Cross-neutralizing antibody against emerging Omicron subvariants of SARS-CoV-2 in infection-naïve individuals with homologous BNT162b2 or BNT162b2(WT + BA.4/5) bivalent booster vaccination.

Since the emergence of SARS-CoV-2, different variants and subvariants successively emerged to dominate global virus circulation as a result of immune evasion, replication fitness or both. COVID-19 vaccines continue to be updated in response to the emergence of antigenically divergent viruses, the first being the bivalent RNA vaccines that encodes for both the Wuhan-like and Omicron BA.5 subvariant spike proteins. Repeated infections and vaccine breakthrough infections have led to complex immune landscapes in populations making it increasingly difficult to assess the intrinsic neutralizing antibody responses elicited by the vaccines. Hong Kong's intensive COVID-19 containment policy through 2020-2021 permitted us to identify sera from a small number of infection-naïve individuals who received 3 doses of the RNA BNT162b2 vaccine encoding the Wuhan-like spike (WT) and were boosted with a fourth dose of the WT vaccine or the bivalent WT and BA.4/5 spike (WT + BA.4/5). While neutralizing antibody to wild-type virus was comparable in both vaccine groups, BNT162b2 (WT + BA.4/BA.5) bivalent vaccine elicited significantly higher plaque neutralizing antibodies to Omicron subvariants BA.5, XBB.1.5, XBB.1.16, XBB.1.9.1, XBB.2.3.2, EG.5.1, HK.3, BA.2.86 and JN.1, compared to BNT162b2 monovalent vaccine. The single amino acid substitution that differentiates the spike of JN.1 from BA.2.86 resulted in a profound antigenic change.

Sex Differences in 90-Day Functional Outcomes for Acute Ischemic Stroke Patients With Obstructive Sleep Apnea.

Background Obstructive sleep apnea (OSA) is characterized by repeated episodes of either full or partial obstruction of the upper airway. OSA is an independent risk factor for acute ischemic stroke (AIS) and a contributor to other key risk factors. OSA may damage endothelial and brain tissues and worsen outcomes following AIS. We aimed to evaluate the impact of sex differences on 90-day functional outcomes following AIS in an OSA population, as measured by the modified Rankin Scale (mRS) score. Methodology We performed a retrospective study of patients with OSA and AIS from the Houston Methodist Hospital Outcomes-Based Prospective Endpoints in Stroke (HOPES) Registry from 2016 to 2022. Patients with charts that noted a diagnosis of OSA before AIS or within the 90 days following AIS were included. A multivariable logistic regression model was constructed adjusting for demographics, first admit National Institutes of Health Stroke Scale (NIHSS), and comorbidities on the binary outcome. The odds ratios (ORs) and 95% confidence intervals (CIs) were reported, providing likelihood estimates of a shift to higher mRS for a given comparison between females (reference category) and males. Statistical significance was defined as two-tailed p-values <0.05 for all tests. Results From the HOPES registry, 291 females and 449 males were found to have OSA. Males had a higher proportion of comorbid conditions such as atrial fibrillation (15% vs. 9%, p = 0.014) and intracranial hemorrhage compared to females (6% vs. 2%, p = 0.020). The multivariate logistic regression model showed that males were at two times higher risk for developing poor functional outcomes at 90 days (OR = 2.35, 95% CI = 1.06-5.19), p < 0.001). Conclusions Males were found to have two times higher risk for developing poor functional outcomes at 90 days. This may be due to more severe oxygen desaturation, increased susceptibility to oxidative stress, and greater frequency of full airway obstruction in males. Greater emphasis on early diagnosis and treatment of OSA may be necessary to reduce the disproportionate incidence of poor functional outcomes, particularly among apneic male stroke survivors.

Targeting TNF-α for COVID-19: Recent Advanced and Controversies.

Recent advances in the pathophysiologic understanding of coronavirus disease 2019 (COVID-19) suggests that cytokine release syndrome (CRS) has an association with the severity of disease, which is characterized by increased tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-2, IL-7, and IL-10. Hence, managing CRS has been recommended for rescuing severe COVID-19 patients. TNF-α, one of the pro-inflammatory cytokines commonly upregulated in acute lung injury, triggers CRS and facilitates SARS-CoV-2 interaction with angiotensin-converting enzyme 2 (ACE2). TNF-α inhibitors, therefore, may serve as an effective therapeutic strategy for attenuating disease progression in severe SARS-CoV-2 infection. Below, we review the possibilities and challenges of targeting the TNF-α pathway in COVID-19 treatment.

Characteristics and Outcomes of Left Ventricular-Assist Device-Associated Cerebrovascular Events in Setting of Infectious Intracranial Aneurysms.

BACKGROUND AND PURPOSE: The study aims to identify the characteristics and neurological outcomes of the left ventricular-assist device (LVAD)-associated cerebrovascular events (CVE) and infections, particularly in the setting of infectious intracranial aneurysms (IIA). METHODS: A single-center retrospective review of patients having undergone LVAD implantation between 2011 and 2017 was conducted using institutional registries and screened for CVE. Patients with CVE were assessed for concurrent bacteremia; neurovascular imaging was then used to isolate patients with IIA. A review of comorbidities, imaging characteristics, and management were performed to determine predictors of neurological outcomes, as defined by the 90-day modified Rankin scale (mRS) scores. RESULTS: Of the 383 HeartMate II LVAD implantations performed, 43 all-cause stroke events were identified across 35 (9%) patients. The majority of the events were hemorrhagic CVE (n=28) with 21 events complicated by bacteremia. Of patients with hemorrhagic CVE and bacteremia, Staphylococcus aureus (n=10) and Pseudomonas aeruginosa (n= 8) infection were the most frequently associated organisms. Severe disability or death (90-day mRS > 4) was observed in 15 patients (63%). Seven patients had confirmed findings of IIA on diagnostic cerebral angiogram and were associated with distal middle cerebral artery (MCA) territory involvement (n=6; 86%) with concurrent Staphylococcus (n=5, 71%) and/or Pseudomonas (n=4, 57%) infections. Overall, a higher incidence of acute and chronic bacteremia was observed in the hemorrhagic CVE subgroup compared to the ischemic CVE subgroup (74% vs 36% & 71% vs 29%, respectively; p <0.05). Despite endovascular and/or surgical intervention in patients with IIA, four patients failed management and elected for comfort measures. CONCLUSION: Our results indicate that P. aeruginosa and S. aureus bacteremia are associated with a greater incidence of intracranial hemorrhage and worse neurological outcomes. Future management considerations may include pre-implantation cerebrovascular imaging to assess vascular pathology including prior aneurysms and intracranial atherosclerotic disease burden as a screen for higher-risk patients, as well as more aggressive antibiotic therapy at bacteremia onset.

Incidence, predictors, and outcomes of post-thrombectomy seizures in the extended time window.

Mechanical thrombectomy 6-24 h after the last time where a patient was known to be without signs or symptoms of a stroke is the standard of care for patients with a stroke due to large vessel occlusion. This is referred to as thrombectomy within an extended time window. There have been very few studies looking at patients who had seizures within the first week (early post-stroke seizures) following mechanical thrombectomy in this extended time window. Our study suggests that this group of patients does not have a higher incidence of early post stroke seizures. Our findings do reveal however, that patients who do have early post-stroke seizures may have a less favorable functional outcome at 90 days than those who did not develop early seizures. Hence, rapid identification and subsequent treatment of seizures in these patients is important.

Severe Cerebral Small Vessel Disease Burden Is Associated With Poor Outcomes After Endovascular Thrombectomy in Acute Ischemic Stroke With Large Vessel Occlusion.

Background Despite recent advancements in the treatment of acute ischemic stroke (AIS) with large vessel occlusion (LVO), infarct progression over time and functional outcomes remain variable. This variation in outcomes may be partially attributed to an underlying state of chronic cerebral hypoperfusion and ischemia affecting small cerebral perforating arterioles, venules, and capillaries of the brain; broadly termed cerebral small vessel disease (CSVD). We investigated the association between CSVD burden and the degree of disability following successful recanalization with endovascular thrombectomy (EVT) in patients with AIS presenting with LVO. Methodology We conducted a single center retrospective analysis of all patients presenting with AIS LVO between May 2016 and May 2019. Patients who were premorbidly independent and presented within six hours from the last known well (LKW) with a proximal anterior circulation occlusion confirmed on computed tomography (CT) angiography of the head or neck were treated with EVT. Patients presenting after six hours and up to 24 hours from LKW with a target ischemic core to perfusion mismatch profile on CT or magnetic resonance (MR) perfusion, or a clinical imaging mismatch on MR diffusion-weighted imaging, were also treated. Patients with successful revascularization, defined as a thrombolysis in cerebral infarction score 2b or 3, were included and evaluated for CSVD burden. The presence of CSVD was quantified using the Fazekas scale (0-3). All patients were further evaluated for disability at 90 days using the modified Rankin Scale (mRS, range 0-6). An mRS score of ≤2 was defined as a good functional outcome. Results Of the 190 patients evaluated, absent (Fazekas grade 0), mild (Fazekas grade 1), moderate (Fazekas grade 2), and severe (Fazekas grade 3) CSVD was present in 33 (17.4%), 84 (44.2%), 35 (18.4%), and 38 (20.0%) patients, respectively. Patients with severe CSVD (Fazekas grade 3) were found to be older, had a higher presenting National Institute of Health Stroke Scale (NIHSS), and had greater proportions of preexisting atrial fibrillation and dementia compared to patients with no CSVD (Fazekas grade 0). Using a multivariate ordinal logistic regression model to adjust for age, presenting NIHSS, thrombus location, LKW to groin puncture time, use of tissue plasminogen activator, ischemic infarct volume, development of a symptomatic intracerebral hemorrhage, and treatment with hemicraniectomy, patients with Fazekas grade 3 were significantly more likely to have poor 90-day functional outcomes compared to patients with Fazekas grade 0 (odds ratio 10.25, 95% confidence interval [3.3-31.84]). Conclusions Based on our analytical cohort of AIS LVO patients treated with EVT, we found that patients with severe CSVD burden had worse functional outcomes at 90 days and increased mortality. These results provide evidence that the burden of CSVD may be considered an independent risk factor of poor clinical outcome and a predictor of mortality in patients with AIS presenting with LVO, despite successful radiographic recanalization with EVT.

H2S attenuates oxidative stress via Nrf2/NF-κB signaling to regulate restenosis after percutaneous transluminal angioplasty.

Restenosis after angioplasty of peripheral arteries is a clinical problem involving oxidative stress. Hydrogen sulfide (H2S) participates in oxidative stress regulation and activates nuclear factor erythroid 2-related factor 2 (Nrf2). This study investigated the effect of H2S and Nrf2 on restenosis-induced arterial injury. Using an in vivo rat model of restenosis, we investigated whether H2S inhibits restenosis after percutaneous transluminal angioplasty (PTA) and the oxidative stress-related mechanisms implicated therein. The involvement of Nrf2 was explored using Nrf2-shRNA. Neointimal formation and the deposition of elastic fibers were assessed histologically. Inflammatory cytokine secretion and the expression of proteins associated with oxidative stress and inflammation were evaluated. The artery of rats subjected to restenosis showed increased arterial intimal thickness, with prominent elastic fiber deposition. Sodium hydrosulfide (NaHS), an H2S donor, counteracted these changes in vivo. Restenosis caused a decrease in anti-oxidative stress signaling. This phenomenon was inhibited by NaHS, but Nrf2-shRNA counteracted the effects of NaHS. In terms of inflammation, inflammatory cytokines were upregulated, whereas NaHS suppressed the induced inflammatory reaction. Similarly, Nrf2 downregulation blocked the effect of NaHS. In vitro studies using aortic endothelial and vascular smooth muscle cells isolated from experimental animals showed consistent results as those of in vivo studies, and the participation of the nuclear factor-kappa B signaling pathway was demonstrated. Collectively, H2S played a role in regulating post-PTA restenosis by alleviating oxidative stress, modulating anti-oxidant defense, and targeting Nrf2-related pathways via nuclear factor-kappa B signaling.

Deep Venous Thrombosis in COVID-19 Patients: A Cohort Analysis.

Deep venous thrombosis (DVT) is a severe complication of coronavirus disease 2019 (COVID-19). The purpose of this study was to study the prevalence, risk factors, anticoagulant therapy and sex differences of DVT in patients with COVID-19. The enrolled 121 hospitalized non-ventilator patients were confirmed positive for COVID-19. All suspected patients received color Doppler ultrasound (US) to screen for DVT in both lower extremities. Multivariate logistic regression was performed to identify risk factors related to DVT in COVID-19 patients. DVT was found in 48% of the asymptomatic COVID-19 patients with an increased PADUA or Caprini index using US scanning. The multivariate logistic regression determined that age (OR, 1.05; p = .0306), C-reactive protein (CRP) (OR, 1.02; p = .0040), and baseline D-dimer (OR, 1.42; p = .0010) were risk factors among COVID-19 patients. Although the most common DVT location was infrapopliteal (classes I and II), higher mortality in DVT-COVID-19 patients was confirmed. DVT-COVID-19 patients presented significant increases in CRP, neutrophil count, and D-dimer throughout the whole inpatient period compared to non-DVT-COVID-19 patients. Although anticoagulation therapy accelerated the recovery of lymphocytopenia in DVT patients, men DVT-COVID-19 patients with anticoagulant therapy showed significant higher CRP and neutrophil count vs. lymphocyte count (N/L) ratio, but showed lower lymphocyte counts compared to women DVT-COVID-19 patients. DVT is common in COVID-19 patients with high-risk factors, especially for older age and higher CRP and baseline D-dimer populations. It is important to consider sex differences in anticoagulant therapy among DVT-COVID-19 patients.

Anesthetic Management of Patients with COVID 19 Infections during Emergency Procedures.

OBJECTIVES: The aim of the present study was to prevent cross-infection in the operating room during emergency procedures for patients with confirmed or suspected 2019 novel coronavirus (2019-nCoV) by following anesthesia management protocols, and to document clinical- and anesthesia-related characteristics of these patients. DESIGN: This was a retrospective, multicenter clinical study. SETTING: This study used a multicenter dataset from 4 hospitals in Wuhan, China. PARTICIPANTS: Patients and health care providers with confirmed or suspected 2019-nCoV from January 23 to 31, 2020, at the Wuhan Union Hospital, the Wuhan Children's Hospital, The Central Hospital of Wuhan, and the Wuhan Fourth Hospital in Wuhan, China. INTERVENTIONS: Anesthetic management and infection control guidelines for emergency procedures for patients with suspected 2019-nCoV were drafted and applied in 4 hospitals in Wuhan. MEASUREMENTS AND MAIN RESULTS: Cross-infection in the operating rooms of the 4 hospitals was effectively reduced by implementing the new measures and procedures. The majority of patients with laboratory-confirmed 2019-nCoV infection or suspected infection were female (23 [62%] of 37), and the mean age was 41.0 years old (standard deviation 19.6; range 4-78). 10 (27%) patients had chronic medical illnesses, including 4 (11%) with diabetes, 8 (22%) with hypertension, and 8 (22%) with digestive system disease. Twenty-five (68%) patients presented with lymphopenia, and 23 (62%) patients exhibited multiple mottling and ground-glass opacity on computed tomography scanning. CONCLUSIONS: The present study indicates that COVID 19-specific guidelines for emergency procedures for patients with confirmed or suspected 2019-nCoV may effectively prevent cross-infection in the operating room. Most patients with confirmed or suspected COVID 19 presented with fever and dry cough and demonstrated bilateral multiple mottling and ground-glass opacity on chest computed tomography scans.

Protective effect of a hydrogen sulfide donor on balloon injury-induced restenosis via the Nrf2/HIF-1α signaling pathway.

Restenosis is liable to occur following treatment with endovascular interventional therapy. Increasing evidence indicates that hydrogen sulfide (H2S) exhibits numerous physiological properties, including antioxidative and cardioprotective disease properties. Thus, the present study aimed to investigate the anti­restenosis effects of H2S and its protective mechanisms. A balloon dilatation restenosis model was used, in which model Sprague­Dawley rats were treated with sodium hydrosulfide (NaHS: A donor of H2S, 30 µmol/kg) by intraperitoneal injection for 4 weeks. Histological observations of the carotid artery were performed, and H2S production and the expression of Nuclear factor­E2­related factor 2 (Nrf2)/hypoxia­inducible factor (HIF)­1α signaling pathway proteins were measured. In addition, human umbilical vein endothelial cells (HUVECs) were treated with NaHS following the inhibition of Nrf2 or HIF­1α expression. The expression of Nrf2/HIF­1α signaling pathway proteins, tube formation and cell migration were evaluated thereafter. The results demonstrated that NaHS treatment significantly increased H2S production in rats with restenosis, and that neointimal thickness decreased significantly in arteries with restenosis. Furthermore, an increase in H2S production enhanced the nuclear accumulation of Nrf2 and expression of its downstream targets, heme oxygenase­1 and superoxide dismutase, as well as HIF­1α. Similar effects of NaHS on the expression of these proteins were observed in HUVECs. Additionally, these findings indicated that NaHS­induced HIF­1α expression was dependent on Nrf2 expression. NaHS treatment also markedly increased tube formation by upregulating vascular endothelial growth factor expression and cell migration, both of which were mediated by the Nrf2/HIF­1α signaling pathway, and suppressed the migration and proliferation of human vascular smooth muscle cells. Thus, NaHS­mediated H2S production was observed to prevent neointimal hyperplasia, promote activation of the Nrf2/HIF­1α signal pathway, and enhance HUVEC tube formation and migration, thereby exerting protective effects on balloon injury­induced restenosis.

The HOPES Registry - Houston Methodist Hospital Outcomes-based Prospective Endpoints in Stroke.

BACKGROUND: We present a single institution registry with the novel feature of 90-day outcome assessments on all hospitalized acute stroke patients, inclusive of every patient with a primary discharge diagnosis of transient ischemic attack (TIA), acute ischemic stroke (AIS), nontraumatic subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH). METHODS: Patient data obtained in the HOPES registry include demographics, comorbid diagnoses, medications, health behaviors, laboratory values, imaging studies, vital signs, and outcome measures, most notably the modified Rankin Scale (mRS) at 90days. RESULTS: From May 2016 to December 31, 2017, 1607 patients were enrolled in the HOPES registry. 90-day outcome assessments were captured on 1555 patients (97%): 1096 AIS, 230 ICH, 110 SAH, and 119 TIA patients. Mortality rates and 90-day outcomes were most favorable for TIA patients. Mortality and 90-day disability scores were poorest for patients in the ICH group. CONCLUSIONS: The inclusion of 90-day outcomes data will allow HOPES to stand apart among stroke registries as a new standard for stroke outcomes research. The registry will provide the necessary comprehensive data that the field needs as we transition our focus of stroke research to poststroke recovery.

Carbon Monoxide and Its Controlled Release: Therapeutic Application, Detection, and Development of Carbon Monoxide Releasing Molecules (CORMs).

Carbon monoxide (CO) is attracting increasing attention because of its role as a gasotransmitter with cytoprotective and homeostatic properties. Carbon monoxide releasing molecules (CORMs) are spatially and temporally controlled CO releasers that exhibit superior and more effective pharmaceutical traits than gaseous CO because of their chemistry and structure. Experimental and preclinical research in animal models has shown the therapeutic potential of inhaled CO and CORMs, and the biological effects of CO and CORMs have also been observed in preclinical trials via the genetic modulation of heme oxygenase-1 (HO-1). In this review, we describe the pharmaceutical use of CO and CORMs, methods of detecting CO release, and developments in CORM design and synthesis. Many valuable clinical CORMs formulated using macromolecules and nanomaterials are also described.

Serum uric acid is associated with increased risk of idiopathic venous thromboembolism in high HDL-C population: A case-control study.

Many studies have indicated that metabolic disorders are positively correlated with idiopathic venous thromboembolism (VTE), whereas the risk factor serum uric acid (SUA) for idiopathic VTE has yet to be investigated. In this retrospective case-control study, 276 idiopathic VTE patients and 536 gender- and age-matched control subjects were included. The subjects in the case and control groups exhibiting common known VTE risk factors and the patients with a first VTE onset in one month were excluded. For the control group, primary and secondary VTE patients were excluded. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, fasting blood glucose, and current smoking were significantly associated with idiopathic VTE in the univariate analysis. Hyperuricemia was detected in 56/276 (20.29%) idiopathic patients compared with 71/536 (13.25%) in the control group. HDL-C was considered the most prominent interactive factor for SUA in idiopathic VTE by the interaction analysis. After testing for the interaction terms, SUA was closely associated with idiopathic VTE in the high HDL-C population (P=0.0026 for interaction), while there was no such correlation in the low HDL-C group. The results indicated no obvious correlation between triglyceride and hypertension to idiopathic VTE. In conclusion, SUA is closely associated with an increased risk of idiopathic VTE in the high HDL-C population. The abnormality of SUA may act as an important linkage between atherosclerosis and idiopathic VTE through HDL-C.