Volatile phenols in wine: overview of origin, formation, analysis, and sensory expression.

Volatile phenols impart particular aromas to wine. Due to their distinctive aroma characteristics and low sensory thresholds, volatile phenols can easily influence and modify the aroma of wine. Since these compounds can be formed in wines in various ways, it is necessary to clarify the possible sources of each volatile phenol to achieve management during the winemaking process. The sources of volatile phenols in wine are divided into berry-derived, fermentation-derived, and oak-derived. The pathways and factors influencing the formation of volatile phenols from each source are then reviewed respectively. In addition, an overview of the sensory impact of volatile phenols is given, both in terms of the aroma these volatile phenols directly bring to the wine and their contribution through aroma interactions. Finally, as an essential basis for exploring the scientific problems of volatile phenols in wine, approaches to quantitation of volatile phenols and their precursors are discussed in detail. With the advancement of analytical techniques, more details on volatile phenols have been discovered. Further exploration is worthwhile to achieve more detailed monitoring and targeted management of volatile phenols in wine.

Associations between types and sources of dietary carbohydrates and cardiovascular disease risk: a prospective cohort study of UK Biobank participants.

BACKGROUND: Recent studies have reported that the associations between dietary carbohydrates and cardiovascular disease (CVD) may depend on the quality, rather than the quantity, of carbohydrates consumed. This study aimed to assess the associations between types and sources of dietary carbohydrates and CVD incidence. A secondary aim was to examine the associations of carbohydrate intakes with triglycerides within lipoprotein subclasses. METHODS: A total of 110,497 UK Biobank participants with ≥ two (maximum five) 24-h dietary assessments who were free from CVD and diabetes at baseline were included. Multivariable-adjusted Cox regressions were used to estimate risks of incident total CVD (4188 cases), ischaemic heart disease (IHD; 3138) and stroke (1124) by carbohydrate intakes over a median follow-up time of 9.4 years, and the effect of modelled dietary substitutions. The associations of carbohydrate intakes with plasma triglycerides within lipoprotein subclasses as measured by nuclear magnetic resonance (NMR) spectroscopy were examined in 26,095 participants with baseline NMR spectroscopy measurements. RESULTS: Total carbohydrate intake was not associated with CVD outcomes. Free sugar intake was positively associated with total CVD (HR; 95% CI per 5% of energy, 1.07;1.03-1.10), IHD (1.06;1.02-1.10), and stroke (1.10;1.04-1.17). Fibre intake was inversely associated with total CVD (HR; 95% CI per 5 g/d, 0.96;0.93-0.99). Modelled isoenergetic substitution of 5% of energy from refined grain starch with wholegrain starch was inversely associated with total CVD (0.94;0.91-0.98) and IHD (0.94;0.90-0.98), and substitution of free sugars with non-free sugars was inversely associated with total CVD (0.95;0.92-0.98) and stroke (0.91;0.86-0.97). Free sugar intake was positively associated with triglycerides within all lipoproteins. CONCLUSIONS: Higher free sugar intake was associated with higher CVD incidence and higher triglyceride concentrations within all lipoproteins. Higher fibre intake and replacement of refined grain starch and free sugars with wholegrain starch and non-free sugars, respectively, may be protective for incident CVD.

Proton pump inhibitor use: systematic review of global trends and practices.

PURPOSE: Proton pump inhibitors (PPIs) reduce acid secretion in the stomach and rank as one of the most widely used acid-suppressing medicines globally. While PPIs are safe in the short-term, emerging evidence shows risks associated with long-term use. Current evidence on global PPI use is scarce. This systematic review aims to evaluate global PPI use in the general population. METHODS: Ovid MEDLINE, Embase, and International Pharmaceutical Abstracts were systematically searched from inception to 31 March 2023 to identify observational studies on oral PPI use among individuals aged ≥ 18 years. PPI use was classified by demographics and medication factors (dose, duration, and PPI types). The absolute numbers of PPI users for each subcategory were summed and expressed as a percentage. RESULTS: The search identified data from 28 million PPI users in 23 countries from 65 articles. This review indicated that nearly one-quarter of adults use a PPI. Of those using PPIs, 63% were less than 65 years. 56% of PPI users were female, and "White" ethnicities accounted for 75% of users. Nearly two-thirds of users were on high doses (≥ defined daily dose (DDD)), 25% of users continued PPIs for > 1 year, and 28% of these continued for > 3 years. CONCLUSION: Given the widespread use PPIs and increasing concern regarding long-term use, this review provides a catalyst to support more rational use, particularly with unnecessary prolonged continuation. Clinicians should review PPI prescriptions regularly and deprescribe when there is no appropriate ongoing indication or evidence of benefit to reduce health harm and treatment cost.

Antibiotic prophylaxis dysregulates dental implant placement surgery-induced osteoimmune wound healing and attenuates the alveolar bone-implant interface in mice.

AIM: Antimicrobial-induced shifts in commensal oral microbiota can dysregulate helper T-cell oral immunity to affect osteoclast-osteoblast actions in alveolar bone. Antibiotic prophylaxis is commonly performed with dental implant placement surgery to prevent post-surgical complications. However, antibiotic prophylaxis effects on osteoimmune processes supporting dental implant osseointegration are unknown. The aim of the study was to discern the impact of antibiotic prophylaxis on dental implant placement surgery-induced osteoimmune wound healing and osseointegration. MATERIALS AND METHODS: We performed SHAM or dental implant placement surgery in mice. Groups were administered prophylactic antibiotics (amoxicillin or clindamycin) or vehicle. Gingival bacteriome was assessed via 16S sequencing. Helper T-cell oral immunity was evaluated by flow cytometry. Osteoclasts and osteoblasts were assessed via histomorphometry. Implant osseointegration was evaluated by micro-computed tomography. RESULTS: Dental implant placement surgery up-regulated TH 1, TH 2 and TREG cells in cervical lymph nodes (CLNs), which infers helper T-cell oral immunity contributes to dental implant placement osseous wound healing. Prophylactic antibiotics with dental implant placement surgery caused a bacterial dysbiosis, suppressed TH 1, TH 2 and TREG cells in CLNs, reduced osteoclasts and osteoblasts lining peri-implant alveolar bone, and attenuated the alveolar bone-implant interface. CONCLUSIONS: Antibiotic prophylaxis dysregulates dental implant placement surgery-induced osteoimmune wound healing and attenuates the alveolar bone-implant interface in mice.

Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence.

Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41-71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients' glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System's pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10-3) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10-3) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer's disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62-5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10-6) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11-0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47-58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings.

Synthesising Programs with Non-trivial Constants.

Program synthesis is the mechanised construction of software. One of the main difficulties is the efficient exploration of the very large solution space, and tools often require a user-provided syntactic restriction of the search space. While useful in general, such syntactic restrictions provide little help for the generation of programs that contain non-trivial constants, unless the user is able to provide the constants in advance. This is a fundamentally difficult task for state-of-the-art synthesisers. We propose a new approach to the synthesis of programs with non-trivial constants that combines the strengths of a counterexample-guided inductive synthesiser with those of a theory solver, exploring the solution space more efficiently without relying on user guidance. We call this approach CEGIS(T), where T is a first-order theory. We present two exemplars, one based on Fourier-Motzkin (FM) variable elimination and one based on first-order satisfiability. We demonstrate the practical value of CEGIS(T) by automatically synthesising programs for a set of intricate benchmarks. Additionally, we present a case study where we integrate CEGIS(T) within the mature synthesiser CVC4 and show that CEGIS(T) improves CVC4's results.

Diets for weight management in adults with type 2 diabetes: an umbrella review of published meta-analyses and systematic review of trials of diets for diabetes remission.

AIMS/HYPOTHESIS: Weight reduction is fundamental for type 2 diabetes management and remission, but uncertainty exists over which diet type is best to achieve and maintain weight loss. We evaluated dietary approaches for weight loss, and remission, in people with type 2 diabetes to inform practice and clinical guidelines. METHODS: First, we conducted a systematic review of published meta-analyses of RCTs of weight-loss diets. We searched MEDLINE (Ovid), PubMed, Web of Science and Cochrane Database of Systematic Reviews, up to 7 May 2021. We synthesised weight loss findings stratified by diet types and assessed meta-analyses quality with A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. We assessed certainty of pooled results of each meta-analysis using Grading of Recommendations, Assessment, Development and Evaluations (GRADE) (PROSPERO CRD42020169258). Second, we conducted a systematic review of any intervention studies reporting type 2 diabetes remission with weight-loss diets, in MEDLINE (via PubMed), Embase and Cochrane Central Register of Controlled Trials, up to 10 May 2021. Findings were synthesised by diet type and study quality (Cochrane Risk of Bias tool 2.0 and Risk Of Bias In Non-randomised Studies - of Interventions [ROBINS-I]), with GRADE applied (PROSPERO CRD42020208878). RESULTS: We identified 19 meta-analyses of weight-loss diets, involving 2-23 primary trials (n = 100-1587), published 2013-2021. Twelve were 'critically low' or 'low' AMSTAR 2 quality, with seven 'high' quality. Greatest weight loss was reported with very low energy diets, 1.7-2.1 MJ/day (400-500 kcal) for 8-12 weeks (high-quality meta-analysis, GRADE low), achieving 6.6 kg (95% CI -9.5, -3.7) greater weight loss than low-energy diets (4.2-6.3 MJ/day [1000-1500 kcal]). Formula meal replacements (high quality, GRADE moderate) achieved 2.4 kg (95% CI -3.3, -1.4) greater weight loss over 12-52 weeks. Low-carbohydrate diets were no better for weight loss than higher-carbohydrate/low-fat diets (high quality, GRADE high). High-protein, Mediterranean, high-monounsaturated-fatty-acid, vegetarian and low-glycaemic-index diets all achieved minimal (0.3-2 kg) or no difference from control diets (low to critically low quality, GRADE very low/moderate). For type 2 diabetes remission, of 373 records, 16 met inclusion criteria. Remissions at 1 year were reported for a median 54% of participants in RCTs including initial low-energy total diet replacement (low-risk-of-bias study, GRADE high), and 11% and 15% for meal replacements and Mediterranean diets, respectively (some concerns for risk of bias in studies, GRADE moderate/low). For ketogenic/very low-carbohydrate and very low-energy food-based diets, the evidence for remission (20% and 22%, respectively) has serious and critical risk of bias, and GRADE certainty is very low. CONCLUSIONS/INTERPRETATION: Published meta-analyses of hypocaloric diets for weight management in people with type 2 diabetes do not support any particular macronutrient profile or style over others. Very low energy diets and formula meal replacement appear the most effective approaches, generally providing less energy than self-administered food-based diets. Programmes including a hypocaloric formula 'total diet replacement' induction phase were most effective for type 2 diabetes remission. Most of the evidence is restricted to 1 year or less. Well-conducted research is needed to assess longer-term impacts on weight, glycaemic control, clinical outcomes and diabetes complications.

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights.

The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives.

Dietary fibre in hypertension and cardiovascular disease management: systematic review and meta-analyses.

BACKGROUND: Higher dietary fibre intakes are associated with a reduced risk of developing cardiovascular disease (CVD), and increasing intake has been shown to reduce blood pressure and other cardiometabolic risk factors. The extent to which dietary fibre can further reduce risk for those with CVD and treated with cardioprotective drugs has not been clearly established. We have examined the evidence for dietary fibre as adjunct therapy in those with CVD or hypertension. METHODS: Ovid MEDLINE, Embase, PubMed, and CENTRAL were searched to June 2021. Prospective observational studies reporting on fibre intakes and mortality in those with pre-existing CVD and controlled trials of increasing fibre intakes on cardiometabolic risk factors in those with CVD or hypertension were eligible. Outcomes were mortality (studies) and cardiometabolic risk factors (trials). Data synthesis was with random effects and dose response. Certainty of evidence was assessed using GRADE. RESULTS: Three prospective studies including 7469 adults with CVD, and 12 trials of 878 adults with CVD or hypertension were identified. Moderate certainty evidence indicates reduced all-cause mortality (relative risk, RR0.75 (95% confidence interval, CI 0.58-0.97)) when comparing higher with lower fibre intakes. Low certainty evidence from trials of adults with cardiovascular disease indicates increasing fibre intakes reduced total (mean difference, MD - 0.42 mmol/L (95%CI - 0.78 to - 0.05) and low-density lipoprotein (LDL) cholesterol (MD - 0.47mmol/L (95%CI - 0.85 to - 0.10)). High certainty evidence from trials of adults with hypertension indicates increasing fibre intakes reduces systolic (MD 4.3 mmHg (95% CI 2.2 to 5.8)) and diastolic blood pressure (MD 3.1 mmHg (95% CI 1.7 to 4.4)). Moderate and low certainty evidence indicated improvements in fasting blood glucose (MD 0.48 mmol/L (- 0.91 to - 0.05)) and LDL cholesterol (MD 0.29 mmol/L (95% CI 0.17 to 0.40)). Benefits were observed irrespective of cardioprotective drug use. CONCLUSIONS: These findings emphasise the likely benefits of promoting greater dietary fibre intakes for patients with CVD and hypertension. Further trials and cohort analyses in this area would increase confidence in these results.

American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

The aim of this document is to provide a concise scientific review of the currently available COVID-19 vaccines and those in development, including mRNA, adenoviral vectors, and recombinant protein approaches. The anticipated use of COVID-19 vaccines in patients with chronic liver disease (CLD) and liver transplant (LT) recipients is reviewed and practical guidance is provided for health care providers involved in the care of patients with liver disease and LT about vaccine prioritization and administration. The Pfizer and Moderna mRNA COVID-19 vaccines are associated with a 94%-95% vaccine efficacy compared to placebo against COVID-19. Local site reactions of pain and tenderness were reported in 70%-90% of clinical trial participants, and systemic reactions of fever and fatigue were reported in 40%-70% of participants, but these reactions were generally mild and self-limited and occurred more frequently in younger persons. Severe hypersensitivity reactions related to the mRNA COVID-19 vaccines are rare and more commonly observed in women and persons with a history of previous drug reactions for unclear reasons. Because patients with advanced liver disease and immunosuppressed patients were excluded from the vaccine licensing trials, additional data regarding the safety and efficacy of COVID-19 vaccines are eagerly awaited in these and other subgroups. Remarkably safe and highly effective mRNA COVID-19 vaccines are now available for widespread use and should be given to all adult patients with CLD and LT recipients. The online companion document located at https://www.aasld.org/about-aasld/covid-19-resources will be updated as additional data become available regarding the safety and efficacy of other COVID-19 vaccines in development.

Gelatinisation and milling whole-wheat increases postprandial blood glucose: randomised crossover study of adults with type 2 diabetes.

AIMS/HYPOTHESES: We examined the effects of milling and cooking whole grains in water to achieve starch gelatinisation on postprandial blood glucose using a randomised crossover open-label design. Participants were adults with type 2 diabetes whose body weight or medications had not changed in at least 3 months. METHODS: Postprandial blood glucose (measured as incremental AUC [iAUC]) was measured following consumption of four nutrient-matched whole-wheat porridge test-meals. Test-meals included gelatinised or native starch and were made with either finely milled or intact whole-wheat. RESULTS: Eighteen adults (63.1 ± 9.8 years, HbA1c 57.0 ± 11.5 mmol/mol [7.4 ± 3.2%]) completed the study. iAUC was higher following cooked meals (gelatinised starch) than following uncooked meals (native starch) (mean difference [MD] 268, 95% CI 188, 348 mmol/l × min). Consuming finely milled whole-wheat produced a higher iAUC compared with intact whole-wheat (MD 173, 95% CI 80, 266 mmol/l × min). There was no evidence of an interaction effect (p = 0.841). CONCLUSIONS: Both the nature of starch and the grain structure of whole-wheat influence the glycaemic response of adults with type 2 diabetes mellitus. FUNDING: Baking Industry Research Trust of New Zealand and the Riddet Centre of Research Excellence. TRIAL REGISTRATION: www.anzctr.org.au ACTRN12617000328370.

Dietary fat intakes and cardiovascular disease risk in adults with type 2 diabetes: a systematic review and meta-analysis.

PURPOSE: Advice regarding the intake of dietary fats is particularly relevant to those with type 2 diabetes, given their increased risk of cardiovascular disease. METHODS: We have undertaken a systematic review of fat intakes and cardiovascular disease risk in adults with type 2 diabetes using an online search strategy to 24 April 2020, augmented with hand searching. Searches, extraction, and risk of bias assessments were undertaken by two researchers. The quality of evidence was assessed with GRADE protocols. RESULTS: We identified five eligible prospective studies of 22,591 participants followed for on average 9.8 years, and one trial of 14 participants with type 2 diabetes. Limited data were available; however, replacement analyses of saturated fat with polyunsaturated fat (RR for 2% energy replacement 0.87 95% CI: 0.77-0.99) or carbohydrate (RR for 5% energy replacement 0.82 95% CI: 0.67-1.00) was associated with reduced cardiovascular disease occurrence. Higher polyunsaturated: saturated fat intake was also associated with reduced cardiovascular disease occurrence (RR 0.75 95% CI: 0.57-0.98). The quality of evidence was low to very-low. CONCLUSION: Although only limited data were available, replacement of saturated fats with other macronutrients, such as polyunsaturated fats, was associated with reduced cardiovascular disease occurrence. Supporting evidence from research in the general population increases confidence in these findings. Until more data are available to better comment on dietary fat intakes in cardiovascular disease risk of those with type 2 diabetes, it appears appropriate that saturated fats be replaced in the diet with other macronutrients, such as polyunsaturated fats.

Dietary fibre and whole grains in diabetes management: Systematic review and meta-analyses.

BACKGROUND: Fibre is promoted as part of a healthy dietary pattern and in diabetes management. We have considered the role of high-fibre diets on mortality and increasing fibre intake on glycaemic control and other cardiometabolic risk factors of adults with prediabetes or diabetes. METHODS AND FINDINGS: We conducted a systematic review of published literature to identify prospective studies or controlled trials that have examined the effects of a higher fibre intake without additional dietary or other lifestyle modification in adults with prediabetes, gestational diabetes, type 1 diabetes, and type 2 diabetes. Meta-analyses were undertaken to determine the effects of higher fibre intake on all-cause and cardiovascular mortality and increasing fibre intake on glycaemic control and a range of cardiometabolic risk factors. For trials, meta regression analyses identified further variables that influenced the pooled findings. Dose response testing was undertaken; Grading of Recommendations Assessment, Development and Evaluation (GRADE) protocols were followed to assess the quality of evidence. Two multicountry cohorts of 8,300 adults with type 1 or type 2 diabetes followed on average for 8.8 years and 42 trials including 1,789 adults with prediabetes, type 1, or type 2 diabetes were identified. Prospective cohort data indicate an absolute reduction of 14 fewer deaths (95% confidence interval (CI) 4-19) per 1,000 participants over the study duration, when comparing a daily dietary fibre intake of 35 g with the average intake of 19 g, with a clear dose response relationship apparent. Increased fibre intakes reduced glycated haemoglobin (HbA1c; mean difference [MD] -2.00 mmol/mol, 95% CI -3.30 to -0.71 from 33 trials), fasting plasma glucose (MD -0.56 mmol/L, 95% CI -0.73 to -0.38 from 34 trials), insulin (standardised mean difference [SMD] -2.03, 95% CI -2.92 to -1.13 from 19 trials), homeostatic model assessment of insulin resistance (HOMA IR; MD -1.24 mg/dL, 95% CI -1.72 to -0.76 from 9 trials), total cholesterol (MD -0.34 mmol/L, 95% CI -0.46 to -0.22 from 27 trials), low-density lipoprotein (LDL) cholesterol (MD -0.17 mmol/L, 95% CI -0.27 to -0.08 from 21 trials), triglycerides (MD -0.16 mmol/L, 95% CI -0.23 to -0.09 from 28 trials), body weight (MD -0.56 kg, 95% CI -0.98 to -0.13 from 18 trials), Body Mass Index (BMI; MD -0.36, 95% CI -0·55 to -0·16 from 14 trials), and C-reactive protein (SMD -2.80, 95% CI -4.52 to -1.09 from 7 trials) when compared with lower fibre diets. All trial analyses were subject to high heterogeneity. Key variables beyond increasing fibre intake were the fibre intake at baseline, the global region where the trials were conducted, and participant inclusion criteria other than diabetes type. Potential limitations were the lack of prospective cohort data in non-European countries and the lack of long-term (12 months or greater) controlled trials of increasing fibre intakes in adults with diabetes. CONCLUSIONS: Higher-fibre diets are an important component of diabetes management, resulting in improvements in measures of glycaemic control, blood lipids, body weight, and inflammation, as well as a reduction in premature mortality. These benefits were not confined to any fibre type or to any type of diabetes and were apparent across the range of intakes, although greater improvements in glycaemic control were observed for those moving from low to moderate or high intakes. Based on these findings, increasing daily fibre intake by 15 g or to 35 g might be a reasonable target that would be expected to reduce risk of premature mortality in adults with diabetes.

Vessel co-option and resistance to anti-angiogenic therapy.

Vessel co-option is a non-angiogenic mechanism of tumour vascularisation in which cancer cells utilise pre-existing blood vessels instead of inducing new blood vessel formation. Vessel co-option has been observed across a range of different tumour types, in both primary cancers and metastatic disease. Importantly, vessel co-option is now implicated as a major mechanism that mediates resistance to conventional anti-angiogenic drugs and this may help to explain the limited efficacy of this therapeutic approach in certain clinical settings. This includes the use of anti-angiogenic drugs to treat advanced-stage/metastatic disease, treatment in the adjuvant setting and the treatment of primary disease. In this article, we review the available evidence linking vessel co-option with resistance to anti-angiogenic therapy in numerous tumour types, including breast, colorectal, lung and pancreatic cancer, glioblastoma, melanoma, hepatocellular carcinoma, and renal cell carcinoma. The finding that vessel co-option is a significant mechanism of resistance to anti-angiogenic therapy may have important implications for the future of anti-cancer therapy, including (a) predicting response to anti-angiogenic drugs, (b) the need to develop therapies that target both angiogenesis and vessel co-option in tumours, and (c) predicting the response to other therapeutic modalities, including immunotherapy.

Carbohydrate quality and human health: a series of systematic reviews and meta-analyses.

BACKGROUND: Previous systematic reviews and meta-analyses explaining the relationship between carbohydrate quality and health have usually examined a single marker and a limited number of clinical outcomes. We aimed to more precisely quantify the predictive potential of several markers, to determine which markers are most useful, and to establish an evidence base for quantitative recommendations for intakes of dietary fibre. METHODS: We did a series of systematic reviews and meta-analyses of prospective studies published from database inception to April 30, 2017, and randomised controlled trials published from database inception to Feb 28, 2018, which reported on indicators of carbohydrate quality and non-communicable disease incidence, mortality, and risk factors. Studies were identified by searches in PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and by hand searching of previous publications. We excluded prospective studies and trials reporting on participants with a chronic disease, and weight loss trials or trials involving supplements. Searches, data extraction, and bias assessment were duplicated independently. Robustness of pooled estimates from random-effects models was considered with sensitivity analyses, meta-regression, dose-response testing, and subgroup analyses. The GRADE approach was used to assess quality of evidence. FINDINGS: Just under 135 million person-years of data from 185 prospective studies and 58 clinical trials with 4635 adult participants were included in the analyses. Observational data suggest a 15-30% decrease in all-cause and cardiovascular related mortality, and incidence of coronary heart disease, stroke incidence and mortality, type 2 diabetes, and colorectal cancer when comparing the highest dietary fibre consumers with the lowest consumers Clinical trials show significantly lower bodyweight, systolic blood pressure, and total cholesterol when comparing higher with lower intakes of dietary fibre. Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. Dose-response curves suggested that higher intakes of dietary fibre could confer even greater benefit to protect against cardiovascular diseases, type 2 diabetes, and colorectal and breast cancer. Similar findings for whole grain intake were observed. Smaller or no risk reductions were found with the observational data when comparing the effects of diets characterised by low rather than higher glycaemic index or load. The certainty of evidence for relationships between carbohydrate quality and critical outcomes was graded as moderate for dietary fibre, low to moderate for whole grains, and low to very low for dietary glycaemic index and glycaemic load. Data relating to other dietary exposures are scarce. INTERPRETATION: Findings from prospective studies and clinical trials associated with relatively high intakes of dietary fibre and whole grains were complementary, and striking dose-response evidence indicates that the relationships to several non-communicable diseases could be causal. Implementation of recommendations to increase dietary fibre intake and to replace refined grains with whole grains is expected to benefit human health. A major strength of the study was the ability to examine key indicators of carbohydrate quality in relation to a range of non-communicable disease outcomes from cohort studies and randomised trials in a single study. Our findings are limited to risk reduction in the population at large rather than those with chronic disease. FUNDING: Health Research Council of New Zealand, WHO, Riddet Centre of Research Excellence, Healthier Lives National Science Challenge, University of Otago, and the Otago Southland Diabetes Research Trust.

Dietary fibre intake in childhood or adolescence and subsequent health outcomes: A systematic review of prospective observational studies.

AIM: To determine whether higher fibre intakes during childhood or adolescence effect a broad range of intermediate markers of cardiometabolic risk or other health related issues. MATERIALS AND METHODS: We used online searches up to January 2020 and manual searches to identify prospective observational studies reporting on childhood or adolescent intakes of dietary fibre, vegetables, fruit and refined or whole grains. Outcomes measured later in life were body weight, blood lipids, blood pressure, glycaemia, bone health, cognition, growth and bowel habits. Potential age-specific ranges for dietary fibre were extrapolated from published adult data. RESULTS: We identified 45 publications reporting on 44 354 participants from 30 cohort studies. Mean age at dietary assessment varied from 1 to 19.3 years. Follow-up duration varied from 4 months to 27 years. Although well-conducted studies reported improvements in body weight, blood lipids and glycaemia, the diverse nature of studies precluded meta analysis. The quality of evidence was very low to low given the limited data available per outcome and the inability to synthesize results from multiple studies. Potential dietary fibre intake begins at 13-16 g a day for 2-year-olds and increases until the age of 10 years, when values are comparable with an adult range of 25-30 g a day. CONCLUSIONS: Given the inconsistency in findings from cohort studies other than an absence of detrimental effects, it seems appropriate that recommendations regarding childhood fibre intake are extrapolated from relevant adult data.

Patient Reaction to Telemedicine for Clinical Management of Hepatitis C Virus Integrated into an Opioid Treatment Program.

Background and Introduction: Virtual integration of hepatitis C virus (HCV) infection management within the opioid treatment program (OTP) through telemedicine may overcome limited treatment uptake encountered when patients are referred offsite. To evaluate the diffusion of telemedicine within the OTP, we conducted a pilot study to assess acceptance of and satisfaction with telemedicine among 45 HCV-infected opioid use disorder (OUD) patients on methadone.Materials and Methods: We administered a modified 11-item telemedicine satisfaction questionnaire after the initial HCV telemedicine evaluation, when initiating HCV treatment, and 3 months post-HCV treatment completion. Among a patient subset, a semistructured interview further assessed issues of participant referral to the telemedicine program as well as convenience and confidentiality with the telemedicine encounters.Results: Patients demonstrated their acceptance of telemedicine-based encounters by referral of additional participants. They highlighted the convenience of on-site treatment with a liver specialist through recognition of the benefit of "one-stop shopping." They also expressed confidence in the privacy and confidentiality of telemedicine encounters.Discussion: In this pilot study, telemedicine appears to be well accepted as a modality for HCV management among OUD patients on methadone. Virtual integration of medical and behavioral therapy through telemedicine warrants further investigation for its use in this population.Conclusions: In this pilot study, we found that a largely racial minority population of substance users grew to accept telemedicine over time with diminished privacy and confidentiality concerns. Telemedicine was well accepted within the OTP community as reflected by participant referral to the program.

Mapping Hypoxia in Renal Carcinoma with Oxygen-enhanced MRI: Comparison with Intrinsic Susceptibility MRI and Pathology.

Purpose To cross-validate T1-weighted oxygen-enhanced (OE) MRI measurements of tumor hypoxia with intrinsic susceptibility MRI measurements and to demonstrate the feasibility of translation of the technique for patients. Materials and Methods Preclinical studies in nine 786-0-R renal cell carcinoma (RCC) xenografts and prospective clinical studies in eight patients with RCC were performed. Longitudinal relaxation rate changes (∆R1) after 100% oxygen inhalation were quantified, reflecting the paramagnetic effect on tissue protons because of the presence of molecular oxygen. Native transverse relaxation rate (R2*) and oxygen-induced R2* change (∆R2*) were measured, reflecting presence of deoxygenated hemoglobin molecules. Median and voxel-wise values of ∆R1 were compared with values of R2* and ∆R2*. Tumor regions with dynamic contrast agent-enhanced MRI perfusion, refractory to signal change at OE MRI (referred to as perfused Oxy-R), were distinguished from perfused oxygen-enhancing (perfused Oxy-E) and nonperfused regions. R2* and ∆R2* values in each tumor subregion were compared by using one-way analysis of variance. Results Tumor-wise and voxel-wise ∆R1 and ∆R2* comparisons did not show correlative relationships. In xenografts, parcellation analysis revealed that perfused Oxy-R regions had faster native R2* (102.4 sec-1 vs 81.7 sec-1) and greater negative ∆R2* (-22.9 sec-1 vs -5.4 sec-1), compared with perfused Oxy-E and nonperfused subregions (all P < .001), respectively. Similar findings were present in human tumors (P < .001). Further, perfused Oxy-R helped identify tumor hypoxia, measured at pathologic analysis, in both xenografts (P = .002) and human tumors (P = .003). Conclusion Intrinsic susceptibility biomarkers provide cross validation of the OE MRI biomarker perfused Oxy-R. Consistent relationship to pathologic analyses was found in xenografts and human tumors, demonstrating biomarker translation. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

The evidence for and against different modes of tumour cell extravasation in the lung: diapedesis, capillary destruction, necroptosis, and endothelialization.

The development of lung metastasis is a significant negative prognostic factor for cancer patients. The extravasation phase of lung metastasis involves interactions of tumour cells with the pulmonary endothelium. These interactions may have broad biological and medical significance, with potential clinical implications ranging from the discovery of lung metastasis biomarkers to the identification of targets for intervention in preventing lung metastases. Because of the potential significance, the mechanisms of tumour cell extravasation require cautious, systematic studies. Here, we discuss the literature pertaining to the proposed mechanisms of extravasation and critically compare a recently proposed mechanism (tumour cell-induced endothelial necroptosis) with the already described extravasation mechanisms in the lung. We also provide novel data that may help to explain the underlying physiological basis for endothelialization as a mechanism of tumour cell extravasation in the lung. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.