Citations

Abstract Background Hemoglobin S (HbS) causes sickling disorders. In the laboratory, confirmation of HbS in patient samples with varying percentages is essential. Assessment is routinely performed using capillary electrophoresis (CE) and/or high-performance liquid chromatography. Sickle solubility (SS) exploits decreased solubility of HbS under reducing conditions and is a confirmatory test. SS is unreliable with low HbS, elevated HbF, severe anemia, erythrocytosis, hyperglobulinemia, extreme leukocytosis, hyperlipidemia, or increased serum proteins. Infant samples commonly have low percentages of HbS, high HbF, and limited sample volume. Intact globin chain Mass Spectrometry (MS) is used to identify abnormal hemoglobin variants by detecting the mass change (normal α/β/γ mass =15127/15867/15996 amu), respectively). MS has potential advantages in sensitivity and efficiency over SS and requires lower input sample volume. Herein we compare the utility of MS versus SS for confirmation of HbS. Methods Twenty-three EDTA-anticoagulated blood samples containing low percentages of HbS were identified. SS was performed on 30μL washed packed cells (requires 200μL whole blood) per standard methods. Intact Quadrupole Time-of-Flight MS (Accurate-Mass Q-TOF LC/MS 6520, Agilent Technologies, California) was performed using 10μL whole blood sample in acetonitrile solution reagent and results were compared. HbS and HbF levels were assayed by capillary electrophoresis (Sebia, France) per standard methods. Results Select results are summarized in Table 1. SS detected HbS percentages to 4.8% when HbF was low but not 6% HbS when Hb F is high. MS showed no HbF interference and identified HbS peaks (at 15837 amu) down to 3.1%. HbS percentages <3.1 were undetected by both methods. Conclusions Overall, MS was superior to SS for confirming HbS, particularly in samples with low variant percentage and/or elevated HbF. MS is also optimal when sample volume is minimal, such as for infants. Percentages of HbS <3% require methods such as IEF or DNA sequencing for confirmation.

BACKGROUND: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes. METHODS: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events. RESULTS: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and corrected QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76–0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83–0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81–0.88]). CONCLUSIONS: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

AbstractThis article aims to assist radiologists in navigating the vascular and biliary anatomy of post-transplant patients, thereby enhancing their diagnostic accuracy and determining the need for potential interventions. We have detailed established methods for anastomosis between the donor and recipient arterial, hepatic venous, portal venous, and biliary systems, while omitting surgical techniques, vascular shunting, and operative procedures, as our primary audience is radiologists. The focus of this review is on inflow and outflow of both blood and bile. Given the numerous possible anastomosis points in hepatic transplantation, familiarizing radiologists with these variations will support their efforts in identifying crucial structures in post-transplant patients.

Three-dimensional reconstruction of airways has shown increased luminal area in patients with COVID-19 and post-acute sequelae of COVID-19 when compared with healthy controls. These findings suggest the role of large conducting airways in the pathogenesis of post-acute sequelae of COVID 19.

Importance While the typical onset of multiple sclerosis (MS) occurs in early adulthood, 2% to 10% of cases initially present prior to age 18 years, and approximately 5% after age 50 years. Guidance on approaches to differential diagnosis in suspected MS specific to these 2 age groups is needed. Observations There are unique biological factors in children younger than 18 years and in adults older than age 50 years compared to typical adult-onset MS. These biological differences, particularly immunological and hormonal, may influence the clinical presentation of MS, resilience to neuronal injury, and differential diagnosis. While mimics of MS at the typical age at onset have been described, a comprehensive approach focused on the younger and older ends of the age spectrum has not been previously published. Conclusions and Relevance An international committee of MS experts in pediatric and adult MS was formed to provide consensus guidance on diagnostic approaches and key clinical and paraclinical red flags for non-MS diagnosis in children and older adults.

OBJECTIVE Correction of mild flexible cervical deformity (CD) via the posterior approach has been described with and without the use of posterior osteotomies (POs), despite a lack of clarity regarding their necessity or risks. The purpose of this study was to determine whether the use of POs when correcting mild flexible CD leads to improved clinical or radiographic outcomes, as well as defining the relative risks in utilizing them. METHODS A prospective multicenter registry of operative CD patients was analyzed. Inclusion criteria were cervical kyphosis > 10°, cervical scoliosis > 10°, cervical sagittal vertical axis (cSVA) > 4 cm, or chin-brow vertical angle > 25°. Mild deformity was defined by a cSVA of 3–5 cm and/or kyphosis < 15°. Flexibility was defined by a C2–7 angular change > 5° on preoperative flexion/extension radiographs. Patients who received a posterior column osteotomy (PCO) (Ames grades 1 and 2) were compared with patients who did not undergo a PCO (noPCO) as well as those who underwent a three-column osteotomy (3CO) (Ames grades 3–6). RESULTS Ninety-five patients (33 PCO, 49 noPCO, 13 3CO) met the inclusion criteria. Both the number of levels fused (9.2 vs 7.7, p = 0.001) and the estimated blood loss (EBL) (1027 vs 486 mL, p = 0.012) were higher in the PCO cohort. Patients in the noPCO group were more likely to have a cervical apex of kyphosis (71.1%, p = 0.046), while those undergoing 3COs were more likely to have a thoracic apex (58.3%, p = 0.005). Preoperative cSVA (PCO vs noPCO: 45.4 vs 37.9 cm, p = 0.084), T1 slope (32.5° vs 29.6°, p = 0.376), C2–7 lordosis (−8.9° vs −9.2°, p = 0.942), and modified Japanese Orthopaedic Association (mJOA) score (13.4 vs 13.5, p = 0.854) were similar; however, both Neck Disability Index (NDI) (55.6 vs 42, p = 0.002) and numeric rating scale (NRS) neck (7.2 vs 5.8, p = 0.028) scores were higher in the PCO group before surgery. When adjusting for the use of an anterior approach, there was no significant difference in 1-year postoperative cSVA (35.7 and 35.6 cm, respectively; p = 0.969), C2–7 lordosis (13.7° and 10.1°, respectively; p = 0.393), and patient-reported outcome measures (NRS, NDI, and mJOA) between the PCO and noPCO groups. Two-year radiographic outcomes were largely similar, except for C2 slope, which was higher in the PCO group (29.1° vs 18°, p = 0.026). The overall complication rates progressively increased with more complex osteotomy use (noPCO 68.8% vs PCO 71.9% vs 3CO 75%) but did not reach significance (p = 0.063). CONCLUSIONS The use of POs for mild flexible adult CD may not be necessary to achieve desirable radiographic correction. They are associated with greater EBL and fusion burden. Further studies are needed to fully delineate the risks of adverse events for various types of osteotomies.

Ototoxicity is among the adverse events related to cancer treatment that can have far-reaching consequences and negative impacts on quality-of-life for cancer patients and survivors of all ages. Ototoxicity management (OtoM) comprises the prevention, diagnosis, monitoring, and treatment, including rehabilitation and therapeutic intervention, of individuals who experience hearing loss, tinnitus, or balance/vestibular difficulties following exposures to ototoxic agents, including platinum chemotherapy (cisplatin, carboplatin) and cranial radiation. Despite the well-established physical, socioeconomic, and psychological consequences of hearing and balance dysfunction, there are no widely adopted standards for clinical management of cancer treatment-related ototoxicity. Consensus recommendations and a roadmap are needed to guide development of effective and feasible OtoM programs, direct research efforts, address the needs of caregivers and patients at all stages of cancer care and survivorship. Here we review current evidence and propose near-term to longer-term goals to advance OtoM in five strategic areas: (1) beneficiary awareness, empowerment, and engagement, (2) workforce enhancement, (3) program development, (4) policy, funding, and sustainability, and (5) research and evaluation. The goal is to identify needs and establish a roadmap to guide worldwide adoption of standardized OtoM for cancer treatment and improved outcomes for patients and survivors.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease provide strategies for the prevention, diagnosis, and treatment of venous thromboembolism (VTE) in adult patients with cancer. VTE is a common and life-threatening condition in patients with cancer, and its management often requires multidisciplinary efforts. The NCCN panel is comprised of specialists spanning various fields, including cardiology, hematology, medical oncology, internal medicine, interventional radiology, and pharmacology. The content featured in this issue specifically addresses the evaluation and recommended treatment options outlined in the NCCN Guidelines for the diverse subtypes of cancer-associated VTE.

Abstract There are limited data assessing the risk scores for primary treatment failure (PTF) in patients with classical Hodgkin lymphoma (cHL; PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs) is a multicenter retrospective cohort of patients with PTF-cHL (aged ≥15 years) diagnosed on or after 1 January 2005, at 15 US medical centers. PTF was defined as 1 of the following patterns of failure: (1) progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); (2) partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); (3) progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR; early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of nonrelapse mortality after auto-HCT were 0.9% and 1.1%, respectively. The median progression-free survival (PFS) and overall survival (OS) after auto-HCT were 4.33 and 10.09 years, respectively. Although those not in CR at the time of auto-HCT were associated with inferior PFS and OS, advanced age and diagnosis before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high-risk disease who are traditionally considered chemotherapy refractory, and will serve as a benchmark for the ongoing transplant vs no transplant trials.