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Background: Acute ischemic stroke (AIS) from distal medium vessel occlusion (DMVO) presents unique treatment challenges. Mechanical thrombectomy (MT) is emerging as a viable option for these patients, yet the role of pre-stroke aspirin treatment is unclear. This study evaluates the impact of pre-stroke low-dose aspirin on outcomes in DMVO patients undergoing MT. Methods: We conducted a multinational, multicenter, propensity score-weighted analysis within the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry. Patients with AIS due to DMVO, treated with MT, were included. We compared outcomes between patients on pre-stroke low-dose aspirin (75–100 mg) and those not on antiplatelet therapy. The primary outcome was functional independence at 90 days (modified Rankin Scale (mRS), 0–2). Secondary outcomes included excellent functional outcome at 90 days (mRS, 0–1), mortality, and day 1 post-MT National Institutes of Health Stroke Scale (NIHSS) score. Safety outcomes focused on hemorrhagic complications, including symptomatic intracerebral hemorrhage (sICH). Results: Among 1354 patients, 150 were on pre-stroke low-dose aspirin. After applying inverse probability of treatment weighting (IPTW), aspirin use was associated with significantly better functional outcomes (mRS, 0–2: odds ratio (OR) = 1.89, 95% confidence interval (CI) = 1.14 to 3.12) and lower 90-day mortality (OR = 0.56, 95% CI = 0.32 to 1.00). The aspirin group had lower NIHSS scores on day 1 (β = −1.5, 95% CI = −2.8 to −0.27). The sICH rate was not significantly different between the groups (OR = 0.92, 95% CI = 0.60 to 1.43). Conclusions: Pre-stroke low-dose aspirin was associated with improved functional outcomes and reduced mortality in patients with DMVO undergoing MT, without a significant increase in sICH. These findings suggest that low-dose aspirin may be safe and associated with more frequent excellent outcomes for this patient population. Further prospective studies are needed to validate these results and assess long-term outcomes.

662 Background: Alkylating-based chemotherapy (ALK) is one of the main treatments used in patients with advanced pancreatic neuroendocrine tumors (PanNETs). Its use has been associated with an increased risk of grade progression and acquisition of a hypermutator phenotype, associated with frequent alterations of the mismatch repair (MMR) genes. This suggests a potential benefit of immune checkpoint inhibitors (ICI) that are otherwise ineffective in ALK-naïve PanNETs, which are mostly hypomutated. We aimed to describe the efficacy of ICI in patients with advanced PanNET pretreated with ALK. Methods: We assembled an international retrospective cohort of patients with advanced PanNET who received at least one cycle of ICI, and who had previously received at least 3 months of ALK. Patients with poorly-differentiated neuroendocrine carcinoma were excluded. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was the objective response rate (ORR). The impact of tumor mutational burden (TMB, high being defined by >10 mut/Mb) and MMR alterations (mutations or IHC) was explored. Results: We included 39 patients (median age 58.7, male sex 62%). All PanNETs were progressive at baseline and presented a median of 3 (IQR, 2-4) metastatic sites. Tumors were predominantly classified as G2 (47%) or G3 (42%), with a median Ki-67 of 18.5% (IQR, 12-35). 23/27 patients with tumor tissue or ctDNA NGS testing had high TMB (median, 35 mut/Mb; IQR, 24-106) and 12/22 had MMR alterations. Patients had previously received an average of 14 cycles (IQR, 7-25) of ALK (temozolomide 78%, streptozotocin 18%, dacarbazine 4%), which had yielded objective response in 72% of cases. In addition, patients had received a median of 4 (IQR, 3-5) other treatments (including platinum drugs in 80% and PRRT in 51%). ICI mainly consisted in an anti-PDL1/PD1 + anti-CTLA4 combination (85%) or a monotherapy (15%), with a median of 3 (IQR, 2-8) cycles. The ORR was 18% and the disease control rate was 46%. Median PFS was 2.8 months (95% CI, 0.62-4.96) and 6-month PFS rate was 31%. 19% of patients had grade 3-4 toxicity. Patients with high TMB had higher ORR (30% vs. 0%, p=0.03) and longer median PFS (4.9 vs. 2.1 months, p=0.004) compared with patients with low/unknown TMB. Patients with altered MMR had higher ORR (42% vs. 7%, p=0.02) and longer median PFS (8.9 vs. 2.5 months, p=0.014) compared with patients with no/unknown MMR alterations. Conclusions: While ICI shows limited efficacy in unselected patients with advanced PanNETs pretreated with ALK, it may be an effective treatment option in case of high TMB and MMR alterations.

Background Current randomized controlled trials are investigating the efficacy and safety of mechanical thrombectomy (MT) in patients with medium vessel occlusion (MeVO) stroke. Whether best medical management (MM) is more efficient than unsuccessful vessel recanalization during MT remains unknown. Methods This was a retrospective cohort study using data from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. Only patients with occlusion of the distal branches (M2 and M3) of the middle cerebral artery territory were included. Unsuccessful MT was defined as a modified Thrombolysis in Cerebral Infarction score of 0–2a. Propensity score matching was used to control for confounders. The primary outcome was functional independence, defined as a modified Rankin Scale (mRS) score of 0–2 at 90 days after treatment. Multivariable regression analysis was used to assess factors associated with the primary outcome. Results Of 2903 patients screened for eligibility, 532 patients were analyzed (266 per group) after propensity score matching. The MM group had superior functional outcomes, with 32% achieving mRS 0–1 at 90 days compared with 21% in the MT group (P=0.011). Patients in the MM group also had significantly lower rates of symptomatic intracranial hemorrhage (sICH) (3.4% vs 16%, P<0.001) and any hemorrhage (18% vs 48%, P<0.001). On multivariable regression, unsuccessful MT was associated with reduced odds of functional independence (OR 0.50, 95% CI 0.29 to 0.85, P=0.011) and increased odds of sICH (OR 4.32, 95% CI 1.84 to 10.10, P<0.001). Mortality rates were similar between groups (27% in MM vs 29% in MT, P=0.73). Conclusion Unsuccessful MT for MeVO was linked to worse outcomes than best MM. These findings highlight the risks of prolonged attempts and emphasize the importance of efficient procedural decision-making to reduce complications and improve patient outcomes.

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

ABSTRACT The Burkholderia cepacia complex (BCC) is a group of Gram-negative bacteria that cause opportunistic infections, most notably in people with cystic fibrosis (CF), and have been associated with outbreaks caused by contaminated medical products. Antimicrobial susceptibility testing (AST) is often used to guide treatment for BCC infections, perhaps most importantly in people with CF who are being considered for lung transplant. However, recent studies have highlighted problems with AST methods. Here, we address limitations from previous studies to further evaluate BCC AST methods. We assessed the performance of reference broth microdilution (BMD), disk diffusion (DD) using Mueller-Hinton agar (MHA) from three manufacturers, agar dilution (AD), and gradient diffusion (ETEST) for ceftazidime (CAZ), levofloxacin (LVX), meropenem (MEM), minocycline (MIN), and trimethoprim-sulfamethoxazole (TMP-SMX) on a set of 205 BCC isolates. The isolate set included 100 isolates from people with CF and 105 isolates from people without CF from a variety of sources, which enabled us to systematically evaluate whether specimen source impacts AST performance. For all BCC isolates, BMD reproducibility was 93%, 98%, 99%, 98%, and 96% for CAZ, LVX, MEM, MIN, and TMP-SMX, respectively. Using BMD as the comparator method, we show that DD, AD, and ETEST perform poorly, with neither MHA manufacturer nor specimen source significantly impacting method performance. Based on our data, we recommend that routine AST should not be performed for BCC isolates. If a provider requests AST, clinical microbiology laboratories should perform Clinical and Laboratory Standards Institute reference methodology for BMD (stored frozen) and report MIC only. IMPORTANCE Antimicrobial susceptibility testing for the Burkholderia cepacia complex (BCC) is often used to determine eligibility for lung transplant in people with cystic fibrosis. However, problems with method performance have been reported. Here, we systematically evaluate the performance of reference broth microdilution, disk diffusion, agar dilution, and gradient diffusion (ETEST) for BCC organisms isolated from people with and without cystic fibrosis. We show that broth microdilution reproducibility is acceptable for levofloxacin, meropenem, minocycline, and trimethoprim-sulfamethoxazole, while ceftazidime was just below the acceptability cut-off. Regardless of specimen source, the results from disk diffusion, agar dilution, and ETEST do not correlate with broth microdilution. Based on these findings, we recommend that antimicrobial susceptibility testing should not be routinely performed for BCC, and if requested by the provider, only broth microdilution following Clinical and Laboratory Standards Institute guidelines should be used. Providers should be aware of the significant limitations of antimicrobial susceptibility testing methods for BCC.

BACKGROUND AND OBJECTIVES Some Minnesota clinicians perceive that the incidence of prophylactic vitamin K refusal is increasing, yet the actual incidence and which populations are most likely to refuse is unknown. Our objective is to identify the incidence of vitamin K refusal and to characterize the maternal-newborn dyads with increased refusal rates. METHODS This retrospective multi-institution study analyzed vitamin K refusal in newborns born from 2015 to 2019. Maternal-newborn dyad delivery and community characteristics (language, religion, population size) were collected and analyzed by univariable and multivariable logistic regression. RESULTS Among 102 451 term infants, 1.3% did not receive intramuscular vitamin K. Refusal increased from 0.9% in 2015 to 1.6% by 2019 (P &lt; .0001). In multivariable analysis, factors associated with increased likelihood of refusal included female sex (odds ratio [OR] 1.22, 95% CI 1.09–1.36), exclusive human milk feeding at hospital discharge (OR 3.46, 95% CI 2.87–4.17), parity greater than 0 (OR ranging from 1.32 [95% CI 1.13–1.54] for parity of 1, to 3.70 [95% CI 2.80–4.90] for parity of 4), having a midwife at delivery (OR 1.70, 95% CI 1.45–2.01), public insurance (OR 1.84, 95% CI 1.60–2.12), and Russian language (OR 4.92, 95% CI 2.90–8.35). Some religious identities had higher refusal rates (ie, Pentecostal 7.0%, Baptist 3.3%). CONCLUSION In a cohort of Minnesota hospital-born infants, the incidence of vitamin K refusal increased between 2015 and 2019. We identified large populations (eg, public insurance, exclusive human milk feeding) and smaller discrete communities (eg, Russian, Pentecostal) with opportunities for increasing prophylactic vitamin K acceptance through targeted community conversations.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

The dorsolateral prefrontal cortex (dlPFC) is increasingly targeted by various noninvasive transcranial magnetic stimulation or transcranial current stimulation protocols in a range of neuropsychiatric and other brain disorders. The rationale for this therapeutic modulation remains elusive. A model is proposed, and up-to-date evidence is discussed, suggesting that the dlPFC is a high-level cortical centre where uncertainty management, movement facilitation, and cardiovascular control processes are intertwined and integrated to deliver optimal behavioural responses in particular environmental or emotional contexts. A summary of the state-of-the-art in the field is provided to accelerate the development of emerging neuromodulation technologies for brain stimulation and recording for patients with mood, sleep, and cognitive disorders in our ageing population.