Effect of Social Isolation on Seizure Susceptibility through GABA-ergic Mechanisms

The ongoing Covid-19 pandemic has incited an array of social, psychological, and emotional burdens among adolescents and adults. The lockdowns, social distancing measures, and general anxiety surrounding the virus have produced an unprecedented and pervasive degree of social isolation, particularly amongst adolescents. Social isolation has deleterious effects on physical and mental well-being and is a critical risk factor for morbidity among adults. However, the neural and physiological underpinnings and consequences of social isolation have yet to be fully explored. Social isolation has been understood as a source of chronic and early stress, with various developmental consequences. In the past decade, researchers have found the stress associated with social isolation to worsen the development of epilepsy, among other neuropsychological disorders. There are various mechanisms and regions involved such as the GABAergic system, which is the neural system regulating GABA neurotransmission. There is a growing consensus in the scientific community that changes in the GABAergic system stemming from social isolation can lead to a lower seizure threshold. This leads us to not only ask whether the GABAergic system, and other systems involved with neurotransmitters, could be affected by social isolation, but also whether this corresponding change in neurophysiology leads to a lowered seizure threshold. Our objective is to better understand the effects of social isolation on epilepsy development. The broad, long-term objective of this work is to provide clinicians with a framework for how to properly intervene and target therapies for neuropsychological disorders that might arise from early life stress

Anesthesia Services in the Time of COVID

Our hospital is a 400-bed Level-1 trauma center with 78 ICU beds serving the greater Louisville metropolitan area. The COVID-19 pandemic forced our hospital to re-evaluate our core business operations and to develop a coherent response to a fluid situation. Between March 15 and May 15, 2020, the University of Louisville Hospital admitted more than 100 COVID-19 inpatients, approximately 30 were admitted to the intensive care unit (ICU) and most required endotracheal intubation. The following review describes our Department of Anesthesiology & Perioperative Medicine foci, actions and rationale during the COVID-19 pandemic. While we hope not to experience another pandemic in the near future, this review may be a helpful starting point for preparing for future respiratory spread pandemics

Quantitative proteomic comparison of salt stress in Chlamydomonas reinhardtii and the snow alga Chlamydomonas nivalis reveals mechanisms for salt-triggered fatty acid accumulation via reallocation of carbon resources

Background Chlamydomonas reinhardtii is a model green alga strain for molecular studies; its fully sequenced genome has enabled omic-based analyses that have been applied to better understand its metabolic responses to stress. Here, we characterised physiological and proteomic changes between a low-starch C. reinhardtii strain and the snow alga Chlamydomonas nivalis, to reveal insights into their contrasting responses to salinity stress. Results Each strain was grown in conditions tailored to their growth requirements to encourage maximal fatty acid (as a proxy measure of lipid) production, with internal controls to allow comparison points. In 0.2 M NaCl, C. nivalis accumulates carbohydrates up to 10.4% DCW at 80 h, and fatty acids up to 52.0% dry cell weight (DCW) over 12 days, however, C. reinhardtii does not show fatty acid accumulation over time, and shows limited carbohydrate accumulation up to 5.5% DCW. Analysis of the C. nivalis fatty acid profiles showed that salt stress improved the biofuel qualities over time. Photosynthesis and respiration rates are reduced in C. reinhardtii relative to C. nivalis in response to 0.2 M NaCl. De novo sequencing and homology matching was used in conjunction with iTRAQ-based quantitative analysis to identify and relatively quantify proteomic alterations in cells exposed to salt stress. There were abundance differences in proteins associated with stress, photosynthesis, carbohydrate and lipid metabolism proteins. In terms of lipid synthesis, salt stress induced an increase in dihydrolipoyl dehydrogenase in C. nivalis (1.1-fold change), whilst levels in C. reinhardtii remained unaffected; this enzyme is involved in acetyl CoA production and has been linked to TAG accumulation in microalgae. In salt-stressed C. nivalis there were decreases in the abundance of UDP-sulfoquinovose (− 1.77-fold change), which is involved in sulfoquinovosyl diacylglycerol metabolism, and in citrate synthase (− 2.7-fold change), also involved in the TCA cycle. Decreases in these enzymes have been shown to lead to increased TAG production as fatty acid biosynthesis is favoured. Data are available via ProteomeXchange with identifier PXD018148. Conclusions These differences in protein abundance have given greater understanding of the mechanism by which salt stress promotes fatty acid accumulation in the un-sequenced microalga C. nivalis as it switches to a non-growth state, whereas C. reinhardtii does not have this response

Public Health Forward: Modernizing the U.S. Public Health System

Public Health Forward: Modernizing the U.S. Public Health System defines a vision for a modernized public health system in the 21st century and provides a framework of practical, prioritized, and bipartisan actions for policymakers and public health officials to guide strategic investments and decision-making to help translate the vision into a reality with a focus on equity. The federal government continues to provide critical leadership and funding to navigate the current pandemic and has a responsibility to make significant investments and changes in public health for the post-pandemic future. Long-term, increased, sustainable funding and policy leadership from the federal government will be crucial to support this five-year vision, framework, and set of actions, as most public health departments are concerned over their funding levels, notwithstanding the recent infusion of money

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Pharmacologic Pain Management Trends among Adults Hospitalized with Cellulitis: An Evidence-Based Practice Project.

BACKGROUND: Nurses commonly administer opioids, following as needed order sets, to patients hospitalized for acute pain conditions like cellulitis. Practice guidelines recommend limiting opioid administration for acute pain management. At two hospitals in the Pacific Northwest, an opioid stewardship committee was formed to align with best practice. AIMS: The main objective was to describe changes to inpatient rates of opioid and non-opioid administration following implementation of evidence-based opioid stewardship efforts. DESIGN: Observational, retrospective, evidence-based practice project. SETTINGS: One 200-bed and one 680-bed hospital in Washington State. PARTICIPANTS/SUBJECTS: Data were included from patients aged 18 years or older hospitalized for cellulitis. METHODS: Demographic and pain-related data were extracted from the electronic health record (n = 4,523 encounters) guided by the symptom management framework. The proportion of patients receiving opioid or non-opioid medications before and after implementation of evidence-based practice opioid stewardship interventions was calculated descriptively. A logistic regression tested factors related to administration of an opioid medication. RESULTS: The proportion of patients receiving an opioid decreased following opioid stewardship efforts while those receiving non-opioid analgesics remained stable. Factors significantly influencing inpatient opioid administration were: average inpatient pain score, pre-hospital opioid prescription, length of stay, and year of hospitalization. CONCLUSIONS: Analgesic administration treating painful, acute cellulitis at two hospitals in the Pacific Northwest included opioid and non-opioid medications. The proportion of patients receiving opioids decreased following best practice opioid stewardship actions. Opportunities may exist for nurses to collaborate with providers to improve inpatient analgesic administration practices

Ignored and distressed: a cross-sectional study of the impact of COVID-19 on last responders

Abstract Background Last responders constitute an occupational category that includes all those that are involved in the postmortem care of deceased persons and their families. Last responders are exposed to several categories of work-related stressors that affect their health and well-being. COVID-19 exacerbated these stressors. Research to understand the consequences of COVID-19 on the health and wellbeing of last responders is nascent. This study aimed to assess COVID-19 related stress, coping and wellbeing among last responders in the United States. Methods We conducted a national cross-sectional survey of last responders in July through September of 2020. The survey measured wellbeing, stress, coping, and stigma; COVID-19 experiences, and socio-demographics. A ridge regression model was fit for the outcome variables. Results Analysis was conducted on 366 respondents from 43 states. Respondents were male (55.4%), age 50 + (57.4%), and White non-Hispanic (90.3%); 54% reported moderate-high stress and 41% endorsed mild-severe anxiety. Seventy-seven percent had experienced at least one form of stigma related to their occupation. Variables associated with higher perceived stress and anxiety included gender (female), shorter length of employment, perceiving a higher impact from COVID-19 on everyday life, and increased perceived stigma. Conclusions Last responders are a critical part of the health care system. Throughout this pandemic, last responders have been frequently ignored and not prioritized for protection and support. Interventions to support last responders cope with stress, and to decrease anxiety are urgently needed. There is also a critical need to challenge community stigma towards last responders

Removing the rose-colored glasses: Resetting U.S. - Turkey relations

In the midst of a shifting global landscape, the U.S.-Turkey relationship is in a volatile state. Although historically allies, Turkey and the U.S. have begun to drift apart as a result of Turkey’s rising selfconfidence and willingness to act against U.S. interests. This self-confidence comes as a result of President Recep Tayyip Erdoğan’s successful consolidation of power under the guise of Islam and the flourishing economy of the past seventeen years which has led Turkey to develop a range of interests that do not always align with the United States. President Erdoğan’s self-confidence allowed him to go after rivals of the state such as the Gülen Movement and the Kurdish community living in Turkey. These preconditions, discussed in our report’s background section, influenced the divergence of U.S.-Turkey relations in other key regions where Turkish and American interests are interwoven. The divergence of U.S.-Turkey interests marks a new era in the Turkish-American partnership. If the United States is to remain partners with Turkey, it must recognize the state of the relationship as it is now and effectively restructure the relationship so that both states can benefit from their prolonged collaboration