Low-frequency inherited complement receptor variants are associated with purpura fulminans.

ABSTRACT: Extreme disease phenotypes can provide key insights into the pathophysiology of common conditions, but studying such cases is challenging due to their rarity and the limited statistical power of existing methods. Herein, we used a novel approach to pathway-based mutational burden testing, the rare variant trend test (RVTT), to investigate genetic risk factors for an extreme form of sepsis-induced coagulopathy, infectious purpura fulminans (PF). In addition to prospective patient sample collection, we electronically screened over 10.4 million medical records from 4 large hospital systems and identified historical cases of PF for which archived specimens were available to perform germline whole-exome sequencing. We found a significantly increased burden of low-frequency, putatively function-altering variants in the complement system in patients with PF compared with unselected patients with sepsis (P = .01). A multivariable logistic regression analysis found that the number of complement system variants per patient was independently associated with PF after controlling for age, sex, and disease acuity (P = .01). Functional characterization of PF-associated variants in the immunomodulatory complement receptors CR3 and CR4 revealed that they result in partial or complete loss of anti-inflammatory CR3 function and/or gain of proinflammatory CR4 function. Taken together, these findings suggest that inherited defects in CR3 and CR4 predispose to the maladaptive hyperinflammation that characterizes severe sepsis with coagulopathy.

Safe peripheral blood stem cell collection in patients less than 10 kg: A single-center review.

INTRODUCTION: Peripheral blood stem cell collection (PBSCC) is well-documented in adults and pediatric patients with larger total blood volume (TBV). However, very little data are available for the successful PBSCC of pediatric patients weighing less than 10 kg. Here, we highlight our institutional approach to PBSCC in this smaller-sized patient population. METHODS: Our protocol, including blood prime, was reviewed for PBSCC for bone marrow transplantation (BMT) in 18 children weighing 4.5-9.9 kg who safely underwent 37 PBSCC procedures at a single institution, Children's Hospital Colorado, between September 2016 and February 2022. RESULTS: We attained the individualized collection goals in all 18 patients with an average yield of 17.03 million CD34+ cells/kg of patient body weight (range: 0.84-67.45 million/kg). The average collection efficiency of the procedures was 41.5% (range: 23.0%-71.5%). We performed all 37 procedures safely and without complication. The estimated average TBV was 587 mL (range: 351-765 mL), the average blood volume processed was 596 mL (range: 351-756 mL), and the average TBVs processed was 2.5 (range: 1-4). CONCLUSION: PBSCC in patients ranging from 4.5 to 9.9 kg is safe and effective for collecting peripheral blood stem cells for BMT.

ABO Blood Groups Are Not Associated With COVID-19 Disease Incidence and Severity When Correcting for Ethnicity Differences in Blood Type.

OBJECTIVES: To determine if blood type is a risk factor for coronavirus disease 2019 (COVID-19) disease incidence and severity after correcting for ethnicity differences between novel infections and known ABO blood type frequency differences. METHODS: We performed a retrospective analysis on all severe acute respiratory system coronavirus 2 (SARS-CoV-2) infections and disease severity across two major testing sites in Colorado. We evaluated all individuals with a SARS-CoV-2 nucleic acid test (NAT) and a known blood type between March 1, 2020, and June 1, 2020. We then created a prediction algorithm based on the corrected blood types by ethnicity using data from the Colorado Department of Health and established blood types by ethnicity. We applied this prediction algorithm to all patients in our sample. RESULTS: Of 8,676 patients, 485 (5.6%) had a positive SARS-CoV-2 NAT test and 8,191 (94.4%) had a negative test. All patients had ABO blood types that mirrored the expected blood type distribution within the state of Colorado (P = .15, χ 2 statistic = 5.31). No differences in expected blood groups were present between ethnicity-adjusted SARS-CoV-2-negative and SARS-CoV-2-positive patients (χ 2 = 3.416313, P = .332). CONCLUSIONS: Blood type is not associated with COVID-19 disease incidence or severity after correcting for ethnicity differences in expected blood type frequencies.

Cellular Therapy in Pediatric Hematologic Malignancies.

Advances in cellular therapies for pediatric patients have created many opportunities for improved survival with reduced morbidity. This article reviews current cellular therapies in pediatric hematological malignancy, including the most updated practices in hematopoietic stem cell transplant and the use of chimeric antigen receptor (CAR) therapy in T cells. Hematopoietic stem cell transplant has evolved with improvements in chemotherapy regimens, immunosuppression, and donor-matching options. Novel therapies in development which will likely further improve the options for patients are reviewed including Natural Killer, Regulatory T-cells and αß depletion.

Robotic-assisted urethrolysis for urethral obstruction after retropubic bladder neck suspension-a case series report.

INTRODUCTION: Urethral/bladder outlet obstruction (BOO) is a recognized complication after most surgical procedures for stress urinary incontinence. The mechanisms involved are thought to be related to an overcorrection of the urethra (by kinking and/or compressing the urethra) or excessive scar formation between the pubis and urethra. The recommended treatment is usually surgical that aims to free up the obstructed urethra (urethrolysis). For retropubic bladder neck suspension (BNS), robotic-assisted surgery offers a less invasive alternative to classical abdominal approach. We report methods and results of performing robotic-assisted urethrolysis in patients with urethral obstruction after Burch colposuspension. PATIENTS AND METHODS: Six patients presented with voiding difficulties and urinary irritative symptoms after an abdominal hysterectomy and Burch colposuspension. BOO was diagnosed based on history, presenting symptoms, and urodynamic findings, including the maximum flow rate (Qmax) of ≤12 mL/second and detrusor pressure at maximum flow (PdetQmax) of ≥20 cmH2O. Patients underwent robotic-assisted urethrolysis, which consisted of the usual robotic exposure of the abdominal cavity, access to the space of Retzius, removal of Burch sutures, and hypermobilization of the urethra. The intraoperative and postoperative complications, recovery time, and outcome of the procedure to successfully address the patients' symptoms were reviewed and herein reported. RESULTS: Postoperatively, five of the six patients had complete resolution of the obstructive and irritative symptoms. All had improvement of the postvoid residual volume with a median of 46.5 mL (range 0-176 mL). Postoperatively, urodynamic studies were repeated in two patients and PdetQmax decreased from 39 cmH2O before surgery to 21 cmH2O after urethrolysis and from 31 to 21 cmH2O, respectively. Qmax increased from 0 to 17 mL/second and from 6 to 10 mL/second, respectively. CONCLUSIONS: Robotic-assisted urethrolysis is a feasible and attractive minimally invasive procedure to treat BOO after retropubic BNS.

Somatosensory timing deficits in schizophrenia.

Schizophrenia is often accompanied by disturbances in motor behavior thought to result from abnormalities in the brain's timing mechanisms. Virtually all behavior has a motor component, and proper regulation of motor behavior is often dependent upon accurate registration of somatosensory input. This study uses the steady-state evoked response (SSR) to quantify the accuracy of timing of the neocortical response to rapidly presented tactile somatosensory stimuli in patients with schizophrenia compared to control subjects. We used magnetic evoked fields and source space projection to estimate the time course of equivalent current sources in somatosensory cortex. Wavelet-based time-frequency analysis was used to compute intertrial timing consistency and amplitudes. SSRs in schizophrenic subjects demonstrated decreased performance in both metrics to contralateral 25-Hz tactile stimulation. Previous studies have reported similar abnormalities in the SSR in both auditory and visual domains. The magnetic SSR to tactile stimuli is thought to reflect activation of layer 3 pyramidal cells in primary sensory cortex. Thus, these findings, as in other sensory domains, are suggestive of impaired GABAergic inhibitory interneuronal control of the timing of pyramidal cell activity. This deficit may be intrinsic to neocortex, or might reflect as well impairment of cerebellar and/or thalamic involvement. These findings reinforce the notion that abnormalities in the brain's timing mechanisms are a central component of the schizophrenia syndrome.

Phonological processing in first-degree relatives of individuals with autism: an fMRI study.

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders. Twin studies have provided heritability estimates as high as 90% for idiopathic ASD. Further evidence for the spectrum's heritability is provided by the presence of the broad autism phenotype (BAP) in unaffected first-degree relatives. Language ability, specifically phonological processing, is proposed to be a core BAP trait. To date, however, no functional neuroimaging investigations of phonological processing in relatives of individuals with ASD have been undertaken. We conducted a functional magnetic resonance imaging (fMRI) study in parents of children with ASD utilizing a priming task probing implicit phonological processing. In our condition that placed heavier demands on phonological recoding, parents exhibited greater hemodynamic responses than controls in a network of cortical regions involved in phonological processing. Across conditions, parents exhibited enhanced priming-induced response suppression suggesting compensatory neural processing. A nonword repetition test used in previous studies of relatives was also administered. Correlations between this measure and our functional measures also suggested compensatory processing in parents. Regions exhibiting atypical responses in parents included regions previously implicated in the spectrum's language impairments and found to exhibit structural abnormalities in a parent study. These results suggest a possible neurobiological substrate of the phonological deficits proposed to be a core BAP trait. However, these results should be considered preliminary. No previous fMRI study has investigated phonological processing in ASD, so replication is required. Furthermore, interpretation of our fMRI results is limited by the fact that the parent group failed to exhibit behavioral evidence of phonological impairments.

Implicit phonological priming during visual word recognition.

Phonology is a lower-level structural aspect of language involving the sounds of a language and their organization in that language. Numerous behavioral studies utilizing priming, which refers to an increased sensitivity to a stimulus following prior experience with that or a related stimulus, have provided evidence for the role of phonology in visual word recognition. However, most language studies utilizing priming in conjunction with functional magnetic resonance imaging (fMRI) have focused on lexical-semantic aspects of language processing. The aim of the present study was to investigate the neurobiological substrates of the automatic, implicit stages of phonological processing. While undergoing fMRI, eighteen individuals performed a lexical decision task (LDT) on prime-target pairs including word-word homophone and pseudoword-word pseudohomophone pairs with a prime presentation below perceptual threshold. Whole-brain analyses revealed several cortical regions exhibiting hemodynamic response suppression due to phonological priming including bilateral superior temporal gyri (STG), middle temporal gyri (MTG), and angular gyri (AG) with additional region of interest (ROI) analyses revealing response suppression in the left lateralized supramarginal gyrus (SMG). Homophone and pseudohomophone priming also resulted in different patterns of hemodynamic responses relative to one another. These results suggest that phonological processing plays a key role in visual word recognition. Furthermore, enhanced hemodynamic responses for unrelated stimuli relative to primed stimuli were observed in midline cortical regions corresponding to the default-mode network (DMN) suggesting that DMN activity can be modulated by task requirements within the context of an implicit task.