Ransomware Cyberattack Associated With Cardiac Arrest Incidence and Outcomes at Untargeted, Adjacent Hospitals.

OBJECTIVES: Healthcare ransomware cyberattacks have been associated with major regional hospital disruptions, but data reporting patient-oriented outcomes in critical conditions such as cardiac arrest (CA) are limited. This study examined the CA incidence and outcomes of untargeted hospitals adjacent to a ransomware-infected healthcare delivery organization (HDO). DESIGN SETTING AND PATIENTS: This cohort study compared the CA incidence and outcomes of two untargeted academic hospitals adjacent to an HDO under a ransomware cyberattack during the pre-attack (April 3-30, 2021), attack (May 1-28, 2021), and post-attack (May 29, 2021-June 25, 2021) phases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Emergency department and hospital mean daily census, number of CAs, mean daily CA incidence per 1,000 admissions, return of spontaneous circulation, survival to discharge, and survival with favorable neurologic outcome were measured. The study evaluated 78 total CAs: 44 out-of-hospital CAs (OHCAs) and 34 in-hospital CAs. The number of total CAs increased from the pre-attack to attack phase (21 vs. 38; p = 0.03), followed by a decrease in the post-attack phase (38 vs. 19; p = 0.01). The number of total CAs exceeded the cyberattack month forecast (May 2021: 41 observed vs. 27 forecasted cases; 95% CI, 17.0-37.4). OHCA cases also exceeded the forecast (May 2021: 24 observed vs. 12 forecasted cases; 95% CI, 6.0-18.8). Survival with favorable neurologic outcome rates for all CAs decreased, driven by increases in OHCA mortality: survival with favorable neurologic rates for OHCAs decreased from the pre-attack phase to attack phase (40.0% vs. 4.5%; p = 0.02) followed by an increase in the post-attack phase (4.5% vs. 41.2%; p = 0.01). CONCLUSIONS: Untargeted hospitals adjacent to ransomware-infected HDOs may see worse outcomes for patients suffering from OHCA. These findings highlight the critical need for cybersecurity disaster planning and resiliency.

Epidemiology, risk factors and outcomes associated with in-hospital reflex-mediated cardiac arrest.

Aim of the study: Overactivation of the parasympathetic nervous system can lead to reflex syncope (RS) and, in extreme cases, trigger an unusual and underrecognized form of cardiac arrest. We characterized the epidemiology and prognosis of reflex-mediated cardiac arrest (RMCA) and hypothesized it is associated with intervenable patient factors. Methods: This retrospective case-control study examined RMCAs at two academic hospitals from 1/2016 to 6/2022 using a resuscitation quality improvement database. RMCA cases were identified as cardiac arrests preceded by vagal trigger(s). Cases of RS, defined as syncope with bradycardia and hypotension preceded by vagal trigger(s), between 1/2021 and 12/2021 were used as controls. For the secondary analysis, RMCA outcomes were compared to in-hospital cardiac arrest (IHCA) of other causes. Results: We identified 46 RMCA and 67 RS cases. Compared to RS patients, RMCA patients were more likely to have spinal cord injury (13.0% vs 1.5%, p = 0.02). Airway clearance i.e., coughing and suctioning triggered a higher proportion of RMCA events than RS events (23.9% vs 3.0%, p < 0.01). Compared to 1,021 IHCAs of other causes, RMCAs had 100% return of spontaneous circulation, were more likely to survive to discharge (84.8% vs 36.2%, p < 0.001) and have favorable neurological outcomes (cerebral performance category 1 or 2, 58.7% vs 26.9%, p < 0.001). Conclusions: RMCA has a favorable prognosis compared to other IHCAs and is potentially preventable. Spinal cord injury and airway clearance were patient factors significantly associated with RMCA.

Incubation with porcine urinary bladder matrix yields a late-stage wound transcriptome in endothelial cells and keratinocytes isolated from both diabetic and non-diabetic subjects.

Proper wound closure requires the functional coordination of endothelial cells (ECs) and keratinocytes. In the late stages of wound healing, keratinocytes become activated and ECs promote the maturation of nascent blood vessels. In diabetes mellitus, decreased keratinocyte activation and impaired angiogenic action of ECs delay wound healing. Porcine urinary bladder matrix (UBM) improves the rate of wound healing, but the effect of exposure to UBM under diabetic conditions remains unclear. We hypothesized that keratinocytes and ECs isolated from both diabetic and non-diabetic donors would exhibit a similar transcriptome representative of the later stages of wound healing following incubation with UBM. Human keratinocytes and dermal ECs isolated from non-diabetic and diabetic donors were incubated with and without UBM particulate. RNA-Seq analysis was performed to identify changes in the transcriptome of these cells associated with exposure to UBM. While diabetic and non-diabetic cells exhibited different transcriptomes, these differences were minimized following incubation with UBM. ECs exposed to UBM exhibited changes in the expression of transcripts suggesting an increase in the endothelial-mesenchymal transition (EndoMT) associated with vessel maturation. Keratinocytes incubated with UBM demonstrated an increase in markers of activation. Comparison of the whole transcriptomes with public datasets suggested increased EndoMT and keratinocyte activation following UBM exposure. Both cell types exhibited loss of pro-inflammatory cytokines and adhesion molecules. These data suggest that application of UBM may accelerate healing by promoting a transition to the later stages of wound healing. This healing phenotype is achieved in cells isolated from both diabetic and non-diabetic donors.

Diabetes is accompanied by secretion of pro-atherosclerotic exosomes from vascular smooth muscle cells.

BACKGROUND: Atherosclerosis is a common co-morbidity of type 2 diabetes mellitus. Monocyte recruitment by an activated endothelium and the pro-inflammatory activity of the resulting macrophages are critical components of atherosclerosis. Exosomal transfer of microRNAs has emerged as a paracrine signaling mechanism regulating atherosclerotic plaque development. MicroRNAs-221 and -222 (miR-221/222) are elevated in vascular smooth muscle cells (VSMCs) of diabetic patients. We hypothesized that the transfer of miR-221/222 via VSMC-derived exosomes from diabetic sources (DVEs) promotes increased vascular inflammation and atherosclerotic plaque development. METHODS: Exosomes were obtained from VSMCs, following exposure to non-targeting or miR-221/-222 siRNA (-KD), isolated from diabetic (DVEs) and non-diabetic (NVEs) sources and their miR-221/-222 content was measured using droplet digital PCR (ddPCR). Expression of adhesion molecules and the adhesion of monocytes was measured following exposure to DVEs and NVEs. Macrophage phenotype following exposure to DVEs was determined by measuring mRNA markers and secreted cytokines. Age-matched apolipoprotein-E-deficient mice null (ApoE-/-) mice were maintained on Western diet for 6 weeks and received injections of saline, NVEs, NVE-KDs, DVEs or DVE-KDs every other day. Atherosclerotic plaque formation was measured using Oil Red Oil staining. RESULTS: Exposure of human umbilical vein and coronary artery endothelial cells to DVEs, but not NVEs, NVE-KDs, or DVE-KDs promoted increased intercellular adhesion molecule-1 expression and monocyte adhesion. DVEs but not NVEs, NVE-KDs, or DVE-KDs also promoted pro-inflammatory polarization of human monocytes in a miR-221/222 dependent manner. Finally, intravenous administration of DVEs, but not NVEs, resulted in a significant increase in atherosclerotic plaque development. CONCLUSION: These data identify a novel paracrine signaling pathway that promotes the cardiovascular complications of diabetes mellitus.

Association Between Metabolic Syndrome Inflammatory Biomarkers and COVID-19 Severity.

Context: Metabolic syndrome (MetS) is associated with increased risk of severe COVID-19. MetS inflammatory biomarkers share similarities with those of COVID-19, yet this association is poorly explored. Objective: Biomarkers of COVID-19 patients with and without MetS, the combination of diabetes, hypertension, obesity, and/or dyslipidemia, were analyzed to identify biological predictors of COVID-19 severity. Methods: In this prospective observational study, at a large academic emergency department in Boston, Massachusetts, clinical and proteomics data were analyzed from March 24 to April 30, 2020. Patients age ≥18 with a clinical concern for COVID-19 upon arrival and acute respiratory distress were included. The main outcome was severe COVID-19 as defined using World Health Organization COVID-19 outcomes scores ≤4, which describes patients who died, required invasive mechanical ventilation, or required supplemental oxygen. Results: Among 155 COVID-19 patients, 90 (58.1%) met the definition of MetS and 65 (41.9%) were identified as Control. The MetS cohort was more likely to have severe COVID-19 compared with the Control cohort (OR 2.67 [CI 1.09-6.55]). Biomarkers, including CXCL10 (OR 1.94 [CI 1.38-2.73]), CXCL9 (OR 1.79 [CI 1.09-2.93]), HGF (OR 3.30 [CI 1.65-6.58]), and IL6 (OR 2.09 [CI 1.49-2.94]) were associated with severe COVID-19. However, when stratified by MetS, only CXCL10 (OR 2.39 [CI 1.38-4.14]) and IL6 (OR 3.14 [CI 1.53-6.45]) were significantly associated with severe COVID-19. Conclusions: MetS-associated severe COVID-19 is characterized by an immune signature of elevated levels of CXCL10 and IL6. Clinical trials targeting CXCL10 or IL6 antagonism in this population may be warranted.

Metabolic Syndrome and Acute Respiratory Distress Syndrome in Hospitalized Patients With COVID-19.

Importance: Obesity, diabetes, and hypertension are common comorbidities in patients with severe COVID-19, yet little is known about the risk of acute respiratory distress syndrome (ARDS) or death in patients with COVID-19 and metabolic syndrome. Objective: To determine whether metabolic syndrome is associated with an increased risk of ARDS and death from COVID-19. Design, Setting, and Participants: This multicenter cohort study used data from the Society of Critical Care Medicine Discovery Viral Respiratory Illness Universal Study collected from 181 hospitals across 26 countries from February 15, 2020, to February 18, 2021. Outcomes were compared between patients with metabolic syndrome (defined as ≥3 of the following criteria: obesity, prediabetes or diabetes, hypertension, and dyslipidemia) and a control population without metabolic syndrome. Participants included adult patients hospitalized for COVID-19 during the study period who had a completed discharge status. Data were analyzed from February 22 to October 5, 2021. Exposures: Exposures were SARS-CoV-2 infection, metabolic syndrome, obesity, prediabetes or diabetes, hypertension, and/or dyslipidemia. Main Outcomes and Measures: The primary outcome was in-hospital mortality. Secondary outcomes included ARDS, intensive care unit (ICU) admission, need for invasive mechanical ventilation, and length of stay (LOS). Results: Among 46 441 patients hospitalized with COVID-19, 29 040 patients (mean [SD] age, 61.2 [17.8] years; 13 059 [45.0%] women and 15713 [54.1%] men; 6797 Black patients [23.4%], 5325 Hispanic patients [18.3%], and 16 507 White patients [57.8%]) met inclusion criteria. A total of 5069 patients (17.5%) with metabolic syndrome were compared with 23 971 control patients (82.5%) without metabolic syndrome. In adjusted analyses, metabolic syndrome was associated with increased risk of ICU admission (adjusted odds ratio [aOR], 1.32 [95% CI, 1.14-1.53]), invasive mechanical ventilation (aOR, 1.45 [95% CI, 1.28-1.65]), ARDS (aOR, 1.36 [95% CI, 1.12-1.66]), and mortality (aOR, 1.19 [95% CI, 1.08-1.31]) and prolonged hospital LOS (median [IQR], 8.0 [4.2-15.8] days vs 6.8 [3.4-13.0] days; P < .001) and ICU LOS (median [IQR], 7.0 [2.8-15.0] days vs 6.4 [2.7-13.0] days; P < .001). Each additional metabolic syndrome criterion was associated with increased risk of ARDS in an additive fashion (1 criterion: 1147 patients with ARDS [10.4%]; P = .83; 2 criteria: 1191 patients with ARDS [15.3%]; P < .001; 3 criteria: 817 patients with ARDS [19.3%]; P < .001; 4 criteria: 203 patients with ARDS [24.3%]; P < .001). Conclusions and Relevance: These findings suggest that metabolic syndrome was associated with increased risks of ARDS and death in patients hospitalized with COVID-19. The association with ARDS was cumulative for each metabolic syndrome criteria present.

Metabolic Syndrome and COVID-19 Mortality Among Adult Black Patients in New Orleans.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) mortality is high in patients with hypertension, obesity, and diabetes. We examined the association between hypertension, obesity, and diabetes, individually and clustered as metabolic syndrome (MetS), and COVID-19 outcomes in patients hospitalized in New Orleans during the peak of the outbreak. RESEARCH DESIGN AND METHODS: Data were collected from 287 consecutive patients with COVID-19 hospitalized at two hospitals in New Orleans, LA from 30 March to 5 April 2020. MetS was identified per World Health Organization criteria. RESULTS: Among 287 patients (mean age 61.5 years; female, 56.8%; non-Hispanic black, 85.4%), MetS was present in 188 (66%). MetS was significantly associated with mortality (adjusted odds ratio [aOR] 3.42 [95% CI 1.52-7.69]), intensive care unit (ICU) (aOR 4.59 [CI 2.53-8.32]), invasive mechanical ventilation (IMV) (aOR 4.71 [CI 2.50-8.87]), and acute respiratory distress syndrome (ARDS) (aOR 4.70 [CI 2.25-9.82]) compared with non-MetS. Multivariable analyses of hypertension, obesity, and diabetes individually showed no association with mortality. Obesity was associated with ICU (aOR 2.18 [CI, 1.25-3.81]), ARDS (aOR 2.44 [CI 1.28-4.65]), and IMV (aOR 2.36 [CI 1.33-4.21]). Diabetes was associated with ICU (aOR 2.22 [CI 1.24-3.98]) and IMV (aOR 2.12 [CI 1.16-3.89]). Hypertension was not significantly associated with any outcome. Inflammatory biomarkers associated with MetS, CRP, and lactate dehydrogenase (LDH) were associated with mortality (CRP [aOR 3.66] [CI 1.22-10.97] and LDH [aOR 3.49] [CI 1.78-6.83]). CONCLUSIONS: In predominantly black patients hospitalized for COVID-19, the clustering of hypertension, obesity, and diabetes as MetS increased the odds of mortality compared with these comorbidities individually.

Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aß pathology and modulates Aß oligomerization.

Increased dietary consumption of docosahexaenoic acid (DHA) is associated with decreased risk for Alzheimer's disease (AD). These effects have been postulated to arise from DHA's pleiotropic effects on AD pathophysiology, including its effects on ß-amyloid (Aß) production, aggregation, and toxicity. While in vitro studies suggest that DHA may inhibit and reverse the formation of toxic Aß oligomers, it remains uncertain whether these mechanisms operate in vivo at the physiological concentrations of DHA attainable through dietary supplementation. We sought to clarify the effects of dietary DHA supplementation on Aß indices in a transgenic APP/PS1 rat model of AD. Animals maintained on a DHA-supplemented diet exhibited reductions in hippocampal Aß plaque density and modest improvements on behavioral testing relative to those maintained on a DHA-depleted diet. However, DHA supplementation also increased overall soluble Aß oligomer levels in the hippocampus. Further quantification of specific conformational populations of Aß oligomers indicated that DHA supplementation increased fibrillar (i.e. putatively less toxic) Aß oligomers and decreased prefibrillar (i.e. putatively more toxic) Aß oligomers. These results provide in vivo evidence suggesting that DHA can modulate Aß aggregation by stabilizing soluble fibrillar Aß oligomers and thus reduce the formation of both Aß plaques and prefibrillar Aß oligomers. However, since fibrillar Aß oligomers still retain inherent neurotoxicity, DHA may need to be combined with other interventions that can additionally reduce fibrillar Aß oligomer levels for more effective prevention of AD in clinical settings.