Severe Variant Research Articles

A cross-sectional study of echocardiographic characteristics of patients diagnosed with SARS-CoV-2 delta strain.

The delta variant of SARS-CoV-2 has been associated with increased mortality and multi-organ failure, affecting various systems in the body. Cardiovascular manifestations including arrhythmias, heart failure, myocarditis, myocardial damage, and thromboembolism are commonly observed in patients infected with the delta variant. This study enrolled 106 individuals who tested positive for the delta strain of SARS-CoV-2 using real-time RT-PCR between May 25, 2020, and October 15, 2021. All patients underwent 2-D echocardiography, and based on the severity of their infection, were divided into two groups: serious and non-serious. Univariate correlation analysis showed significant positive correlations between right ventricular (RV) diameter and hs-TnI and D-dimer levels. Conversely, left ventricular ejection fraction (LVEF) was negatively correlated with hs-TnI, C-reactive protein (CRP), and D-dimer levels. Additionally, RV fractional area change (RV-FAC) showed a negative correlation with D-dimer and hs-TnI levels but not with CRP levels. RV dysfunction has been identified as an important predictor of mortality in various patient populations, including those infected with the delta variant of SARS-CoV-2. A significant proportion of severe delta variant cases require mechanical ventilation, which can have hemodynamic effects on the ventricular performance. Mechanical ventilation can increase pulmonary arterial pressure and worsen right heart dysfunction, especially when lung-protective ventilation strategies are not optimized. Our study highlights that patients with severe delta variants, particularly those with cardiac injury, may exhibit biventricular systolic dysfunction. Echocardiographic parameters such as LVEF, RV diameter, and RV-FAC were found to be associated with laboratory markers of poor prognosis, including elevated hs-TnI, CRP, and D-dimer levels. 2-D echocardiography can be a valuable tool in identifying early signs of ventricular dysfunction, aiding in the management of this patient population.

Dyskeratosis congenita: natural history of the disease through the study of a cohort of patients diagnosed in childhood.

Dyskeratosis congenita (DC) is a multisystem and ultra-rare hereditary disease characterized by somatic involvement, bone marrow failure, and predisposition to cancer. The main objective of this study is to describe the natural history of DC through a cohort of patients diagnosed in childhood and followed up for a long period of time. Multicenter, retrospective, longitudinal study conducted in patients followed up to 24 years since being diagnosed in childhood (between 1998 and 2020). Fourteen patients were diagnosed with DC between the ages of 3 and 17 years (median, 8.5 years). They all had hematologic manifestations at diagnosis, and nine developed mucocutaneous manifestations during the first decade of life. Seven presented severe DC variants. All developed non-hematologic manifestations during follow-up. Mutations were identified in 12 patients. Thirteen progressed to bone marrow failure at a median age of 8 years [range, 3-18 years], and eight received a hematopoietic stem cell transplant. Median follow-up time was 9 years [range, 2-24 years]. Six patients died, the median age was 13 years [range, 6-24 years]. As of November 2022, eight patients were still alive, with a median age of 18 years [range, 6-32 years]. None of them have developed myeloblastic syndrome or cancer. DC was associated with high morbidity and mortality in our series. Hematologic manifestations appeared early and consistently. Non-hematologic manifestations developed progressively. No patient developed cancer possibly due to their young age. Due to the complexity of the disease multidisciplinary follow-up and adequate transition to adult care are essential.

Brodalumab in the Treatment of Plaque Psoriasis Localized in Difficult-to-Treat Areas: A Narrative Review.

Psoriasis is a common chronic, immune-mediated, inflammatory skin disease that in certain localization results difficult to treat. Psoriatic lesions in difficult-to-treat areas might be hardly managed as no standardized therapeutic approach and the application of topical treatments might have great limitations. Systemic agents, including biologic therapies, have been proven effective in treating this subgroup of patients. In particular, current evidence has shown beneficial effects with the use of brodalumab, a fully human IgG2 monoclonal antibody antagonizing the IL-17 receptor A subunit (IL-17RA). The aim of this narrative review was to collect published data about efficacy and safety of brodalumab in the treatment of psoriasis occurring in difficult-to-treat areas. Data on brodalumab effectiveness and safety deriving from both trials and real-world setting that had been published in the last 15 years were collected for this review, together with clinical findings issued during international meetings. In phase 3 trials, brodalumab demonstrated to be effective in promoting a rapid response in scalp psoriasis as well as in generalized pustular psoriasis and erythrodermic psoriasis. Nail psoriasis demonstrated marked clinical improvement after treatment with brodalumab. Amelioration of palmoplantar psoriasis was also described in brodalumab-treated patients. Various retrospective real-world studies reported a complete clearance of psoriatic lesions in difficult-to-treat areas, including genitalia, through short-term brodalumab treatment. Brodalumab, combining rapid and sustained efficacy with a favorable safety profile, may be a valid therapeutic option for severe variants of psoriasis as well as for psoriasis localized in difficult-to-treat areas.

Association Between Genotype and Phenotype Severity in ABCA4-Associated Retinopathy

ABCA4-associated retinopathy is a common inherited retinal disease, and its phenotype spans from late-onset macular dystrophy to extensive cone-rod degeneration. Over 2000 disease-causing variants in the ABCA4 gene have been identified. To investigate genotype-phenotype correlations in ABCA4-associated retinopathy. This cohort study took place at a single referral center for inherited retinal diseases in Italy. Data were prospectively acquired from January 2015 to June 2022. Patients diagnosed with an inherited retinal disease related to biallelic ABCA4 variants were included for analysis. Genotype, classified into 4 groups according to the presence of the (1) p.Gly1961Glu allele, (2) a hypomorphic allele, (3) at least 1 moderate variant (moderate genotypes), or (4) 2 biallelic severe variants (severe genotypes). Total decreased autofluorescence (TDAF) and definitely decreased autofluorescence (DDAF) areas, inner and outer retinal volumes, and the respective progression rate. A total of 71 patients (median [IQR] age, 34 [22.4-47.2] years; 40 [56%] female) were included in the study, and 54 (76%) were followed up for a median (IQR) of 3.5 (1.6-4.7) years. Compared with moderate genotypes, those with the p.Gly1961Glu allele had smaller TDAF lesions by 61% (95% CI, -78% to -33%; P < .001) and DDAF lesions by 77% (95% CI, -93% to -18%; P = .02), along with slower growth rates for both TDAF (0.05 mm/y; 95% CI, 0.01-0.07; P < .001) and DDAF (0.06 mm/y; 95% CI, 0-0.12; P = .004). Hypomorphic alleles were associated with a thicker inner (+0.19 mm3; 95% CI, +0.02 to +0.36; P = .03) and outer retinal volume (+0.16 mm3; 95% CI, +0.03 to +0.28; P = .01) compared with moderate genotypes as well as a slower TDAF growth rate (0.05 mm/y; 95% CI, 0.01-0.08; P = .007). Severe genotypes had a 7-fold larger TDAF area (95% CI, 3.4-14.7; P < .001) and 11-fold larger DDAF area (95% CI, 2.9-42.1; P < .001) compared with moderate genotypes, along with faster growth rates estimated at 0.16 mm/y for TDAF (95% CI, 0.12-0.20; P < .001) and 0.17 mm/y for DDAF (95% CI, 0.12-0.23; P < .001). In this study of ABCA4-associated retinopathy, a 4-tier classification of genotypes was found to capture substantial variation in disease phenotype severity. These findings could prove beneficial for the prognostication of patients and warrant consideration of genotype in the design of future clinical trials.

Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9-/- mice exhibited hypoactivity in novel environments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.

Basaloid squamous cell carcinoma: A rare and aggressive cancer of the oral cavity

Basaloid squamous cell carcinoma (BSCC) is an uncommon and severe variant of squamous cell carcinoma (SCC). The tumor arises most commonly in the region of the head-and-neck. It is normally seen in the epiglottis, pyriform fossa, and the base of the tongue. It also occurs less frequently in areas like the palate, buccal mucosa, gingiva and the floor of mouth. Once compared to SCC, BSCC is documented for its aggressiveness in the head-and-neck area, along with its recurrence in local and cervical lymph nodes for its distant metastasis to the lungs. In addition, local lymph nodes are more common in regular recurrence rates. BSCC in the head and neck is more likely to spread to other parts of the body. It has an increased tendency to metastasize when compared with other tumors. We report a rare case of a BSCC arising in the buccal mucosa in a 65-year-old male patient and explain its clinicopathologic characteristics.

Inflammatory characteristics of central compartment atopic disease.

Central compartment atopic disease (CCAD) is an emerging phenotype of chronic rhinosinusitis with nasal polyposis (CRSwNP) characterized by prominent central nasal inflammatory changes. This study compares the inflammatory characteristics of CCAD relative to other phenotypes of CRSwNP. A cross-sectional analysis of data from a prospective clinical study was performed on patients with CRSwNP who were undergoing endoscopic sinus surgery (ESS). Patients with CCAD, aspirin-exacerbated respiratory disease (AERD), allergic fungal rhinosinusitis (AFRS), and non-typed CRSwNP (CRSwNP NOS) were included and mucus cytokine levels and demographic data were analyzed for each group. Chi-squared/Mann-Whitney U tests and partial least squares discriminant analysis (PLS-DA) were performed for comparison and classification. A total of 253 patients were analyzed (CRSwNP, n=137; AFRS, n=50; AERD, n=42; CCAD, n=24). Patients with CCAD were the least likely to have comorbid asthma (p=0.0004). The incidence of allergic rhinitis in CCAD patients did not vary significantly compared to patients with AFRS and AERD, but was higher compared to patients with CRSwNP NOS (p=0.04). On univariate analysis, CCAD was characterized by less inflammatory burden, with reduced levels of interleukin 6 (IL-6), IL-8, interferon gamma (IFN-γ), and eotaxin relative to other groups and significantly lower type 2 cytokines (IL-5, IL-13) relative to both AERD and AFRS. These findings were supported by multivariate PLS-DA, which clustered CCAD patients into a relatively homogenous low-inflammatory cytokine profile. CCAD has unique endotypic features compared to other patients with CRSwNP. The lower inflammatory burden may be reflective of a less severe variant of CRSwNP.

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) in a Middle Eastern patient cohort

ObjectiveThis is a comprehensive characteristic study of Kawasaki disease (KD) and Multi system inflammatory syndrome in children (MIS-C) in the Middle East that creates a formula to differentiate between the two.MethodsWe conducted a descriptive comparative study of KD and MIS-C in the United Arab Emirates. Retrospective MIS-C and KD cohorts were recruited between January 2017 until August 2021.We compared clinical and laboratory characteristics between both groups. Our data were compared with 87 patients with KD or MIS-C from the literature.ResultsWe report on123 patients. Sixty-seven (54%) met the criteria for KD (36 male, 43 Arab), and fifty-six (46%) met the criteria for MIS-C (28 male, 35 Arab). The median age was 2.2 years range (0.15–10.7) in the KD group and 7.3 years (0.7–15.2) in the MIS-C group (P < 0.001). The clinical features on admission showed an increase in gastrointestinal manifestations in MIS-C compared with KD (84% vs. 31%, P < 0.001). Laboratory tests on admission revealed a significant increase in the following tests in KD compared with MIS-C; white blood cells (mean 16.30 10(3) µcL vs. 11.56 10(3) µcL, P < 0.001), absolute neutrophils (mean 10.72 10(3) µcL vs. 8.21 10(3) µcL, P 0.008), absolute lymphocytes (mean 3.92 10(3) µcL vs. 2.59 10(3) µcL, P 0.003), erythrocyte sedimentation rate (mean 73 mm/hr vs. 51 mm/hr, P < 0.001) and platelets (median {390 10(3) µcL vs. 236 10(3) µcL, P < 0.001}). In contrast, procalcitonin and ferritin were increased in the MIS-C group (2.4 )ng/mL, 370 ng/mL; P < 0.001). Cardiac dysfunction and admission to the pediatric intensive care unit were higher in MIS-C than in KD (21% vs. 8% and 33% vs. 7.5%, respectively, P < 0.001).ConclusionThis study showed vast similarities between KD and MIS-C, suggesting that they lie along the same clinical spectrum. However, there are several differences between the two disease entities suggesting that MIS-C most likely represents a new severe variant of KD. Based on our findings in this study, we created a formula to differentiate between KD and MIS-C.

Eficacia y seguridad de la administración de plasma de convaleciente en pacientes con COVID-19

IntroductionDuring the COVID-19 pandemic, several strategies were suggested for the management of the disease, including pharmacological and non-pharmacological treatments such as convalescent plasma (CP). The use of CP was suggested due to the beneficial results shown in treating other viral diseases. ObjectiveTo determine the efficacy and safety of CP obtained from whole blood in patients with COVID-19. MethodsPilot clinical trial in patients with COVID-19 from a general hospital. The subjects were separated into three groups that received the transfusion of 400ml of CP (n=23) or 400ml of standard plasma (SP) (n=19) and a non-transfused group (NT) (n=37). Patients also received the standard available medical treatment for COVID-19. Subjects were followed up daily from admission to day 21. ResultsThe CP did not improve the survival curve in moderate and severe variants of COVID-19, nor did it reduce the degree of severity of the disease evaluated with the COVID-19 WHO and SOFA clinical progression scale. No patient had a severe post-transfusion reaction to CP. ConclusionsTreatment with CP does not reduce the mortality of patients even when its administration has a high degree of safety.

Abcd1 deficiency accelerates cuprizone-induced oligodendrocyte loss and axonopathy in a demyelinating mouse model of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD), the most frequent, inherited peroxisomal disease, is caused by mutations in the ABCD1 gene encoding a peroxisomal lipid transporter importing very long-chain fatty acids (VLCFAs) from the cytosol into peroxisomes for degradation via β-oxidation. ABCD1 deficiency results in accumulation of VLCFAs in tissues and body fluids of X-ALD patients with a wide range of phenotypic manifestations. The most severe variant, cerebral X-ALD (CALD) is characterized by progressive inflammation, loss of the myelin-producing oligodendrocytes and demyelination of the cerebral white matter. Whether the oligodendrocyte loss and demyelination in CALD are caused by a primary cell autonomous defect or injury to oligodendrocytes or by a secondary effect of the inflammatory reaction remains unresolved. To address the role of X-ALD oligodendrocytes in demyelinating pathophysiology, we combined the Abcd1 deficient X-ALD mouse model, in which VLCFAs accumulate without spontaneous demyelination, with the cuprizone model of toxic demyelination. In mice, the copper chelator cuprizone induces reproducible demyelination in the corpus callosum, followed by remyelination upon cuprizone removal. By immunohistochemical analyses of oligodendrocytes, myelin, axonal damage and microglia activation during de-and remyelination, we found that the mature oligodendrocytes of Abcd1 KO mice are more susceptible to cuprizone-induced cell death compared to WT mice in the early demyelinating phase. Furthermore, this effect was mirrored by a greater extent of acute axonal damage during demyelination in the KO mice. Abcd1 deficiency did not affect the function of microglia in either phase of the treatment. Also, the proliferation and differentiation of oligodendrocyte precursor cells and remyelination progressed at similar rates in both genotypes. Taken together, our findings point to an effect of Abcd1 deficiency on mature oligodendrocytes and the oligodendrocyte-axon unit, leading to increased vulnerability in the context of a demyelinating insult.

Rectovaginal endometriosis with nodular smooth muscle metaplasia diagnosed via transrectal ultrasound-guided fine-needle aspiration cytology: An underused minimally invasive diagnostic technique?

Rectovaginal endometriosis is a severe variant of deeply infiltrating endometriosis. Laparoscopic assessment with tissue sampling remains the gold standard for diagnosis of endometriosis. However, transvaginal (TVUS) and transrectal ultrasound (TRUS) have been shown to be especially helpful in the diagnosis of deep endometriosis. We present the case of a 49-year-old female with menorrhagia, dysmenorrhea, and constipation. Upon pelvic examination, an incidental mass was palpated. A computed tomography (CT) scan revealed an anterior rectal wall mass and colonoscopy was non-diagnostic. Further work-up with MRI showed a 3.9 cm mass centered within the upper rectovaginal septum. TRUS guided fine-needle aspiration (TRUS-FNA) revealed cohesive epithelial cell groups without significant cytologic atypia and a second population of bland spindle cells. Cell block slides showed glandular epithelium with associated stroma that exhibited endometrial morphology and immunophenotype. Nodular fragments of spindle cells with smooth muscle immunophenotype and fibrosis were also present. The overall morphologic findings were consistent with rectovaginal endometriosis with nodular smooth muscle metaplasia. Medical management with nonsteroidal aromatase inhibitor with radiologic follow-up was selected. Rectovaginal endometriosis represents a type of deep endometriosis usually associated with severe pelvic symptoms. Metaplastic smooth muscle cells are a frequent component of endometriosis in the rectovaginal pouch with nodular growth and may present diagnostic challenges. TRUS-FNA is a minimally invasive procedure that can provide an accurate diagnosis of endometriosis, even in this variant of deep infiltrating disease.

#3760 CYTOSKELETON-ORGANELLE INTERACTION IN LIVING CELL EXPRESSING INF2 VARIANTS CAUSING FSGS AND PERIPHERAL NEUROPATHY

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a common glomerular injury and represents a leading cause of ESRD. Studies with genetic FSGS show that a majority of genes are associated with regulation of podocyte cytoskeletons. INF2 is an actin assembly factor that mediates both polymerization and depolymerization and is the most frequent cause of dominant inherited FSGS. INF2 mutations located in the proximal half of DID (residues Leu57 to Glu184) typically cause CMT with early-onset FSGS, whereas that situating in the distal half (residues Glu184 to Leu245) cause FSGS alone. Previous studies disclosed that INF2 mutations primarily disorganize actin network and alter mitochondria shapes and vesicle motility. However, it remains elusive how the cytoskeletal network is concerted with the organelle morphology and functions in the disease cells. This study aims to characterize the interaction between cytoskeleton and organelle in cells expressing INF2 FSGS or CMT/FSGS variants. Method We characterized the cytoskeletal-organelle interaction in live HeLa or COS-7 cells expressing pathogenic INF2 variants in our cohort of FSGS. We performed a triple labeling by co-transfection of GFP-INF2, cytoskeletal markers (Lifeact-mCherry or EMTB-mScarletI), and by the uptake of organelle markers (Lysotracker or Mitotracker). To clarify the detailed pattern and dynamics of cytoskeletons and organelles, we employed the Spinning Disk Confocal Microscope DragonFly, which allows real-time super-resolution imaging with 70nm resolution. Results Wild-type-INF2 (WT-INF2) cells showed an ER pattern with perinuclear, Golgi accumulation. Mild INF2 variants causing FSGS alone (T161N, N202S) preserved the subcellular distribution essential similar to WT-INF2, while showing focal irregularity of ER networks. In contrast, severe INF2 variants leading to CMT/FSGS (G73D) exhibited a diffuse coarse ER pattern with few Golgi clusters and occasional peripheral accumulation in both cell poles. In live imaging of cells coexpressing GFP-INF2 and Lifeact-mCherry, actin stress fibers were pronouncedly reduced in CMT/FSGS variant (G73D) cells, but were mildly decreased FSGS variant (T161N and N202S) cells, compared with WT-INF2 cells. The filopodia in cells expressing T161N variant were less mobile (n = 10, P&amp;lt; 0.01) but were longer (n = 10, P&amp;lt; 0.0001) than those in cells expressing WT-INF2. T161N variant reduced expression of cortactin that stabilizes actin-branching and narrowed area of cortical actin meshwork compared to the WT-INF2 (n = 11, P&amp;lt; 0.01), suggesting that INF2 could serve the cortical actin formation. HeLa cells coexpressing T161N variant and EMTB showed a bipolar cell elongation along the longitudinal axis (n≥30, P&amp;lt; 0.0001) and disarranged microtubule bundles aligned in parallel, compared with those expressing WT-INF2. A time-lapse imaging of living COS-7 cells revealed that T161N variant increases mitochondrial fragmentation as well as mitochondria-ER interfaces more prominent than WT-INF2. Moreover, T161N variant induced the mitochondria misdistribution at the cell periphery (filopodia and cell edge) in both cell poles. Such aberrant patterns frequently coexisted with disarranged microtubules. Moreover, in lysotracker-labeled living COS-7, T161N variant reduced the motility of the lysosomal vesicles in cortical actin meshwork area, compared with WT-INF2 (n = 100, P&amp;lt; 0.0001). These observations suggest that INF2 variants perturbate the trafficking of organelles through disorganization of actin-microtubule network. Conclusion Our results indicate that INF2 CMT/FSGS variants cause more global and severe organelle dysfunction by disrupting the organelle-cytoskeletal interaction, than INF2 FSGS variants. The microtubule disarrangement might be due to an insufficient capping mechanism by which the microtubules are stably tethered to the cortical actin meshwork. Elucidation of cell-specific factors will help better understanding why podocyte and Schwann cell are susceptible to the cytoskeletal disarrangement.

#4808 DIFFERENTIATING POSTPARTUM HELLP SYNDROME FROM ATYPICAL HEMOLYTIC UREMIC SYNDROME

Abstract Background and Aims HELLP (hemolysis, elevated liver enzymes, low platelets) is a severe variant of preeclampsia whose pathogenesis remains unknown but likely involves abnormal placentation, endothelial dysfunction and release of vasoactive substances. Complement dysregulation is implicated in the pathogenesis of atypical hemolytic uremic syndrome (aHUS) and there is growing evidence to support its role in HELLP syndrome. Here we present a case of postpartum thrombotic microangiopathy (TMA) in the setting of HELLP syndrome. Method We present a case report. Ethics approval was obtained by the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. Results A 22 year old G1P1 Caucasian woman presents at 37 weeks gestation with abdominal pain and severe hypertension. Labs demonstrated TMA including hemoglobin 95, platelets 30, LDH 2597, and schistocytes. She had severe transaminitis with AST 1845 and ALT 830, and proteinuric acute kidney injury. She was diagnosed with HELLP syndrome and treated with anti-hypertensives and emergency Caesarean section. Unfortunately, the infant did not survive, and there was no placental abruption. Platelets recovered by day 5 postpartum, LDH by day 7. However, renal function worsened and by day 6 postpartum, she required hemodialysis. A renal biopsy revealed acute and chronic TMA. She did not have cortical necrosis. Further workup revealed normal C3, C4 and ADAMTS13 levels. Dialysis was stopped after two weeks. By 6 months, her renal function and proteinuria returned to normal. Complement function testing revealed negative complement factor H autoantibody, but elevated soluble C5b-9 (sC5b-9) level (0.42 mg/L, normal &amp;lt;0.3). Ex-vivo serum C5b-9 deposition on human microvascular endothelial cells was assessed both on resting (182%, normal &amp;lt;150%) and on ADP-activated endothelial cells (273%, normal &amp;lt;150%). This test was repeated 6 months postpartum when renal function had normalized, and results were persistently abnormal both on resting (215%, normal &amp;lt;150%) and on ADP-activated endothelial cells (282%, normal &amp;lt;150%). aHUS genetic testing was negative. Conclusion Results from Burwick et al suggest that this patient had a very high likelihood of clinical aHUS in association with HELLP syndrome (elevated LDH &amp;gt;1832 U/L and creatinine &amp;gt;1.9 mg/dL) [1]. Identifiable aHUS genetic mutations only occur in 50% of aHUS patients. Complement function testing is not routinely assessed for postpartum HELLP; however, the severity of her HELLP syndrome prompted further investigation (C5b-9 deposition testing). The persistence of increased C5b-9 deposition 6 months postpartum for this patient mimics the findings of patients who have confirmed aHUS [2]. Our patient's unique results suggest the patient may be at risk for recurrent TMA/aHUS in her lifetime, particularly if another pregnancy is being considered. Future research should explore which pregnancy associated TMA patients may benefit from anti-complement therapy.

Brain structural and functional correlates of the heterogenous progression of mixed transcortical aphasia

Mixed transcortical aphasia (MTCA) is characterized by non-fluent speech and comprehension deficits coexisting with preserved repetition. MTCA may evolve to less severe variants of aphasias or even to full language recovery. Mechanistically, MCTA has traditionally been attributed to a disconnection between the spared left perisylvian language network (PSLN) responsible for preserved verbal repetition, and damaged left extrasylvian networks, which are responsible for language production and comprehension impairments. However, despite significant advances in in vivo neuroimaging, the structural and functional status of the PSLN network in MTCA and its evolution has not been investigated. Thus, the aim of the present study is to examine the status of the PSLN, both in terms of its functional activity and structural integrity, in four cases who developed acute post-stroke MTCA and progressed to different types of aphasia. For it, we conducted a neuroimaging-behavioral study performed in the chronic stage of four patients. The behavioral profile of MTCA persisted in one patient, whereas the other three patients progressed to less severe types of aphasias. Neuroimaging findings suggest that preserved verbal repetition in MTCA does not always depend on the optimal status of the PSLN and its dorsal connections. Instead, the right hemisphere or the left ventral pathway may also play a role in supporting verbal repetition. The variability in the clinical evolution of MTCA may be explained by the varying degree of PSLN alteration and individual premorbid neuroanatomical language substrates. This study offers a fresh perspective of MTCA through the lens of modern neuroscience and unveils novel insights into the neural underpinnings of repetition.

The Spectrum of Neurological and Sensory Abnormalities in Gaucher Disease Patients: A Multidisciplinary Study (SENOPRO).

Gaucher disease (GD) has been increasingly recognized as a continuum of phenotypes with variable neurological and sensory involvement. No study has yet specifically explored the spectrum of neuropsychiatric and sensory abnormalities in GD patients through a multidisciplinary approach. Abnormalities involving the nervous system, including sensory abnormalities, cognitive disturbances, and psychiatric comorbidities, have been identified in GD1 and GD3 patients. In this prospective study, named SENOPRO, we performed neurological, neuroradiological, neuropsychological, ophthalmological, and hearing assessments in 22 GD patients: 19 GD1 and 3 GD3. First, we highlighted a high rate of parkinsonian motor and non-motor symptoms (including high rates of excessive daytime sleepiness), especially in GD1 patients harboring severe glucocerebrosidase variants. Secondly, neuropsychological evaluations revealed a high prevalence of cognitive impairment and psychiatric disturbances, both in patients initially classified as GD1 and GD3. Thirdly, hippocampal brain volume reduction was associated with impaired short- and long-term performance in an episodic memory test. Fourthly, audiometric assessment showed an impaired speech perception in noise in the majority of patients, indicative of an impaired central processing of hearing, associated with high rates of slight hearing loss both in GD1 and GD3 patients. Finally, relevant structural and functional abnormalities along the visual system were found both in GD1 and GD3 patients by means of visual evoked potentials and optical coherence tomography. Overall, our findings support the concept of GD as a spectrum of disease subtypes, and support the importance of in-depth periodic monitoring of cognitive and motor performances, mood, sleep patterns, and sensory abnormalities in all patients with GD, independently from the patient's initial classification.

VEGFA rs3025039 is associated with phenotype severity of myelofibrosis-type megakaryocyte dysplasia.

VEGFA rs3025039 is associated with phenotype severity of myelofibrosis-type megakaryocyte dysplasia.

Systemic juvenile idiopathic arthritis in the pediatric practice of Donetsk region

Juvenile idiopathic arthritis with systemic onset is a special, rare and the most severe variant of juvenile idiopathic arthritis. The article analyzes the clinical features of the onset and course of juvenile idiopathic arthritis with systemic onset in children living in the ecologically disadvantaged Donetsk region and the efficacy of therapy. Clinical cases are described. According to its clinical manifestations, the systemic variant of juvenile idiopathic arthritis is characterized by the severity of the general inflammatory response, a bright clinical picture, severe damage to internal organs, the development of polyserositis, can lead to the development of life-threatening conditions, such as macrophage activation syndrome, and also leads to the formation of deforming arthritis with early disability of the sick child. The relevance of studying the problem of juvenile idiopathic arthritis with a systemic onset is related to the late diagnosis of the disease, because at the onset of the disease there may be no joint syndrome, and therefore it is impossible to use the criteria of the International League of Rheumatology Associations to verify the diagnosis, which leads to diagnostic errors. Nonsteroidal anti-inflammatory drugs, glucocorticosteroids, and immunosuppressants are used for treatment. The prescription of genetic engineering biological therapy, the choice of the drug, is carried out according to the recommendations of the American College of Rheumatology, depending on the preference for systemic or joint manifestations of the disease. But the question of the optimal approach to regimens of dose reduction, duration of biological therapy, and rules for its withdrawal remains open. Until now, the optimal approach to the treatment of juvenile idiopathic arthritis with a systemic onset is unknown. To date, the issue of treatment in patients with pharmacoresistant variants and persistent course of the disease has not been solved. Therefore, further in-depth study of this problem, optimization of the diagnostic algorithm and an individual approach to therapy are needed.

A comprehensive knowledgebase of known and predicted human genetic variants associated with COVID-19 susceptibility and severity

Host genetic susceptibility is a key risk factor for severe illness associated with COVID-19. Despite numerous studies of COVID-19 host genetics, our knowledge of COVID-19-associated variants is still limited, and there is no resource comprising all the published variants and categorizing them based on their confidence level. Also, there are currently no computational tools available to predict novel COVID-19 severity variants. Therefore, we collated 820 host genetic variants reported to affect COVID-19 susceptibility by means of a systematic literature search and confidence evaluation, and obtained 196 high-confidence variants. We then developed the first machine learning classifier of severe COVID-19 variants to perform a genome-wide prediction of COVID-19 severity for 82,468,698 missense variants in the human genome. We further evaluated the classifier's predictions using feature importance analyses to investigate the biological properties of COVID-19 susceptibility variants, which identified conservation scores as the most impactful predictive features. The results of enrichment analyses revealed that genes carrying high-confidence COVID-19 susceptibility variants shared pathways, networks, diseases and biological functions, with the immune system and infectious disease being the most significant categories. Additionally, we investigated the pleiotropic effects of COVID-19-associated variants using phenome-wide association studies (PheWAS) in ~40,000 BioMe BioBank genotyped individuals, revealing pre-existing conditions that could serve to increase the risk of severe COVID-19 such as chronic liver disease and thromboembolism. Lastly, we generated a web-based interface for exploring, downloading and submitting genetic variants associated with COVID-19 susceptibility for use in both research and clinical settings (https://itanlab.shinyapps.io/COVID19webpage/). Taken together, our work provides the most comprehensive COVID-19 host genetics knowledgebase to date for the known and predicted genetic determinants of severe COVID-19, a resource that should further contribute to our understanding of the biology underlying COVID-19 susceptibility and facilitate the identification of individuals at high risk for severe COVID-19.

An End-to-End Localizer for Long-Term Topological Localization in Large-Scale Changing Environments

Long-term localization is an essential task for unmanned ground vehicles (UGVs), however, it suffers from scene changes due to various environmental conditions (e.g., lighting conditions, seasonal shifts, viewpoint changes or occlusions). In this paper, we propose a novel end-to-end localizer for robust long-term localization in changing environments. Firstly, a lightweight two-head place classification network is proposed, in which a place is regarded as a category. Considering seasonal changes lead to severe variants of local structures, large-sized filters in the first layer and a large-scale average pooling strategy are designed to focus regional context features of scenes. Motivated by the reward and punishment mechanisms in reinforcement learning, an incremental learning strategy is proposed to distinguish distinctive scenes for robust topological localization. Extensive experiments tested on three datasets whose collecting periods are over a year are utilized to validate the feasibility and performance of our method.

Urethral advancement and glanuloplasty versus tubularized incised plate urethroplasty for distal hypospadias repair: a prospective randomized study

BackgroundAbout one in 200 to one in 300 male births has hypospadias. The prevalence of this congenital anomaly varies worldwide. The meatus is located distally in approximately 70% of cases. Several surgical techniques were described for distal hypospadias repair; despite this, there is no ideal approach. This study compares urethral advancement &glanuloplasty, and TIP techniques in terms of feasibility, duration of operation, and complications. Patients and.MethodsThis prospective randomized comparative study was conducted at Al-Azhar University Hospitals from April 2022 to October 2022. Fifty-seven cases with different types of hypospadias were assessed for eligibility. Among them, seven cases were excluded due to the presence of severe chordee (n = 3), proximal variant (n = 2), and recurrent cases of hypospadias (n = 2). Fifty cases were randomly divided into two groups using a 1:1 ratio (computer-generated randomization). Twenty-five cases were subjected to urethral advancement and glanuloplasty, and the rest were subjected to tubularized incised plate (TIP) urethroplasty.ResultsThe mean age of all studied cases was 4.2 years. Approximately 52% had coronal or sub-coronal meatus, whereas 48% had glandular meatus. Both groups were matched according to age and meatus location (p > 0.05). No statistically significant difference was observed between the two groups regarding duration of operation, postoperative pain, and postoperative hospital stay. In addition, both groups did not differ significantly in late complications (meatal stenosis, meatal retraction, fistula, and glans dehiscence).ConclusionsBoth urethral advancement &glanuloplasty, and TIP urethroplasty have comparable short-term outcomes. Urethral advancement and glanuloplasty is preferred in certain conditions, especially in circumcised children or those with a narrow urethral plate.Trial registrationThe study protocol was approved by the Pan African Clinical Trials Registry (number for the registry is: PACTR202211757905870) on (29/11/2022). All procedures were performed per the Helsinki Declaration.