In multiple sclerosis (MS) patients under therapy, the increase of serum glial fibrillary acidic protein (sGFAP) concentrations is associated with the course of 'progression in absence of relapse' (PIRA). While serum neurofilament light chain (sNfL) reflects both response as well as insufficient or lack of efficiency of disease-modifying therapies (DMT), the longitudinal course of sGFAP levels as a drug response marker for future PIRA in relation to specific types of DMT is less clear. We aimed to compare the predictive capacity of sGFAP and sNfL for PIRA and relapse activity and the longitudinal course in people with MS (PwMS) treated with fingolimod, based on Z scores derived from normative values. Overall, 420 PwMS under fingolimod treatment with follow-up of 9.1 years (interquartile range: 7.0-11.0) from the Swiss MS Cohort, contributing 2935 longitudinal serum samples, were included. A reference data set for sGFAP established from 4297 healthy controls across three European and North American cohorts was used to calculate Z scores. The longitudinal course and the predictive capacity of biomarkers for time to PIRA and relapse were assessed by Cox proportional hazards and linear mixed-effects models. In controls, sGFAP concentrations were 13.6% higher in females than males and increased exponentially with age. Altogether, 31.0% of PwMS experienced ≥1 PIRA event. Elevated sGFAP Z scores (>0.75) were associated with increased risk of PIRA [hazard ratio (HR): 1.64; 95% confidence interval (CI): 1.16-2.32; P = 0.006], while this was not the case for sNfL. Conversely, elevated sNfL predicted relapses (HR: 1.58; 95% CI: 1.13-2.23; P = 0.008), while sGFAP did not. Both biomarkers decreased under treatment: sGFAP by 0.19 Z score units (ZSU)/10 years (95% CI: -0.27 to -0.11; P < 0.001) and sNfL by 0.16 ZSU/10 years (95% CI: -0.27 to -0.06; P = 0.002). Serum GFAP remained elevated in PwMS with future PIRA events (estimate: 0.29; 95% CI: 0.07-0.50; P = 0.009); no such association was found for sNfL. Serum GFAP and sNfL Z scores provide complementary predictive capacity for PIRA and relapse risk. The decrease of sGFAP under fingolimod is a feature not observed with other types of DMT and may hint to a specific anti-neurodegenerative effect of Sphingosine-1-phosphate-receptor modulators on astrocytes.
The phase II GeparNuevo trial investigated whether adding durvalumab to neoadjuvant chemotherapy (NACT) only in patients with early triple-negative breast cancer cT1b-cT4a-d would improve pathologic complete response (pCR) rate and patient survival. Hundred and seventy-four patients were randomly assigned to receive durvalumab or placebo concurrently with nab-paclitaxel once per week and followed by dose-dense epirubicin and cyclophosphamide. With 86.4 months of median follow-up compared with the previously reported 43.7 months, durvalumab showed sustained significant improvements in long-term outcomes as defined by STEEP compared with placebo regarding not only invasive disease-free survival (iDFS; hazard ratio [HR], 0.56 [95% CI, 0.32 to 0.99]; stratified log-rank P = .0431), but also distant disease-free survival (DDFS; HR, 0.41 [95% CI, 0.21 to 0.80]; P = .0069) and overall survival (OS; HR, 0.33 [95% CI, 0.14 to 0.79]; P = .0085). All analyses were stratified by stromal tumor-infiltrating lymphocytes (sTILs) at baseline (low [≤10%], intermediate [11%-59%], high [≥60%]). In exploratory subgroup analysis, patients with nodal involvement at baseline demonstrated a greater iDFS benefit (HR, 0.33 [95% CI, 0.144 to 0.771]; P = .01; Pinteraction = 0.045). sTILs in residual disease (RD) could be assessed in 39/71 patients without pCR. Post hoc analyses by sTILs high (>10%) versus low (≤10%) in RD showed estimated 7-year iDFS rates of 92.3% (95% CI, 56.6 to 98.9) and 51.4% (95% CI, 29.2 to 69.7), respectively. Hence, adding durvalumab to dose-dense NACT without adjuvant continuation of checkpoint inhibition improved long-term survival outcomes, irrespective of the extent of pathologic response. This underscores the necessity to re-evaluate the adjuvant continuation of checkpoint inhibition.
OBJECTIVE:Evaluate long-term mortality and the role of causative pathogens in periprosthetic joint infection (PJI) following total hip arthroplasty (THA). METHODS:Retrospective nationwide cohort study of adults undergoing THA (2012-2022) using data from the Swiss Joint Registry, Center for Infection Prevention and civil registry. Primary outcome was up to 10-year survival with or without PJI. Adjusted hazard ratios (aHR) were estimated via Gompertz regression, controlling for sex, age, BMI, and ASA. Pathogen-specific mortality hazard was analyzed. RESULTS:Of 215,678 patients, 89,709 met inclusion criteria (51.3% women; median age 69 years). PJI occurred in 745 (0.8%) patients, 2 752 (3.1%) underwent aseptic revision. PJI was associated with increased mortality (aHR 2.15; 95% CI, 1.79-2.57; p<0.001) compared to no PJI/revision, aseptic revisions were not (aHR 0.92; 95% CI, 0.80-1.06; p=0.27). Pathogens associated with increased mortality included Enterobacterales (aHR 3.17; 95% CI, 2.09-4.83, p<0.001), Staphylococcus aureus (aHR 2.32; 95% CI, 1.65-3.27; p<0.001), Cutibacterium acnes (aHR 2.31; 95% CI, 1.20-4.45; p=0.01), and coagulase-negative staphylococci (aHR 1.65; 95% CI, 1.16-2.35; p=0.006). Streptococcal infections showed no significant association (aHR 1.24; 95% CI, 0.62-2.49; p=0.54). CONCLUSION:PJI following THA was associated with an approximately twofold increase in long-term mortality hazard. C. acnes presented an unexpectedly high mortality hazard.
BACKGROUND:People with human immunodeficiency virus (HIV) are at increased risk of low trauma fractures (LTFs). Published data on LTF incidence trends over time have not been uniform. This study sought to analyze LTF time trends in the Swiss HIV Cohort Study (SHCS) over the time period 2009-2022. METHODS:Fractures are prospectively captured in the SHCS. Since 2008, using a standardized form, each fracture and its low trauma nature was validated by the treating HIV physician and the main investigators. Applying negative binomial regression, we estimated the LTF incidence rate ratio per calendar year univariably and adjusting for time-updated clinical and HIV-related risk factors, plus a genome-wide polygenic risk score associated with bone mineral density. RESULTS:Between 2009 and 2022, 7524 SHCS participants accumulated 71 983 participant-years of observation and 235 validated LTFs, for an LTF incidence of 0.33 (95% confidence interval [CI], .29-.37) per 100 participant-years. There were statistically significant changes over time in multiple demographic, clinical, and HIV-related variables potentially associated with better bone health. The LTF incidence rate declined by 9.2% (95% CI, 5.6%-12.6%) per year on average in univariable analysis and by 7.5% (95% CI, 2.9%-11.9%) per year in the full multivariable model. Declining LTF time trends were noted in men and women, younger and older age groups, and participants with favorable and unfavorable genetic background. CONCLUSIONS:LTFs have considerably decreased in people with HIV in Switzerland over a 14-year period. The LTF decline likely is multifactorial and occurred concomitant with favorable trends in antiretroviral therapy, demographic, and lifestyle variables that may contribute to better bone health.
BACKGROUND:Minimally invasive surgery (MIS) for hallux valgus correction has demonstrated excellent clinical and radiographic outcomes. However, there are occasions where there is limited bone formation and remodelling despite successful union. This study investigated whether demineralised bone matrix fibre allograft augmentation could be associated with greater radiographic bone formation compared with standard percutaneous technique. METHODS:A retrospective comparative study of patients undergoing fourth-generation percutaneous hallux valgus correction with demineralised bone matrix fibre allograft augmentation (DBM group) or without (NDBM group). Primary outcome was radiographic healing assessed at 6 weeks, 3 months, and 6 months using a validated classification system. Secondary outcomes included patient-reported outcome measures (Manchester-Oxford Foot Questionnaire [MOXFQ], EuroQol 5-dimension, 5-level [EQ-5D-5L], visual analogue scale [VAS] Pain), and radiographic parameters (intermetatarsal angle, hallux valgus angle). RESULTS:Between September 2022 and July 2024, a total of 215 patients (191 female; 24 male; 316 feet) underwent fourth-generation percutaneous metatarsal extra-capsular transverse osteotomy for hallux valgus correction. Patients were divided into 2 groups: DBM, 222 feet; and NDBM, 94 feet. Radiographic follow-up was available for 75.2% (167 feet) of DBM and 79.8% (75 feet) of NDBM cases. The DBM group showed significantly improved radiographic union scores at 3 and 6 months (P = .005-.027) but not 6 weeks (P = .06). There were no significant differences between groups in terms of final patient-reported outcome measures or radiographic deformity correction (P > .05). Multivariable regression analysis adjusting for baseline confounders found that DBM was associated with a statistically but not clinically significant improvement in patient-reported outcome measures (PROMs; based on the minimal clinically important difference); however, PROM findings should be interpreted cautiously, given baseline imbalance and approximately 50% loss to follow-up. The additional cost of bone graft augmentation was USD$1780 per procedure. CONCLUSION:The addition of demineralised bone matrix fibre allograft to the lateral healing zone, was associated with higher radiographic healing scores and a greater proportion classified radiographically as united at scheduled time points following percutaneous hallux valgus surgery. Future studies should investigate whether other biological adjuncts could further optimize healing in specific patient populations or identify those that may not demonstrate bony remodelling.
