Citations

ABSTRACT Pathogenic variants in AMMECR1 have been associated with a rare multisystem disorder characterized by midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHIEN). To date, most reported cases involve copy number variants or presumed loss‐of‐function alterations, with only a single prior report describing a missense variant supported by functional studies. Here, we report a patient with a heterozygous de novo AMMECR1 missense variant, NM_015365.3:c.649G>A p.(Val217Met) presenting with clinical features consistent with MFHIEN, including midface hypoplasia, partial hearing impairment, nephrocalcinosis, and elliptocytosis identified on peripheral blood smear. Comparative review of the literature highlights that while previously reported missense variants in AMMECR1 demonstrated altered intranuclear protein distribution and reduced expression in functional assays, clinical evidence supporting pathogenicity of non‐truncating variants remains limited. The phenotypic overlap between our patient and prior report strengthens the association between missense variations and the MFHIEN phenotype. Our findings support the pathogenic relevance of missense variation in AMMECR1 and emphasize the importance of integrating detailed phenotyping, including hematologic evaluation, with genomic data in the diagnosis of rare multisystem disorders. Additional cases and functional studies are needed to clarify genotype–phenotype correlations and underlying disease mechanisms.

Importance Adjuvant radiotherapy can improve locoregional control and survival in patients with olfactory neuroblastoma (ONB), particularly with advanced-stage and histologic-grade disease. Standard radiotherapy treatment is with intensity-modulated radiotherapy (IMRT). Proton beam radiotherapy (PBRT) provides theoretical advantages in greater sparing of dose to uninvolved organs at risk. Objective To investigate if there are differences in the effectiveness and radiation treatment–related adverse events (RTAEs) between adjuvant IMRT and PBRT for patients with ONB. Design, Setting, and Participants This propensity score–matched cohort study included patients with ONB treated between February 2005 and April 2021 with either IMRT or PBRT at 9 academic tertiary care centers in North America. Patients were matched 1:2 based on age, modified Kadish stage, and Hyams grade. Data were analyzed from July 2024 to January 2025. Exposure Adjuvant IMRT or adjuvant PBRT. Main Outcomes and Measures Local recurrence-free survival (RFS), any RFS, and overall survival (OS). RTAEs, ie, grade 2 events or higher based on Common Terminology Criteria for Adverse Events, were recorded for both modalities. Results Of 54 included patients, 27 (50%) were female, and the mean (SD) age was 46.2 (15.4) years. A total of 18 were treated with PBRT and 36 were treated with IMRT. Most patients had modified Kadish stage C disease (33 of 54 [61%]), and 24 patients (44%) had Hyams grade III or IV disease. The RTAE rate was 20% (8 of 40); IMRT had a rate of 21% (6 of 29), and PBRT had a rate of 18% (2 of 11). The difference in the point estimates for 10-year RFS showed a potential clinical benefit favoring IMRT, although the wide confidence interval indicates uncertainty (10-year RFS: IMRT, 63.3%; 95% CI, 44.6-89.8; PBRT, 37.8%; 95% CI, 14.2-100; difference, 25.5 percentage points; 95% CI, −17.6 to 68.6). There were no clinically meaningful differences in 10-year local RFS (IMRT, 75.6%; 95% CI, 59.8-95.4; PBRT, 72.7%; 95% CI, 45.2-100; difference, 2.9 percentage points; 95% CI, −35.9 to 41.7) or 10-year OS (IMRT, 61.8%; 95% CI, 42.8-89.1; PBRT, 57.1%; 95% CI, 24.3-100; difference, 4.7 percentage points; 95% CI, −49.2 to 58.6), although wide confidence intervals indicate considerable uncertainty. Conclusions and Relevance Due to the imprecision of estimates, no definitive conclusions can be made regarding the comparative effectiveness of IMRT vs PBRT for patients with ONB. These preliminary data may inform the design of appropriately powered prospective studies evaluating the efficacy of PBRT vs IMRT in this population.

ABSTRACT Post‐translational modifications, such as glycosylation and phosphorylation, play a critical role in protein trafficking, interactions, and stability. Disruptions in these pathways can lead to glycosylphosphatidylinositol (GPI) deficiencies, which present with a spectrum of clinical features, including congenital anomalies, dysmorphic features, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGV , a key mannosyltransferase in GPI biosynthesis, cause Hyperphosphatasia with Impaired Intellectual Development Syndrome 1 (HPMRS1), a rare disorder characterized by hyperphosphatasia, seizures, developmental delay, hypotonia, abnormal MRI findings, and distinct facial dysmorphisms. Fewer than 30 cases have been reported to date. We conducted a case study and literature review; with clinical data obtained from medical records. A 2‐year‐old female presented with developmental delay, myoclonic epilepsy, hypotonia, and mild facial dysmorphism. Laboratory results showed elevated alkaline phosphatase (899 U/L) and low pyridoxal 5′‐phosphate levels in cerebrospinal fluid (CSF). Brain MRI revealed diffuse cerebral volume loss and ventriculomegaly. Trio genome sequencing identified two PIGV variants: c.1415T>C‐p.(Leu472Pro) and c.524T>C‐p.(Leu175Pro). Functional studies using PIGV ‐knockout HEK293 cells transfected with wild‐type or mutant PIGV constructs demonstrated reduced GPI‐anchored protein (GPI‐AP) expression under weaker promoters, indicating impaired enzymatic activity. We report two novel PIGV variants associated with HPMRS1, emphasizing the value of functional assays in variant interpretation. Our findings also highlight the diagnostic relevance of alkaline phosphatase measurement in patients with refractory seizures.

Abstract Postoperative pain control after total knee arthroplasty (TKA) remains challenging, particularly in patients utilizing chronic opioids preoperatively. Our study aimed to evaluate the effect of regional nerve blockade on perioperative pain control outcomes after TKA in patients using or not using chronic preoperative opioids. A retrospective review of our institutional database identified 434 chronic opioid patients defined as documented ongoing use greater than 3 months prior to contemporary TKA. Patients were 1:1 matched to nonopioid users based upon age, sex, body mass index, and regional block type (single-shot adductor canal block [ACB, 29%], 3-day ACB catheter [31%], or no block [41%]). All patients underwent primary TKA using periarticular injections and contemporary multimodal pain management. Immediate and 90-day postoperative outcomes, including Knee Osteoarthritis Outcome Score, Junior (KOOS, Jr), were compared via univariate analysis among the matched cohort and regional block type among chronic opioid patients. Chronic opioid patients demonstrated higher inpatient opioid use than controls (90 vs. 65 oral morphine equivalents [OMEs], respectively, p < 0.01), but no significant differences existed in length of stay (LOS), discharge pain scores, 90-day readmission or KOOS, Jr (all p ≥ 0.05). When comparing chronic opioid patients according to block type, those receiving no block had the highest LOS (1.6 days, p < 0.01), discharge pain score (5.0, p < 0.01), and inpatient opioid use (80 OMEs, p < 0.01) compared with either ACB. The subgroup receiving an ACB catheter demonstrated a significantly higher 90-day readmission rate (9%, p < 0.05). Patients utilizing chronic opioids preoperatively require more opioids in the immediate postoperative period after TKA compared with nonopioid users despite contemporary modalities. Nonetheless, the use of any type of ACB provides improved pain control in these patients.

Background: Orthopaedic surgeons routinely delay surgical management of femoral neck fractures in patients taking direct oral anticoagulants (DOACs) to decrease perioperative bleeding and associated complications. However, this practice contradicts the principles of hip fracture management, as early surgery is associated with morbidity and mortality benefits. The purpose of this study was to quantify the association of DOAC use and perioperative outcomes in patients who underwent hemiarthroplasty (HA) or total hip arthroplasty (THA) for femoral neck fractures. We hypothesized that early surgical intervention on a patient taking a DOAC medication would not lead to worse perioperative outcomes. Methods: A retrospective cohort study was conducted on 2,833 patients who underwent primary THA or HA for femoral neck fractures between December 31, 2017, and January 29, 2024, across our hospital system. The patients taking a DOAC were divided into 3 groups based on the time since the last DOAC intake: 1 day, 2 days, and ≥3 days. Propensity matching was performed 1:1, accounting for age, sex, Elixhauser Comorbidity Index, preoperative chronic kidney disease stage, preoperative hemoglobin, body mass index, and hospital type. Subanalyses utilizing linear and conditional logistic regression models were performed to assess differences in outcomes between the groups that had a DOAC withheld and the control groups. Results: The mean age of all patients was 81 ± 10 years, 1,805 patients (64%) were women, and 207 patients (7%) were taking a DOAC prior to surgery. Despite comparable preoperative and postoperative hemoglobin levels between the groups that had a DOAC withheld and the control groups (all p > 0.05), the patients who had a DOAC withheld for 1 day were more likely to receive a postoperative blood transfusion (23.1% compared with 0%; p = 0.002). This difference in transfusion rate was not observed in other cohorts. There were no differences in medical complications, reoperation, discharge disposition, or mortality between the groups that had a DOAC withheld and the matched controls at any time point. Conclusions: Delaying surgical management due to DOAC medications may be unnecessary in patients undergoing arthroplasty for femoral neck fractures. Consideration should be given to adjusting transfusion triggers to reduce unwarranted blood transfusions in patients taking a DOAC. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Case: We present a 55-year-old woman with a very short transfemoral amputation who underwent osseointegration. We compared gait analyses before and following osseointegration, demonstrating improvements in kinematics. At follow-up, the patient wore the prosthetic for 16 hours and averaged 10,000 steps daily. She achieved her goal of walking the beach with her prosthetic limb and often traveled without an assistive device. Conclusion: This case study of a patient with a very short transfemoral amputation demonstrated continued improvements in gait and significantly increased prosthetic use over time.

Introduction Surgical site infections (SSI) continue to be a risk associated with surgery. The Centers for Disease Control (CDC) uses surgical wound class (SWC) to predict SSI postoperatively. Prior studies have shown that the current wound class definitions are unreliable for surgical subspecialties. Therefore, an alternative surgical wound classification (ASWC) was created to more accurately reflect risk of SSI following orthopedic procedures. The purpose of this study was to compare the two systems. Methods Seventy patients who developed 90-day SSI following total joint arthroplasty (TJA) were matched 1:1 to patients without postoperative SSI. The SWC was recorded from operative reports. Wounds were then retrospectively reclassified according to the ASWC based on preoperative history from the medical record. The degree of agreement and degree of association with occurrence of SSI was compared between the two systems. Results The proportion of agreement between the systems was poor (41.4%). The current SWC was associated with risk of SSI in both unadjusted (p=0.045) and multivariable analysis (p=0.050). Comparatively, the ASWC demonstrated a stronger association with SSI in both unadjusted (p=0.001) and multivariable analysis (p=0.001). Conclusion The results of this study suggest that the ASWC is more predictive for SSI following TJA than the current SWC definitions for total joint arthroplasty.

Abstract Background Radiation‐associated soft tissue sarcomas (RA‐STS) are rare complications of patients receiving radiation therapy (RT) and are generally associated with a poor prognosis. Most of the literature surrounding RA‐STS of the chest is centered on angiosarcoma. Therefore, we aim to document the management and outcome of patients with non‐angiosarcoma RA‐STS of the chest. Methods We reviewed 17 patients (all female, median age 65 years) diagnosed with RA‐STS. The most common primary malignancy was breast carcinoma ( n = 15), with a median RT dose of 57.9 Gy. All patients underwent surgical resection; five patients (29%) received radiotherapy; and five patients (29%) received peri‐operative chemotherapy. Results The 5‐year local recurrence and metastatic‐free survival were 61% and 60%, while the 5‐year disease‐specific survival was 53%. Local recurrence was associated with death due to disease (HR 9.06, p = 0.01). Complications occurred in nine of patients, most commonly due to a wound complication ( n = 7). At the most recent follow‐up, the median Musculoskeletal Tumor Society Score was 63%. Conclusion RA‐STS involving the chest wall are aggressive tumors with a high risk of local relapse and death due to disease. Local recurrence was associated with death due to disease; as such, we recommend aggressive surgical management with evaluation for adjuvant therapies.

AimsPrior cost-effectiveness analyses on osseointegrated prosthesis for transfemoral unilateral amputees have analyzed outcomes in non-USA countries using generic quality of life instruments, which may not be appropriate when evaluating disease-specific quality of life. These prior analyses have also focused only on patients who had failed a socket-based prosthesis. The aim of the current study is to use a disease-specific quality of life instrument, which can more accurately reflect a patient’s quality of life with this condition in order to evaluate cost-effectiveness, examining both treatment-naïve and socket refractory patients.MethodsLifetime Markov models were developed evaluating active healthy middle-aged male amputees. Costs of the prostheses, associated complications, use/non-use, and annual costs of arthroplasty parts and service for both a socket and osseointegrated (OPRA) prosthesis were included. Effectiveness was evaluated using the questionnaire for persons with a transfemoral amputation (Q-TFA) until death. All costs and Q-TFA were discounted at 3% annually. Sensitivity analyses on those cost variables which affected a change in treatment (OPRA to socket, or socket to OPRA) were evaluated to determine threshold values. Incremental cost-effectiveness ratios (ICERs) were calculated.ResultsFor treatment-naïve patients, the lifetime ICER for OPRA was $279/quality-adjusted life-year (QALY). For treatment-refractory patients the ICER was $273/QALY. In sensitivity analysis, the variable thresholds that would affect a change in the course of treatment based on cost (from socket to OPRA), included the following for the treatment-naïve group: yearly replacement components for socket > $8,511; cost yearly replacement parts OPRA < $1,758; and for treatment-refractory group: yearly replacement component for socket of > $12,467.ConclusionThe use of the OPRA prosthesis in physically active transfemoral amputees should be considered as a cost-effective alternative in both treatment-naïve and treatment-refractory socket prosthesis patients. Disease-specific quality of life assessments such as Q-TFA are more sensitive when evaluating cost-effectiveness.Cite this article: Bone Jt Open 2024;5(3):218–226.