Immune response and safety to inactivated COVID-19 vaccine: A comparison between People Living with HIV and HIV-naive individuals

Background: Multi-types COVID-19 vaccines have shown safety and efficacy against COVID-19 in adults. Although current guidelines encourage people living with HIV(PLWH) to take COVID-19 vaccines, whether their immune response to COVID-19 vaccines is distinct from HIV-free individuals is still unclear. Methods: Between March to June 2021, 48 PLWH and 40 HNC, aged 18 to 59 years, were enrolled in the study in Wuchang district of Wuhan city. All of them received inactivated COVID-19 vaccine at day 0 and the second dose at day 28. The primary safety outcome was the combined adverse reactions within 7days after each injection. The primary immunogenicity outcomes were neutralizing antibodies (nAbs) responses by chemiluminescence and total specific IgM and IgG antibodies responses by ELISA and colloidal gold at baseline (day 0), day 14, day 28, day 42, and day 70.Results: In total, the study included 46 PLWH and 38 HNC who finished 70 days’ follow-up. The frequency of adverse reactions to the first and second dose was not different between PLWH (30% and 11%) vs HNC (32% and 24%). There were no serious adverse events. NAbs responses among PLWH peaked at day 70, while among HNC peaked at day 42. At day 42, the geometric mean concentration (GMC) and seroconversion rate of nAbs among PLWH were 4.46 binding antibody units (BAU)/mL (95% CI, 3.18-5.87) and 26% (95% CI, 14-41), which were lower than that among HNC [GMC (18.28 BAU/mL, 95% CI, 10.33-32.33), seroconversion rate (63%, 95% CI, 44-79)]. IgG responses among both PLWH and HNC peaked at day 70. At day 70, the geometric mean ELISA units (GMEU) and seroconversion rate of IgG among PLWH were 0.193 ELISA units (EU)/mL (95% CI, 0.119-0.313) and 51% (95% CI, 34-69), which was lower than that among HNC [GMEU (0.379 BAU/mL, 95% CI, 0.224-0.653), seroconversion rate (86%, 95% CI, 64-97)]. Conclusion: Early humoral immune response to the inactivated COVID-19 vaccine was weaker and delayed among the PLWH population than that among HNC. This observation remained consistent regardless of a high CD4 count and a low HIV viral load suppressed by antiretroviral therapy (ART).

Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol

Background Tenecteplase has higher fibrin specificity with a longer half-life and the potential to achieve higher rates of recanalization than alteplase. A critical limitation of tenecteplase is no commercial use in Japan and no experience with its administration to Japanese patients. Hypothesis Tenecteplase is superior to alteplase in achieving recanalization on the initial angiogram when administered ≤4.5-hour of stroke onset in patients planned for mechanical thrombectomy (MT) in Japan where alteplase at the unique dose of 0.6mg/kg is officially used. Methods The Tenecteplase versus alteplase For LArge Vessel Occlusion Recanalization (T-FLAVOR) trial is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, masked-endpoint, superiority study. Eligibility criteria include acute ischemic stroke with pre-stroke modified Rankin Scale score ≤3 and large vessel occlusion (internal carotid artery, middle cerebral artery, or basilar artery) eligible for intravenous thrombolysis ≤4.5-hour and MT ≤6-hour of stroke onset. After completing the safety confirmation phase involving three patients who received non-masked tenecteplase (0.25 mg/kg), 220 patients will be randomized to two groups (1:1), intravenous alteplase (0.6mg/kg, n = 110) or tenecteplase (0.25mg/kg, n = 110), prior to MT. Outcomes In the safety confirmation phase, the primary outcome is symptomatic intracranial hemorrhage (sICH) ≤24-36-hour. In the randomized, comparative phase, the primary efficacy outcome is substantial angiographic reperfusion (mTICI grade 2b/2c/3) or absence of retrievable thrombus on the initial angiogram. The primary safety outcome is sICH ≤24-36-hour and 90-day mortality. Discussion T-FLAVOR may help determine if tenecteplase should be recommended as a routine clinical strategy before MT for Japanese stroke patients. Trial registration jRCTs051210055

A novel endovascular method of atherectomy for calcified common femoral and popliteal disease using the crosser system: Crossbow and Rambow techniques

Objectives This study aims to report the efficacy and safety of new atherectomy methods using the Crosser system for calcified lesions in the common femoral and popliteal artery: the Crosser system supported by bended 0.014 wire (Crossbow) technique and retrograde approach of sheathless Crosser system supported by bended 0.014 wire (Rambow) technique. Materials and Methods This report describes a single-center, retrospective study. A total of 23 patients (mean ± SD age, 73 ± 10 years; 19 men) with symptomatic peripheral artery disease received the Crossbow technique and Rambow technique for treatment of calcified common femoral and popliteal disease; these patients were enrolled between October 2013 and October 2015. The primary efficacy outcome was acute technical success, defined as achievement of residual stenosis < 30% for stenting and < 50% for angioplasty or atherectomy. The primary safety outcome was assessed on the basis of angiographic complications. Results The Crossbow and Rambow techniques were undertaken in 100% and 17% of the patients, respectively. Acute technical success was achieved in 96% of the patients. There were two embolic events. Conclusion Crossbow and Rambow techniques could be effective atherectomy methods of calcified common femoral and popliteal disease. Regarding safety, embolic protection devices may be needed for our atherectomy methods.

BioMimics 3D vascular stent system for femoropopliteal interventions

Summary: Background: The MIMICS-3D study aimed to assess the safety and effectiveness of the BioMimics 3D Vascular Stent System for the treatment of symptomatic femoropopliteal artery disease in a real-world patient population. Patients and methods: Consecutive participants who were scheduled for implantation of the BioMimics 3D stent were enrolled in the prospective, observational, multicenter study. The primary effectiveness outcome was freedom from clinically driven target lesion revascularization at 12 months and the primary safety outcome was a composite of major adverse events comprising death, major target limb amputation, or clinically driven target lesion revascularization at 30 days. Outcomes through 24 months are reported. Results: A total of 507 patients (70±10 years, 65.5% male sex) were enrolled and treated with the study stent. 24.0% had critical limb-threatening ischemia, lesion length was 127±92 mm, and 56.8% of lesions were totally occluded. The Kaplan-Meier (KM) estimate of freedom from clinically driven target lesion revascularization at twelve-months was 90.6% (95% CI: 87.9%–93.3%) and the 30-day primary safety outcome occurred in 1.2% (95% CI: 0.5%–2.7%) of participants. At 24 months, clinical improvement was achieved in 86.6% and the KM estimate of freedom from clinically driven target lesion revascularization was 82.8% (95% CI: 79.4%–86.4%). The KM estimate of freedom from loss of primary patency according to PSVR >2.4 was 78.6% (95% CI: 74.7%–82.4%). Survival distribution functions regarding primary patency were lower with long lesions (>150 mm; log-rank p<0.001) but did not differ significantly between participants with or without critical limb-threatening ischemia (log-rank p=0.07). Conclusions: Endovascular treatment of atherosclerotic femoropopliteal lesions with the BioMimics 3D Vascular Stent System is efficacious and safe in a real-world setting.

Tenofovir alafenamide plasma concentrations are reduced in pregnant women living with HIV: data from the PANNA Network

Background Tenofovir alafenamide (TAF), a prodrug of tenofovir (TFV), is included in the majority of the recommended first-line antiretroviral regimens for patients living with HIV, but there are limited data on TAF use in pregnant women. We aimed to examine the plasma pharmacokinetics of TAF and TFV in pregnant women from Europe. Methods Pregnant women living with HIV were included from treatment centers across Europe, and intensive pharmacokinetic sampling in the third trimester and postpartum was performed. Pharmacokinetic parameters of TAF and TFV were determined with noncompartmental analysis. The proportion of women with a TAF AUCtau below the target of 53.1 ng*h/mL was determined. Clinical efficacy and safety outcome parameters were reported. Results In total, 20 pregnant women living with HIV were included. At the third trimester, geometric mean TAF AUClast and Cmax were decreased by 46% and 52%, respectively, compared with postpartum. TFV AUC0-24h, Cmax, and Ctrough decreased by 33%, 30% and 34%, respectively. The proportion of women with a TAF AUClast &lt;53.1 ng*h/mL was 6% at third trimester and 0% postpartum. One out of 20 women had a viral load &gt;50 copies/mL at third trimester and no mother-to-child transmission occurred. Conclusions TAF plasma concentrations were reduced by about half in women living with HIV during third trimester of pregnancy, but remained above the predefined efficacy target in the majority of the pregnant women. TFV concentrations were reduced by approximately 30% during third trimester. Despite the observed exposure decrease, high virologic efficacy was observed in this study.

TIMolol nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia (HHT) – study protocol of the prospective, randomized, double-blind, controlled cross-over TIM-HHT trial

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an inherited orphan disease, in which the absence of capillary beds between arterioles and venules lead to arteriovenous shunts. Epistaxis is the core symptom. Several case reports have described the nonselective beta-adrenergic receptor antagonist timolol as a successful treatment method of nosebleeds due in HHT patients. OBJECTIVE: TIM-HHT is a single-site, prospective, randomized, placebo-controlled, double-blind, cross-over study to investigate whether the efficacy of standard laser treatment of epistaxis in HHT patients can be increased by the additional use of timolol nasal spray (1 mg/d). METHODS: Twenty patients will be randomly allocated to one of two treatment sequences. Primary outcome is the severity of epistaxis determined by the Epistaxis Severity Score (ESS). Secondary outcomes are subjective satisfaction, quality of life, as well as the hemoglobin, ferritin, and transferrin levels of the participating patients. Safety outcome is assessed by means of pulse, blood pressure, and adverse events. CONCLUSION: TIM-HHT will evaluate the efficacy and safety of timolol as an additional treatment of epistaxis in HHT patients in a three-month trial period. Benzalkonium chloride is used as a placebo, which has no documented positive effect on the nasal mucosa and hence on epistaxis in HHT patients (in contrast to saline). TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00020994. Registered on 10 March 2020

Off-Label Under- and Overdosing of Direct Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis

Background: Prescriptions of off-label under- and overdosing of direct oral anticoagulants (DOACs) are common for patients with atrial fibrillation, but their efficacy and safety remain unknown. Methods: Databases were searched for randomized controlled trial or adjusted observational study that compared an off-label versus on-label dosing of DOACs through June 15, 2021. The primary efficacy outcome was ischemic stroke/system embolism (IS/SE), and primary safety outcome was major bleeding. Net clinical outcome was generally defined as the composite of IS/SE, major bleeding, and all-cause death. Hazard ratios (HRs) with 95% CIs were pooled with random-effects models with Hartung-Knapp-Sidik-Jonkman method for adjustment. Results: Sixteen studies with 130 609 patients were included. Compared with on-labeling dosing, off-label underdosing of DOACs was associated with a higher risk of IS/SE (HR, 1.22 [95% CI, 1.05–1.42], P =0.01). The incidence of major bleeding was similar (HR, 0.95 [95% CI, 0.82–1.11], P =0.48). Off-label underdosing was associated with a higher risk of net clinical outcome (HR, 1.19 [95% CI, 1.04–1.40], P =0.04) and all-cause death (HR, 1.24 [95% CI, 1.04–1.48], P =0.02). Stratified analysis of off-label underdosing of DOACs for IS/SE showed subgroup differences among different DOAC types and study regions. Limited data showed that off-label overdosing was associated with a higher risk of IS/SE (HR, 1.26 [95% CI, 1.11–1.43], P =0.003) and major bleeding (HR, 1.30 [95% CI, 1.04–1.62], P =0.025). Conclusions: Compared with on-label dosing, off-label underdosing of DOACs increased the risk of thromboembolic events but did not decrease the risk of bleeding. Limited data for off-label overdosing showed higher risks of thromboembolic and bleeding. Further studies are warranted to confirm the results of off-label overdosing DOACs and subgroup results of underdosing DOACs.

Glutamatergic medications as adjunctive therapy for moderate to severe obsessive-compulsive disorder in adults: a systematic review and meta-analysis

Background Obsessive-compulsive disorder (OCD) is among the most disabling neuropsychiatric conditions characterized by the presence of repetitive intrusive thoughts, impulses, or images (obsessions) and/or ritualized mental or physical acts (compulsions). Serotonergic medications, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), are the first-line treatments for patients with OCD. Recently, dysregulation of glutamatergic system has been proposed to be involved in the etiology of OCD. We designed this systematic review and meta-analysis to evaluate clinical efficacy of glutamatergic medications in patients with OCD, according to the guidelines of Cochrane collaboration. Method We searched Medline, Scopus, and Cochrane library without applying any language filter. Two of the authors independently reviewed search results for irrelevant and duplicate studies and extracted data and assessed methodological quality of the studies. We transformed data into a common rubric and calculated a weighted treatment effect across studies using Review Manager. Results We found 476 references in 3 databases, and after exclusion of irrelevant and duplicate studies, 17 studies with total number of 759 patients with OCD were included. In the present review we found evidence for several drugs such as memantine, N-acetylcysteine (NAC), Minocycline, L-carnosine and riluzole. Glutamaterigic drug plus SSRIs were superior to SSRI+ Placebo with regard to Y-BOCS scale [standardized mean difference (SMD = − 3.81 95% CI = − 4.4, − 3.23). Conclusion Augmentation of glutamatergic medications with SSRIs are beneficial in obsessive-compulsive patients, no harmful significant differences in any safety outcome were found between the groups.

Abstract 1122‐000115: Coiling of Wide‐Necked Ruptured Aneurysms: A Subset Analysis of the SMART Registry

Introduction : The purpose of this study was to assess the 1‐year clinical outcomes of wide‐necked ruptured aneurysms treated with coiling. Methods : Data on patients with a wide‐necked ruptured aneurysm were extracted from a prospective multicenter registry (SMART) that enrolled patients with intracranial aneurysm or other neurovascular abnormality who underwent coiling. A wide neck was defined as a neck width of at least 4 mm or as a dome‐to‐neck ratio (largest diameter / neck width) of less than 2. Enrollment was not limited by Hunt and Hess grade. The primary safety outcome was device‐related serious adverse events within 24 hours, and the primary effectiveness outcome was retreatment through follow‐up. Results : Of the 995 adults enrolled in the SMART registry, 144 had a wide‐necked ruptured aneurysm (Table). Average patient age was 59.3 years (SD 14.3), and 74.3% were female. Lesion locations were internal carotid artery, 31.3%; anterior communicating artery, 31.9%; middle communicating artery, 10.4%; and posterior circulation, 26.4%. Aneurysm sizes were small, 27.1%; medium, 54.2%; large, 18.1%; and giant, 0.7%. The most common aneurysm type was saccular (88.8%, 127/143). Coiling was stent assisted in 10.4% of patients and balloon assisted in 36.1% of patients. The rate of device‐related serious adverse events within 24 hours was 3.5%. The rate of retreatment through follow‐up was 20.6% (20/97). At 1 year, 82.6% (76/92) of patients had a Raymond–Roy Occlusion Classification of I or II, 32.6% (30/92) had progressive occlusion, and 46.7% (43/92) had stable occlusion. The 1‐year all‐cause mortality rate was 12.5%. At 1‐year follow‐up, 58.3% (42/72) of patients had a modified Rankin Scale score of 0 to 2. Conclusions : Treatment of wide‐necked ruptured aneurysms with coiling has acceptable occlusion and retreatment rates at 1‐year follow‐up.

Oral Anticoagulation Timing in Patients with Acute Ischaemic Stroke and Atrial Fibrillation

Background and Purpose: Oral anticoagulants (OACs) prevent stroke recurrence and vascular embolism in patients with acute ischaemic stroke (AIS) and atrial fibrillation (AF). Current guidance recommends a “1-3-6-12 day”’ rule to resume OACs after AIS, based mainly on empirical consensus. This study investigated the suitability of guideline-recommended timing for OAC initiation. Methods: To overcome immortal time bias, we emulated a sequence of randomized placebo-controlled trials and constructed 90 propensity score-matched cohorts of 12,307 patients with AF and AIS from 2012 to 2016. We compared the risk of composite effectiveness and safety outcome in the early vs no OAC use group and in the delayed vs no OAC use. Indirect comparison between early and delayed use was conducted using a network meta-analysis. Results: Across the groups of AIS severity, the risks of composite outcome or effectiveness outcome were lower in the OAC use group than the no use group and the risks were similar between the early and delayed use groups. In patients with severe AIS, those receiving early OACs use had an increased risk of safety outcome, with HR of 2.10 (CI: 1.13-3.92) compared with those without OAC use, and HR of 1·44 (CI: 0·99-2·09) compared with those receiving delayed use. Conclusions: In AF patients with severe AIS, early OAC use before the guideline-recommended days appeared to increase the risk of bleeding events, although the OAC initiation time seemed not to affect the risk of serious vascular events. The optimal severity-specific timing for OAC initiation after AIS requires further evaluation