Citations

Abstract Recent clinical trials on slowing dementia progression have led to renewed focus on finding safer, more effective treatments. One approach to identify plausible candidates is to assess whether existing medications for other conditions may affect dementia risk. We conducted a systematic review to identify studies adopting a data‐driven approach to investigate the association between a wide range of prescribed medications and dementia risk. We included 14 studies using administrative or medical records data for more than 130 million individuals and 1 million dementia cases. Despite inconsistencies in identifying specific drugs that may modify Alzheimer's or dementia risk, some themes emerged for drug classes with biological plausibility. Antimicrobials, vaccinations, and anti‐inflammatories were associated with reduced risk, while diabetes drugs, vitamins and supplements, and antipsychotics were associated with increased risk. We found conflicting evidence for antihypertensives and antidepressants. Drug repurposing for use in dementia is an urgent priority. Our findings offer a basis for prioritizing candidates and exploring underlying mechanisms. Highlights We present a systematic review of studies reporting association between drugs prescribed for other conditions and risk of dementia including 139 million people and 1 million cases of dementia. Our work supports some previously reported associations, for example, showing decreased risk of dementia with drugs to treat inflammatory disease and increased risk with antipsychotic treatment. Antimicrobial treatment was perhaps more surprisingly associated with decreased risk, supportive of recent increased interest in this potential therapeutic avenue. Our work should help prioritize drugs for entry into adaptive platform trials in Alzheimer's disease and will serve as a useful resource for those investigating drugs or classes of drugs and risk of dementia.

Background and Significance Diffuse large B-cell lymphoma (DLBCL) and other LBCLs account for 35-40% of non-Hodgkin lymphoma cases in North America, Europe, and East Asia. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), typically administered for 6 cycles, is the standard therapy for DLBCL and is curative in ~60-70% of patients (pts). However, 30-40% of pts have relapsed/refractory (RR) DLBCL following treatment with R-CHOP, with poor clinical outcomes. International Prognostic Index (IPI) scores of 3-5 are used to identify high-risk (HR) pts who are more likely to be RR following treatment. Additionally, pts with IPI scores of 1-2 who also have bulky disease and/or very high lactate dehydrogenase levels (LDH), have been identified as a HR subset with similar outcomes to pts with an IPI score of 3 (Maurer et al. ASH 2023, #4512). First-line therapy represents the greatest opportunity to address the unmet need for these pts. Golcadomide (GOLCA) is a potential first-in-class oral cereblon E3 ligase modulator (CELMoD™) agent purposefully designed for the treatment of lymphoma. GOLCA co-opts cereblon to induce targeted degradation of the transcription factors Ikaros/Aiolos, inducing deep, rapid, and extensive tumor killing, independent of cell of origin, and enhanced immunostimulatory activity. In the phase 1b study CC-220-DLBCL-001, GOLCA combined with R-CHOP was well tolerated, showing promising activity and combinability with high rates of durable responses irrespective of cell of origin in pts with previously untreated aggressive BCL, including those with HR disease (Hoffmann et al. EHA 2024, S235). Additionally, GOLCA has shown encouraging efficacy and safety profiles in pts with RR DLBCL, both as a monotherapy (Michot et al. ICML 2023, P90) and in combination with rituximab (Chavez et al. ASH 2023, P4496). The efficacy and safety data observed in early-phase studies suggest promising activity and a manageable safety profile. This supports further investigation of the GOLCA + R-CHOP combination in the phase 3 setting. Here, we present the study design of GOLSEEK-1, a multicenter, randomized, double-blind, placebo-controlled phase 3 study (NCT06356129) comparing the efficacy and safety of GOLCA + R-CHOP vs placebo + R-CHOP in pts with previously untreated HR LBCL. Study Design and Methods Approximately 850 pts with previously untreated LBCL will be randomized 1:1 to either GOLCA + R-CHOP or placebo + R-CHOP. Pts must have a histologically confirmed diagnosis of LBCL according to WHO 2022 classification, including: DLBCL, not otherwise specified (NOS) including ABC and GCB subtypes; high-grade B-cell lymphoma with MYC and BCL2 rearrangements, or NOS; T-cell/histiocyte-rich LBCL; Epstein-Barr Virus-Positive DLBCL. Other key inclusion criteria include an IPI score of 1 or 2 considered HR (LDH > 1.3 × upper limit of normal and/or bulky disease, defined as a single lesion of ≥ 7 cm [Maurer et al. ASH 2023, #4512]), or IPI score ≥ 3; and measurable disease as defined by the Lugano classification. Key exclusion criteria include other lymphoma subtypes such as primary mediastinal LBCL; primary cutaneous DLBCL-leg type, grade 3b follicular lymphoma (FL); transformed indolent lymphoma; anaplastic lymphoma kinase (ALK)-positive LBCL; primary effusion lymphoma; and Burkitt lymphoma, as well as documented or suspected central nervous system involvement. Randomization will be stratified by IPI score (1-2 with risk factors and 3 vs 4-5) and bulky disease (> 7 cm vs ≤ 7 cm). After a screening period of ≤ 4 weeks, pts will receive GOLCA (0.4 mg) or placebo orally once daily for 7 consecutive days in each of 6 cycles in combination with R-CHOP in 21-day cycles. The primary endpoint of this study is progression-free survival (PFS) in untreated HR LBCL, assessed by investigator based on the Lugano Response Criteria. Key secondary endpoints include PFS in untreated non-high-grade BCL, event-free survival in pts with untreated HR LBCL, independently assessed complete metabolic response rate, undetectable minimal residual disease by PhasED-Seq (defined as undetectable circulating tumor DNA levels at treatment end), and overall survival. Patient follow-up will occur for up to approximately 67 months after beginning treatment. This study is recruiting at 293 sites in 37 countries, across the United States, Europe, Latin America, and East Asia.

Background The most common cause of preventable death after injury is haemorrhage. Resuscitative endovascular balloon occlusion of the aorta is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis. Objective To compare standard care plus resuscitative endovascular balloon occlusion of the aorta versus standard care in patients with exsanguinating haemorrhage in the emergency department. Design Pragmatic, multicentre, Bayesian, group-sequential, registry-enabled, open-label, parallel-group randomised controlled trial to determine the clinical and cost-effectiveness of standard care plus resuscitative endovascular balloon occlusion of the aorta, compared to standard care alone. Setting United Kingdom Major Trauma Centres. Participants Trauma patients aged 16 years or older with confirmed or suspected life-threatening torso haemorrhage deemed amenable to adjunctive treatment with resuscitative endovascular balloon occlusion of the aorta. Interventions Participants were randomly assigned 1 : 1 to: standard care, as expected in a major trauma centre standard care plus resuscitative endovascular balloon occlusion of the aorta. Main outcome measures Primary: Mortality at 90 days. Secondary: Mortality at 6 months, while in hospital, and within 24, 6 and 3 hours; need for haemorrhage control procedures, time to commencement of haemorrhage procedure, complications, length of stay (hospital and intensive care unit-free days), blood product use. Health economic: Expected United Kingdom National Health Service perspective costs, life-years and quality-adjusted life-years, modelled over a lifetime horizon. Data sources Case report forms, Trauma Audit and Research Network registry, NHS Digital (Hospital Episode Statistics and Office of National Statistics data). Results Ninety patients were enrolled: 46 were randomised to standard care plus resuscitative endovascular balloon occlusion of the aorta and 44 to standard care. Mortality at 90 days was higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group (54%) compared to the standard care group (42%). The odds ratio was 1.58 (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (indicating increased odds of death with resuscitative endovascular balloon occlusion of the aorta) was 86.9%. The overall effect did not change when an enthusiastic prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3, 6 and 24 hours mortality), the posterior probability that standard care plus resuscitative endovascular balloon occlusion of the aorta was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at any time point. Death due to haemorrhage was more common in the standard care plus resuscitative endovascular balloon occlusion of the aorta group than in the standard care group. There were no serious adverse device effects. Resuscitative endovascular balloon occlusion of the aorta is less costly (probability 99%), due to the competing mortality risk but also substantially less effective in terms of lifetime quality-adjusted life-years (probability 91%). Limitations The size of the study reflects the relative infrequency of exsanguinating traumatic haemorrhage in the United Kingdom. There were some baseline imbalances between groups, but adjusted analyses had little effect on the estimates. Conclusions This is the first randomised trial of the addition of resuscitative endovascular balloon occlusion of the aorta to standard care in the management of exsanguinating haemorrhage. All the analyses suggest that a strategy of standard care plus resuscitative endovascular balloon occlusion of the aorta is potentially harmful. Future work The role (if any) of resuscitative endovascular balloon occlusion of the aorta in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required. Trial registration This trial is registered as ISRCTN16184981. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and is published in full in Health Technology Assessment; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information.

Abstract Spinal implant infections are a serious complications of instrumented spinal fusion surgeries, carrying high morbidity and complex management challenges. Early postoperative infections may manifest with wound-healing issues, back pain, and fevers. Magnetic resonance imaging (MRI) is the preferred imaging modality, but can be limited by metal artifacts. For cases with stable implants, surgical debridement with implant retention combined with at least 12 weeks of antibiotics is currently considered appropriate treatment. Staphylococcal infections are ideally treated with biofilm-active antibiotics. Suppressive antibiotic therapy can be considered when surgical debridement has been delayed or is incomplete, and for those who are poor surgical candidates for another surgery. Chronic infections may present insidiously with implant failure or pseudarthrosis; implant removal or revision is generally pursued. As current guidance is heavily based on the periprosthetic joint infection literature and low-level studies on spinal implant infections, further research on optimizing diagnostic and treatment approaches is needed.

Abstract Background The first-line management strategy for acute periprosthetic joint infections (PJIs) is debridement, antibiotics, and implant retention (DAIR). Suppressive antibiotic therapy (SAT) after DAIR is proposed to improve outcomes, yet its efficacy remains under scrutiny. Methods We conducted a multicenter retrospective study in patients with acute PJI of the hip or knee who were treated with DAIR in centers from Europe and the United States. We analyzed the effect of SAT using a Cox model landmarked at 12 weeks. The primary covariate of interest was SAT, which was analyzed as a time-varying covariate. Patients who experienced treatment failure or were lost to follow-up within 12 weeks were excluded from the analysis. Results The study included 510 patients with 66 treatment failures with a median follow-up of 801 days. We did not find a statistically significant association between SAT and treatment failure (hazard ratio, 1.37; 95% CI, .79–2.39; P = .27). Subgroup analyses for joint, country cohort, and type of infection (early or late acute) did not show benefit for SAT. Secondary analysis of country cohorts showed a trend toward benefit for the US cohort (hazard ratio, 0.36; 95% CI, .11–1.15; P = .09), which also had the highest risk of treatment failure. Conclusions The utility of routine SAT as a strategy for enhancing DAIR's success in acute PJI remains uncertain. Our results suggest that SAT's benefits might be restricted to specific groups of patients, underscoring the need for randomized controlled trials. Identifying patients most likely to benefit from SAT should be a priority in future studies.