Citations

ABSTRACT The purpose of this case series is to review the endoscopic detection of anal intraepithelial neoplasia and anal squamous cell carcinoma including the role of rectal retroflexion and narrow-band imaging. Four cases of anal intraepithelial neoplasia were incidentally discovered in women aged 55–71 years. Anal lesions identified included sessile polyps, nodular mucosa, and circumferential polyps. A fifth patient, who presented with abdominal pain, was found to have a 3 cm anal squamous cell carcinoma on diagnostic colonoscopy, despite a negative colonoscopy 21 months earlier. In the absence of contraindications, retroflexion should be performed on all patients. Suspicious anal mucosa warrants biopsy.

Background COVID‐19 is an infectious illness, featured by an increased risk of thromboembolism. However, no standard antithrombotic therapy is currently recommended for patients hospitalized with COVID‐19. The aim of this study was to evaluate safety and efficacy of additional therapy with aspirin over prophylactic anticoagulation (PAC) in patients hospitalized with COVID‐19 and its impact on survival. Methods and Results A total of 8168 patients hospitalized for COVID‐19 were enrolled in a multicenter‐international prospective registry (HOPE COVID‐19). Clinical data and in‐hospital complications, including mortality, were recorded. Study population included patients treated with PAC or with PAC and aspirin. A comparison of clinical outcomes between patients treated with PAC versus PAC and aspirin was performed using an adjusted analysis with propensity score matching. Of 7824 patients with complete data, 360 (4.6%) received PAC and aspirin and 2949 (37.6%) PAC. Propensity‐score matching yielded 298 patients from each group. In the propensity score‐matched population, cumulative incidence of in‐hospital mortality was lower in patients treated with PAC and aspirin versus PAC (15% versus 21%, Log Rank P =0.01). At multivariable analysis in propensity matched population of patients with COVID‐19, including age, sex, hypertension, diabetes, kidney failure, and invasive ventilation, aspirin treatment was associated with lower risk of in‐hospital mortality (hazard ratio [HR], 0.62; [95% CI 0.42–0.92], P =0.018). Conclusions Combination PAC and aspirin was associated with lower mortality risk among patients hospitalized with COVID‐19 in a propensity score matched population compared to PAC alone.

Abstract Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Abstract Rationale The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non–COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.

AbstractIntroductionTo assess the risk for COVID‐19 of police officers, we are studying the seroprevalence in a cohort. The baseline cross‐sectional investigation was performed before a vaccination campaign in January/February 2021, and demonstrated a seroprevalence of 12.9%. Here, we demonstrate serosurveillance results after a vaccination campaign.MethodsThe cohort consists of 1022 study participants. The 3‐ and 6‐month follow‐up visits were performed in April/May and September 2021. Data on infection and vaccination rates were obtained via measuring antibodies to the nucleocapsid protein and spike protein and online questionnaires.ResultsThe mean age of the population was 41 (SD 8.8) years, 72% were male and 76% had no comorbidity. Seroconversion was identified in 1.05% of the study population at the 3‐month visit and in 0.73% at the 6‐month visit, resulting in an infection rate of 1.8% over a time period of 6 months. In comparison, the infection rate in the general population over the same time period was higher (3.18%, p = .018). At the 6‐month visit, 77.8% of participants reported being vaccinated once and 70.5% twice; 81% had an anti‐S antibody titer of >250 U/ml and 87.1% of ≥2 U/ml. No significant association between infection and job role within the department, working region, or years of experience in the job was found. Anti‐spike antibody titers of vaccinated study participants showed a calculated decreasing trend 150–200 days after the second vaccine dose.ConclusionThese data confirm the value of the vaccination campaign in an exposed group other than healthcare professionals.

Abstract Purpose Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD. Materials and Methods Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis. Results The prevalence rate of TD was 5.1%. In comparison to the TD− group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics. Conclusions This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD.

Abstract Structural discovery of guanine nucleotide exchange factor (GEF) protein complexes is likely to become increasingly relevant with the development of new therapeutics targeting small GTPases and development of new classes of small molecules that inhibit protein‐protein interactions. Syx (also known as PLEKHG5 in humans) is a RhoA GEF implicated in the pathology of glioblastoma (GBM). Here we investigated protein expression and purification of ten different human Syx constructs and performed biophysical characterizations and computational studies that provide insights into why expression of this protein was previously intractable. We show that human Syx can be expressed and isolated and Syx is folded as observed by circular dichroism (CD) spectroscopy and actively binds to RhoA as determined by co‐elution during size exclusion chromatography (SEC). This characterization may provide critical insights into the expression and purification of other recalcitrant members of the large class of oncogenic—Diffuse B‐cell lymphoma (Dbl) homology GEF proteins. In addition, we performed detailed homology modeling and molecular dynamics simulations on the surface of a physiologically realistic membrane. These simulations reveal novel insights into GEF activity and allosteric modulation by the plekstrin homology (PH) domain. These newly revealed interactions between the GEF PH domain and the membrane embedded region of RhoA support previously unexplained experimental findings regarding the allosteric effects of the PH domain from numerous activity studies of Dbl homology GEF proteins. This work establishes new hypotheses for structural interactivity and allosteric signal modulation in Dbl homology RhoGEFs.

Calcinosis cutis (CC) is the umbrella term for calcium salt deposition on skin and subcutaneous tissue. We present a unique case of CC associated with anti-Mi2-positive dermatomyositis, having a distinctive distribution of subcutaneous calcifications appearing as a ‘lumbar belt’. Treatment of CC remains challenging for clinicians due to a lack of high-quality evidence. Corticosteroids, methotrexate, bisphosphonates, intravenous immunoglobulin replacement, rituximab and sodium thiosulfate failed to halt calcinosis progression in this case. Newer therapies, such as Janus kinase inhibitors, should be considered.