Citations

Abstract Background The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs. Methods We conducted a retrospective analysis of 757 UDN participants diagnosed from 2015 until 2023 using the cohort database, which were divided into a cohort with IMDs (n = 194; 27%) and a cohort whose phenotypes were not explained by an IMD (n = 563; 73%), based on the International Classification of Inherited Metabolic Disorders (ICIMD). Then, we divided the causes of the metabolic 194 diagnoses into seven groups that included all the ICIMD categories. We inspected which clinical and laboratory approaches contributed to a final UDN diagnosis. We also present a UDN case example from each group to highlight the diagnostic yields that resulted from combining newer diagnostic approaches in the UDN and illustrate potential pitfalls of current NGS methods. Results These 194 cases of IMDs included examples from 21/25 (84%) of the ICIMD categories. Of the UDN subjects 164/194 (85%) were diagnosed with IMDs through NGS. Conclusion The spectrum of IMDs detected in the UDN cohort is large and growing and appropriate use of newer multiple diagnostic approaches should further increase diagnosis of IMDs that are presently missed by the traditional laboratory screening methods.

Background: Facial shape is significantly influenced by the underlying facial bony skeleton. Sexual dimorphisms in these structures are crucial for craniofacial, aesthetic, and gender-affirming surgery. Previous studies have examined the orbits and upper face, but less is known about the midface. This study aimed to elucidate the sexual dimorphism in the midface region, focusing on the maxilla and zygomatic bones. Methods: A retrospective review was conducted using facial computed tomography scans from 101 White patients aged 20–79 years, using Materialise Mimics and 3-Matics for segmentation and 3D reconstruction. Measurements and statistical shape modeling of the midfacial skeleton were performed. Results: Our results show a distinct sexual dimorphism in the midfacial skeletal structure across all age groups. Women typically had a narrower bizygomatic width by 1.5 mm (P = 0.04), a shallower maxillary depth by 1.6 mm (P < 0.01), and a midfacial vertical height that was 4 mm shorter than that of men (P = 0.018). In contrast, men exhibited a greater distance between the frontozygomatic sutures by 5.4 mm (P < 0.01), a 3-mm greater interorbitale distance (P < 0.01), and a 2.1-mm wider infraorbital foramina distance (P = 0.007). There were no significant differences in the pyriform and maxillary angles (P = 0.15 and P = 0.52, respectively). Conclusions: Our analysis of midfacial skeletal anatomy revealed sexual dimorphism differences. Men exhibited more pronounced facial features than women, with a broader horizontal midfacial skeleton, a longer midfacial vertical height, and greater maxillary depths compared with women.

Abstract Purpose The 2025 ASHP Pharmacy Forecast report is written to identify and contextualize emerging trends that will influence healthcare, health systems, and the pharmacy profession. It provides recommendations to inform strategic planning that should prompt action by pharmacists and health-system leaders. Methods Drawing on the “wisdom of crowds” concept, a survey was constructed by an advisory committee with 6 themes, each with 7 focused statements and a seventh theme on preparedness (54 survey items in total). A survey panel of 321 pharmacy leaders was purposefully designed to capture opinions from a wide range of pharmacists across the United States. Panelists were asked to consider the likelihood of the statements occurring in the next 5 years as being likely, somewhat likely, somewhat unlikely, or very unlikely to occur. Forecast panelists also assessed health systems’ preparedness (from very unprepared to very prepared) for 12 of the statements. Results The 6 survey themes identified were The Business of Healthcare: Challenges in Health-System Pharmacy, Managing Ultra-High-Cost Drugs, Addressing the Gap in Primary Care, Whole Person Health, Navigating Generative Artificial Intelligence: Opportunity and Risk, and Stabilizing the Pharmacy Workforce. The survey was completed by 269 respondents, yielding an 84% response rate. Descriptive statistics of the survey results were provided to chapter authors to inform commentary and strategic recommendations for each theme. Conclusion The Pharmacy Forecast provides insights on large-scale, long-term trends that will influence healthcare and the pharmacy profession over the years ahead. Insight from the report can stimulate strategic thinking and provides a starting point to proactively position leaders, their teams, and departments for potential future trends.

BACKGROUND AND OBJECTIVES: Awake minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) generates minimal surrounding tissue damage and has been shown to be a safe, time-effective, and cost-reductive technique in single-level procedures. The purpose of this study was to advocate for the utilization of multilevel MIS-TLIF even in challenging cases as it has demonstrated positive outcomes. METHODS: Chart review was conducted for consecutive patients undergoing awake multilevel MIS-TLIF from 2020 to 2023. Various demographic, preoperative, and postoperative variables were collected and descriptively analyzed. RESULTS: Sixteen patients underwent multilevel awake MIS-TLIF at our institution during the specified period. Among them, 87.5% underwent a two-level procedure and 12.5% a three-level procedure. The median age ± IQR was 69.5 ± 11 years, with a slight male predominance (56.25%). Common comorbidities included hypertension (56.25%), obesity (37.5%), sleep apnea (25%), and type 2 diabetes (18.75%). The American Society of Anesthesiologists risk was 2 in 43.75% of patients and 3 in 56.25%. All patients presented pain, and 12.5% showed motor deficit. Intraoperative data showed a median of 196 minutes in the operating room where 156 ± 27.75 minutes corresponded to actual procedure time. The median estimated blood loss was 50 ± 70 cc. In the immediate postoperative period, 1 patient had nausea and emesis, and 1 reported fatigue. The median pain score during this period was 4.6 ± 2.03. Pain control medications were required for various patients, with methocarbamol (50%), hydromorphone (37.5%), and oxycodone (25%) being the most commonly prescribed in the postanesthesia care unit. No patient had new neurological deficits after the surgical intervention. The median length of stay was 2 days ±1.25. All patients were discharged with no complications. CONCLUSION: Multilevel awake MIS-TLIF emerges as a safe and effective technique for complex cases, enhancing patient quality of life with minimal blood loss and postoperative pain.

ABSTRACTFrataxin is an evolutionarily conserved mitochondrial protein responsible for iron homeostasis and metabolism. A deficiency of frataxin (encoded by FXN) leads to Friedreich's ataxia (FRDA), a progressive disorder that affects both the central and peripheral nervous systems, most commonly via a pathogenic GAA trinucleotide expansion. In contrast, pathogenic variants in ALG1 in humans cause a form of congenital disorder of glycosylation. Here, we present a 15‐year‐old boy with a clinical presentation that raised concern for complex hereditary spastic paraplegia (HSP), with motor features including progressive spastic paraparesis, cervical dystonia, cerebellar dysfunction, and diminished lower extremity reflexes. The proband was initially found to have a novel compound heterozygous variant in ALG1 on exome sequencing, along with N‐glycan profiling revealing evidence of defective mannosylation and Western blot analysis demonstrating an 84% reduction in ALG1 expression. Although several of his clinical features could be explained by the ALG1 variant specifically or considered as part of the presentation of CDGs in general, there were additional phenotypes that suggested an alternative, or additional, genetic diagnosis. Subsequently, he was found to have biallelic pathogenic GAA repeat expansions in FXN on genome sequencing, leading to a diagnosis of FRDA. Given that FRDA explained all his clinical features, the ALG1 variant may have been a hypomorphic form and/or a biochemical phenotype. Our findings underscore the importance of considering FRDA as a differential diagnosis in cases of complex HSP and demonstrate the utility of unbiased genome sequencing approaches that include detection of trinucleotide repeat expansions for progressive motor disorders.

ObjectiveDe novo variants in cullin‐3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype–phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient‐derived T‐cells.ResultsWe assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss‐of‐function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin‐protein conjugates in vitro. Notably, we show that 4E‐BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient‐derived cells.InterpretationOur study further refines the clinical and mutational spectrum of CUL3‐associated NDDs, expands the spectrum of cullin RING E3 ligase‐associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2025;97:76–89

Abstract Background NRG Oncology NSABP B-39/RTOG 0413 compared whole-breast irradiation (WBI) to accelerated partial-breast irradiation (APBI). APBI was not equivalent to WBI in local tumor control. Secondary outcome was quality of life (QOL). Methods The QOL sub-study used validated self-report questionnaires, including the Breast Cancer Treatment Outcome Scale (BCTOS) and the 36-Item Short Form Health Survey (SF-36) vitality scale. Assessments occurred before random assignment, at treatment completion (chemotherapy or radiotherapy), 4 weeks later, at 6, 12, 24, and 36 months. Primary aims: cosmesis change equivalency (baseline to 3 years; a priori margin of equivalence 0.4 standard deviations) and fatigue change superiority (baseline to end of treatment [EOT]) for APBI vs WBI, by patient groups treated with or without chemotherapy when appropriate. Results From March 21, 2005 to May 25, 2009, 975 patients enrolled in this sub-study; 950 had follow-up data. APBI had 3-year cosmesis equivalent to WBI (95% CI = -0.0001 to -0.16; equivalence margin -0.22 to -0.22) in all patients. The APBI group without chemotherapy had less EOT fatigue (P = .011; mean score APBI 63 vs WBI 59); the APBI group receiving chemotherapy had worse EOT fatigue (P = .011; APBI 43 vs WBI 49). The APBI group reported less pain (BCTOS) at EOT (WBI 2.29 vs APBI 1.97) but worse pain at 3 years (WBI 1.62 vs APBI 1.71). APBI patients reported greater convenience of care than with WBI and reported less symptom severity at EOT and 4 weeks later. Conclusion Cosmetic outcomes were similar for the APBI and WBI groups, with small statistically significant differences in other outcomes that varied over time. Differences in fatigue and other symptoms appeared to resolve by ≥6 months. APBI may be preferred by some patients, for whom extended treatment is burdensome. ClinicalTrials.gov NCT00103181.