Outbreaks of SARS-CoV-2 Infections in Nursing Homes during Periods of Delta and Omicron Predominance, United States, July 2021-March 2022.

SARS-CoV-2 infections among vaccinated nursing home residents increased after the Omicron variant emerged. Data on booster dose effectiveness in this population are limited. During July 2021-March 2022, nursing home outbreaks in 11 US jurisdictions involving >3 infections within 14 days among residents who had received at least the primary COVID-19 vaccine(s) were monitored. Among 2,188 nursing homes, 1,247 outbreaks were reported in the periods of Delta (n = 356, 29%), mixed Delta/Omicron (n = 354, 28%), and Omicron (n = 536, 43%) predominance. During the Omicron-predominant period, the risk for infection within 14 days of an outbreak start was lower among boosted residents than among residents who had received the primary vaccine series alone (risk ratio [RR] 0.25, 95% CI 0.19-0.33). Once infected, boosted residents were at lower risk for all-cause hospitalization (RR 0.48, 95% CI 0.40-0.49) and death (RR 0.45, 95% CI 0.34-0.59) than primary vaccine-only residents.

Length of Stay and Home Discharge for Patients with Inpatient Stroke Rehabilitation.

OBJECTIVE: To examine temporal trends and geographic variations and predict inpatient rehabilitation (IPR) length of stay (LOS) and home discharge for stroke patients. METHODS: Patients aged ≥18 years who were admitted to an IPR facility in Alberta, Canada, between 04/2014 and 03/2018 (years 2014-2017) were included. Predictors of LOS and home discharge were examined using 2014-2016 data and validated using 2017 data. Multivariable linear regression (MLR), multivariable negative binomial (MNB), and multivariable quantile regressions (MQR) were used to examine LOS, and logistic regression was used for home discharge. RESULTS: We included 2686 rehabilitation admissions between 2014 and 2017. The mean LOS decreased (2014: 71 days; 2017: 62.1 days; p = 0.003) during the study period and was shortest in Edmonton (59.1 days) compared to Calgary (66 days) or other localities (70.8 days; p < 0.001). Three-quarters of patients were discharged home and this proportion remained unchanged between 2014 and 2017. Calgary patients were more likely to be discharged home than those in Edmonton (OR = 0.62; p = 0.019) or other localities (OR = 0.39; p = 0.011). The MLR and MNB models provided accurate prediction for the mean LOS (predicted = 59.9 and 60.8 days, respectively, vs. actual = 62.1 days; both p > 0.5), while the MQR model did so for the median LOS (predicted = 44.3 days vs. actual = 44 days; p = 0.09). The logistic regression resulted in 82.4% of correct prediction, a sensitivity of 91.6%, and a specificity of 50.7% for home discharge. CONCLUSIONS: Rehabilitation LOS decreased while the proportion of home discharge remained unchanged during the study period. Both varied across health zones. Identifiable statistical models provided accurate prediction with a separate patient cohort.

Effect of strain rates on the mechanical response of whole muscle bundle.

Muscle injuries frequently happen during sports activities and exercise, which could have serious consequences if not diagnosed and treated promptly. This research aims to investigate the quasi-static and dynamic responses of over 30 fresh frog semitendinosus muscles utilizing Split Hopkinson Pressure Bars (SHPB) and a material testing system under strain rates between 0.001 ~ 200 s-1. To accommodate the special shape of muscle-tendon-bone samples, PLA clampers were produced by the 3D printer to properly hold and prevent slipping during the testing process. The mechanical characteristics of the whole muscle bundle, including Young's modulus and stress-strain curve, are illustrated at various strain rates. The findings showed that the muscle properties were sensitive to strain rate when under passive deformation. Both maximum stress and Young's modulus increased with the rise of strain rate, and modulus at 200 s-1 can be as high as 10 times compared with quasi-static conditions.

Preclinical Pharmacokinetics and Safety of Intravenous RTD-1.

Severe illness caused by coronavirus disease 2019 (COVID-19) is characterized by an overexuberant inflammatory response resulting in acute respiratory distress syndrome (ARDS) and progressive respiratory failure (A. Gupta, M. V. Madhavan, K. Sehgal, N. Nair, et al., Nat Med 26:1017-1032, 2020, https://doi.org/10.1038/s41591-020-0968-3). Rhesus theta (θ) defensin-1 (RTD-1) is a macrocyclic host defense peptide exhibiting antimicrobial and immunomodulatory activities. RTD-1 treatment significantly improved survival in murine models of a severe acute respiratory syndrome (SARS-CoV-1) and endotoxin-induced acute lung injury (ALI) (C. L. Wohlford-Lenane, D. K. Meyerholz, S. Perlman, H. Zhou, et al., J Virol 83:11385-11390, 2009, https://doi.org/10.1128/JVI.01363-09; J. G. Jayne, T. J. Bensman, J. B. Schaal, A. Y. J. Park, et al., Am J Respir Cell Mol Biol 58:310-319, 2018, https://doi.org/10.1165/rcmb.2016-0428OC). This investigation aimed to characterize the preclinical pharmacokinetics (PK) and safety of intravenous (i.v.) RTD-1. Based on the lack of adverse findings, the no observed adverse effect level (NOAEL) was established at 10 mg/kg/day in rats and 15 mg/kg/day in monkeys. Analysis of single ascending dose studies in both species revealed greater-than-dose-proportional increases in the area under the curve extrapolated to infinity (AUC0-∞) (e.g., 8-fold increase from 5 mg/kg to 20 mg/kg in rats) suggestive of nonlinear PK. The volume of distribution at steady state (Vss) ranged between 550 and 1,461 mL/kg, indicating extensive tissue distribution, which was validated in a biodistribution study of [14C]RTD-1 in rats. Based on interspecies allometric scaling, the predicted human clearance and Vss are 6.48 L/h and 28.0 L, respectively, for an adult (70 kg). To achieve plasma exposures associated with therapeutic efficacy established in a murine model of ALI, the estimated human equivalent dose (HED) is between 0.36 and 0.83 mg/kg/day. The excellent safety profile demonstrated in these studies and the efficacy observed in the murine models support the clinical investigation of RTD-1 for treatment of COVID-19 or other pulmonary inflammatory diseases.

Treg-associated monogenic autoimmune disorders and gut microbial dysbiosis.

Primary immunodeficiency diseases (PIDs) caused by a single-gene defect generally are referred to as monogenic autoimmune disorders. For example, mutations in the transcription factor autoimmune regulator (AIRE) result in a condition called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; while mutations in forkhead box P3 lead to regulatory T cell (Treg)-deficiency-induced multiorgan inflammation, which in humans is called "immune dysregulation, polyendocrinopathy, enteropathy with X-linked inheritance" (or IPEX syndrome). Previous studies concluded that monogenic diseases are insensitive to commensal microbial regulation because they develop even in germ-free (GF) animals, a conclusion that has limited the number of studies determining the role of microbiota in monogenic PIDs. However, emerging evidence shows that although the onset of the disease is independent of the microbiota, several monogenic PIDs vary in severity in association with the microbiome. In this review, we focus on monogenic PIDs associated with Treg deficiency/dysfunction, summarizing the gut microbial dysbiosis that has been shown to be linked to these diseases. From limited studies, we have gleaned several mechanistic insights that may prove to be of therapeutic importance in the early stages of life. IMPACT: This review paper serves to refute the concept that monogenic PIDs are not linked to the microbiome. The onset of monogenic PIDs is independent of microbiota; single-gene mutations such as AIRE or Foxp3 that affect central or peripheral immune tolerance produce monogenic diseases even in a GF environment. However, the severity and outcome of PIDs are markedly impacted by the microbial composition. We suggest that future research for these conditions may focus on targeting the microbiome.

Ticagrelor and Dapagliflozin Have Additive Effects in Ameliorating Diabetic Nephropathy in Mice with Type-2 Diabetes Mellitus.

PURPOSE: Ticagrelor and dapagliflozin can suppress the activation of the NOD-like receptor 3 (NLRP3)-inflammasome and activate AMP-activated protein kinase (AMPK). The anti-inflammatory effects of dapagliflozin has been shown to depend on AMPK activation. Dapagliflozin and ticagrelor have been shown to have additive effects on the progression of diabetic cardiomyopathy in BTBR ob/ob mice with type-2 diabetes. We assessed whether dapagliflozin and ticagrelor have additive effects on the activation of the NLRP3-inflammasome and the progression of diabetic nephropathy in mice with type-2 diabetes. METHODS: Eight-week-old BTBR received either no-drug, dapagliflozin (1.5 mg/kg/d), ticagrelor (100 mg/kg/d), or their combination for 12 weeks. Blood was assessed weekly for glucose and urine for glucose and albumin. After 12 weeks, blood creatinine, cystatin C, inflammasome activation, and insulin were assessed by ELISA. Renal cortex samples were assessed by hematoxylin and eosin and periodic acid-Schiff staining. RT-PCR and immunoblotting were used to evaluate fibrosis and the activation of Akt, AMPK and the inflammasome. RESULTS: Both ticagrelor and dapagliflozin reduced serum creatinine and cystatin C levels and urinary albumin. Both drugs attenuated the increase in glomerular area and mesangial matrix index. Both drugs decreased collagen-1 and collagen-3 expression and the activation of the NLRP3-inflammasome. Both drugs increased P-AMPK levels, but only dapagliflozin increased P-Akt levels. Overall, the protective effects of dapagliflozin and ticagrelor were additive. CONCLUSIONS: Dapagliflozin and ticagrelor attenuated the progression of diabetic nephropathy in BTBR ob/ob mice with additive effects of the combination. This was associated with AMPK activation and reduced activation of the NLRP3 inflammasome, whereas only dapagliflozin increased Akt activation.

Acute Complete Oculomotor Nerve Palsy in a Young Male Due to a Skull Base Myofibroma.

ABSTRACT: A 25-year-old male patient visited the ophthalmology clinic because of upper eye lid ptosis in the right eye, binocular double vision, and light sensitivity. He was diagnosed with a complete third nerve palsy caused by a skull base myofibroma, a rare clinical entity that has not been described before in oculomotor nerve palsy.

The Association of Gut Microbiota and Treg Dysfunction in Autoimmune Diseases.

Autoimmune conditions affect 23 million Americans or 7% of the US population. There are more than 100 autoimmune disorders, affecting every major organ system in humans. This chapter aims to further explain Treg dysfunction autoimmune disorders, including monogenic primary immune deficiency such as immune dysregulation polyendocrinopathy, enteropathy, X-linked inheritance (IPEX) syndrome, and polygenic autoimmune diseases with Treg dysfunction such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and food allergy. These conditions are associated with an abnormal small intestinal and colonic microbiome. Some disorders clearly improve with therapies aimed at microbial modification, including probiotics and fecal microbiota transplantation (FMT). Approaches to prevent and treat these disorders will need to focus on the acquisition and maintenance of a healthy colonic microbiota, in addition to more focused approaches at immune suppression during acute disease exacerbations.

Fast Li-Ion Conduction in Spinel-Structured Solids.

Spinel-structured solids were studied to understand if fast Li+ ion conduction can be achieved with Li occupying multiple crystallographic sites of the structure to form a "Li-stuffed" spinel, and if the concept is applicable to prepare a high mixed electronic-ionic conductive, electrochemically active solid solution of the Li+ stuffed spinel with spinel-structured Li-ion battery electrodes. This could enable a single-phase fully solid electrode eliminating multi-phase interface incompatibility and impedance commonly observed in multi-phase solid electrolyte-cathode composites. Materials of composition Li1.25M(III)0.25TiO4, M(III) = Cr or Al were prepared through solid-state methods. The room-temperature bulk Li+-ion conductivity is 1.63 × 10-4 S cm-1 for the composition Li1.25Cr0.25Ti1.5O4. Addition of Li3BO3 (LBO) increases ionic and electronic conductivity reaching a bulk Li+ ion conductivity averaging 6.8 × 10-4 S cm-1, a total Li-ion conductivity averaging 4.2 × 10-4 S cm-1, and electronic conductivity averaging 3.8 × 10-4 S cm-1 for the composition Li1.25Cr0.25Ti1.5O4 with 1 wt. % LBO. An electrochemically active solid solution of Li1.25Cr0.25Mn1.5O4 and LiNi0.5Mn1.5O4 was prepared. This work proves that Li-stuffed spinels can achieve fast Li-ion conduction and that the concept is potentially useful to enable a single-phase fully solid electrode without interphase impedance.

Highly regio- and stereoselective phosphinylphosphination of terminal alkynes with tetraphenyldiphosphine monoxide under radical conditions.

The homolytic cleavage of the PV(O)-PIII bond in tetraphenyldiphosphine monoxide simultaneously provides both pentavalent and trivalent phosphorus-centered radicals with different reactivities. The method using V-40 as an initiator is successfully investigated for the regio- and stereoselective phosphinylphosphination of terminal alkynes giving the corresponding trans-isomers of 1-diphenylphosphinyl-2-diphenylthiophosphinyl-1-alkenes in good yields. The protocol can be applied to a wide variety of terminal alkynes including both alkyl- and arylalkynes.

Origin of High Activity and Durability of Twisty Nanowire Alloy Catalysts under Oxygen Reduction and Fuel Cell Operating Conditions.

The ability to control the surface composition and morphology of alloy catalysts is critical for achieving high activity and durability of catalysts for oxygen reduction reaction (ORR) and fuel cells. This report describes an efficient surfactant-free synthesis route for producing a twisty nanowire (TNW) shaped platinum-iron (PtFe) alloy catalyst (denoted as PtFe TNWs) with controllable bimetallic compositions. PtFe TNWs with an optimal initial composition of ∼24% Pt are shown to exhibit the highest mass activity (3.4 A/mgPt, ∼20 times higher than that of commercial Pt catalyst) and the highest durability (<2% loss of activity after 40 000 cycles and <30% loss after 120 000 cycles) among all PtFe-based nanocatalysts under ORR or fuel cell operating conditions reported so far. Using ex situ and in situ synchrotron X-ray diffraction coupled with atomic pair distribution function (PDF) analysis and 3D modeling, the PtFe TNWs are shown to exhibit mixed face-centered cubic (fcc)-body-centered cubic (bcc) alloy structure and a significant lattice strain. A striking finding is that the activity strongly depends on the composition of the as-synthesized catalysts and this dependence remains unchanged despite the evolution of the composition of the different catalysts and their lattice constants under ORR or fuel cell operating conditions. Notably, dealloying under fuel cell operating condition starts at phase-segregated domain sites leading to a final fcc alloy structure with subtle differences in surface morphology. Due to a subsequent realloying and the morphology of TNWs, the surface lattice strain observed with the as-synthesized catalysts is largely preserved. This strain and the particular facets exhibited by the TNWs are believed to be responsible for the observed activity and durability enhancements. These findings provide new insights into the correlation between the structure, activity, and durability of nanoalloy catalysts and are expected to energize the ongoing effort to develop highly active and durable low-Pt-content nanowire catalysts by controlling their alloy structure and morphology.

Water Conservation with Managed Aquifer Recharge under Increased Drought Risk.

Economic analysis of managed aquifer recharge (MAR) typically focuses on identifying the quantity of water to add cost-effectively to natural rates of recharge. However, to the extent that MAR is successful, higher groundwater levels or at least slower depletion are likely to influence crop choice and groundwater pumping dynamics. Using a landscape-level model, we maximize farm net returns taking into account MAR and on-farm surface reservoir storage, crop choice, and the impacts of drought on groundwater use in Eastern Arkansas, USA, over 120 years. We find that drought frequency (risk) has a stronger influence on groundwater pumping and MAR use compared with drought severity. There is evidence of a substantial slippage, the percentage of the increase in groundwater use with versus without MAR divided by the MAR use, under a range of MAR cost and drought scenarios. Total slippage ranges from about 32 to 75% of total MAR water, indicating that only 68-25% of the MAR water raises groundwater levels. Even if the costs of MAR are relatively high and slippage is present, the total net returns to farms in this region are higher, and the variability in those returns are less with MAR.

RTD-1 therapeutically normalizes synovial gene signatures in rat autoimmune arthritis and suppresses proinflammatory mediators in RA synovial fibroblasts.

Rhesus theta defensin-1 (RTD-1), a macrocyclic immunomodulatory host defense peptide from Old World monkeys, is therapeutic in pristane-induced arthritis (PIA) in rats, a model of rheumatoid arthritis (RA). RNA-sequence (RNA-Seq) analysis was used to interrogate the changes in gene expression in PIA rats, which identified 617 differentially expressed genes (DEGs) in PIA synovial tissue of diseased rats. Upstream regulator analysis showed upregulation of gene expression pathways regulated by TNF, IL1B, IL6, proinflammatory cytokines, and matrix metalloproteases (MMPs) involved in RA. In contrast, ligand-dependent nuclear receptors like the liver X-receptors NR1H2 and NR1H3 and peroxisome proliferator-activated receptor gamma (PPARG) were downregulated in arthritic synovia. Daily RTD-1 treatment of PIA rats for 1-5 days following disease presentation modulated 340 of the 617 disease genes, and synovial gene expression in PIA rats treated 5 days with RTD-1 closely resembled the gene signature of naive synovium. Systemic RTD-1 inhibited proinflammatory upstream regulators such as TNF, IL1, and IL6 and activated antiarthritic ligand-dependent nuclear receptor pathways, including PPARG, NR1H2, and NR1H3, that were suppressed in untreated PIA rats. RTD-1 also inhibited proinflammatory responses in IL-1ß-stimulated human RA fibroblast-like synoviocytes (FLS) in vitro and diminished expression of human orthologs of disease genes that are induced in rat PIA synovium. Thus, the antiarthritic mechanisms of systemic RTD-1 include homeostatic regulation of arthritogenic gene networks in a manner that correlates temporally with clinical resolution of rat PIA.

Macrocyclic θ-defensins suppress tumor necrosis factor-α (TNF-α) shedding by inhibition of TNF-α-converting enzyme.

Theta-defensins (θ-defensins) are macrocyclic peptides expressed exclusively in granulocytes and selected epithelia of Old World monkeys. They contribute to anti-pathogen host defense responses by directly killing a diverse range of microbes. Of note, θ-defensins also modulate microbe-induced inflammation by affecting the production of soluble tumor necrosis factor (sTNF) and other proinflammatory cytokines. Here, we report that natural rhesus macaque θ-defensin (RTD) isoforms regulate sTNF cellular release by inhibiting TNF-α-converting enzyme (TACE; also known as adisintegrin and metalloprotease 17; ADAM17), the primary pro-TNF sheddase. Dose-dependent inhibition of cellular TACE activity by RTDs occurred when leukocytes were stimulated with live Escherichia coli cells as well as numerous Toll-like receptor agonists. Moreover, the relative inhibitory potencies of the RTD isoforms strongly correlated with their suppression of TNF release by stimulated blood leukocytes and THP-1 monocytes. RTD isoforms also inhibited ADAM10, a sheddase closely related to TACE. TACE inhibition was abrogated by introducing a single opening in the RTD-1 backbone, demonstrating that the intact macrocycle is required for enzyme inhibition. Enzymologic analyses showed that RTD-1 is a fast binding, reversible, non-competitive inhibitor of TACE. We conclude that θ-defensin-mediated inhibition of pro-TNF proteolysis by TACE represents a rapid mechanism for the regulation of sTNF and TNF-dependent inflammatory pathways. Molecules with structural and functional features mimicking those of θ-defensins may have clinical utility as TACE inhibitors for managing TNF-driven diseases.

Lactobacillus reuteri DSM 17938 feeding of healthy newborn mice regulates immune responses while modulating gut microbiota and boosting beneficial metabolites.

Early administration of Lactobacillus reuteri DSM 17938 (LR) prevents necrotizing enterocolitis and inhibits regulatory T-cell (Treg)-deficiency-associated autoimmunity in mice. In humans, LR reduces crying time in breastfed infants with colic, modifies severity in infants with acute diarrheal illnesses, and improves pain in children with functional bowel disorders. In healthy breastfed newborns with evolving microbial colonization, it is unclear if early administration of LR can modulate gut microbiota and their metabolites in such a way as to promote homeostasis. We gavaged LR (107 colony-forming units/day, daily) to C57BL/6J mice at age of day 8 for 2 wk. Both male and female mice were investigated in these experiments. We found that feeding LR did not affect clinical phenotype or inflammatory biomarkers in plasma and stool, but LR increased the proportion of Foxp3+ regulatory T cells (Tregs) in the intestine. LR also increased bacterial diversity and the relative abundance of p_Firmicutes, f_Lachnospiraceae, f_Ruminococcaceae, and genera Clostridium and Candidatus arthromitus, while decreasing the relative abundance of p_Bacteriodetes, f_Bacteroidaceae, f_Verrucomicrobiaceae, and genera Bacteroides, Ruminococcus, Akkermansia, and Sutterella. Finally, LR exerted a major impact on the plasma metabolome, upregulating amino acid metabolites formed via the urea, tricarboxylic acid, and methionine cycles and increasing tryptophan metabolism. In conclusion, early oral administration of LR to healthy breastfed mice led to microbial and metabolic changes which could be beneficial to general health.NEW & NOTEWORTHY Oral administration of Lactobacillus reuteri DSM 17938 (LR) to healthy breastfed mice promotes intestinal immune tolerance and is linked to proliferation of beneficial gut microbiota. LR upregulates plasma metabolites that are involved in the urea cycle, the TCA cycle, methionine methylation, and the polyamine pathway. Herein, we show that LR given to newborn mice specifically increases levels of tryptophan metabolites and the purine nucleoside adenosine that are known to enhance tolerance to inflammatory stimuli.

Ticagrelor Improves Remodeling, Reduces Apoptosis, Inflammation and Fibrosis and Increases the Number of Progenitor Stem Cells After Myocardial Infarction in a Rat Model of Ischemia Reperfusion.

BACKGROUND/AIMS: We assessed the effects of ticagrelor, aspirin and prasugrel, started 7days after myocardial ischemia-reperfusion injury on remodeling, inflammation and fibrosis in the rat. We examined whether ticagrelor can affect the number of progenitor cells in the border zone. Ticagrelor, started 24h after myocardial ischemia-reperfusion injury, attenuates the decrease in heart function and adverse remodeling, an effect which is blocked by aspirin. METHODS: Rats underwent 40min ischemia followed by reperfusion. Oral dosing with vehicle, ticagrelor (300mg/kg/d), aspirin (20mg/kg/d), their combination or prasugrel (15mg/kg/d) started 7days after infarction. Echocardiography was used to assess systolic function. Heart tissue were analyzed by rt-PCR, immunoblotting, ELISA and immunohistochemistry 2weeks after infarction. RESULTS: Both ticagrelor and aspirin attenuated the decrease in systolic function and remodeling, an effect that was blocked by their combination. Ticagrelor and aspirin attenuated the increase in ANP, BNP, collagen-I and collagen-III. Again, the effect was blocked by their combination. Ticagrelor increased c-Kit, Sca-1, Ki-67, CD34, attenuated the decrease in CD105 mRNA levels, and attenuated the increase in CD31, whereas aspirin increased Ki-67, suppressed the increase in CD31 and attenuated the decrease in CD105 mRNA levels. Prasugrel did not display any effects. CONCLUSION: Ticagrelor attenuated adverse remodeling and deterioration of left ventricular systolic function despite starting treatment after the myocardial ischemia-reperfusion injury is completed. Aspirin had similar effects; however, when combined with ticagrelor, the protective effects were significantly attenuated. Ticagrelor increased the levels of several markers of stem cells and regeneration, suggesting cardiac healing by recruiting regenerative cells into the infarct.

DPP-4 inhibition by linagliptin prevents cardiac dysfunction and inflammation by targeting the Nlrp3/ASC inflammasome.

We compared the effects of linagliptin (Lina, a DPP4 inhibitor) and GLP-1 receptor activation by exenatide followed by exendin-4 in an infusion pump (EX) on infarct size (IS), post-infarction activation of the inflammasome and remodeling in wild-type (WT) and db/db diabetic mice. Mice underwent 30 min ischemia followed by 24 h reperfusion. IS was assessed by TTC. Additional mice underwent permanent coronary artery occlusion. Echocardiography was performed 2w after infarction. Activation of the inflammasome in the border zone of the infarction was assessed by rt-PCR and ELISA 2w after reperfusion. Further in vitro experiments were done using primary human cardiofibroblasts and cardiomyocytes exposed to simulated ischemia-reoxygenation. Lina and EX limited IS in both the WT and the db/db mice. Lina and EX equally improved ejection fraction in both the WT and the db/db mice. mRNA levels of ASC, NALP3, IL-1ß, IL-6, Collagen-1, and Collagen-3 were higher in the db/db mice than in the WT mice. Infarction increased these levels in the WT and db/db mice. Lina more than EX attenuated the increase in ASC, NALP3, IL-1ß, IL-6, Collagen-1 and Collagen-3, TNFα and IL-1ß, and decreased apoptosis, especially in the db/db mice. In vitro experiments showed that Lina, but not EX, attenuated the increase in TLR4 expression, an effect that was dependent on p38 activation with downstream upregulation of Let-7i and miR-146b levels. Lina and EX had similar effects on IS and post-infarction function, but Lina attenuated the activation of the inflammasome and the upregulation of collagen-1 and collagen-3 more than direct GLP-1 receptor activation. This effect depends on p38 activation with downstream upregulation of miR-146b levels that suppresses TLR4 expression.

Palladium-Catalyzed Diarylation of Isocyanides with Tetraarylleads for the Selective Synthesis of Imines and α-Diimines.

Using tetraaryllead compounds (PbAr4) as arylating reagents, isocyanides undergo selective diarylation in the presence of palladium catalysts such as Pd(OAc)2 or Pd(PPh3)4 to afford imines and/or α-diimines based on the isocyanide employed. With aliphatic isocyanides, imines are obtained preferentially, whereas α-diimines are formed in the case of electron-rich aromatic isocyanides. The differences in imine/α-diimine selectivity can be attributed to the stability of imidoylpalladium intermediates formed in this catalytic reaction. Compared with other arylating reagents, tetraaryllead compounds are excellent candidates for use in the selective transformations to imines and/or α-diimines, especially in terms of inhibiting the oligomerization of isocyanides, which results in a lower product selectivity in many transition-metal-catalyzed reactions of isocyanides.

Population-based study of early-onset neonatal sepsis in Canada.

OBJECTIVE: To determine the incidence, types of organisms and resistance patterns involved in early-onset neonatal sepsis in Canada. STUDY DESIGN: Early-onset neonatal sepsis cases were identified through the Canadian Paediatric Surveillance Program. Neonates were excluded if they were asymptomatic or if intracranial procedures preceded a positive cerebrospinal fluid culture. RESULTS: One hundred and twenty-seven cases were identified (0.17 cases per 1000 live births). Group B Streptococcus accounted for 41.7%, Escherichia coli for 35.4%. Antibiotic resistance was present in 33.9% of all cases. 55.6% of E coli cases were resistant, most commonly to ampicillin. Infecting organism species were associated with gestational age, being very low birth weight, time at sepsis presentation, maternal antibiotic prophylaxis and rupture of membranes lasting over 18 hours. Group B Streptococcus was most common in term and E coli in preterm neonates. Twenty-two per cent of E coli cases presented after 48 hours, compared to 6% of Group B Streptococcus cases. CONCLUSION: We identify a lower rate of early-onset neonatal sepsis than historically suggested, with differing dominant organisms based on gestational ages and other factors, as well as high rates of resistance especially among E coli cases.

Publicly funded clinical research in Canada.

Clinical research is funded by industry, governments, charities, and hospitals. It is important to know the economic commitment of the various funding bodies, but until now there has been no national source available which provides these data. We surveyed the major funders to provide such a measure. There is evidence that government and charity funding of medical research is a trigger for private sector research investment; therefore, tracking all sources of funding for clinical research will provide policy-makers with an overall picture of health research funding. These data support policy decision-making related to clinical research in Canada.