The Hepatic Compensatory Response to Elevated Systemic Sulfide Promotes Diabetes

Impaired hepatic glucose and lipid metabolism are hallmarks of type 2 diabetes. Increased sulfide production or sulfide donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver- enriched mitochondrial SOP enzyme thiosulfate sulfurtransferase (Tst−/− mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia, and fatty liver. Unexpectedly, hepatic sulfide levels are normal in Tst−/− mice because of exaggerated induction of sulfide disposal, with associated suppression of global protein persulfidation and nuclear respiratory factor 2 target protein levels. Hepatic proteomic and persulfidomic profiles converge on gluconeogenesis and lipid metabolism, revealing a selective deficit in medium-chain fatty acid oxidation in Tst−/− mice. We reveal a critical role of TST in hepatic metabolism that has implications for sulfide donor strategies in the context of metabolic disease

Phenology Across Scales:An Intercontinental Analysis of Leaf-Out Dates in Temperate Deciduous Tree Communities

Aim: To quantify the intra-community variability of leaf-out (ICVLo) among dominant trees in temperate deciduous forests, assess its links with specific and phylogenetic diversity, identify its environmental drivers and deduce its ecological consequences with regard to radiation received and exposure to late frost.Location: Eastern North America (ENA) and Europe (EUR).Time Period: 2009–2022.Major Taxa Studied: Temperate deciduous forest trees.Methods: We developed an approach to quantify ICVLo through the analysis of RGB images taken from phenological cameras. We related ICVLo to species richness, phylogenetic diversity and environmental conditions. We quantified the intra-community variability of the amount of radiation received and of exposure to late frost.Results: Leaf-out occurred over a longer time interval in ENA than in EUR. The sensitivity of leaf-out to temperature was identical in both regions (−3.4 days per °C). The distributions of ICVLo were similar in EUR and ENA forests, despite the latter being more species-rich and phylogenetically diverse. In both regions, cooler conditions and an earlier occurrence of leaf-out resulted in higher ICVLo. ICVLo resulted in ca. 8% difference of radiation received from leaf-out to September among individual trees. Forest communities in ENA had shorter safety margins as regards the exposure to late frosts, and were actually more frequently exposed to late frosts.Main Conclusions: We conducted the first intercontinental analysis of the variability of leaf-out at the scale of tree communities. North American and European forests showed similar ICVLo, in spite of their differences in terms of species richness and phylogenetic diversity, highlighting the relevance of environmental controls on ICVLo. We quantified two ecological implications of ICVLo (difference in terms of radiation received and exposure to late frost), which should be explored in the context of ongoing climate change, which affects trees differently according to their phenological niche

Phenology Across Scales: An Intercontinental Analysis of Leaf‐Out Dates in Temperate Deciduous Tree Communities

Aim: To quantify the intra-community variability of leaf-out (ICVLo) among dominant trees in temperate deciduous forests, assess its links with specific and phylogenetic diversity, identify its environmental drivers and deduce its ecological consequences with regard to radiation received and exposure to late frost. Location: Eastern North America (ENA) and Europe (EUR). Time Period: 2009–2022. Major Taxa Studied: Temperate deciduous forest trees. Methods: We developed an approach to quantify ICVLo through the analysis of RGB images taken from phenological cameras. We related ICVLo to species richness, phylogenetic diversity and environmental conditions. We quantified the intra- community variability of the amount of radiation received and of exposure to late fros

Physiological changes to the swallowing mechanism following (Chemo)radiotherapy for head and neck cancer: a systematic review

Emerging research suggests that preventative swallowing rehabilitation, undertaken before or during (chemo)radiotherapy ([C]RT), can significantly improve early swallowing outcomes for head and neck cancer (HNC) patients. However, these treatment protocols are highly variable. Determining specific physiological swallowing parameters that are most likely to be impacted post-(C)RT would assist in refining clear targets for preventative rehabilitation. Therefore, this systematic review (1) examined the frequency and prevalence of physiological swallowing deficits observed post-(C)RT for HNC, and (2) determined the patterns of prevalence of these key physiological deficits over time post-treatment. Online databases were searched for relevant papers published between January 1998 and March 2013. A total of 153 papers were identified and appraised for methodological quality and suitability based on exclusionary criteria. Ultimately, 19 publications met the study’s inclusion criteria. Collation of reported prevalence of physiological swallowing deficits revealed reduced laryngeal excursion, base-of-tongue (BOT) dysfunction, reduced pharyngeal contraction, and impaired epiglottic movement as most frequently reported. BOT dysfunction and impaired epiglottic movement showed a collective prevalence of over 75 % in the majority of patient cohorts, whilst reduced laryngeal elevation and pharyngeal contraction had a prevalence of over 50 %. Subanalysis suggested a trend that the prevalence of these key deficits is dynamic although persistent over time. These findings can be used by clinicians to inform preventative intervention and support the use of specific, evidence-based therapy tasks explicitly selected to target the highly prevalent deficits post-(C)RT for HNC

A prospective study of nomogram-based adaptation of prostate radiotherapy target volumes

Background: A prospective clinical trial was conducted to evaluate the feasibility of a novel approach to the treatment of patients with high risk prostate cancer (HRPC) through the use of a nomogram to tailor radiotherapy target volumes. Methods: Twenty seven subjects with HRPC were treated with a mildly hypofractionated radiotherapy regimen using image-guided IMRT technique between Jun/2013-Jan/2015. A set of validated prognostic factors were inputted into the Memorial-Sloan-Kettering Cancer Center (MSKCC) prostate cancer nomogram to estimate risk of loco-regional spread (LRS). The nomogram risk estimates for extra-capsular extension (ECE), seminal vesicles involvement (SVI), and pelvic lymph nodes involvement (LNI) were used to adapt radiotherapy treatment volumes based on a risk threshold of ≥15% in all cases. A planning guide was used to delineate target volumes and organs at risk (OAR). Up to three dose levels were administered over 28 fractions; 70Gy for gross disease in the prostate +/- seminal vesicles (2.5Gy/fraction), 61.6Gy for subclinical peri-prostatic disease (2.2Gy/fraction) and 50.4Gy to pelvic nodes (1.8Gy/fraction). Data regarding protocol adherence, nomogram use, radiotherapy dose distribution, and acute toxicity were collected. Results: Nomogram use: 100% of patients were treated for ECE, 88.9% for SVI, and 70.4% for LNI. The three areas at risk of LRS were appropriately treated according to the study protocol in 98.8% cases. The MSKCC nomogram estimates for LRS differed significantly between the time of recruitment and analysis. Contouring protocol compliance: Compliance with the trial contouring protocol for up to seven target volumes was 93.0% (159/171). Compliance with protocol for small bowel contouring was poor (59.3%). Dose constraints compliance: Compliance with dose constraints for target volumes was 97.4% (191/196). Compliance with dose constraints for OAR was 88.2% (285/323). Acute toxicity: There were no grade 3 acute toxicities observed. 20/27 (74.1%) and 6/27 (22.2%) patients experienced a grade 2 genitourinary and gastrointestinal toxicity respectively. Conclusions: We have demonstrated the feasibility of this novel risk-adapted radiation treatment protocol for HRPC. This study has identified key learning points regarding this approach, including the importance of standardization and updating of risk quantification tools, and the utility of an observer to verify their correct use

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Pharmacist-Led Interventions for the Management of Cardiovascular Disease: Opportunities and Obstacles

Given the documented treatment gap for patients with cardiovascular disease, there are numerous opportunities for pharmacists to become more extensively involved in the delivery of care to these high-risk patients. In published trials, pharmacists have demonstrated improved surrogate outcomes for patients with cardiovascular disease by managing hyperlipidemia, hypertension, and secondary prevention medications. A concentrated effort by pharmacists in the inpatient setting, using a combination of direct provider and patient interventions, has been shown to improve adherence to evidence-based guidelines and to help optimize patient care outcomes for acute coronary syndromes. In ambulatory care, there are numerous examples of how pharmacists can help optimize medication regimens for cardiovascular disease and cardiovascular risk factor control. Community pharmacists have been successful in helping treat hyperlipidemia in patients with cardiovascular disease. While these studies have demonstrated that pharmacy-based interventions improve surrogate outcomes, there are limited well designed, randomized, controlled trials that have demonstrated that pharmacist-managed interventions improve clinical or humanistic outcomes in patients with cardiovascular disease or that such programs are cost effective. Opportunities for pharmacists exist at each stage of cardiovascular disease management. A needs assessment should be performed to determine the level of risk factor control and appropriate medication utilization within an organization, institution, or practice site. Physician support and collaboration among multidisciplinary teams are essential to the success of the service. Potential funding sources for establishing a service should be researched, and justification for the investment must be made. Limited time and compensation are likely to be the greatest obstacles to pharmacists instituting cardiovascular services. Other key elements include employing well trained, experienced staff, utilizing a medication protocol and patient tracking database, and implementing safety measures. An opportunity exists to conduct rigorous, well designed studies to evaluate the outcomes of pharmacist-led interventions for patients with cardiovascular disease.Cardiovascular-disorders, Pharmaceutical-care-programmes, Pharmaceutical-services

Ku can contribute to telomere lengthening in yeast at multiple positions in the telomerase RNP

Unlike ribonucleoprotein complexes that have a highly ordered overall architecture, such as the ribosome, yeast telomerase appears to be much more loosely constrained. Here, we investigate the importance of positioning of the Ku subunit within the 1157-nt yeast telomerase RNA (TLC1). Deletion of the 48-nt Ku-binding hairpin in TLC1 RNA (tlc1Δ48) reduces telomere length, survival of cells with gross chromosomal rearrangements, and de novo telomere addition at a broken chromosome end. To test the function of Ku at novel positions in the telomerase RNP, we reintroduced its binding site into tlc1Δ48 RNA at position 446 or 1029. We found that Ku bound to these repositioned sites in vivo and telomere length increased slightly, but statistically significantly. The ability of telomerase to promote survival of cells with gross chromosomal rearrangements by healing damaged chromosome arms was also partially restored, whereas the kinetics of DNA addition to a specific chromosome break was delayed. Having two Ku sites in TLC1 caused progressive hyperelongation of a variable subset of telomeres, consistent with Ku's role in telomerase recruitment to chromosome ends. The number of Ku-binding sites in TLC1 contributed to telomerase RNA abundance in vivo but was only partially responsible for telomere length phenotypes. Thus, telomerase RNA levels and telomere length regulation can be modulated by the number of Ku sites in telomerase RNA. Furthermore, there is substantial flexibility in the relative positioning of Ku in the telomerase RNP for native telomere length maintenance, although not as much flexibility as for the essential Est1p subunit

Earliest Pottery on New Guinea Mainland Reveals Austronesian Influences in Highland Environments 3000 Years Ago

<div><p>Austronesian speaking peoples left Southeast Asia and entered the Western Pacific c.4000-3000 years ago, continuing on to colonise Remote Oceania for the first time, where they became the ancestral populations of Polynesians. Understanding the impact of these peoples on the mainland of New Guinea before they entered Remote Oceania has eluded archaeologists. New research from the archaeological site of Wañelek in the New Guinea Highlands has broken this silence. Petrographic and geochemical data from pottery and new radiocarbon dating demonstrates that Austronesian influences penetrated into the highland interior by 3000 years ago. One potsherd was manufactured along the northeast coast of New Guinea, whereas others were manufactured from inland materials. These findings represent the oldest securely dated pottery from an archaeological context on the island of New Guinea. Additionally, the pottery comes from the interior, suggesting the movements of people and technological practices, as well as objects at this time. The antiquity of the Wañelek pottery is coincident with the expansion of Lapita pottery in the Western Pacific. Such occupation also occurs at the same time that changes have been identified in subsistence strategies in the archaeological record at Kuk Swamp suggesting a possible link between the two.</p></div