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Importance Little research has been done on post-COVID symptoms at 24 months postinfection and on the association these may have on health-related quality of life (HRQOL). Objective We assessed the prevalence and severity of post-COVID symptoms and quantified EuroQol 5 Dimension 5 Level (EQ-5D-5L), self-perceived health question (EuroQol Visual Analogue Scale (EQ-VAS)) and health utility scores (HUS) up to 24 months follow-up. Design The longitudinal multiple cohort CORona Follow-Up (CORFU) study combines seven COVID-19 patient cohorts and a survey among the general public. The participants received questionnaires on several time points. Participants were stratified by: without a known SARS-CoV-2 infection (control group), proven SARS-CoV-2 infection but non-hospitalised, proven SARS-CoV-2 infection hospitalised to the ward, and proven SARS-CoV-2 infection hospitalised to the intensive care unit (ICU). Setting In this study, data of seven COVID-19 patient cohorts and a survey among the general public are included. Participants Former COVID-19 patients and controls participated in this cohort study. Main outcomes and measures Former COVID-19 patients and non-COVID-19 controls were sent questionnaires on symptoms associated with post-COVID condition. The CORFU questionnaire included 14 symptom questions on post-COVID condition using a five-level Likert-scale format. Furthermore, HRQOL was quantified using the EuroQol EQ-5D-5L questionnaire: EQ-VAS and the EQ-5D-5L utility score. The EQ-5D-5L questionnaire includes five domains that are scored on a five-point Likert scale: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Results A total of 901 participants (and 434 controls) responded at 24 months follow-up. In all former COVID-19 patients, the presence of post-COVID condition at 24 months was observed in 62 (42.5%, 95% CI 34.3% to 50.9%) of the non-hospitalised patients, 333 (65.0%, 95% CI 60.7% to 69.2%) of the hospitalised ward patients and 156 (63.2%, 95% CI 56.8% to 69.2%) of the ICU patients, respectively (p<0.001). The most common symptoms included fatigue, sleep problems, muscle weakness/pain and breathing issues, with hospitalised participants reporting most often having symptoms. Multiple post-COVID symptoms were significantly associated with EQ-5D-5L measures. The mean and SD of the EQ-VAS were 71.6 (17.9), 70.0 (17.3) and 71.4 (17.5) for non-hospitalised, ward and ICU participants, respectively, and 75.6 (17.7) for the controls (p<0.001). The HUS resulted in 0.81 (0.20), 0.77 (0.19) and 0.79 (0.22) for non-hospitalised, hospitalised ward and ICU participants, respectively, and 0.84 (0.19) for the control group (CG) (p<0.001). Conclusions Many former COVID-19 patients experience post-COVID symptoms at 24 months follow-up, with the highest prevalence in hospitalised participants. Also, former patients reported a lower HRQOL. Trial registration number The CORFU study was registered at clinicaltrials.gov (registration number NCT05240742).

Background: The authors present a novel microsurgical model to investigate ischemia-reperfusion (I/R) injury in composite tissue (muscle/skin) using a musculocutaneous flap. I/R was induced in a rodent biceps femoris musculocutaneous flap through collateral ligation and arteriovenous clamping. The authors hypothesized that I/R flaps would show greater tissue damage compared with sham. Methods: Male rats were randomized into I/R ( n = 10) and sham ( n = 9) groups. The I/R group underwent flap elevation, collateral ligation, 3 hours of arteriovenous clamping, followed by reperfusion. The sham group had flap elevation only. Perfusion was monitored using laser-speckle imaging, and flap discoloration was assessed with blinded skin ischemia necrosis scores. Serum and the composite tissue (skin/muscle) were analyzed for injury on postoperative days (PODs) 1 or 3. Results: Clamping reduced perfusion ( P = 0.00), whereas unclamping increased perfusion ( P <0.00). Over time, flaps exposed to I/R were more ischemic (estimate, 0.39; P = 0.02). At POD1, the injury group had higher serum creatine kinase ( P = 0.04) and potassium ( P = 0.00) than the sham group. The injury group had more muscle apoptosis (34.7% versus 5.2%; P = 0.03), myonecrosis (30.3% versus 14.1%; P = 0.04), and inflammation (13.7% versus 4.9%; P = 0.02) than the sham group; myonecrosis and inflammation persisted into POD3. Skin apoptosis and inflammation were similar. Conclusions: This model reliably reproduces I/R injury with a 3-hour ischemic period followed by early reperfusion. Animals subjected to the authors’ technique showed greater tissue damage than the sham group, with muscle being more vulnerable than skin. Serum showed peak muscle injury at 24 hours, and histologic analysis showed myonecrosis and inflammation through 72 hours. This suggests that less than 24 hours’ reperfusion (eg, critical window) may serve as the optimal time for possible intervention. Clinical Relevance Statement: I/R injury is a complex phenomenon affecting vascular composite tissues. The mitochondrial superoxide dismutase may be more specific for I/R injury. There may be a critical window within which to mitigate injury (<24 hours after reperfusion). The authors’ model helps investigate muscle/skin I/R injury.

Previous studies about the COVID-19 pandemic on STEMI patient outcomes have conflicting results. It remains unclear if this may be attributed to regional differences and/or differences during COVID-19 wave periods. Using the American Heart Association Get With The Guidelines–Coronary Artery Disease registry data, we evaluated (1) time metrics related to STEMI system goals and (2) regional variation in STEMI incidence and in-hospital mortality during pandemic wave time periods. The study included all patients 18–100 years old admitted with STEMI (n = 72,516) to 1 of 435 American Heart Association Get With The Guidelines–Coronary Artery Disease hospitals (1 October 2019–31 December 2021). Of these, 70.8% were male and 73.0% non-Hispanic White, with a median age of 63 (IQR 18) years. Compared to pre-pandemic time frames, patients with STEMI had a higher risk profile, delayed time to treatment, were treated with fibrinolytic therapy or primary PCI, and were transferred for primary PCI at similar rates, and had higher adjusted in-hospital mortality (during the second wave in the South and Midwest). Preservation of STEMI systems of care resulted in an overall lower in-hospital mortality rate than predicted, although opportunities exist to improve treatment delays. Regional differences in mortality rates require further study.

ABSTRACT The purpose of this study was to establish tentative Clinical and Laboratory Standards Institute (CLSI) M45 MIC and disk diffusion (DD) breakpoints (BPs) for Pseudomonas other than Pseudomonas aeruginosa (POPA). Mechanisms of antimicrobial resistance (AMR) and the modified carbapenem inactivation method (mCIM) to detect carbapenemase production were also evaluated. MIC data from P. aeruginosa and POPA from 2013 to 2022 were evaluated to compare the MIC distributions and modal MICs relative to the CLSI M100 P. aeruginosa BPs. A disk-to-MIC correlation study with 83 isolates was completed by testing reference broth microdilution and DD from the same inoculum, and the error-rate bounded method was used to establish DD BPs. For most antimicrobials, the modal MICs between P. aeruginosa and POPA were within 1-doubling dilution and lower than the M100 P. aeruginosa- susceptible BP. For amikacin, the modal MIC for POPA was 2-doubling dilutions lower than P. aeruginosa and was evaluated relative to the Enterobacterales BP. For aztreonam and trimethoprim-sulfamethoxazole, the modal MICs were elevated, and no BPs were set. New DD correlates were established for most antimicrobial agents, except for fluoroquinolones, where the P. aeruginosa correlates were suitable. AMR genes conferring resistance to multiple antimicrobial classes were identified by WGS. Beta-lactamase genes were identified in 30 (36.1%) isolates, with metallo-beta-lactamases (90.6%) predominating. The mCIM had a sensitivity and specificity of 100%. Upon review, the CLSI M45 committee proposed tentative MIC and DD BPs for expanded-spectrum cephalosporins (ceftazidime and cefepime), carbapenems (meropenem and imipenem), fluoroquinolones (ciprofloxacin and levofloxacin), and the aminoglycosides (amikacin and tobramycin). IMPORTANCE Pseudomonas species other than Pseudomonas aeruginosa (POPA) can cause opportunistic infections which may be difficult to treat due to a variety of antimicrobial resistance mechanisms. Antimicrobial susceptibility testing is a critical component of patient management for these infections. Currently, the Clinical and Laboratory Standards Institute (CLSI) M100 non-Enterobacterales breakpoints and methodology are utilized for POPA by US clinical laboratories and likely do not accurately predict susceptibility results. The purpose of this study was to establish tentative CLSI M45 MIC and disk diffusion breakpoints for POPA. Mechanisms of antimicrobial resistance and the modified carbapenem inactivation method to detect carbapenemase production were also evaluated. We present the data used by the volunteers tasked by CLSI to develop POPA breakpoints in the M45 guidelines.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

Abstract Olfactory neuroblastoma (ONB) is a rare head and neck cancer arising from the upper nasal cavity, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to utilize a patient-level genomic repository to identify potential therapeutic targets and improve disease modeling in ONB. Retrospective genomic analysis. Data analysis was performed using the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database. Patients with confirmed ONB who have undergone targeted sequencing within GENIE. Data were analyzed for recurrent somatic mutations, along with their clinical and demographic correlations, with significance set at p < 0.05. A high prevalence of mutations in TP53 (tumor protein p53) and FRK (fibroblast growth factor receptor kinase) genes was identified. A moderate prevalence of mutations in NOTCH3 (notch receptor 3), SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4), RET (rearranged during transfection), and CTCF (CCCTC-binding factor) was also identified. The mutation patterns differed between pediatric and adult ONB cases. Specific mutations were enriched in metastatic tumors compared with primary tumors. This study provides a genomic profile for ONB, identifying key mutations and potential therapeutic targets. The identification of frequently mutated genes like TP53 and FRK suggests potential targets for novel therapies. The observation that certain genes are mutated in pediatric ONB but not adult ONB (and vice versa), and the presence of specific mutations in metastatic tumors that are absent in primary tumors, offers valuable insights for future precision medicine and the design of targeted therapeutic interventions for these distinct clinical presentations.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

AimsCeramic-on-ceramic (CoC) articulations in total hip arthroplasty (THA) have the advantage of low wear but the unique risk of fracture. After revision for CoC-bearing fracture, third-body ceramic particles can lead to massive wear of cobalt-chrome (CoCr) bearings, causing extremely elevated blood cobalt. We present a multicentre series of five cases where patients sustained fractures of ceramic liners, were revised using a CoCr articulation, and rapidly developed severe cobalt toxicity.MethodsWe identified five cases of cobalt toxicity after fractured CoC THA treated with revision to CoCr on polyethylene bearings. Mean follow-up was three years (5 to 72 months) after re-revision to remove the CoCr bearing.ResultsSymptoms of cobalt toxicity occurred at a mean ten months (6 to 12) after revision for ceramic fracture. All patients developed vision and hearing loss, balance difficulties, and peripheral neuropathy. Several had cardiomyopathy, endocrine abnormalities, and local skin discolouration. Only two reported hip pain. Repeat revision for recognized cobalt toxicity occurred at a mean 22 months after revision for ceramic fracture. Mean serum cobalt level at re-revision was 991 ng/ml (normal value < 1 ng/ml; 734 to 1,302). All CoCr femoral heads exhibited massive wear, and deep tissues showed prominent metal staining. Treatment consisted of debridement and revision to a ceramic femoral head with highly cross-linked polyethylene (HXLPE) liner. Serum cobalt improved to a mean 25 μg/l (1 to 76) at final follow-up. All patients reported partial improvement in vision and hearing, however their peripheral neuropathy and balance difficulties did not recover.ConclusionSystemic cobalt toxicity is a devastating complication of ceramic-bearing fracture in THA treated with CoCr bearings, which may not present with hip symptoms. The diagnosis of this syndrome of systemic cobalt toxicity was significantly delayed following systemic symptoms in this series. Debridement and re-revision to a ceramic-on-HXLPE bearing leads to improvement, but not full resolution, of cobalt toxicity complications.Cite this article: Bone Joint J 2025;107-B(6 Supple B):92–100.