Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study.

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA

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

Evaluation of seed treatment insecticides for management of the rice water weevil, Lissorhoptrus oryzophilus Kuschel (Coleoptera: Curculionidae), in commercial rice fields in Louisiana

The rice water weevil, Lissorhoptrus oryzophilus Kuschel (Coleoptera: Curculionidae), is the most injurious insect pest in US rice production. Yield losses in excess of 25% can occur from severe infestations. Management demonstrations were conducted in the 2008, 2009, 2010, and 2011 growing seasons to evaluate the use of commercially available insecticides to control L.oryzophilus in commercial rice fields. The demonstration tests, conducted on farms throughout Louisiana, compared the efficacies of recently registered seed treatment insecticides to untreated controls and to foliar applications of pyrethroids. Efficacy was assessed by collecting root/soil core samples three to four weeks after application of permanent flood and counting numbers of larvae and pupae in core samples. Tests were replicated across locations in multiple rice-producing Louisiana parishes. Densities of larvae and pupae in core samples exceeded the larval threshold (three larvae or pupae per core sample) in over 80% of untreated plots/cuts, confirming the ubiquity and severity of this insect as a pest of rice. Use of chlorantraniliprole (Dermacor® X-100, DuPont™ Crop Protection, Wilmington, DE), thiamethoxam (CruiserMaxx® Rice, Syngenta® Crop Protection, Greensboro, NC), and clothianidin (NipsIt Inside®, Valent® USA Corporation, Walnut Creek, CA) seed treatments significantly reduced L.oryzophilus infestation compared to untreated checks. Fewer larvae and pupae were observed in rice treated with chlorantraniliprole than in rice treated with other insecticides. © 2014 Elsevier Ltd

Monitoring and first discovery of the Mexican rice borer eoreuma loftini (Lepidoptera: Crambidae) in Louisiana

Eoreuma loftini has expanded its range from the LRGV to east Texas, and now into southwest Louisiana. LDAF and LSU AgCenter scientists forecast that natural and unintended artificial movement will result in the continued spread of E. loftini toward the heart of Louisiana\u27s rice and sugarcane-growing regions. The 12-XII-2008 collection was the first confirmation of this pest in the state. By catching E. loftini early in its natural advancement into Louisiana, additional rapid and proactive responses will allow producers to become educated on the best management practices for the pest in sugarcane and rice. These best management practices include planting resistant varieties, use of pheromone trapassisted scouting, applications of narrow-range minimum-risk insecticides, minimizing plant stress through manipulation of irrigation and fertilization practices, and processing of cane at the closest mill to minimize spread. Also, the continued prohibition of the east Texas sugarcane shipments into Louisiana for processing is likely the most important step to avoid any artificial spread of E. loftini

White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways

Objective: Fat depots with thermogenic activity have been identified in humans. In mice, the appearance of thermogenic adipocytes within white adipose depots (so-called brown-in-white i.e., brite or beige adipocytes) protects from obesity and insulin resistance. Brite adipocytes may originate from direct conversion of white adipocytes. The purpose of this work was to characterize the metabolism of human brite adipocytes. Methods: Human multipotent adipose-derived stem cells were differentiated into white adipocytes and then treated with peroxisome proliferator-activated receptor (PPAR)γ or PPARα agonists between day 14 and day 18. Gene expression profiling was determined using DNA microarrays and RT-qPCR. Variations of mRNA levels were confirmed in differentiated human preadipocytes from primary cultures. Fatty acid and glucose metabolism was investigated using radiolabelled tracers, Western blot analyses and assessment of oxygen consumption. Pyruvate dehydrogenase kinase 4 (PDK4) knockdown was achieved using siRNA. In vivo, wild type and PPARα-null mice were treated with a β3-adrenergic receptor agonist (CL316,243) to induce appearance of brite adipocytes in white fat depot. Determination of mRNA and protein levels was performed on inguinal white adipose tissue. Results: PPAR agonists promote a conversion of white adipocytes into cells displaying a brite molecular pattern. This conversion is associated with transcriptional changes leading to major metabolic adaptations. Fatty acid anabolism i.e., fatty acid esterification into triglycerides, and catabolism i.e., lipolysis and fatty acid oxidation, are increased. Glucose utilization is redirected from oxidation towards glycerol-3-phophate production for triglyceride synthesis. This metabolic shift is dependent on the activation of PDK4 through inactivation of the pyruvate dehydrogenase complex. In vivo, PDK4 expression is markedly induced in wild-type mice in response to CL316,243, while this increase is blunted in PPARα-null mice displaying an impaired britening response. Conclusions: Conversion of human white fat cells into brite adipocytes results in a major metabolic reprogramming inducing fatty acid anabolic and catabolic pathways. PDK4 redirects glucose from oxidation towards triglyceride synthesis and favors the use of fatty acids as energy source for uncoupling mitochondria. Keywords: Brite/beige adipocyte, Peroxisome proliferator-activated receptor, Fatty acid metabolism, Glycerol metabolism, Pyruvate dehydrogenase kinase