Citations

Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are key enzymes that catabolize thiopurines. Decreased or no‐function alleles in TPMT and NUDT15 are associated with reduced or no enzyme activity and predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines. Genetic variants in these genes are present in all world populations; however, their frequency varies by ancestry. In this updated guideline, we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes, including for individuals with variants in both genes (updates on www.clinpgx.org ).

Abstract The use of antibiotics in the hospice setting is complicated by differing patient goals, elevated side effects, and limited information regarding effectiveness. Here, we describe a case and apply the four-quadrant approach (4QA). This includes analyzing the case through the lenses of (1) medical indications related to improving function and reducing symptoms; (2) patient preferences, which vary among patients from complete avoidance of antibiotics to a therapeutic dosage to treat infection; (3) quality-of-life factors that include managing infectious symptoms versus antibiotic side effects; and (4) contextual features, which include antimicrobial resistance concerns and cost considerations. Antibiotics may be beneficial in some cases and should not be denied to patients enrolled in hospice care. More robust evidence-based information about outcomes is needed to inform discussions at the time of enrollment. Applying the 4QA to a case can help determine the best approach for each individual patient.

Abstract Background Native vertebral osteomyelitis (NVO) is a life-threatening spinal infection with rising incidence and significant morbidity. Despite its growing burden, long-term data on clinical characteristics, management trends, and outcomes remain limited. Methods We conducted a 26-year multicenter retrospective cohort study of adults (≥18 years) diagnosed with NVO at Mayo Clinic sites between 1999 and 2024. Demographic, microbiologic, treatment, and outcome data were analyzed across five time periods. Predictors of treatment failure were assessed using a multivariable competing risk model. Results Among 1255 patients (median age 67; 66% male), lumbosacral involvement was most common (65%), and 21% had multilevel involvement. Pathogens were identified in 77%, most commonly Staphylococcus aureus (49%; Methicillin-susceptible S. aureus 37%, methicillin-resistant S. aureus 13%). Over time from 1999–2004 to 2020–2024, Gram-negative bacilli increased from 6% to 14% (P = .048). Comorbidities including chronic kidney disease (10% to 21%), active chemotherapy (6% to 11%), and immunosuppression (8% to 17%) increased significantly. Additionally, 1-year treatment failure declined (16% to 10%). In multivariable analysis, diabetes mellitus (subdistribution hazard ratio [sHR] 1.92, 95% CI 1.18–3.13) and multilevel involvement (sHR 1.67, 95% CI 1.17–2.38) were associated with increased incidence of treatment failure, while concurrent infections (sHR 0.57, 95% CI 0.37–0.87) and higher Charlson Comorbidity Index (sHR 0.62, 95% CI 0.43–0.90) were associated with lower failure. Conclusions This large multicenter cohort highlights increasing host complexity, shifting microbiology, and predictors of failure, emphasizing the importance of early risk stratification and tailored strategies, such as multidisciplinary evaluation and close follow-up of high-risk patients to improve outcomes.

Abstract In adult-type diffuse gliomas CDKN2A and/or CDKN2B (CDKN2A/B) deletions often co-occur with deletion of MTAP, suggesting that MTAP immunohistochemistry (IHC) may be a surrogate marker of CDKN2A/B status. However, the association between CDKN2A/B and MTAP deletion at the genomic level remains unknown. We assessed CDKN2A/B and MTAP deletions by chromosomal microarray in 333 adult-type diffuse gliomas and performed MTAP IHC on a subset (n = 63). CDKN2A/B and MTAP deletions were detected in 216 and 215 cases, respectively, and were concurrent in 99.5% (215/216). While most tumors with CDKN2A/B homozygous deletion (n = 148) showed concurrent MTAP homozygous deletion (108/148; 73.0%), a subset harbored MTAP heterozygous deletion (39/148; 26.4%). By analyzing the size of the chromosomal alterations, we demonstrate that initial large chromosomal 9p losses result in concurrent heterozygous deletion of CDKN2A/B and MTAP whereas smaller “second hit” deletions leading to homozygous CDKN2A/B deletion do not always encompass the MTAP locus. Discordant CDKN2A/B and MTAP tumors affect the association between MTAP IHC and copy number status of MTAP and CDKN2A/B. These findings suggest that adult-type diffuse gliomas, regardless of IDH status, follow a stereotypic pathway involving concurrent CDKN2A/B and MTAP heterozygous deletion but may diverge for CDKN2A/B and MTAP homozygous deletion.

Abstract Acute, traumatic meniscus tears are common and should be repaired whenever possible. However, the biological age of the patient, along with the specific tear morphology, may significantly influence the selection of the repair technique, expected clinical outcomes and the postoperative rehabilitation protocol. Risk factors for failure of meniscus repair, such as ligament laxity, need to be addressed to improve the healing potential of the meniscus. Biologic augmentation strategies, including bone marrow stimulation, platelet‐rich plasma, fibrin clot, mesenchymal stem cells or meniscal wrapping, can be used to enhance healing and reduce failure of meniscus repair rates. However, the clinical evidence remains limited and of low quality. As such, the routine use of biologic augmentation in meniscus repair warrants critical evaluation. In patients with post‐meniscectomy syndrome, meniscus allograft transplantation (MAT) may be a viable option to reduce pain and joint degeneration and improve knee function. Meniscus implants provide alternatives to traditional MAT; however, their long‐term efficacy, chondroprotective effects and integration within the knee joint require further research. Meniscus reconstruction using tendon autografts has been described as an alternative treatment option in patients with meniscus loss. Emerging methods, such as gene therapy and repurposed drugs, demonstrate in vitro potential for advancing meniscal repair, although their clinical applications are still in their infancy. Future research is necessary to optimize meniscal repair techniques, enhance clinical efficacy, and ultimately, improve outcomes in patients. Level of Evidence Level V.

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

Introduction: Nasal analysis is a challenging skill that otolaryngology trainees must demonstrate competency in on-board examinations. Study objective: To compare where experts and trainees focus their gaze when completing nasal analysis of a patient, as measured by eye tracking software. Methods: Participants of various training levels ( n = 27) were shown photographs of six faces from all standard angles for photographic nasal analysis. Eye-tracking data were collected. Heat and gaze maps, the time to first fixation on areas of interest, duration, and number of fixations were extracted. These metrics were compared between experts and trainees using t -tests and one-way ANOVA. Results: Qualitative comparisons of gaze patterns reveal a more comprehensive and organized approach among experts than trainees. However, quantitative measures of eye-tracking metrics, including the time to first fixations, duration, and number of fixations made by experts and trainees, were similar. Conclusions: Gaze tracking reveals more thorough and efficient eye movements among experts than trainees during nasal analysis. Further study may be useful in the development of learning tools to guide effective nasal analyses.

Abstract Objectives Discuss the current status of advanced practice providers (APPs) onboarding to headache medicine (HM) practices in the United States and present recommendations of the American Headache Society (AHS) APP Work Group to improve the onboarding process. Background A high demand for care, national shortage of specialists, and multiple advancements in HM have led to an increasing interest and presence of APPs of various backgrounds in the field, currently without a unifying onboarding process. Efforts to standardize and optimize the onboarding process for APPs in HM practices are necessary, to ensure high standards in quality of care. Methods The APP Work Group of the AHS Practice Management Committee developed comprehensive recommendations through literature review, survey of AHS members, and expert consensus. A modified Delphi protocol was used to establish key onboarding goals, definitions, and best practice recommendations. Results Recommendations are made regarding duration of onboarding, appropriate supervision, formal education and procedural skills, scope of practice, grading and documentation of competence, and reciprocal feedback. Conclusion Currently, there are no standard onboarding and training guidelines for APPs in the field of HM. We provide recommendations for a more systematic approach to help develop qualified providers and enhance their retention in HM practices.