In this study, observations of live fuel moisture content (LFMC) for predominantly sampled fuels in six distinct regions of California were examined from 2000 to 2021. To gather the necessary data, ...an open-access database called the Fuel Moisture Repository (FMR), was developed. By harnessing the extensive data aggregation and query capabilities of the FMR, which draws upon the National Fuel Moisture Database, valuable insights into the live fuel moisture seasonality were obtained. Specifically, our analysis revealed a distinct downtrend in LFMC across all regions, with the exception of the two Northernmost regions. The uptrends of LFMC seen in those regions are insignificant to the general downtrend seen across all of the regions. Although the regions do not share the same trends over the temporal span of the study, from 2017 to 2021, all the regions experienced a downtrend two times more severe than the general 22-year downtrend. Further analysis of the fuel types in each of the six regions, revealed significant variability in LFMC across different fuel types and regions. To understand potential drivers of this variability, the relationship between LFMC and drought conditions was investigated. This analysis found that LFMC fluctuations were closely linked to water deficits. However, the drought conditions varied across the examined regions, contributing to extreme LFMC variability. Notably, during prolonged drought periods of 2 or more years, fuels adapted to their environment by stabilizing or even increasing their maximum and minimum moisture values, contrary to the expected continual decrease. These LFMC trends have been found to correlate to wildfire activity and the specific LFMC threshold of 79% has been proposed as trigger of an increased likelihood of large fires. By analyzing the LFMC and fire activity data in each region, we found that more optimal local thresholds can be defined, highlighting the spatial variability of the fire response to the LFMC. This work expands on existing literature regarding the connections between drought and LFMC, as well as fire activity and LFMC. The study presents a 22-year dataset of LFMC spanning the entirety of California and analyses the LFMC trends in California that haven’t been rigorously studied before.
Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in the gastrointestinal tract. GLP-1 actions regulate blood glucose, whereas GLP-2 exerts trophic effects on intestinal mucosal ...epithelium. Although GLP-1 actions are preserved in diseases such as diabetes, GLP-2 action has not been extensively studied in the setting of intestinal disease. We have now evaluated the biological effects of a human GLP-2 analog in the setting of experimental murine nonsteroidal antiinflammatory drug-induced enteritis. Human (h)Gly(2)GLP-2 significantly improved survival whether administered before, concomitant with, or after indomethacin. hGly(2)GLP-2-treated mice exhibited reduced histological evidence of disease activity, fewer intestinal ulcerations, and decreased myeloperoxidase activity in the small bowel (P < 0.05, hGly(2)GLP-2- vs. saline-treated controls). hGly(2)GLP-2 significantly reduced cytokine induction, bacteremia, and the percentage of positive splenic and hepatic bacterial cultures (P < 0.05). hGly(2)GLP-2 enhanced epithelial proliferation (P < 0.05 for increased crypt cell proliferation in hGly(2)GLP-2- vs. saline-treated mice after indomethacin) and reduced apoptosis in the crypt compartment (P < 0.02). These observations demonstrate that a human GLP-2 analog exerts multiple complementary actions that serve to preserve the integrity of the mucosal epithelium in experimental gastrointestinal injury in vivo.
We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and ...glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
Incretins are gastrointestinal hormones that act on the pancreas to potentiate glucose-stimulated insulin secretion. Despite the physiological importance of the enteroinsular axis, disruption of ...glucagon-like peptide (GLP)-1 action is associated with only modest glucose intolerance in GLP-1 receptor -/- (GLP-1R -/-) mice. We show here that GLP-1R -/- mice exhibit compensatory changes in the enteroinsular axis via increased glucose-dependent insulinotropic polypeptide (GIP) secretion and enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were significantly elevated versus those in +/+ control mice after an oral glucose tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P < or = 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a significantly greater insulin response in GLP-1R -/- than in +/+ mice (P < or = 0.02-0.05). In contrast, no significant perturbation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1R -/- mice. Total pancreatic insulin but not glucagon content was significantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs. 121 +/- 10 pmol/mg protein; P < or = 0.005). These observations suggest that upregulation of the GIP component of the enteroinsular axis, at the levels of GIP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo.
Chemotherapeutic agents produce cytotoxicity via induction of apoptosis and cell cycle arrest. Rapidly proliferating cells in the bone marrow and intestinal crypts are highly susceptible to ...chemotherapy, and damage to these cellular compartments may preclude maximally effective chemotherapy administration. Glucagon-like peptide (GLP)-2 is an enteroendocrine-derived regulatory peptide that inhibits crypt cell apoptosis after administration of agents that damage the intestinal epithelium. We report here that a human degradation-resistant GLP-2 analogue, hGly2-GLP-2 significantly improves survival, reduces bacteremia, attenuates epithelial injury, and inhibits crypt apoptosis in the murine gastrointestinal tract after administration of topoisomerase I inhibitor irinotecan hydrochloride or the antimetabolite 5-fluorouracil. hGly2-GLP-2 significantly improved survival and reduced weight loss but did not impair chemotherapy effectiveness in tumor-bearing mice treated with cyclical irinotecan. Furthermore, hGly2-GLP-2 reduced chemotherapy-induced apoptosis, decreased activation of caspase-8 and -3, and inhibited poly(ADP-ribose) polymerase cleavage in heterologous cells transfected with the GLP-2 receptor. These observations demonstrate that the antiapoptotic effects of GLP-2 on intestinal crypt cells may be useful for the attenuation of chemotherapy-induced intestinal mucositis.
Abstract Objective Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) ...signaling are being explored for the treatment of diabetes or obesity. However, the cardiovascular consequences of manipulating glucagon action are poorly understood. Methods We assessed infarct size and the following outcomes following left anterior descending (LAD) coronary artery ligation; cardiac gene and protein expression, acylcarnitine profiles, and cardiomyocyte survival in normoglycemic non-obese wildtype mice, and in newly generated mice with selective inactivation of the cardiomyocyte Gcgr. Complementary experiments analyzed Gcgr signaling and cell survival in cardiomyocyte cultures and cell lines, in the presence or absence of exogenous glucagon. Results Exogenous glucagon administration directly impaired recovery of ventricular pressure in ischemic mouse hearts ex vivo , and increased mortality from myocardial infarction after LAD coronary artery ligation in mice in a p38 MAPK-dependent manner. In contrast, cardiomyocyte-specific reduction of glucagon action in adult GcgrCM−/− mice significantly improved survival, and reduced hypertrophy and infarct size following myocardial infarction. Metabolic profiling of hearts from GcgrCM−/− mice revealed a marked reduction in long chain acylcarnitines in both aerobic and ischemic hearts, and following high fat feeding, consistent with an essential role for Gcgr signaling in the control of cardiac fatty acid utilization. Conclusions Activation or reduction of cardiac Gcgr signaling in the ischemic heart produces substantial cardiac phenotypes, findings with implications for therapeutic strategies designed to augment or inhibit Gcgr signaling for the treatment of metabolic disorders.
Summary
Background
The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment ...effectiveness across trials.
Objectives
To develop a core outcome set (COS), a minimum set of agreed‐upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC.
Methods
One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored ‘critically important’ (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants.
Results
A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient‐reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence‐free survival, (vi) progression‐free survival and (vii) disease‐specific survival.
Conclusions
In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.
What is already known about this topic?
Although many outcomes have been measured in studies of cutaneous squamous cell carcinoma (cSCC), lack of a standardized set of such outcomes is an obstacle to the synthesis of evidence across trials.
What does this study add?
This study reports the development of a core outcome set for treatment of cSCC based on a systematic literature search, stakeholder interviews, and an international e‐Delphi consensus process among patients and physicians.
The minimum set of outcomes to be reported in clinical trials of cSCC comprises (i) serious or persistent adverse events, (ii) patient‐reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence‐free survival, (vi) progression‐free survival and (vii) disease‐specific survival.
What are the clinical implications of this work?
Adoption of this core outcome set by investigators is likely to reduce selective reporting bias, facilitate systematic reviews and meta‐analyses, permit refinement of treatment guidelines, and ultimately improve patient outcomes.
Summary
This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23–24 April 2015 (HOME IV). The aim of the meeting was ...to achieve consensus over the preferred outcome instruments for measuring patient‐reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient‐reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient‐reported symptoms were discussed including the Patient‐Oriented SCOring Atopic Dermatitis index, Patient‐Oriented Eczema Measure (POEM), Self‐Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score and, by consensus, POEM was selected as the preferred instrument to measure patient‐reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.
What's already known about this topic?
Previous meetings of the Harmonising Outcome Measures for Eczema (HOME) initiative have achieved international consensus that the domains of clinician‐reported signs, patient‐reported symptoms, quality of life and long‐term control should be measured as the core outcomes for atopic eczema clinical trials.
It has been recommended that clinician‐reported signs should be measured using the Eczema Area and Severity Index.
What does this study add?
During the HOME IV meeting (Spring 2015, Malmö, Sweden), a consensus was achieved that the Patient‐Oriented Eczema Measure should be used to capture patient‐reported symptoms in future atopic eczema trials.
The remaining two core outcome domains of quality of life and long‐term control require further work to determine the preferred core outcome measurement instruments.
Abstract
Background
Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex ...could estimate risk of glioma as well as identify glioma subtypes.
Methods
Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray.
Results
Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85.
Conclusions
These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups.
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