Optimizing nicotinic acid delivery for durable antilipolysis and improved metabolic control

Type 2 diabetes is a devastating disease affecting hundreds of millions worldwide. Lipid accumulation in peripheral non-adipose tissues is a major driver of insulin resistance, a central pathophysiological defect of this disease. Plasma free fatty acids (FFA), derived from adipose tissue lipolysis, are an important source of the intracellular lipid pools. Hence, adipose tissue antilipolysis may be an approach for reversing peripheral tissue lipid overload and the down-stream negative consequences, including insulin resistance. Nicotinic acid (NiAc) is a potent inhibitor of adipose lipolysis, acutely reducing plasma FFA concentrations. However, a major FFA rebound occurs upon abrupt NiAc washout and sustained exposures are associated with tolerance development, with FFA returning to pre-dose levels. A key principle of this work was the use of precisely defined plasma NiAc exposure profiles, produced using a programmable, implantable mini-pump. Metabolic consequences of NiAc-induced FFA lowering were assessed in a translationally relevant preclinical model of the metabolic syndrome, the obese Zucker rat. A feedback turnover model adequately described acute FFA responses to NiAc. This model aided in designing a gradual NiAc termination protocol which minimized FFA rebound. The strategy of around-the-clock exposure failed to deliver sustained FFA lowering, due to tolerance development. By contrast, an intermittent strategy succeeded in preserving acute FFA lowering and insulin sensitizing effects. A more complex model was required in order to capture the development of complete tolerance in response to sustained NiAc exposure. Further experiments revealed that NiAc timed to feeding decreased triglycerides in liver and heart and reduced plasma fructosamine. During an oral glucose tolerance test, plasma FFA levels were reduced with amelio¬ration of hyperglycemia and hypertriglyceridemia. By contrast, NiAc timed to fasting did not reduce tissue lipids, ameliorate glucose intolerance or dyslipidemia. In conclusion, the NiAc exposure profile has a major influence on metabolic control. A macro-pharmacologic approach succeed in identifying a rational NiAc delivery profile that suppressed rebound and tolerance and profoundly improved metabolic control in obese Zucker rats. The work shows the power of a multi-disciplinary drug discovery approach, using a comprehensive understanding of the relationship between pharmacokinetics and pharmacodynamics combined with knowledge of metabolic physiology

BMP4 gene therapy enhances insulin sensitivity but not adipose tissue browning in obese mice

Bone morphogenetic protein 4 (BMP4) adeno-associated viral vectors of serotype 8 (AAV8) gene therapy targeting the liver prevents the development of obesity in initially lean mice by browning the large subcutaneous white adipose tissue (WAT) and enhancing energy expenditure. Here, we examine whether this approach could also reduce established obesity. Dietary-induced obese C57BL6/N mice received AAV8 BMP4 gene therapy at 17-18 weeks of age. They were kept on a high-fat diet and phenotypically characterized for an additional 10-12 weeks. Following termination, the mice underwent additional characterization in vitro. Surprisingly, we observed no effect on body weight, browning of WAT, or energy expenditure in these obese mice, but whole-body insulin sensitivity and glucose tolerance were robustly improved. Insulin signaling and insulin-stimulated glucose uptake were increased in both adipose cells and skeletal muscle. BMP4 also decreased hepatic glucose production and reduced gluconeogenic enzymes in the liver, but not in the kidney, in addition to enhancing insulin action in the liver. Our findings show that BMP4 prevents, but does not reverse, established obesity in adult mice, while it improves insulin sensitivity independent of weight reduction. The BMP antagonist Noggin was increased in WAT in obesity, which may account for the lack of browning

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Att utnyttja IT i undervisningen

Det här arbetet undersöker användandet av informationsteknik så som datorer, internet och digitala lärresurser i skolors undervisning, med fokus på grundskolor som har ”en till en”-projekt. Ett ”en till en”-projekt innebär att varje elev får tillgång till en egen dator. Arbetet försöker besvara frågan om hur det är att arbeta på en skola med ett "en till en"-projekt och hur IT påverkar undervisningen där. Svaren på denna frågeställning fås genom ett antal intervjuer med grundskollärare som arbetar i ”en till en”-projekt. Dessa intervjusvar jämförs också med vad litteratur och aktuell forskning säger om användandet av informationsteknik i skolan och undervisning. Intervjufrågorna tillsammans med litteratur och forskningsrapporter, som ger svar på hur man kan se på lärande och IT och vilka positiva effekter informationstekniken kan ha, ger en bild av hur det är att arbeta på en skola med ett "en till en"-projekt och hur IT påverkar undervisningen där. Några av de saker som besvarades under intervjuerna är: elevers och lärares digitala kompetens, vilka kompetensbehov som finns, vilka mål man har med sitt ”en till en”-projekt, positiva och negativa effekter av projektet samt hur man som lärare förändrat sin undervisning

Att utnyttja IT i undervisningen

Det här arbetet undersöker användandet av informationsteknik så som datorer, internetoch digitala lärresurser i skolors undervisning, med fokus på grundskolor som har ”en till en”-projekt. Ett ”en till en”-projekt innebär att varje elev får tillgång till en egen dator. Arbetet försöker besvara frågan om hur det är att arbeta på en skola med ett "en till en"-projekt och hur IT påverkar undervisningen där.Svaren på denna frågeställning fås genom ett antal intervjuer med grundskollärare somarbetar i ”en till en”-projekt. Dessa intervjusvar jämförs också med vad litteratur och aktuell forskning säger om användandet av informationsteknik i skolan och undervisning.Intervjufrågorna tillsammans med litteratur och forskningsrapporter, som ger svar påhur man kan se på lärande och IT och vilka positiva effekter informationstekniken kanha, ger en bild av hur det är att arbeta på en skola med ett "en till en"-projekt och hur IT påverkar undervisningen där. Några av de saker som besvarades under intervjuerna är: elevers och lärares digitala kompetens, vilka kompetensbehov som finns, vilka mål manhar med sitt ”en till en”-projekt, positiva och negativa effekter av projektet samt hurman som lärare förändrat sin undervisning

DEVELOP AND ANALYZE INSTRUCTIONS USING COGNITIVE LOAD THEORY: ANIMATION VS STATIC IMAGES

Undersökningen ämnade se vilka fördelar och nackdelar som finns med animerade instruktioner jämfört med bildinstruktioner. För att göra detta så fick ett antal personer testa att vika origami med hjälp av antingen bildinstruktioner eller animerade instruktioner. Resultatet baserades på aspekterna tid, resultat samt utveckling. Undersökningen visade att animerade instruktioner hade mycket högre läsbarhet än bildinstruktioner men att det var svårt att se huruvida personer blev bättre på att vika origami