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And the best they could do is copy Ford's EcoBoost 3.5-liter engine and 10-speed, Ram's coil-spring rear suspension, and GM's "styling"? - Eric Weitze Jupiter, FL Tesla says that on a 250-kW Supercharger, its cars can gain 200 miles of range in 15 minutes - Ed. It's funny how hard Ford is working to distance itself from the white Ford Bronco of yesteryear. - Bill Robinson Oklahoma City, OK Ford is already attempting your product-planning idea with the current Escape, and while it's selling well, it's not quite ruling the segment - Ed. [Extracted from the article]

We have identified an underrecognized severe adverse drug reaction (ADR) of trimethoprim-sulfamethoxazole (TMP-SMX) associated respiratory failure in previously healthy children and young adults. We investigated potential genetic risk factors associated with TMP-SMX induced respiratory failure in a cohort of seven patients. We explored whole genome sequence among seven patients representing nearly half of all reported cases worldwide and 63 unrelated control individuals in two stages: (1) human leukocyte antigen (HLA) locus variation as several other ADRs have been associated HLA genetic variants and (2) coding variation to catalog and explore potential rare variants contributing to this devastating reaction. All cases were either heterozygous (carriers) or homozygous for the common HLA-B*07:02–HLA-C*07:02haplotype. Despite the small sample size, this observation is statistically significant both in conservative comparison to maximum reported population frequencies (binomial P= 0.00017 for HLA-B and P= 0.00028 for HLA-C) and to our control population assessed by same HLA genotyping approach (binomial P= 0.000001 for HLA-B and P= 0.000018 for HLA-C). No gene elsewhere in the genome harnessed shared rare case enriched coding variation. Our results suggests that HLA-B*07:02and HLA-C*07:02are necessary for a patient to develop respiratory failure due to TMP-SMX.

IMPORTANCE: In the treatment of type 2 diabetes, evidence of the comparative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs sulfonylureas—the second most widely used antihyperglycemic class after metformin—is lacking. OBJECTIVE: To evaluate the comparative effectiveness of SGLT2 inhibitors and sulfonylureas associated with the risk of all-cause mortality among patients with type 2 diabetes using metformin. DESIGN, SETTING, AND PARTICIPANTS: A cohort study used data from the US Department of Veterans Affairs compared the use of SGLT2 inhibitors vs sulfonylureas in individuals receiving metformin for treatment of type 2 diabetes. A total of 23 870 individuals with new use of SGLT2 inhibitors and 104 423 individuals with new use of sulfonylureas were enrolled between October 1, 2016, and February 29, 2020, and followed up until January 31, 2021. EXPOSURES: New use of SGLT2 inhibitors or sulfonylureas. MAIN OUTCOMES AND MEASURES: This study examined the outcome of all-cause mortality. Predefined variables and covariates identified by a high-dimensional variable selection algorithm were used to build propensity scores. The overlap weighting method based on the propensity scores was used to estimate the intention-to-treat effect sizes of SGLT2 inhibitor compared with sulfonylurea therapy. The inverse probability of the treatment adherence weighting method was used to estimate the per-protocol effect sizes. RESULTS: Among the 128 293 participants (mean [SD] age, 64.60 [9.84] years; 122 096 [95.17%] men), 23 870 received an SGLT2 inhibitor and 104 423 received a sulfonylurea. Compared with sulfonylureas, SGLT2 inhibitors were associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.81; 95% CI, 0.75-0.87), yielding an event rate difference of −5.15 (95% CI, −7.16 to −3.02) deaths per 1000 person-years. Compared with sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of death, regardless of cardiovascular disease status, in several categories of estimated glomerular filtration rate (including rates from >90 to ≤30 mL/min/1.73 m2) and in participants with no albuminuria (albumin to creatinine ratio [ACR] ≤30 mg/g), microalbuminuria (ACR >30 to ≤300 mg/g), and macroalbuminuria (ACR >300 mg/g). In per-protocol analyses, continued use of SGLT2 inhibitors was associated with a reduced risk of death compared with continued use of sulfonylureas (HR, 0.66; 95% CI, 0.60-0.74; event rate difference, −10.10; 95% CI, −12.97 to −7.24 deaths per 1000 person-years). In additional per-protocol analyses, continued use of SGLT2 inhibitors with metformin was associated with a reduced risk of death compared with SGLT2 inhibitor treatment without metformin (HR, 0.70; 95% CI, 0.50-0.97; event rate difference, −7.62; 95% CI, −17.12 to −0.48 deaths per 1000 person-years). CONCLUSIONS AND RELEVANCE: In this comparative effectiveness study analyzing data from the US Department of Veterans Affairs, among patients with type 2 diabetes receiving metformin therapy, SGLT2 inhibitor treatment was associated with a reduced risk of all-cause mortality compared with sulfonylureas. The results provide data from a real-world setting that might help guide the choice of antihyperglycemic therapy.

A highly convergent synthesis of c-Met kinase inhibitor 1has been demonstrated on a multikilogram scale using three key fragments: dihalotricyclic core 2, chiral sulfamide side chain 3, and pyrazole boronic ester 4. The chirality in sulfamide side chain 3was installed using the cheap and readily available starting material (S)-epichlorohydrin. A total of 2.71 kg of 1were isolated in seven steps (the longest linear sequence).

Closure of an abdominal stoma, a common elective operation, is associated with frequent complications; one of the commonest and impactful is incisional hernia formation. We aimed to investigate whether biological mesh (collagen tissue matrix) can safely reduce the incidence of incisional hernias at the stoma closure site.

The measurement of strain is a fundamental and widely studied parameter in engineering, rock mechanics, construction and materials testing. Contact sensors often used in these fields require contact with the target surface throughout the duration of a strain event. Non-contact methods typically require that that the measurement surface is prepared and often coated prior to testing. This paper considers the potential application of near infrared spectroscopy as a non-contact technique for the measurement of strain on natural surfaces. Excellent correlation was found between surface measurements of visible-NIR spectra and longitudinal strain taken during indirect Brazilian Disc Test for samples of sandstone, marble and basalt.

ABSTRACTThe work from home regime has created a shift in the thinking of how to operate multiuse buildings in city environments. One of the thoughts apply to the future of these spaces and the function of many cities.

The wellbeing and livelihood of farmers in impoverished regions of the world is intrinsically linked to the health and welfare of their livestock; hence improved animal health is a pragmatic component of poverty alleviation. Prerequisite knowledge and understanding of the animal health challenges facing cattle keepers in Malawi is constrained by the lack of veterinary infrastructure, which inevitably accompanies under-resourced rural development in a poor country. We collaborated with public and private paraveterinary services to locate 62 village Zebu calves and 60 dairy co-operative calves dispersed over a wide geographical area. All calves were visited twice about 2 to 3 weeks apart, when they were clinically examined and faecal samples were collected. The calves were treated with 7.5 mg/kg of a locally-available albendazole drench on the first visit, and pre- and post- treatment trichostrongyle and Toxocarafaecal egg counts were performed using a modified McMaster method. Our clinical findings point towards a generally poor level of animal health, implying a role of ticks and tick-transmitted diseases in village calves and need for improvement in neonatal calf husbandry in the dairy co-operative holdings. High faecal trichostrongyle egg counts were not intuitive, based on our interpretation of the animal management information that was provided. This shows the need for better understanding of nematode parasite epidemiology within the context of local husbandry and environmental conditions. The albendazole anthelmintic was effective against Toxocara, while efficacy against trichostrongyle nematodes was poor in both village and dairy co-operative calves, demonstrating the need for further research to inform sustainable drug use. Here we describe the potential value of faecal nematode egg counting as a platform for communicating with and gaining access to cattle keepers and their animals, respectively, in southern Malawi, with the aim of providing informative background knowledge and understanding that may aid in the establishment of effective veterinary services in an under-resourced community.

The common FcR?, an immunoreceptor tyrosine-based activation motif (ITAM)- containing adaptor protein, associates with multiple leukocyte receptor complexes and mediates signal transduction through the ITAM in the cytoplasmic domain. The presence of multiple serine and threonine residues within this motif suggests the potential for serine/threonine phosphorylation in modulating signaling events. Single-site mutational analysis of these residues in RBL-2H3 cells indicates that each may contribute to net FcR?-mediated signaling, and mass spectrometry of WT human FcR? from receptor-stimulated cells shows consistent preferential phosphorylation of the serine residue at position 51. Immunoblot analysis, mass spectrometry, and mutational analyses showed that phosphorylation of serine 51 in the 7-residue spacer between the 2 YxxL sequences regulates FcR? signaling by inhibiting tyrosine phosphorylation at the membrane proximal Y47 position of the ITAM, but not phosphorylation at position Y58. This inhibition results in reduced Syk recruitment and activation. With in vitro kinase assays, PKC-d and PKA show preferential phosphorylation of S51. Serine/threonine phosphorylation of the FcR? ITAM, which functions as an integrator of multiple signaling elements, may explain in part the contribution of variants in PKC-d and other PKC isoforms to some autoimmune phenotypes.