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In a phase 3 trial involving 1035 outpatients who were at increased risk for severe Covid-19, those who received two monoclonal antibodies targeting SARS-CoV-2 had a significant reduction in the viral load and a significantly lower incidence of progression to severe illness than those who received placebo.

Prolonged immobility during a critical illness may predispose patients to the development of joint contracture. We sought to document the incidence of, the risk factors for and the reversibility of joint contractures among patients who stayed in a tertiary intensive care unit (ICU) for 2 weeks or longer. We conducted a chart review to collect data on the presence of and risk factors for joint contractures in the shoulders, elbows, hips, knees and ankles among patients admitted to the ICU between January 2003 and March 2005. At the time of transfer out of the ICU, at least 1 joint contracture was recorded in 61 (39%) of 155 patients; 52 (34%) of the patients had joint contractures of an extent documented to impair function. Time spent in the ICU was a significant risk factor for contracture: a stay of 8 weeks or longer was associated with a significantly greater risk of any joint contracture than a stay of 2 to 3 weeks (adjusted odds ratio [OR] 7.09, 95% confidence interval (CI) 1.29-38.9; p = 0.02). Among the variables tested, only the use of steroids conferred a protective effect against joint contractures (adjusted OR 0.35, 95% CI 0.14-0.83; p = 0.02). At the time of discharge to home, which occurred a median of 6.6 weeks after transfer out of intensive care, 50 (34%) of the 147 patients not lost to follow-up still had 1 or more joint contractures, and 34 (23%) of the patients had at least 1 functionally significant joint contracture. Following a prolonged stay in the ICU, a functionally significant contracture of a major joint occurred in more than one-third of patients, and most of these contractures persisted until the time of discharge to home.

Death is universal, yet relatively little is known about how Canadians experience their death. Using novel decedent interview data from the Canadian Longitudinal Study on Aging we describe the prevalence and characteristics of peace with dying among older Canadians. We conducted a secondary analysis of decedent interview data from the Canadian Longitudinal Study on Aging. Proxies of deceased Canadian Longitudinal Study on Aging participants reported on participants' end-of-life experiences between January 2012 to March 2022. We examined end-of-life characteristics and their association with proxy reports of experiencing peace with dying. We conducted regression analysis to explore the association between demographic and end-of-life characteristics and experiencing peace with dying. Of 3,672 deceased participants, 1,287 (35.0%) had a completed decedent questionnaire and were included in the analysis. Respondents reported that two-thirds (66.0%) of the deceased experienced peace with dying and 17% did not experience peace with dying. The unadjusted odds of experiencing peace with dying were higher for those with an appointed power of attorney (OR 1.80; CI 1.39-2.33), those who died of cancer (OR 1.71; CI 1.27-2.30), those in hospice/receiving palliative care (OR 1.67; CI 1.19-2.37), individuals older than 75 years (OR 1.55; CI 1.04-2.30), or widowed (OR 1.53; CI 1.12-2.10). Widowhood (OR 1.51; CI 1.01-2.29), having an end-of-life SDM (OR 1.58; CI 1.14-2.17), and dying of cancer (OR 1.67; CI 1.19-2.23) increased the adjusted odds of dying with peace. Close to 1 in 5 older Canadians may not experience peace with dying, which supports greater focus on improving the end-of-life care. Our findings suggest that advanced planning may enhance the experience of a peaceful death in Canada.

In the present work, room temperature epitaxial growth of Zn-doped iron oxide films (Zn: FeO x ) was achieved by pulsed laser deposition, on c-cut sapphire substrates without any high temperature thermal treatments before the growth. The nature of the oxide phases (wüstite and/or spinel) present in the films depends on the oxygen pressure during the laser ablation. At the residual vacuum (2 × 10 − 7 mbar), the (111) wüstite (Zn: FeO) textures was obtained in the films, while oxygen pressures between 2 × 10 − 5 to 2 × 10 − 3 mbar led to the growth of the spinel (Zn: Fe 3 O 4 ) phase on the c-cut sapphire substrate. Moreover, the species emitted by the target in the 2 × 10 − 7 to 2 × 10 − 5 mbar range, preserve their high kinetic energy which allows an easy crystallization of the film on the substrate at room temperature, leading to the epitaxial growth of the wustite and spinel phases. Magnetic properties through M(H) curves at 10 K and 300 K, of the wüstite-based film grown under 2 × 10 − 7 mbar were studied, and an exchange bias due to the presence of Fe 3+ cation in the film is observed. Finally, the possible mechanisms of the room temperature epitaxial growth of the oxide films on the substrate are presented and discussed.

Post-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Despite the widespread use of this model, the mechanisms that underlie the persistent behavioural changes after the transient peripheral inflammatory response remain elusive. The study of the metabolome, the collection of all the small molecule metabolites in a sample, combined with multivariate statistical techniques provides a way of studying biochemical pathways influenced by an LPS challenge. Adult male CD-1 mice received an intraperitoneal injection of either LPS (0.83 mg/kg) or saline, and were assessed for depressive-like behaviour 24 h later. In a separate mouse cohort, pro-inflammatory cytokine gene expression and 1H nuclear magnetic resonance (NMR) metabolomics measurements were made in brain tissue and blood. Statistical analyses included Independent Sample t-tests for gene expression data, and supervised multi-variate analysis using orthogonal partial least squares discriminant analysis for metabolomics. Both plasma and brain metabolites in male mice were altered following a single peripheral LPS challenge that led to depressive-like behaviour in the forced swim test. The plasma metabolites altered by LPS are involved in energy metabolism, including lipoproteins, glucose, creatine, and isoleucine. In the brain, glutamate, serine, and N-acetylaspartate (NAA) were reduced after LPS, whereas glutamine was increased. Serine-modulated glutamatergic signalling and changes in bioenergetics may mediate the behavioural phenotype induced by LPS. In light of other data supporting a central imbalance of glutamate-glutamine cycling in depression, our results suggest that aberrant central glutaminergic signalling may underpin the depressive-like behaviours that result from both inflammation and non-immune pathophysiology. Normalising glutaminergic signalling, rather than seeking to increase serotonergic signalling, might prove to be a more coherent approach to the development of new treatments for mood disorder.

Through these partnerships, the food industry seeks to emphasize that inactivity - not the promotion and consumption of its calorie-rich products - is the prime cause of obesity. According to Particip ACTION, in a Coca-Cola co-branded press release highlighting \"the inactivity crisis,\" \"Experts have stated that for the first time in history, inactivity may cause this generation of youth to die younger than their parents.\"1 It cites a 2005 New England Journal of Medicine article titled \"A potential decline in life expectancy in the United States in the 21st century.\"9 However, that article mentions inactivity only in passing. A Hershey's partnership with the American Dietetic Association offers an online survey of registered dietitians that promotes the daily inclusion of chocolate as part of a \"balanced lifestyle.\"10 In another example, Dr. Dean Ornish, president of the Preventive Medicine Research Institute, headlines a Mars Inc. web page stating, \"it's important to find a balance between what we eat and how much we exercise, and it's important to balance enjoying snack foods along with eating a variety of other types of foods.\"11

Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K⁺ levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K⁺ secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K⁺ channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in Xenopus oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K⁺ secretion.

Mutations in the serine-threonine kinases WNK1 and WNK4 [with no lysine (K) at a key catalytic residue] cause pseudohypoaldosteronism type II (PHAII), a Mendelian disease featuring hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis. Both kinases are expressed in the distal nephron, although the regulators and targets of WNK signaling cascades are unknown. The Cl-dependence of PHAII phenotypes, their sensitivity to thiazide diuretics, and the observation that they constitute a \"mirror image\" of the phenotypes resulting from loss of function mutations in the thiazide-sensitive Na-Cl cotransporter (NCCT) suggest that PHAII may result from increased NCCT activity due to altered WNK signaling. To address this possibility, we measured NCCT-mediated Na+influx and membrane expression in the presence of wild-type and mutant WNK4 by heterologous expression in Xenopus oocytes. Wild-type WNK4 inhibits NCCT-mediated Na-influx by reducing membrane expression of the cotransporter (22Na-influx reduced 50%,$P < 1 \\times 10^{-9}$, surface expression reduced 75%,$P < 1 \\times 10^{-14}$in the presence of WNK4). This inhibition depends on WNK4 kinase activity, because missense mutations that abrogate kinase function prevent this effect. PHAII-causing missense mutations, which are remote from the kinase domain, also prevent inhibition of NCCT activity, providing insight into the pathophysiology of the disorder. The specificity of this effect is indicated by the finding that WNK4 and the carboxyl terminus of NCCT coimmunoprecipitate when expressed in HEK 293T cells. Together, these findings demonstrate that WNK4 negatively regulates surface expression of NCCT and implicate loss of this regulation in the molecular pathogenesis of an inherited form of hypertension.

The electroneutral cation-chloride-coupled cotransporter gene family ( SLC12) was identified initially at the molecular level in fish and then in mammals. This nine-member gene family encompasses two major branches, one including two bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporters and the thiazide-sensitive Na(+):Cl(-) cotransporter. Two of the genes in this branch ( SLC12A1 and SLC12A3), exhibit kidney-specific expression and function in renal salt reabsorption, whereas the third gene ( SLC12A2) is expressed ubiquitously and plays a key role in epithelial salt secretion and cell volume regulation. The functional characterization of both alternatively-spliced mammalian Na(+)-K(+)-2Cl(-) cotransporter isoforms and orthologs from distantly related species has generated important structure-function data. The second branch includes four genes ( SLC12A4- 7) encoding electroneutral K(+)-Cl(-) cotransporters. The relative expression level of the neuron-specific SLC12A5 and the Na(+)-K(+)-2Cl(-) cotransporter SLC12A2 appears to determine whether neurons respond to GABA with a depolarizing, excitatory response or with a hyperpolarizing, inhibitory response. The four K(+)-Cl(-) cotransporter genes are co-expressed to varying degrees in most tissues, with further roles in cell volume regulation, transepithelial salt transport, hearing, and function of the peripheral nervous system. The transported substrates of the remaining two SLC12 family members, SLC12A8 and SLC12A9, are as yet unknown. Inactivating mutations in three members of the SLC12 gene family result in Mendelian disease; Bartter syndrome type I in the case of SLC12A1, Gitelman syndrome for SLC12A3, and peripheral neuropathy in the case of SLC12A6. In addition, knockout mice for many members of this family have generated important new information regarding their respective physiological roles.

The Na⁺:K⁺:2Cl⁻ cotransporter (NKCC2) is the target of loop diuretics and is mutated in Bartter's syndrome, a heterogeneous autosomal recessive disease that impairs salt reabsorption in the kidney's thick ascending limb (TAL). Despite the importance of this cation/chloride cotransporter (CCC), the mechanisms that underlie its regulation are largely unknown. Here, we show that intracellular chloride depletion in Xenopus laevis oocytes, achieved by either coexpression of the K-Cl cotransporter KCC2 or low-chloride hypotonic stress, activates NKCC2 by promoting the phosphorylation of three highly conserved threonines (96, 101, and 111) in the amino terminus. Elimination of these residues renders NKCC2 unresponsive to reductions of $[{\\rm Cl}^{-}]_{{\\rm i}}$. The chloride-sensitive activation of NKCC2 requires the interaction of two serine-threonine kinases, WNK3 (related to WNK1 and WNK4, genes mutated in a Mendelian form of hypertension) and SPAK (a Ste20-type kinase known to interact with and phosphorylate other CCCs). WNK3 is positioned upstream of SPAK and appears to be the chloride-sensitive kinase. Elimination of WNK3's unique SPAK-binding motif prevents its activation of NKCC2, as does the mutation of threonines 96, 101, and 111. A catalytically inactive WNK3 mutant also completely prevents NKCC2 activation by intracellular chloride depletion. Together these data reveal a chloride-sensing mechanism that regulates NKCC2 and provide insight into how increases in the level of intracellular chloride in TAL cells, as seen in certain pathological states, could drastically impair renal salt reabsorption.