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BackgroundTsetse flies (Glossina sp.) are the vectors of human and animal trypanosomiasis throughout sub-Saharan Africa. Tsetse flies are distinguished from other Diptera by unique adaptations, including lactation and the birthing of live young (obligate viviparity), a vertebrate blood-specific diet by both sexes, and obligate bacterial symbiosis. This work describes the comparative analysis of six Glossina genomes representing three sub-genera: Morsitans (G. morsitans morsitans, G. pallidipes, G. austeni), Palpalis (G. palpalis, G. fuscipes), and Fusca (G. brevipalpis) which represent different habitats, host preferences, and vectorial capacity.ResultsGenomic analyses validate established evolutionary relationships and sub-genera. Syntenic analysis of Glossina relative to Drosophila melanogaster shows reduced structural conservation across the sex-linked X chromosome. Sex-linked scaffolds show increased rates of female-specific gene expression and lower evolutionary rates relative to autosome associated genes. Tsetse-specific genes are enriched in protease, odorant-binding, and helicase activities. Lactation-associated genes are conserved across all Glossina species while male seminal proteins are rapidly evolving. Olfactory and gustatory genes are reduced across the genus relative to other insects. Vision-associated Rhodopsin genes show conservation of motion detection/tracking functions and variance in the Rhodopsin detecting colors in the blue wavelength ranges.ConclusionsExpanded genomic discoveries reveal the genetics underlying Glossina biology and provide a rich body of knowledge for basic science and disease control. They also provide insight into the evolutionary biology underlying novel adaptations and are relevant to applied aspects of vector control such as trap design and discovery of novel pest and disease control strategies.

Background: Tsetse flies (Glossina sp.) are the sole vectors of human and animal trypanosomiasis throughout sub-Saharan Africa. Tsetse are distinguished from other Diptera by unique adaptations, including lactation and the birthing of live young (obligate viviparity), a vertebrate blood specific diet by both sexes and obligate bacterial symbiosis. This work describes comparative analysis of six Glossina genomes representing three sub-genera: Morsitans (G. morsitans morsitans (G.m. morsitans), G. pallidipes, G. austeni), Palpalis (G. palpalis, G. fuscipes) and Fusca (G. brevipalpis) which represent different habitats, host preferences and vectorial capacity. Results: Genomic analyses validate established evolutionary relationships and sub-genera. Syntenic analysis of Glossina relative to Drosophila melanogaster shows reduced structural conservation across the sex-linked X chromosome. Sex linked scaffolds show increased rates of female specific gene expression and lower evolutionary rates relative to autosome associated genes. Tsetse specific genes are enriched in protease, odorant binding and helicase activities. Lactation associated genes are conserved across all Glossina species while male seminal proteins are rapidly evolving. Olfactory and gustatory genes are reduced across the genus relative to other characterized insects. Vision associated Rhodopsin genes show conservation of motion detection/tracking functions and significant variance in the Rhodopsin detecting colors in the blue wavelength ranges. Conclusions: Expanded genomic discoveries reveal the genetics underlying Glossina biology and provide a rich body of knowledge for basic science and disease control. They also provide insight into the evolutionary biology underlying novel adaptations and are relevant to applied aspects of vector control such as trap design and discovery of novel pest and disease control strategies.

OBJECTIVE: Developments in pharmacotherapy and management of type 2 diabetes may have shifted the balance of treatment benefits versus harms and costs over the past decades. This study aimed to describe the trends in this balance. RESEARCH DESIGN AND METHODS: We followed the Danish population with type 2 diabetes between 2002 and 2020, analyzing their medication use in relation to treatment benefits (such as mortality and diabetes-related outcomes), adverse events, and medication costs. Using multivariate analyses, we adjusted for potential confounders, including age, sex, and socioeconomic status. RESULTS: The study included 461,805 individuals. From 2002 to 2020, the median age increased from 66 to 68 years, and the mean number of comorbidities increased from 5.2 to 8.8. The overall incidence of cardiovascular, renal, and other important adverse clinical outcomes decreased. Similarly, the rate of some adverse events, such as gastric bleeding, hypoglycemia, and falls declined, whereas the incidence of electrolyte imbalances and ketoacidosis increased. The average per-patient cost was reduced by 8%, but total medication expenses increased by 148% due to an expanding population size, lowered costs of most cardiovascular medications, and increasing costs for glucose-lowering drugs. CONCLUSIONS: Advancements in type 2 diabetes management have led to reduced risk of both diabetes-related outcomes and treatment harms, while maintaining relatively stable per-patient medication expenses. Although these trends are multifactorial, they suggest more rational pharmacotherapy. Still, increased risk of certain adverse events, along with increasing costs for glucose-lowering medications, underscores the need for ongoing vigilance and risk-benefit analysis. [ABSTRACT FROM AUTHOR]

Context Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of patients with type 2 diabetes. Hyperglucagonemia may develop due to steatosis-induced hepatic glucagon resistance resulting in impaired hepatic amino acid turnover and ensuing elevations of circulating glucagonotropic amino acids. Objective We evaluated whether glucagon resistance could be induced in healthy individuals by a hypercaloric diet intervention designed to increase hepatic fat content. Methods We recruited 20 healthy male individuals to follow a hypercaloric diet and a sedentary lifestyle for 2 weeks. Amino acid concentrations in response to infusion of glucagon were assessed during a pancreatic clamp with somatostatin and basal insulin. The reversibility of any metabolic changes was assessed 8 weeks after the intervention. Hepatic steatosis was assessed by magnetic resonance spectroscopy. Results The intervention led to increased hepatic fat content (382% [206%; 705%], P <.01). Glucagon infusion led to a decrease in the concentration of total amino acids on all experimental days, but the percentage change in total amino acids was reduced (−2.5% ± 0.5% vs −0.2% ± 0.7%, P =.015) and the average slope of the decline in the total amino acid concentration was less steep (−2.0 ± 1.2 vs −1.2 ± 0.3 μM/min, P =.016) after the intervention compared to baseline. The changes were normalized at follow-up. Conclusion Our results indicate that short-term unhealthy behavior, which increases hepatic fat content, causes a reversible resistance to the effect of glucagon on amino acid concentrations in healthy individuals, which may explain the hyperglucagonemia associated with obesity and diabetes. [ABSTRACT FROM AUTHOR]

Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.

Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.

Aim: To explore the impact of type 2 diabetes (T2D), glycaemic control and use of glucose‐lowering medication on clinical outcomes in hospitalized patients with COVID‐19. Materials and Methods: For all patients admitted to a hospital in the Capital Region of Denmark (1 March 2020 to 1 December 2021) with confirmed COVID‐19, we extracted data on mortality, admission to intensive care unit (ICU), demographics, comorbidities, medication use and laboratory tests from the electronic health record system. We compared patients with T2D to patients without diabetes using Cox proportional hazards models adjusted for available confounding variables. Outcomes were 30‐day mortality and admission to an ICU. For patients with T2D, we also analysed the association of baseline haemoglobin A1c (HbA1c) levels and use of specific glucose‐lowering medications with the outcomes. Results: In total, 4430 patients were analysed, 1236 with T2D and 2194 without diabetes. The overall 30‐day mortality was 19% (n = 850) and 10% (n = 421) were admitted to an ICU. Crude analyses showed that patients with T2D both had increased mortality [hazard ratio (HR) 1.37; 95% CI 1.19‐1.58] and increased risk of ICU admission (HR 1.28; 95% CI 1.04‐1.57). When adjusted for available confounders, this discrepancy was attenuated for both mortality (adjusted HR 1.13; 95% CI 0.95‐1.33) and risk of ICU admission (adjusted HR 1.01; 95% CI 0.79‐1.29). Neither baseline haemoglobin A1c nor specific glucose‐lowering medication use were significantly associated with the outcomes. Conclusion: Among those hospitalized for COVID‐19, patients with T2D did not have a higher risk of death and ICU admission, when adjusting for confounders. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Chylothorax is a complex condition and many different pharmacological agents have been tried as treatment. Octreotide is used off-label to treat chylothorax, but the efficacy of octreotide remains unclear. A decrease in lymph production is suggested as the mechanism. In this cross-over study, we explore the direct effect of octreotide on human lymphatic drainage. METHODS Pre-clinical: the effect of octreotide on force generation was assessed during acute and prolonged drug incubation on human lymphatic vessels mounted in a myograph. Clinical: in a double-blinded, randomized, cross-over trial including 16 healthy adults, we administered either octreotide or saline as an intravenous infusion for 2.5 h. Near-infrared fluorescence imaging was used to examine spontaneous lymphatic contractions and lymph pressure in peripheral lymphatic vessels and plethysmography was performed to assess the capillary filtration rate, capillary filtration coefficient and isovolumetric pressures of the lower leg. RESULTS Pre-clinical: human thoracic duct (n  = 12) contraction rate was concentration-dependently stimulated by octreotide with a maximum effect at 10 and 100 nmol/l in the myograph chamber. Clinical: spontaneous lymphatic contractions and lymph pressure evaluated by near-infrared fluorescence did not differ between octreotide or placebo (P  = 0.36). Plethysmography revealed similar capillary filtration coefficients (P  = 0.057), but almost a doubling of the isovolumetric pressures (P  = 0.005) during octreotide infusion. CONCLUSIONS Octreotide stimulated lymphatic contractility in the pre-clinical setup but did not affect the spontaneous lymphatic contractions or lymph pressure in healthy individuals. Plethysmography revealed a doubling in the isovolumetric pressure. These results suggest that octreotide increases lymphatic drainage capacity in situations with high lymphatic afterload. [ABSTRACT FROM AUTHOR]