Cardiovascular Complications of COVID-19: A Scoping Review of Evidence.

This scoping review sought to identify the nature and extent of clinical evidence regarding the acute and long-term cardiovascular complications associated with COVID-19. Forty-nine studies published between 2020 and 2023 were selected for review. The studies were divided into two groups. The referential group included 22 studies. The second group of 27 studies was used for a detailed review to assess the strength of the evidence. The aggregate evidence indicates that the most common cardiac complications associated with COVID-19 include but are not limited to acute pericarditis, acute myocardial injury, acute myocarditis, various arrhythmias, microvascular angiopathy, left ventricular dysfunction, heart failure, acute cardiac injury, and acute coronary syndrome. Clinical and epidemiological implications of the findings are investigated, and future research recommendations are proposed.

Andy Golden: Mentorship through the Years.

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Importin α/ß promote Kif18B microtubule association and enhance microtubule destabilization activity.

Tight regulation of microtubule (MT) dynamics is necessary for proper spindle assembly and chromosome segregation. The MT destabilizing Kinesin-8, Kif18B, controls astral MT dynamics and spindle positioning. Kif18B interacts with importin α/ß as well as with the plus-tip tracking protein EB1, but how these associations modulate Kif18B is not known. We mapped the key binding sites on Kif18B, made residue-specific mutations, and assessed their impact on Kif18B function. Blocking EB1 interaction disrupted Kif18B MT plus-end accumulation and inhibited its ability to control MT length on monopolar spindles in cells. Blocking importin α/ß interaction disrupted Kif18B localization without affecting aster size. In vitro, importin α/ß increased Kif18B MT association by increasing the on-rate and decreasing the off-rate from MTs, which stimulated MT destabilization. In contrast, EB1 promoted MT destabilization without increasing lattice binding in vitro, which suggests that EB1 and importin α/ß have distinct roles in the regulation of Kif18B-mediated MT destabilization. We propose that importin α/ß spatially modulate Kif18B association with MTs to facilitate its MT destabilization activity. Our results suggest that Ran regulation is important not only to control molecular motor function near chromatin but also to provide a spatial control mechanism to modulate MT binding of nuclear localization signal-containing spindle assembly factors.

Audit of Clinical Care Received by COVID-19 Patients Treated at a Tertiary Care Hospital of Nepal in 2021.

Like the world over, Nepal was also hard hit by the second wave of COVID-19. We audited the clinical care provided to COVID-19 patients admitted from April to June 2021 in a tertiary care hospital of Nepal. This was a cohort study using routinely collected hospital data. There were 620 patients, and most (458, 74%) had severe illness. The majority (600, 97%) of the patients were eligible for admission as per national guidelines. Laboratory tests helping to predict the outcome of COVID-19, such as D-dimer and C-reactive protein, were missing in about 25% of patients. Nearly all (>95%) patients with severe disease received corticosteroids, anticoagulants and oxygen. The use of remdesivir was low (22%). About 70% of the patients received antibiotics. Hospital exit outcomes of most (>95%) patients with mild and moderate illness were favorable (alive and discharged). Among patients with severe illness, about 25% died and 4% were critically ill, needing further referral. This is the first study from Nepal to audit and document COVID-19 clinical care provision in a tertiary care hospital, thus filling the evidence gap in this area from resource-limited settings. Adherence to admission guidelines was excellent. Laboratory testing, access to essential drugs and data management needs to be improved.

Sudden Unexpected Death in Epilepsy.

Epilepsy is a complex neurological condition with numerous etiologies and treatment options. In a subset of these patients, sudden unexpected death can occur, and to date, there are numerous explanations as to the pathophysiological mechanisms and how to mitigate these catastrophic outcomes. Approximately 2.3 million Americans have epilepsy, and nearly 150,000 people develop the condition each year. Sudden unexpected death in epilepsy (SUDEP) accounts for 2-18% of all epilepsy-related deaths and this is equivalent to one death in 1000 person-years of diagnosed epilepsy. It is more common in young adults aged 20-45. Seizures in the past year; the absence of terminal remission in the last five years; increased seizure frequency, particularly GTCS; and nocturnal seizures are the most potent modifiable risk factors for SUDEP. Patients not receiving any antiepileptic drug therapy are at higher risk of SUDEP. Patient education on medication compliance; care plans for seizure clusters (rescue medicines); epilepsy self-management programs; and lifestyle changes to avoid seizure-triggering factors, including avoiding excessive alcohol use and sleep deprivation, should be provided by health care providers. Continued research into SUDEP will hopefully lead to effective interventions to minimize occurrences. At present, aggressive control of epilepsy and enhanced education for individuals and the public are the most effective weapons for combating SUDEP. This narrative review focuses on updated information related to SUDEP epidemiology; pathophysiology; risk factor treatment options; and finally, a discussion of important clinical studies. We seek to encourage clinicians who care for patients with epilepsy to be aggressive in controlling seizure activity and diligent in their review of risk factors and education of patients and their families about SUDEP.

Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans.

Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1) is a rare, autosomal recessive disorder caused by mutations in the NFU1 gene. NFU1 is responsible for delivery of iron-sulfur clusters (ISCs) to recipient proteins which require these metallic cofactors for their function. Pathogenic variants of NFU1 lead to dysfunction of its target proteins within mitochondria. To date, 20 NFU1 variants have been reported and the unique contributions of each variant to MMDS1 pathogenesis is unknown. Given that over half of MMDS1 individuals are compound heterozygous for different NFU1 variants, it is valuable to investigate individual variants in an isogenic background. In order to understand the shared and unique phenotypes of NFU1 variants, we used CRISPR/Cas9 gene editing to recreate exact patient variants of NFU1 in the orthologous gene, nfu-1 (formerly lpd-8), in C. elegans. Five mutant C. elegans alleles focused on the presumptive iron-sulfur cluster interaction domain were generated and analyzed for mitochondrial phenotypes including respiratory dysfunction and oxidative stress. Phenotypes were variable between the mutant nfu-1 alleles and generally presented as an allelic series indicating that not all variants have lost complete function. Furthermore, reactive iron within mitochondria was evident in some, but not all, nfu-1 mutants indicating that iron dyshomeostasis may contribute to disease pathogenesis in some MMDS1 individuals.

Persistent Symptoms in Post-COVID-19 Patients Attending Follow-Up OPD at Sukraraj Tropical and Infectious Disease Hospital (STIDH), Kathmandu, Nepal.

The long-term effects of COVID-19 among survivors is a matter of concern. This research aimed to study persistent symptoms in post-COVID-19 patients attending a follow-up clinic at a tertiary care hospital in Nepal. All patients, presenting to the outpatient clinic during the study duration of six weeks, with history of positive reverse transcriptase- polymerase chain reaction for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) at least two weeks prior to presentation, were included. The duration of follow-up ranged from 15 till 150 days with the mean duration of 28 days after diagnosis of COVID-19. Of 118 patients, 43 (36.4%) had a history of mild COVID-19, 15 (12.8%) had moderate, and 60 (50.8%) had severe. At the time of presentation, 97 (82.2%) patients reported that they had at least one persistent/new symptom beyond two weeks from the diagnosis of COVID-19. Dyspnea, fatigue, chest heaviness, and cough were the commonest persistent complaints in 48 (40.7%), 39 (33.1%), 33 (28%), and 32 (27.1%) patients, respectively. The findings in our study highlight the need for extended monitoring of post-COVID-19 patients following discharge, in order to understand and mitigate long-term implications of the disease.

Clinical Mortality Review of COVID-19 Patients at Sukraraj Tropical and Infectious Disease Hospital, Nepal; A Retrospective Study.

Coronavirus Disease 2019 (COVID-19) has challenged the health system worldwide, including the low and middle income countries like Nepal. In view of the rising number of infections and prediction of multiple waves of this disease, mortalities due to COVID-19 need to be critically analyzed so that every possible effort could be made to prevent COVID-19 related mortalities in future. Main aim of this research was to study about the mortalities due to COVID-19 at a tertiary level hospital, in Nepal. This was a retrospective, observational study that included all inpatients from Sukraraj Tropical and Infectious Disease Hospital, who were reverse transcriptase polymerase chain reaction positive for SARS-COV-2 and died during hospital stay from January 2020 till January 2021. Medical records of the patients were evaluated. Out of 860 total admissions in a year, there were 50 mortalities in the study center. Out of 50 mortalities, majority were males (76%) with male to female ratio of 3.17:1. Most were above 65 years of age (72%) and had two or more comorbidities (64%). The most common comorbidities among the patients who had died during hospital stay were hypertension (58%) followed by diabetes mellitus (50%) and chronic obstructive airway disease (24%). The median duration from the symptom onset to death was 18 days, ranged from the minimum of 2 days till maximum of 39 days. D-dimer was found to be >1 mg/L in 58% cases and ferritin was >500 ng/ml in 42% patients at presentation. A total of 42% patients had thrombocytopenia, 80% patients had lymphocytopenia and 60% had Neutrophil to Lymphocyte ratio >11.75 with the mean NLR of 18.38. Of total mortalities, 16% patients also showed microbiological evidence of secondary infection; Male gender, age more than 65 years, multiple comorbidities with lymphocytopenia, elevated Neutrophil lymphocyte ratio and elevated inflammatory markers were risk factors found in majority of mortalities in our study. These findings could be utilized for early triage and risk assessment in COVID-19 patients so that aggressive treatment strategies could be employed at the earliest to reduce mortalities due to COVID-19 in future.

Emerging Insights into the Function of Kinesin-8 Proteins in Microtubule Length Regulation.

Proper regulation of microtubules (MTs) is critical for the execution of diverse cellular processes, including mitotic spindle assembly and chromosome segregation. There are a multitude of cellular factors that regulate the dynamicity of MTs and play critical roles in mitosis. Members of the Kinesin-8 family of motor proteins act as MT-destabilizing factors to control MT length in a spatially and temporally regulated manner. In this review, we focus on recent advances in our understanding of the structure and function of the Kinesin-8 motor domain, and the emerging contributions of the C-terminal tail of Kinesin-8 proteins to regulate motor activity and localization.

Specificity of testing in a cardiac rehabilitation setting resulting in a patient's return to high-intensity outdoor activity following aortic dissection repair.

A 66-year-old man who had undergone aortic dissection repair a year earlier sought to assess the feasibility of returning to the high-intensity outdoor activities he had long enjoyed. In response to his inquiry, the cardiac rehabilitation staff at Baylor Hamilton Heart and Vascular Hospital designed a comprehensive testing plan that simulated the specific movements and anticipated cardiac requirements associated with his goal activities. The activities included 1) lifting and manipulating a 50-pound suitcase, 2) hiking to the top of Half Dome in California's Yosemite National Park, and 3) scuba diving. To illustrate our approach, we describe some of the tests that were performed and report the results. After analyzing the detailed physiological data collected during testing, we provided the patient with an exercise prescription and specific guidelines that he could use to gauge his level of physical exertion during his outdoor adventures. Within approximately 6 months of testing, he successfully performed the goal activities without adverse symptoms.

High-intensity cardiac rehabilitation training of a commercial pilot who, after percutaneous coronary intervention, wanted to continue participating in a rigorous strength and conditioning program.

After undergoing elective percutaneous coronary intervention, a 64-year-old commercial pilot was referred to cardiac rehabilitation. His stated goals were to continue participating in a rigorous strength and conditioning program at a community workout facility and to resume working as a pilot. To help him meet those goals, we designed and implemented a regimen of high-intensity exercises, with quick transitions between a variety of tasks that are not typically included in cardiac rehabilitation programs (e.g., medicine ball throws, push-ups, dead lifts, squats, military presses, sprints, and lunges). The training was symptom limited, enabling the patient to reach extreme levels of physical exertion in a controlled, monitored setting. By studying his training data (heart rate, blood pressure, and rating of perceived exertion), we were able to give him specific recommendations for controlling his exercise intensity after graduating from our program. More than 18 months later, he continues to exercise vigorously 3 days per week and is working as a commercial pilot.

Grb7 and Filamin-a associate and are colocalized to cell membrane ruffles upon EGF stimulation.

Grb7 is an adaptor molecule mediating signal transduction from multiple cell surface receptors to diverse downstream pathways. Grb7, along with Grb10 and Grb14, make up the Grb7 protein family. This protein family has been shown to be overexpressed in certain cancers and cancer cell lines. Grb7 and a receptor tyrosine kinase, ErbB2, are overexpressed in 20-30% of breast cancers. Grb7 overexpression has been linked to enhanced cell migration and metastasis, although the participants in these pathways have not been fully determined. In this study, we report the Grb7 protein interacts with Filamin-a, an actin-crosslinking component of the cell cytoskeleton. Additionally, we have demonstrated the interaction between Grb7 and Flna is specific to the RA-PH domains of Grb7, and the immunoglobulin-like repeat 16-19 domains of Flna. We demonstrate that full-length Grb7 and Flna interact in the mammalian cellular environment, as well as in vitro. Immunofluorescent microscopy shows potential co-localization of Grb7 and Flna in membrane ruffles upon epidermal growth factor stimulation. These studies are amongst the first to establish a clear connection between Grb7 signaling and cytoskeletal remodeling.

PRC1 controls spindle polarization and recruitment of cytokinetic factors during monopolar cytokinesis.

The central spindle is a postanaphase array of microtubules that plays an essential role in organizing the signaling machinery for cytokinesis. The model by which the central spindle organizes the cytokinetic apparatus is premised on an antiparallel arrangement of microtubules, yet cells lacking spindle bipolarity are capable of generating a distal domain of ectopic furrowing when forced into mitotic exit. Because protein regulator of cytokinesis (PRC1) and kinesin family member 4A (KIF4A) are believed to play a principal role in organizing the antiparallel midzone array, we sought to clarify their roles in monopolar cytokinesis. Although both factors localized to the distal ends of microtubules during monopolar cytokinesis, depletion of PRC1 and KIF4A displayed different phenotypes. Cells depleted of PRC1 failed to form a polarized microtubule array or ectopic furrows following mitotic exit, and recruitment of Aurora B kinase, male germ cell Rac GTPase-activating protein, and RhoA to the cortex was impaired. In contrast, KIF4A depletion impaired neither polarization nor ectopic furrowing, but it did result in elongated spindles with a diffuse distribution of cytokinetic factors. Thus, even in the absence of spindle bipolarity, PRC1 appears to be essential for polarizing parallel microtubules and concentrating the factors responsible for contractile ring assembly, whereas KIF4A is required for limiting the length of anaphase microtubules.

Mutual dependence of Mob1 and the chromosomal passenger complex for localization during mitosis.

The spatial and temporal coordination of chromosome segregation with cytokinesis is essential to ensure that each daughter cell receives the correct complement of chromosomal and cytoplasmic material. In yeast, mitotic exit and cytokinesis are coordinated by signaling cascades whose terminal components include a nuclear Dbf2-related family kinase and a noncatalytic subunit, Mps one binding (Mob) 1. There are five human Mob1 isoforms, all of which display redundant localization patterns at the spindle poles and kinetochores in early mitosis, and the spindle midzone during cytokinesis. Mob1 shares similar localization patterns to Polo-like kinase (Plk1) and the chromosomal passenger complex (CPC), and although depletion of Plk1 resulted in a loss of Mob1 from the spindle poles, Mob1 recruitment to kinetochores was unaffected. Conversely, disruption of CPC signaling resulted in a loss of Mob1 from kinetochores without disrupting recruitment to the spindle poles. In Mob1-depleted cells, the relocalization of the CPC and mitotic kinesin-like protein (MKLP) 2 to the spindle midzone was delayed during early anaphase, and as a consequence, the midzone recruitment of MKLP1 also was affected. Together, these results suggest that Mob1 and the other mammalian orthologues of the mitotic exit network regulate mitotic progression by facilitating the timely mobilization of the CPC to the spindle midzone.