at the same time enhancing their activity.

From the Ground Up: Improving Pregnancy and Birth Experiences Through the Provision of Extraordinary Learning Opportunities in Australia.

A collaborative project formally titled "Working together to improve pregnancy and birth experiences for women and provide extraordinary learning opportunities for midwifery students" was launched in April 2017, after several years of consultation and planning. The opportunity to adopt an integrated response to the needs of incarcerated pregnant women and the learning needs of midwifery students was identified and supported by the university offering a graduate-entry midwifery program, a women's correctional center, and a health service in a regional area of Australia. Incarcerated women who are pregnant require pregnancy, birth, and postnatal support distinct from their clinical care, while at the same time, midwifery students need to recruit pregnant women for continuity-of-care experiences. This article presents an overview of the implementation of the pilot project. It also discusses the project team and the challenges and successes of and unanticipated opportunities for practice modification and change.

Chemical Probe Identification Platform for Orphan GPCRs Using Focused Compound Screening: GPR39 as a Case Example.

Orphan G protein-coupled receptors (oGPCRs) are a class of integral membrane proteins for which endogenous ligands or transmitters have not yet been discovered. Transgenic animal technologies have uncovered potential roles for many of these oGPCRs, providing new targets for the treatment of various diseases. Understanding signaling pathways of oGPCRs and validating these receptors as potential drug targets requires the identification of chemical probe compounds to be used in place of endogenous ligands to interrogate these receptors. A novel chemical probe identification platform was created in which GPCR-focused libraries were screened against sets of oGPCR targets, with a goal of discovering fit-for-purpose chemical probes for the more druggable members of the set. Application of the platform to a set of oGPCRs resulted in the discovery of the first reported small molecule agonists for GPR39, a receptor implicated in the regulation of insulin secretion and preservation of beta cells in the pancreas. Compound 1 stimulated intracellular calcium mobilization in recombinant and native cells in a GPR39-specific manner but did not potentiate glucose-stimulated insulin secretion in human islet preparations.

Emerging perspectives in the restoration of biodiversity-based ecosystem services.

Given the large-scale anthropogenic alteration of natural habitats, ecological restoration is emerging as one of the most important disciplines in environmental science. Once habitats are physically restored, an important goal of restoration is to recover the ecosystem services provided by the diversity of species and their interactions (e.g., seed dispersal, pollination, pest control, and invasion resistance). However, current understanding of the ecological processes underlying this recovery is often incomplete and poorly integrated across different ecosystems. Here, we highlight recent conceptual findings in biodiversity-ecosystem functioning, food-web theory, and metacommunity theory that are relevant to restoration. We also identify knowledge gaps that will contribute to moving restoration from a site- and situation-specific discipline to a more globally applicable science.

Discovery of new piperidine amide triazolobenzodiazepinones as intestinal-selective CCK1 receptor agonists.

New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R's located within the intestinal wall.

Using simulated patients to develop doctors' skills in facilitating behaviour change: addressing childhood obesity.

OBJECTIVES: This study aimed to describe the application, feasibility and outcomes of using simulated patients (SPs) to increase the skills of general practitioners (GPs) delivering a behavioural intervention to reduce childhood overweight and mild obesity. METHODS: Five female actors were trained as SPs. A total of 67 GPs from 46 general practices in Melbourne, Victoria, Australia, conducted two simulated consultation visits regarding healthy lifestyle family behaviour change, during which they practised their skills and received formative feedback. The GPs and SPs rated GP performance immediately after each consultation. Subsequently, 139 parents of overweight or obese 5-9-year-old children rated GP performance during real-life consultations. Other measures included child body mass index (BMI) Z-scores (at baseline and at a 9-month follow-up) and GP-reported levels of comfort and competence and the perceived value of SP visits. RESULTS: Simulated patient ratings, but not GP self-ratings, of GP performance predicted both parent ratings of real-life consultations (Spearman's rho 0.39 for correlation with SP rating at Visit 1) and subsequent reductions in BMI Z-scores between baseline and follow-up (Visit 1, rho-0.45; Visit 2, rho-0.46). GP levels of comfort and competence were maintained during and after the SP visits. A total of 95% of GPs rated simulated consultations as useful, although only 18% said they would pay for them. CONCLUSIONS: Simulated patient assessment may predict real patient feedback and clinical outcomes, helping to identify doctors who require further training in behaviour change techniques. Randomised controlled trials may establish whether SPs actually raise skills or improve outcomes.

Mating system of the Eurasian badger, Meles meles, in a high density population.

Badgers are facultatively social, forming large groups at high density. Group-living appears to have high reproductive costs for females, and may lead to increased levels of inbreeding. The extent of female competition for reproduction has been estimated from field data, but knowledge of male reproductive success and the extent of extra-group paternity remains limited. Combining field data with genetic data (16 microsatellite loci), we studied the mating system of 10 badger social groups across 14 years in a high-density population. From 923 badgers, including 425 cubs, we were able to assign maternity to 307 cubs, with both parents assigned to 199 cubs (47%) with 80% confidence, and 14% with 95% confidence. Age had a significant effect on the probability of reproduction, seemingly as a result of a deficit of individuals aged two years and greater than eight years attaining parentage. We estimate that approximately 30% of the female population successfully reproduced in any given year, with a similar proportion of the male population gaining paternity across the same area. While it was known there was a cost to female reproduction in high density populations, it appears that males suffer similar, but not greater, costs. Roughly half of assigned paternity was attributed to extra-group males, the majority of which were from neighbouring social groups. Few successful matings occurred between individuals born in the same social group (22%). The high rate of extra-group mating, previously unquantified, may help reduce inbreeding, potentially making philopatry a less costly strategy.