Strokes in Patients With Injection Drug Use and Tricuspid Valve Endocarditis - A Case Series.

Research Design: In this study, we describe patients from a tertiary care safety-net hospital endocarditis registry with tricuspid valve infective endocarditis (TVIE), and concomitant acute or subacute ischemic stroke predominantly associated with injection drug use (IDU). We retrospectively obtained data pertinent to neurologic examinations, history of injection drug use (IDU), blood cultures, transthoracic/transesophageal echocardiography (TTE/TEE), neuroimaging, and Modified Rankin Scale (mRS) scores at discharge. Only those patients with bacteremia, tricuspid valve vegetations, and neuroimaging consistent with acute to subacute ischemic infarction and microhemorrhages in two cases were included in this series. Results: Of 188 patients in the registry, 66 patients had TVIE and 10 of these were complicated by ischemic stroke. Neurologic symptoms were largely non-specific, eight patients had altered mental status and only 3 had focal deficits. Nine cases were associated with IDU. Two patients had evidence of a patent foramen ovale on echocardiography. Blood cultures grew S. aureus species in 9 of the patients, all associated with IDU. Three patients died during hospitalization. The mRS score at discharge for survivors ranged 0-4. Conclusions: Patients with strokes from TVIE had heterogeneous presentations and putative mechanisms. We noted that robust neuroimaging is lacking for patients with TVIE from IDU and that such patients may benefit from neuroimaging as a screen for strokes to assist peri-operative management. Further inquiry is needed to elucidate stroke mechanisms in these patients.

COVID-19 and the brain.

Entering the third year into the pandemic, overwhelming evidence demonstrates that Coronavirus disease 2019 (COVID-19) infection is a systemic illness, often with involvement of the central nervous system. Multiple mechanisms may underlie the development of neurologic manifestations of illness, including hypoxia, systemic illness, hypercoagulability, endothelial dysfunction, general critical illness, inflammatory response, and neurotropism of the severe acute respiratory syndrome coronavirus 2 (SARS-Co-V2) virus. COVID-19 infection is associated with neurologic involvement in all stages; acute infection, subacute/post-infection, and growing evidence also suggests during a chronic phase, the post-acute sequalae of COVID-19 (PASC). With over 20,000 published articles on COVID and the brain at the time of writing, it is virtually impossible to present an unbiased comprehensive review of how SARS-Co-V2 impacts the nervous system. In this review, we will present an overview of common neurologic manifestations, in particular focusing on the cerebrovascular complications, and proposed pathophysiology.

Validation of a Crisis Standards of Care Model for Prioritization of Limited Resources During the Coronavirus Disease 2019 Crisis in an Urban, Safety-Net, Academic Medical Center.

OBJECTIVES: The coronavirus disease 2019 pandemic has overwhelmed healthcare resources even in wealthy nations, necessitating rationing of limited resources without previously established crisis standards of care protocols. In Massachusetts, triage guidelines were designed based on acute illness and chronic life-limiting conditions. In this study, we sought to retrospectively validate this protocol to cohorts of critically ill patients from our hospital. DESIGN: We applied our hospital-adopted guidelines, which defined severe and major chronic conditions as those associated with a greater than 50% likelihood of 1- and 5-year mortality, respectively, to a critically ill patient population. We investigated mortality for the same intervals. SETTING: An urban safety-net hospital ICU. PATIENTS: All adults hospitalized during April of 2015 and April 2019 identified through a clinical database search. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 365 admitted patients, 15.89% had one or more defined chronic life-limiting conditions. These patients had higher 1-year (46.55% vs 13.68%; p < 0.01) and 5-year (50.00% vs 17.22%; p < 0.01) mortality rates than those without underlying conditions. Irrespective of classification of disease severity, patients with metastatic cancer, congestive heart failure, end-stage renal disease, and neurodegenerative disease had greater than 50% 1-year mortality, whereas patients with chronic lung disease and cirrhosis had less than 50% 1-year mortality. Observed 1- and 5-year mortality for cirrhosis, heart failure, and metastatic cancer were more variable when subdivided into severe and major categories. CONCLUSIONS: Patients with major and severe chronic medical conditions overall had 46.55% and 50.00% mortality at 1 and 5 years, respectively. However, mortality varied between conditions. Our findings appear to support a crisis standards protocol which focuses on acute illness severity and only considers underlying conditions carrying a greater than 50% predicted likelihood of 1-year mortality. Modifications to the chronic lung disease, congestive heart failure, and cirrhosis criteria should be refined if they are to be included in future models.

Ligand-promoted protein folding by biased kinetic partitioning.

Protein folding in cells occurs in the presence of high concentrations of endogenous binding partners, and exogenous binding partners have been exploited as pharmacological chaperones. A combined mathematical modeling and experimental approach shows that a ligand improves the folding of a destabilized protein by biasing the kinetic partitioning between folding and alternative fates (aggregation or degradation). Computationally predicted inhibition of test protein aggregation and degradation as a function of ligand concentration are validated by experiments in two disparate cellular systems.

Comparing protein folding in vitro and in vivo: foldability meets the fitness challenge.

In this review, we compare and contrast current knowledge about in vitro and in vivo protein folding. Major advances in understanding fundamental principles underlying protein folding in optimized in vitro conditions have yielded detailed physicochemical principles of folding landscapes for small, single domain proteins. In addition, there has been increased research focusing on the key features of protein folding in the cell that differentiate it from in vitro folding, such as co-translational folding, chaperone-facilitated folding, and folding in crowded conditions with many weak interactions. Yet these two research areas have not been bridged effectively in research carried out to date. This review points to gaps between the two that are ripe for future research. Moreover, we emphasize the biological selection pressures that impact protein folding in vivo and how fitness drives the evolution of protein sequences in ways that may place foldability in tension with other requirements on a given protein. We suggest that viewing the physicochemical process of protein folding through the lens of evolution will unveil new insights and pose novel challenges about in-cell folding landscapes.

Mechanism of cadmium-mediated inhibition of Msh2-Msh6 function in DNA mismatch repair.

The observation that Cadmium (Cd(2+)) inhibits Msh2-Msh6, which is responsible for identifying base pair mismatches and other discrepancies in DNA, has led to the proposal that selective targeting of this protein and consequent suppression of DNA repair or apoptosis promote the carcinogenic effects of the heavy metal toxin. It has been suggested that Cd(2+) binding to specific sites on Msh2-Msh6 blocks its DNA binding and ATPase activities. To investigate the mechanism of inhibition, we measured Cd(2+) binding to Msh2-Msh6, directly and by monitoring changes in protein structure and enzymatic activity. Global fitting of the data to a multiligand binding model revealed that binding of about 100 Cd(2+) ions per Msh2-Msh6 results in its inactivation. This finding indicates that the inhibitory effect of Cd(2+) occurs via a nonspecific mechanism. Cd(2+) and Msh2-Msh6 interactions involve cysteine sulfhydryl groups, and the high Cd(2+):Msh2-Msh6 ratio implicates other ligands such as histidine, aspartate, glutamate, and the peptide backbone as well. Our study also shows that cadmium inactivates several unrelated enzymes similarly, consistent with a nonspecific mechanism of inhibition. Targeting of a variety of proteins, including Msh2-Msh6, in this generic manner would explain the marked broad-spectrum impact of Cd(2+) on biological processes. We propose that the presence of multiple nonspecific Cd(2+) binding sites on proteins and their propensity to change conformation on interaction with Cd(2+) are critical determinants of the susceptibility of corresponding biological systems to cadmium toxicity.