Citations

Abstract Objectives We investigated coronavirus disease 2019 (COVID-19) vaccine safety in pregnant and breastfeeding women with autoimmune diseases (AID) in the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. Methods Delayed-onset (>7 days) vaccine-related adverse events (AE), disease flares and AID-related treatment modifications were analysed upon diagnosis of AID vs healthy controls (HC) and the pregnancy/breastfeeding status at the time of at least one dose of vaccine. Results Among the 9201 participants to the self-administered online survey, 6787 (73.8%) were women. Forty pregnant and 52 breastfeeding patients with AID were identified, of whom the majority had received at least one dose of COVID-19 vaccine (100% and 96.2%, respectively). AE were reported significantly more frequently in pregnant than in non-pregnant patients (overall AE 45% vs 26%, P = 0.01; minor AE 40% vs 25.9%, P = 0.03; major AE 17.5% vs 4.6%, P < 0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC with respect to AE. Post-vaccination disease flares were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18.3% of age- and disease-matched non-pregnant and non-breastfeeding patients (n = 262). All pregnant/breastfeeding patients who experienced a disease flare were managed with glucocorticoids; 28.6% and 20% of them required initiation or change in immunosuppressants, respectively. Conclusion This study provides reassuring insights into the safety of COVID-19 vaccines administered to women with AID during the gestational and post-partum periods, helping overcome hesitant attitudes, as the benefits for the mother and for the fetus by passive immunization appear to outweigh potential risks.

AbstractBackgroundFor aggressive maxillary sinus and pterygopalatine fossa (PPF) tumors, an en‐bloc pterygomaxillectomy may be indicated.MethodsFive head specimens were used to study the feasibility of an en‐bloc pterygomaxillectomy. Eighty‐five non‐pathological CT scans were used to compare the superior edge of the inferior turbinate (IT) and the middle turbinate tail (MT) as landmarks for the pterygoid osteotomy.ResultsThrough a combined sublabial–subperiosteal incision and transoral route, a mid‐sagittal osteotomy through the hard palate and an axial osteotomy below the infraorbital foramen were performed. For the endoscopic pterygoid osteotomy, an infra‐vidian transpterygoid approach was performed, subsequently removing the pterygomaxillectomy en‐bloc. As landmarks, the osteotomies at the level of the MT tail and IT resected the pterygoid plates completely, but the IT osteotomy was further away from the vidian canal (7.5 vs. 6 mm).ConclusionsThe endoscopic‐assisted en‐bloc pterygomaxillectomy is feasible. The IT landmark is safe and ensures complete resection of the pterygoid plates.

Abstract Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

AbstractBackground and PurposeTo determine the incidence of acute neuroimaging (NI) findings and comorbidities in the coronavirus disease of 2019 (COVID‐19)‐infected subjects in seven U.S. and four European hospitals.MethodsThis is a retrospective study of COVID‐19‐positive subjects with the following inclusion criteria: age >18, lab‐confirmed COVID‐19 infection, and acute NI findings (NI+) attributed to COVID‐19 on CT or MRI brain. NI+ and comorbidities in total hospitalized COVID‐19‐positive (TN) subjects were assessed.ResultsA total of 37,950 COVID‐19‐positive subjects were reviewed and 4342 underwent NI. NI+ incidence in subjects with NI was 10.1% (442/4342) including 7.9% (294/3701) in the United States and 22.8% (148/647) in Europe. NI+ incidence in TN was 1.16% (442/37,950). In NI (4342), incidence of ischemic stroke was 6.4% followed by intracranial hemorrhage (ICH) (3.8%), encephalitis (0.5%), sinus venous thrombosis (0.2%), and acute disseminated encephalomyelitis (ADEM) (0.2%). White matter involvement was seen in 57% of NI+. Hypertension was the most common comorbidity (54%) before cardiac disease (28.8%) and diabetes mellitus (27.7%). Cardiac disease (p < .025), diabetes (p < .014), and chronic kidney disease (p < .012) were more common in the United States.ConclusionThis multicenter, multinational study investigated the incidence and spectrum of NI+ in 37,950 hospitalized adult COVID‐19 subjects including regional differences in incidences of NI+, associated comorbidities, and other demographics. NI+ incidence in TN was 1.16% including 0.95% in the United States and 2.09% in Europe. ICH, encephalitis, and ADEM were common in Europe, while ischemic strokes were more common in the United States. In this cohort, incidence and distribution of NI+ helped characterize the neurological complications of COVID‐19.

Abstract Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

Introduction: COVID-19 pandemic has had an unprecedented impact worldwide, co-infections with neglected tropical diseases like Malaria can occur and affect the heart. Objective: Describe a unique case of Malaria and SARS CoV2 infection occurring concurrently with cardiac complications. Clinical Case: A 69-year-old male, retired canoeing athlete, with well-controlled arterial hypertension, presented odynophagia, cough, and dyspnea on slight exertion for 2 days. On examination, O2 saturation was 91%, blood pressure 100/60 mmHg, regular heart rate of 110 bpm, positive PCR for SARS-CoV-2, elevated D-Dimer, and chest X-ray with evidence of viral pneumonia. He received supplemental oxygen, steroids, and paracetamol. Two days later, he presented with choluria, afternoon episodes of high fever preceded by chills and myalgia, and a thick blood smear showed Plasmodium falciparum (PF) trophozoites. Antimalarial treatment was started with primaquine 15mg, 20 mg of artemether, and 120 mg of Lumefantrine daily with the disappearance of fever until day 14 of onset of symptoms when he presented with acute heart failure (AHF) with a reduced ejection fraction of 45%. NYHA Class IV, arterial hypotension, sudden onset palpitations, and afternoon febrile episode. The electrocardiogram showed atrial fibrillation (AF) with a rapid irregular ventricular response of 120 bpm; The echocardiogram revealed a 7mm circumferential pericardial effusion, right ventricular dysfunction. Treatment with colchicine, enoxaparin, spironolactone, and bisoprolol was started. A new thick smear demonstrated the persistence of PF. A new antimalarial regimen was restarted, with the disappearance of the fever 48 hours after its onset, with the reversion of AF to sinus rhythm. Discussion: A unique case of concurrent COVID-19 and Malaria, which cause challenges to the heart and lead to cardiovascular complications. Conclusion: An exceptional case is presented, the coexistence of SARS-CoV-2 and PF infection-associated complications of myocarditis, pericarditis, new-onset AF, and AHF. This interaction should not go unnoticed, physicians’ awareness is key, and early diagnosis and treatment can be lifesaving, mitigate and offer the best chance of cure.

Introduction: Leadless pacing(LP) technology has been expanding in recent practice as an alternative to traditional pacing This technology is associated with reduce complications such as infection, dislodgment, and hardware burden. There has been recent reports on effusions with its implantation .Historically the manufacturer has recommend bolus of heparin or infusions We present the results and operative outcomes of patients who received a LP without initial heparinization or infusion from 2016 to 2021 at a single center. Objective We sought to describe the outcomes of LP implantation without the need of heparin administration. Methods: We report the clinical outcomes and operative findings of 200 patients who underwent LP implantation without initial heparin loading or infusions . An aggressive flushing strategy of the sheaths before and during the procedures was performed Data recorded include indication, ejection fraction (EF) R waves, capture thresholds, ventricular ectopy on deployment,recaptures, procedure times, and complications. Patients on chronic anticoagulation were excluded Results: A total of 200 patients were included , average age was 77 years and 20 (10%) had a reduced EF (<40%) pre-procedure. The most common indications included complete AV block (97, 48.5%) and atrial fibrillation with slow ventricular response (76, 38%). All patients (100%) had successful establishment of ventricular pacing with no short-term complications postoperatively. Average R waves after deployment were 9.7 with average capture thresholds of 0.84 @ 0.24 Ventricular ectopy was seen for 134 (67%) of patients upon deployment with 62 (31%) patients requiring recaptures, and 29 (14.5%) requiring more than one recapture. There was no evidence of thrombus in the sheaths or implanting instruments . There were no embolic or thrombotic complications. Conclusions: LP implantation is highly effective and efficacious in establishing single-chamber ventricular pacing for a variety of conduction pathologies with minimal complications postoperatively. It appears that an aggressive flushing strategy of the implanting equipment & sheaths is safe & effective without the need of heparinization. Further studies will be require to validate this strategy