Baseline electrolyte abnormalities would be related to poor prognosis in hospitalized coronavirus disease 2019 patients.

Electrolyte abnormalities are not uncommon in coronavirus disease 2019 (COVID-19). Several studies have suggested that various electrolyte imbalances seem to have an impact on disease prognosis. However, no study has primarily focused on the effect of baseline electrolyte abnormalities on disease outcome. In this study, we assessed the validity of the hypothesis that baseline electrolyte imbalances may be related to unfavourable outcomes in hospitalized COVID-19 patients. Design of the study was retrospective and observational. We included 408 hospitalized individuals with COVID-19 over 18 years old. Baseline levels of sodium, potassium, calcium and chloride were assessed and the effects of abnormalities in these electrolytes on requirement for intensive care unit and mechanical ventilation, hospitalization duration and treatment outcome were evaluated. Patients were clustered based on electrolyte levels and clusters were compared according to outcome variables. Frequency of other severe disease indices was compared between the clusters. Lastly, we evaluated the independent factors related to COVID-19-associated deaths with multivariate analyses. In all, 228 (55.8%) of the patients had at least one electrolyte imbalance at baseline. Hyponatraemia was the most frequent electrolyte abnormality. Patients with hyponatraemia, hypochloraemia or hypocalcaemia had, respectively, more frequent requirement for intensive care unit and mechanical ventilation, higher mortality rate and longer hospitalization. The clusters associated with electrolyte abnormalities had unfavourable outcomes. Also, Clinical and laboratory features associated with severe disease were detected more often in those clusters. Hyponatraemia was an independent factor related to death from COVID-19 (OR 10.33; 95% CI 1.62-65.62; p 0.01). Furthermore, baseline electrolyte imbalances, primarily hyponatraemia, were related to poor prognosis in COVID-19 and baseline electrolyte assessment would be beneficial for evaluating the risk of severe COVID-19.

Regional process redesign of lung cancer care: a learning health system pilot project.

BACKGROUND: The Ottawa Hospital (toh) defined delay to timely lung cancer care as a system design problem. Recognizing the patient need for an integrated journey and the need for dynamic alignment of providers, toh used a learning health system (lhs) vision to redesign regional diagnostic processes. A lhs is driven by feedback utilizing operational and clinical information to drive system optimization and innovation. An essential component of a lhs is a collaborative platform that provides connectivity across silos, organizations, and professions. METHODS: To operationalize a lhs, we developed the Ottawa Health Transformation Model (ohtm) as a consensus approach that addresses process barriers, resistance to change, and conflicting priorities. A regional Community of Practice (cop) was established to engage stakeholders, and a dedicated transformation team supported process improvements and implementation. RESULTS: The project operationalized the lung cancer diagnostic pathway and optimized patient flow from referral to initiation of treatment. Twelve major processes in referral, review, diagnostics, assessment, triage, and consult were redesigned. The Ottawa Hospital now provides a diagnosis to 80% of referrals within the provincial target of 28 days. The median patient journey from referral to initial treatment decreased by 48% from 92 to 47 days. CONCLUSIONS: The initiative optimized regional integration from referral to initial treatment. Use of a lhs lens enabled the creation of a system that is standardized to best practice and open to ongoing innovation. Continued transformation initiatives across the continuum of care are needed to incorporate best practice and optimize delivery systems for regional populations.

Phosphorylation-dependent localization of microtubule-associated protein MAP2c to the actin cytoskeleton.

Microtubule-associated protein 2 (MAP2) is a neuronal phosphoprotein that promotes net microtubule growth and actin cross-linking and bundling in vitro. Little is known about MAP2 regulation or its interaction with the cytoskeleton in vivo. Here we investigate the in vivo function of three specific sites of phosphorylation on MAP2. cAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells and promotes MAP2c localization to peripheral membrane ruffles enriched in actin. cAMP-dependent protein kinase phosphorylates serines within three KXGS motifs, one within each tubulin-binding repeat. These highly conserved motifs are also found in homologous proteins tau and MAP4. Phosphorylation at two of these sites was detected in brain tissue. Constitutive phosphorylation at these sites was mimicked by single, double, and triple mutations to glutamic acid. Biochemical and microscopy-based assays indicated that mutation of a single residue was adequate to disrupt the MAP2-microtubule interaction in HeLa cells. Double or triple point mutation promoted MAP2c localization to the actin cytoskeleton. Specific association between MAP2c and the actin cytoskeleton was demonstrated by retention of MAP2c-actin colocalization after detergent extraction. Specific phosphorylation states may enhance the interaction of MAP2 with the actin cytoskeleton, thereby providing a regulated mechanism for MAP2 function within distinct cytoskeletal domains.

Higher order iminodiacetic acid libraries for probing protein-protein interactions.

Full details of the preparation of iminodiacetic acid diamide dimer (2040 compounds), trimer (560 compounds), and tetramer (1596 compounds) libraries by multistep convergent solution-phase synthesis for studying protein-protein interactions are provided. The libraries were assembled in a format providing small 8-10 compound mixtures and the deconvolution of many of the small mixtures to identify screening leads by resynthesis of the individual components have been conducted for 320 of the individual compounds to date. A representative example of the subsequent exploration of the structure-activity relationships for an identified receptor binding antagonist (200 additional individual compounds) and steps taken for potential elaboration to a receptor dimerization agonist are defined with preparation of representative linked dimers (70 compounds).

N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.

Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.