I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations.

INTRODUCTION: The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021. METHODS AND ANALYSIS: The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing. ETHICS AND DISSEMINATION: ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04488081.

Rationale of using the dual chemokine receptor CCR2/CCR5 inhibitor cenicriviroc for the treatment of COVID-19.

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created a global pandemic infecting over 230 million people and costing millions of lives. Therapies to attenuate severe disease are desperately needed. Cenicriviroc (CVC), a C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist, an agent previously studied in advanced clinical trials for patients with HIV or nonalcoholic steatohepatitis (NASH), may have the potential to reduce respiratory and cardiovascular organ failures related to COVID-19. Inhibiting the CCR2 and CCR5 pathways could attenuate or prevent inflammation or fibrosis in both early and late stages of the disease and improve outcomes of COVID-19. Clinical trials using CVC either in addition to standard of care (SoC; e.g., dexamethasone) or in combination with other investigational agents in patients with COVID-19 are currently ongoing. These trials intend to leverage the anti-inflammatory actions of CVC for ameliorating the clinical course of COVID-19 and prevent complications. This article reviews the literature surrounding the CCR2 and CCR5 pathways, their proposed role in COVID-19, and the potential role of CVC to improve outcomes.

Detection of Cognitive Impairment after Critical Illness with the Medicare Annual Wellness Visit: A Cohort Study.

Rationale: Cognitive impairment after critical illness is common in observational studies of older intensive care unit (ICU) survivors. The rate of screening for and diagnosis of cognitive impairment in ICU survivors in nonresearch settings is unknown. Objectives: To determine how often cognitive impairment was detected in older adults in the year after critical illness at an academic medical center as part of 1) the Medicare Annual Wellness Visit (AWV) and 2) routine clinical care. Methods: This study was a retrospective cohort study conducted at an urban academic medical center. The study included 696 patients aged 65 years and older admitted to the medical ICU between October 1, 2016, and October 1, 2018, and discharged alive. Patients were also required to have a health system-affiliated primary care provider. Patients were followed for 1 year. We defined cognitive impairment detected in the AWV as either an indicated diagnosis of cognitive impairment or dementia or patient, family, or provider indication of memory concerns during the AWV. We modeled the incidence of AWV completion and the detection of cognitive impairment using semiparametric additive models accounting for the competing risk of death. Results: Over 1 year of follow-up, the cumulative incidence of mortality was 23.0% (95% confidence interval [CI], 19.9-26.1%), with 24.7% (95% CI, 21.5-27.9%) completing the AWV. The cumulative incidence of cognitive impairment first detected through the AWV was 3.4% (95% CI, 1.8-5.0%) at 1 year, with a higher cumulative incidence for diagnoses of cognitive impairment or dementia first indicated via encounter diagnosis codes or the electronic health record problem list (5.9%; 95% CI, 3.9-7.9%). Conclusions: The results of our study suggest that the currently implemented AWV is unlikely to be an adequate mechanism for detecting cognitive impairment in a high-risk population such as those recovering from critical illness.

Cardiac troponin T and fast skeletal muscle denervation in ageing.

BACKGROUND: Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle-specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown. METHODS: Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real-time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ. RESULTS: Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region-but mainly in the fast-twitch, not the slow-twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIß are enriched at, the NMJ-again, preferentially in fast-twitch but not slow-twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ. CONCLUSIONS: Cardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast-twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age-related decline in muscle function.

Angioedema.

OBJECTIVES: Angioedema is a potentially life-threatening occurrence that is encountered by critical care providers. The mechanistic understanding of angioedema syndromes has improved in recent years, and novel medications are available that improve outcomes from these syndromes. This clinically focused review will describe the underlying genetics, pathophysiology, classification and treatment of angioedema syndromes, with an emphasis on the novel pharmacologic agents that have recently become available for acute treatment. DATA SOURCES: A MEDLINE search was conducted with the MeSH terms angioedema, acquired angioedema, hereditary angioedema type III, and angiotensin converting enzyme inhibitor-induced angioedema. STUDY SELECTION: Selected publications describing angioedema, clinical trials, diagnosis, management, and genetics were retrieved (reviews, guidelines, clinical trials, case series), and their bibliographies were also reviewed to identify relevant publications. DATA EXTRACTION: Data from the relevant publications were reviewed, summarized and the information synthesized. DATA SYNTHESIS: The data obtained were used to describe the current state of diagnosis and management of various angioedema syndromes. CONCLUSIONS: Angioedema is a life-threatening syndrome with multiple subtypes, each with a distinct pathophysiology. We present an evidence-based approach to the diagnosis and suggested management of various subtypes of angioedema. Securing the airway remains the most important intervention, followed by administration of both established and more novel pharmacologic interventions based on disease pathology.

BDA-410 Treatment Reduces Body Weight and Fat Content by Enhancing Lipolysis in Sedentary Senescent Mice.

Loss of muscle mass and force with age leads to fall risk, mobility impairment, and reduced quality of life. This article shows that BDA-410, a calpain inhibitor, induced loss of body weight and fat but not lean mass or skeletal muscle proteins in a cohort of sedentary 23-month-old mice. Food and water intake and locomotor activity were not modified, whereas BDA-410 treatment decreased intramyocellular lipid and perigonadal fat, increased serum nonesterified fatty acids, and upregulated the genes mediating lipolysis and oxidation, lean phenotype, muscle contraction, muscle transcription regulation, and oxidative stress response. This finding is consistent with our recent report that lipid accumulation in skeletal myofibers is significantly correlated with slower fiber-contraction kinetics and diminished power in obese older adult mice. A proteomic analysis and immunoblot showed downregulation of the phosphatase PPP1R12B, which increases phosphorylated myosin half-life and modulates the calcium sensitivity of the contractile apparatus. This study demonstrates that BDA-410 exerts a beneficial effect on skeletal muscle contractility through new, alternative mechanisms, including enhanced lipolysis, upregulation of "lean phenotype-related genes," downregulation of the PP1R12B phosphatase, and enhanced excitation-contraction coupling. This single compound holds promise for treating age-dependent decline in muscle composition and strength.

Opiate Injection-associated Infective Endocarditis in the Southeastern United States.

BACKGROUND: Opiate pain reliever (OPR) misuse by injection is increasing in the United States. Infective endocarditis (IE), a devastating complication of injection OPR use, has been understudied. METHODS: We conducted a retrospective chart review of IE cases at an academic tertiary care hospital in North Carolina. Hospital admissions from 2009-2014 were screened for cases of definite IE. Subjects reporting injection drug use (IDU) were classified as IDU-IE, and compared to those without reported IDU, classified as No IDU-IE. Rates of IDU-IE and No IDU-IE, patient demographics, microbiologic data and outcomes were compared between the groups. RESULTS: A total of 127 incident admissions for IE were identified, 48 (37.8%) were classified as IDU-IE and 79 (62.2%) as No IDU-IE. IDU-IE cases increased from 14% of hospitalizations for IE in 2009 to 56% in 2014; reporting of OPR injection increased in 2012 and continued through the study period. IDU-IE subjects were younger (32.6 ± 11.7 versus 54.4 ± 13.1, P < 0.0001), more likely to be single (n = 33 [68.8%] versus n = 23 [29.1%], P < 0.0001) and to reside in rural communities (n = 36 [75.0%] versus n = 25 [31.6%], P < 0.0001) than No IDU-IE subjects. Hospital length of stay (26 days versus 12 days, P < 0.0001) and intensive care unit length of stay (2 days versus 1 day, P = 0.04) were longer for IDU-IE patients and hospital mortality did not differ (10.4% IDU-IE versus 8.9% No IDU-IE, P = 0.77). CONCLUSIONS: IDU-IE rates increased over time, and OPR injection use in rural communities appears to be a major contributor. Interventions to reduce IDU-IE and OPR misuse are needed to halt this growing epidemic in at-risk rural communities.

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice.

Loss of strength in human and animal models of aging can be partially attributed to a well-recognized decrease in muscle mass; however, starting at middle-age, the normalized force (force/muscle cross-sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca(2+) channel α1 subunit (Cav1.1) with aging leads to excitation-contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full-length TnT3 (FL-TnT3) and its carboxyl-terminal (CT-TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA-410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.

Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner.

INTRODUCTION: Fibrosis, or scar formation, is a pathological condition characterized by excessive production and accumulation of collagen, loss of tissue architecture, and organ failure in response to uncontrolled wound healing. Several cellular populations have been implicated, including bone marrow-derived circulating fibrocytes, endothelial cells, resident fibroblasts, epithelial cells, and recently, perivascular cells called pericytes. We previously demonstrated pericyte functional heterogeneity in skeletal muscle. Whether pericyte subtypes are present in other tissues and whether a specific pericyte subset contributes to organ fibrosis are unknown. METHODS: Here, we report the presence of two pericyte subtypes, type-1 (Nestin-GFP-/NG2-DsRed+) and type-2 (Nestin-GFP+/NG2-DsRed+), surrounding blood vessels in lungs, kidneys, heart, spinal cord, and brain. Using Nestin-GFP/NG2-DsRed transgenic mice, we induced pulmonary, renal, cardiac, spinal cord, and cortical injuries to investigate the contributions of pericyte subtypes to fibrous tissue formation in vivo. RESULTS: A fraction of the lung's collagen-producing cells corresponds to type-1 pericytes and kidney and heart pericytes do not produce collagen in pathological fibrosis. Note that type-1, but not type-2, pericytes increase and accumulate near the fibrotic tissue in all organs analyzed. Surprisingly, after CNS injury, type-1 pericytes differ from scar-forming PDGFRß + cells. CONCLUSIONS: Pericyte subpopulations respond differentially to tissue injury, and the production of collagen by type-1 pericytes is organ-dependent. Characterization of the mechanisms underlying scar formation generates cellular targets for future anti-fibrotic therapeutics.

A retrospective characterization of African- and European American asthmatic children in a pediatric critical care unit.

OBJECTIVE: To determine if African American and European American children with asthma admitted to an intensive care unit (ICU) had different characteristics, we conducted a retrospective chart review of asthma admissions to the region's only pediatric ICU. PATIENTS AND METHODS: A chart review was performed on 125 patients with asthma admitted to the pediatric critical care unit at Vanderbilt Children's Hospital. Descriptive statistics, clinical characteristics, and disparities in care were compared using either Fisher's exact tests or Wilcoxon ranksum tests. RESULTS: Most of the children reported previous admissions to a pediatric ICU (63%) or a hospital (82%) for asthma. Despite this, only 48% of the children were taking inhaled corticosteroids before admission. Only 28% of the children reported being followed by an asthma specialist, but, of these, 97% were taking corticosteroids. There were no racial/ethnic disparities in medication use, treatment, or outcomes. CONCLUSION: We found no racial/ethnic disparities in inpatient/outpatient medication usage, treatment, or outcomes between African American and European American children in our cohort. Recurrent admissions to the ICU among children with severe asthma are common, and inhaled corticosteroids usage is relatively low. Asthmatic children with ICU admissions should be followed and treated aggressively by an asthma specialist.