Citations

Abstract Asparagine‐linked glycosylation 13 homolog ( ALG13 ) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐ N ‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13‐CDG. Twenty‐four previously reported ALG13‐CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13‐CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13‐deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13 . This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

Abstract The COVID‐19 pandemic and subsequent social distancing protocols have accelerated the shift to online teaching across the globe. In Science, Technology, Engineering, and Mathematics (STEM) programs this means a shift from face‐to‐face laboratory instruction to self‐directed learning with e‐learning tools. Unfortunately, selecting and integrating an e‐learning tool into a curriculum can be daunting. This article highlights key questions and practical suggestions instructors should consider in choosing the most effective option for their course and learners.

OBJECTIVE Residency interviews are integral to the recruitment process yet imperfect. Through surveys of neurosurgery residency applicants, the authors describe interview content and the perceived utility and stress of topics from the applicant’s perspective. METHODS All 2018–2019 neurosurgery resident applicants applying to three particular programs were surveyed. Across 10 interview topics, survey questions assessed topic frequency and the applicant’s opinion of the utility and stress of each topic (Likert scale 1–5). Analyses included descriptive statistics, Spearman’s rank correlation, and logistic regression. RESULTS One hundred thirty-three of 265 surveyed US residency applicants (50%) responded. Extracurricular activities, research, future career, non-medicine interests, and small talk were discussed in all interviews. The least frequent topics included neurosurgical knowledge assessment (79%) and manual dexterity tests (45%). The most useful topics according to respondents were future career objectives (4.78 ± 0.49) and prior research (4.76 ± 0.50); the least useful were neurosurgical knowledge assessment (2.67 ± 1.09) and manual dexterity tests (2.95 ± 1.05). The most stressful topics were neurosurgical knowledge assessment (3.66 ± 1.23) and ethical/behavioral scenarios (2.94 ± 1.28). The utility and stress of manual dexterity tests and neurosurgical knowledge assessments were inversely correlated (r = −0.40, p < 0.01; r = −0.36, p < 0.01), whereas no such correlation existed for ethical/behavioral questions (r = −0.12, p = 0.18), indicating that ethical/behavioral questions may have been stressful but were potentially useful topics. Respondents who attended ≥ 15 interviews were more likely to be asked about the three most stressful topics (each p < 0.05). Respondents with children were less likely to be asked about ethical/behavioral scenarios (OR 0.13, 95% CI 0.03–0.52, p < 0.01). CONCLUSIONS Applicants found several of the most frequently discussed topics to be less useful, indicating a potential disconnect between applicant opinion and the faculty’s preferred questions. Ethical/behavioral scenarios were rated as stressful but still useful, representing a potentially worthwhile type of question. These data provide several avenues for potential standardization and improvement of the interview process.

Abstract NRAS Q61 mutations are prevalent in advanced/relapsed multiple myeloma (MM) and correlate with poor patient outcomes. Thus, we generated a novel MM model by conditionally activating expression of endogenous NrasQ61R and an MYC transgene in germinal center (GC) B cells (VQ mice). VQ mice developed a highly malignant MM characterized by a high proliferation index, hyperactivation of extracellular signal-regulated kinase and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved programmed cell death protein 1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain immune-checkpoint pathways, and expression of human high-risk MM gene signatures. VQ MM mice recapitulate most of the biological and clinical features of human advanced/high-risk MM. These MM phenotypes are serially transplantable in syngeneic recipients. Two MM cell lines were also derived to facilitate future genetic manipulations. Combination therapies based on MEK inhibition significantly prolonged the survival of VQ mice with advanced-stage MM. Our study provides a strong rationale to develop MEK inhibition–based therapies for treating advanced/relapsed MM.

The NCCN Guidelines for Rectal Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with rectal cancer. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines. These updates include clarifying the definition of rectum and differentiating the rectum from the sigmoid colon; the total neoadjuvant therapy approach for localized rectal cancer; and biomarker-targeted therapy for metastatic colorectal cancer, with a focus on new treatment options for patients with BRAF V600E– or HER2 amplification–positive disease.

Background: Childhood obesity is associated with dyslipidemia, fatty liver disease, and type 2 diabetes. Expert guidelines recommend screening for these conditions in children with obesity. Aims and objectives: The objective of the study was to compare rates of laboratory screening for dyslipidemia, fatty liver disease, and type 2 diabetes in children with obesity prior to and following implementation of a point-of-care decision support tool. Methods: We performed a retrospective record review of children with body mass index (BMI) ≥95th percentile for age and gender (age 7–18 years) undergoing well-child/sports examination visits. Multivariable logistic regression models were used to adjust for patient and provider confounders. Results: There was no increase in the rates of screening following implementation of the point-of-care decision support tool. Tests were more likely to be recommended in children with severe obesity and in females. Conclusions: The implementation of a point-of-care decision support tool was not associated with improvement in screening rates for dyslipidemia, fatty liver disease, and type 2 diabetes for children with obesity. Further strategies are needed to improve rates of screening for obesity-related comorbid conditions in children with obesity.

Background and objectives The erector spinae plane (ESP) block is a relatively new interfascial block technique. Previous cadaveric studies have shown extensive cephalocaudal spread with a single ESP injection at the thoracic level. However, little data exist for lumbar ESP block. The objective of this study was to examine the anatomical spread of dye following an ultrasound-guided lumbar ESP block in a human cadaveric model. Methods An ultrasound-guided ESP block was performed in unembalmed human cadavers using an in-plane approach with a curvilinear transducer oriented longitudinally. 20 mL of 0.166% methylene blue was injected into the plane between the distal end of the L4 transverse process and erector spinae muscle bilaterally in four specimens and unilaterally in one specimen (nine ESP blocks in total). The superficial and deep back muscles were dissected, and the extent of dye spread was documented in both cephalocaudal and medial–lateral directions. Results There was cephalocaudal spread from L3 to L5 in all specimens with extension to L2 in four specimens. Medial–lateral spread was documented from the multifidus muscle to the lateral edge of the thoracolumbar fascia. There was extensive dye in and around the erector spinae musculature and spread to the dorsal rami in all specimens. There was no dye spread anteriorly into the dorsal root ganglion, ventral rami, or paravertebral space. Conclusions A lumbar ESP injection has limited craniocaudal spread compared with injection in the thoracic region. It has consistent spread to dorsal rami, but no anterior spread to ventral rami or paravertebral space.

LBA3 Background: Bortezomib (btz) combined with lenalidomide (len) and dexamethasone (dex) (VRd) is a standard initial therapy for NDMM. Carfilzomib (cfz), a next-generation proteasome inhibitor, in combination with len-dex (KRd) has shown higher efficacy in phase II trials. This randomized phase III trial was designed to examine if KRd improves progression free survival (PFS) compared to VRd in NDMM (current results), and whether indefinite maintenance with len improves OS compared with two-year maintenance (to be analyzed once data matures). Methods: Patients (Pts) with NDMM, were randomized to receive VRd or KRd in a 1:1 fashion for 36 weeks followed by a second randomization (1:1) to indefinite versus two years of len maintenance. Pts without del17p, t (14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included btz 1.3 mg/m2 on days(d) 1, 4, 8, and 11 (d 1, 8 for cycles 9-12), len 25 mg d 1-14, and dex 40 mg d 1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received cfz 36 mg/m2 d 1, 2, 8, 9, 15, 16 with len 25 mg daily on d 1-21 and dex 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance included len 15mg d 1-21 every 4 wks. The study was designed to detect a hazard ratio (HR)=0.75 with 80% power at 1-sided 2.5% alpha and 399 PFS events (progression or death regardless of intervening therapy). Results: The study accrued 1087 pts (VRd=542, KRd=545). The median age was 65y. Treatment, efficacy, and toxicity data are in the table. At the second of 3 planned interim analyses, with PFS HR=1.04 (95% CI, 0.8 to 1.3, p=0.74), futility was met. Median PFS was VRd=34.4m and KRd=34.6m; no differences were seen based on age (<65 or ≥65), presence or absence of t(4;14) or ISS stage. The three-year OS (95% CI) was similar: VRd 84% (80 to 88) and KRd 86% (82 to 89). Conclusions: In this randomized phase 3 trial, KRd did not improve PFS compared with VRd in NDMM. A significantly higher rate of cardio-pulmonary and renal toxicity was observed with KRd, while neuropathy rates were higher with VRd. VRd remains the standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . [Table: see text]