Citations

ABSTRACT Objective With regulatory approval of HPV‐specific immunotherapy for recurrent respiratory papillomatosis (RRP) and growing experience with systemic bevacizumab, a management algorithm incorporating these medical treatments is warranted. Data Sources and Methods RRP Foundation (RRPF) Key Opinion Leaders offer a proposed management algorithm for adults with RRP considering published literature and commercial drug availability. Results Preventative HPV vaccination should be considered for all patients. Determination of HPV type and pulmonary imaging are important for contemporary RRP patient care and assist in decision making. Risks and benefits of papilloma debulking as needed versus medical management of RRP must be deliberated on a patient case‐by‐case basis. HPV ‐specific immunotherapy that induces an HPV ‐specific T cell response to target the underlying HPV infection that is the cause of RRP is safe, offers the possibility of durable disease control following a short treatment course and is the recommended first‐line medical treatment for patients who wish to avoid the risks of repeat procedural management. Papilloma disease control with systemic bevacizumab, which carries defined risks and must be continued for clinical benefit is the recommended second‐line medical treatment for patients who do not achieve a complete response with immunotherapy and wish to continue medical management. For patients who elect to be treated with debulking procedures as needed, use of locally‐administered adjuvant should be considered. Conclusion This proposed management algorithm from the RRPF serves as a contemporary resource and information guide for adult patients with RRP and their physicians considering treatment options. Level of Evidence 5

Background: ALG13-CDG is an X-linked N-linked glycosylation disorder caused by pathogenic variants in the glycosyltransferase ALG13, leading to severe neurological manifestations. Despite the clear CNS involvement, the impact of ALG13 dysfunction on human brain glycosylation and neurodevelopment remains unknown. We hypothesize that ALG13-CDG causes brain-specific hypoglycosylation that disrupts neurodevelopmental pathways and contributes directly to cortical network dysfunction. Methods: We generated iPSC-derived human cortical organoids (hCOs) from individuals with ALG13-CDG to define the impact of hypoglycosylation on cortical development and function. Electrophysiological activity was assessed using MEA recordings and integrated with multiomic profiling, including scRNA-seq, proteomics, glycoproteomics, N-glycan imaging, lipidomics, and metabolomics. X-inactivation status was evaluated in both iPSCs and hCOs. Results: ALG13-CDG hCOs showed reduced glycosylation of proteins involved in ECM organization, neuronal migration, lipid metabolism, calcium homeostasis, and neuronal excitability. These pathway disruptions were supported by proteomic and scRNA-seq data and included altered intercellular communication. Trajectory analyses revealed mistimed neuronal maturation with early inhibitory and delayed excitatory development, indicating an E/I imbalance. MEA recordings demonstrated early network hypoactivity with reduced firing rates, immature burst structure, and shortened axonal projections, while transcriptomic and proteomic signatures suggested emerging hyperexcitability. Altered lipid and GlcNAc metabolism, along with skewed X-inactivation, were also observed. Conclusions: Our study reveals that ALG13-CDG is a disorder of brain-specific hypoglycosylation that disrupts key neurodevelopmental pathways and destabilizes cortical network function. Through integrated multiomic and functional analyses, we identify early network hypoactivity, mistimed neuronal maturation, and evolving E/I imbalance that progresses to compensatory hyperexcitability, providing a mechanistic basis for seizure vulnerability. These findings redefine ALG13-CDG as disorders of cortical network instability, offering a new framework for targeted therapeutic intervention.

Abstract Objective: Outpatient parenteral antimicrobial therapy (OPAT) is a mainstay of clinical infectious diseases practice, and OPAT-related publications continue to be prominent in journals. The objective of this article is to summarize ten clinically important OPAT-related publications from 2024. Design: Narrative review. Methods: Eighty-one articles were found in a literature search, and 56 met inclusion criteria. A survey containing 25 articles was sent to an email listserv of clinicians with OPAT experience. Results: This article summarizes the top 10 OPAT articles published in 2024, based on those survey results. Conclusions: Common themes from the top 10 OPAT articles published in 2024 included OPAT clinician workload, patient perspectives of OPAT, tools for OPAT work, and dalbavancin use.

TPS259 Background: Despite currently approved therapies, most patients with metastatic colorectal cancer (mCRC) progress through all approved treatments and eventually succumb to their disease. Thus, novel therapies for chemotherapy-refractory mCRC are desperately needed. Inhibition of the DNA unwinding enzyme TOP1 is a well-characterized and clinically successful treatment strategy for mCRC. CBX-12 is a novel peptide-drug conjugate comprised of an exatecan warhead linked to a pH-Low Insertion Peptide (pHLIP). The principle behind this targeting mechanism is based on the Warburg effect, in which tumors establish a low pH extracellular environment. The pHLIP moiety of CBX-12 preferentially forms a unidirectional, transmembrane alpha helix in a low-pH extracellular environment. Thus, CBX-12 delivers its exatecan cytotoxic warhead preferentially into tumor cells. In mouse xenograft models, CBX-12 inhibited the HCT116 CRC xenograft model more potently than an equimolar dose of free exatecan. The phase 1 study of CBX-12 reported cytopenias as the predominant AEs and confirmed responses in several solid tumors including mCRC. Methods: This is a single-arm, phase 2 trial, with a Simon 2-stage design assessing CBX-12 for the treatment of chemotherapy-refractory mCRC. The primary objective is efficacy determined by RECIST v1.1 response rate. Secondary and exploratory objectives include evaluating the PK and PD as well as the progression-free survival (PFS) on CBX-12. Key inclusion criteria include: age ≥18 years, ECOG performance status ≤1, histologically or cytologically confirmed mCRC that is MSS/pMMR based on CLIA-approved testing, and progression on 2 or more lines of chemotherapy. This design requires 17 patients for stage 1, with termination if 1 or fewer objective responses are seen out of 17. If 2 or more patients out of 17 responds, then an additional 18 patients will be enrolled for stage 2. If 5 out of the total of 35 patients (14%) respond, then the trial would be declared successful. Correlative studies will include tumor plus peripheral blood PK to evaluate effectiveness of CBX-12 tumor targeting, ctDNA, and several tumor PD markers including TOP1-DNA trapping, SLFN11 expression, DNA damage, and apoptosis. The trial opened to enrollment on 8/21/25. Clinical trial information: NCT06730100 .

378 Background: RATIONALE-305 (NCT03777657) enrolled the highest number of pts with PM among similar trials and stratified pts with advanced GC/GEJC by presence of PM. We used statistical modeling to evaluate the impact of varying PM levels on outcomes with TIS+CT. Methods: We randomized adults with GC/GEJC (1:1) to TIS or placebo (PBO) + CT. Primary endpoints: OS in intent-to-treat (ITT) population and pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5%. We weighted pts using the method of moments to match a hypothetical population to ITT, with the same distribution of sex, primary tumor location, PD-L1 (TAP score <5% vs ≥5%), number of metastatic sites (0-2 vs 3+), and liver metastasis. PM representation was set from 20% to 45%. Weighted OS, PFS, and objective response rate (ORR) were estimated. Results: Of 997 pts enrolled, 434 (43.5%) had PM. Among pts with PD-L1 TAP scores ≥5% (54.8%), 39.7% had PM, and among pts with scores ≥1% (88.9%), 43.6% had PM (data cutoff Feb 28, 2024). Fewer pts with (+) PM had PD-L1 high tumors (TAP score ≥5%: 50.0%) and more had primary stomach tumors (86.6%) compared to those without (-) PM (58.4% and 75.5%). TIS+CT improved OS, PFS, and ORR in ITT and in pts +/- PM vs PBO+CT (Table). Across 20%–45% PM, TIS+CT showed consistent benefit, with stable HRs for OS and PFS (20% and 45% shown). TIS+CT showed survival benefits in pts with PM and PD-L1 TAP score ≥5% (OS: HR=0.71; PFS: HR=0.65) and ≥1% (OS: HR=0.79; PFS: HR=0.79) vs PBO+CT. ORR was higher with TIS+CT vs PBO+CT in pts + PM and PD-L1 TAP scores ≥5% (47.3% vs 30.8%) and ≥1% (44.2% vs 33.2%). Conclusions: Our analysis showed that lowering PM representation marginally improved OS and ORR, underscoring the poor prognosis of peritoneal disease. In RATIONALE-305, TIS+CT provides clinically meaningful response and survival benefits irrespective of PM, with higher responses in PD-L1+ GC/GEJC. Clinical trial information: NCT03777657 . Arm(95% CI) ITT + PM - PM 20%+ PM 45%+ PM OS, months TIS+CT 15.0 (13.6, 16.5) 12.3 (10.6, 14.3) 17.3 (15.0, 20.3) 15.4 (13.9, 18.0) 15.0 (13.5, 16.5) PBO+CT 12.9 (12.1, 14.1) 11.8 (10.5, 13.0) 14.0 (12.6, 16.0) 13.1 (12.3, 14.5) 12.8 (12.1, 14.1) HR 0.79 (0.69, 0.91) 0.78 (0.64, 0.96) 0.79 (0.65, 0.95) 0.81 (0.69, 0.95) 0.79 (0.69, 0.90) PFS, months TIS+CT 6.9 (5.7, 7.2) 5.8 (5.6, 7.3) 7.0 (5.7, 8.4) 6.9 (5.7, 7.3) 6.9 (5.7, 7.2) PBO+CT 6.2 (5.6, 6.9) 5.7 (5.3, 6.9) 6.9 (5.7, 7.1) 6.5 (5.6, 7.0) 6.2 (5.6, 6.9) HR 0.79 (0.68, 0.91) 0.80 (0.64, 0.98) 0.77 (0.64, 0.94) 0.79 (0.67, 0.94) 0.79 (0.69, 0.91) ORR, % TIS+CT 47.3 (42.9, 51.8) 43.6 (37.0, 50.5) 50.2 (44.2, 56.2) 48.0(42.9, 53.1) 47.3 (42.8, 51.8) PBO+CT 40.5 (36.2, 45.0) 32.2 (26.0, 39.0) 46.8 (40.9, 52.8) 43.1(38.1, 48.3) 40.3(36.0, 44.8) ORR difference, % 6.8 (0.6, 12.9) 11.4 (2.3, 20.3) 3.4 (-4.9, 11.6) 4.9 (-2.2, 11.9) 6.9 (0.8, 13.0)

Abstract Background Ten years after the original publication, the Centiloid framework is now broadly used to harmonize amyloid‐PET quantification, facilitate data sharing and comparison across cohorts, and even assist visual interpretation in clinical settings. We evaluated the global implementation of Centiloids by comparing their distribution and corresponding positivity thresholds across cohorts. Methods We gathered data from publicly available cohorts and reached out to investigators across the world to collect cross‐sectional Centiloids, demographic and clinical information, and visual read data. Gaussian mixture models (GMM, k=2) were fitted to Centiloid values for each cohort and cutoffs were calculated as mean + 2SD of the lower Gaussian. When visual reads were available, we determined Centiloid cutoffs that maximized correspondence with visual reads (Cohen's kappa). Data was combined across cohorts using random effects meta‐analyses. Results As of January 2025, we included 37 cohorts ( n = 41,678 participants) with heterogeneous pipelines, radiotracers, and clinical and demographic characteristics (Table‐1). The low Gaussian peaks ranged from ‐9 to 10CL; the meta‐analysis identified a common peak at 1CL. The second peaks were more heterogeneous (range=38‐102CL; meta‐analysis outcome=64CL). Across cohorts, the proportion of cognitively unimpaired versus impaired participants impacted the position of both peaks, with better separation in cohorts enriched in impaired individuals (Figure 1C). The meta‐analysis indicated a GMM‐based cutoff of 19CL (95%CI: 16‐21CL, Figure 1B); subgroup analyses showed no evidence of significant effect between single versus multicenter settings (17 versus 20CL, p = 0.30), MRI‐based or PET‐only processing (18 versus 19CL, p = 0.88), and no evidence of difference across radiotracers (Flutemetamol: 16CL; PIB: 17CL, Flutafuranol: 18CL, Florbetaben: 19CL, Florbetapir: 20CL, p = 0.78). In a subset of 29,496 participants with visual reads available, binary visual reads corresponded well to Centiloids (common kappa=0.86, Figure 2A). The visual read‐based cutoff of 24CL (95%CI: 21‐27CL, Figure 2B) maximized correspondence between visual read and quantification and was slightly higher than the GMM‐based cutoff. All meta‐analysis models showed high non‐random heterogeneity (I 2 >80%) across studies, suggesting non‐random differences in peaks and cutoffs. Conclusions Meta‐analysis‐based cutoffs align well with thresholds from the existing literature. High heterogeneity among studies underscores the need to investigate contributing factors, raising concerns about applying common cutoffs.

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.

Abstract INTRODUCTION We standardized positron emission tomography (PET) data across multiple cohorts and tracers to characterize the frequency of amyloid and tau PET severity along the clinical continuum. METHODS Clinical stage was defined using cohort‐specific criteria and included cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia. Amyloid severity was staged using Centiloids (CL). Tau severity was staged using a hierarchical Braak‐based schema. The cumulative probabilities of PET‐based stages were estimated using ordinal logistic regressions. RESULTS Among 10,396 individuals (mean [standard deviation] age: 71.9 [7.1] years), amyloid levels ≥ 25 CL increased with age among CU and MCI, while amyloid levels ≥ 100 CL were most common in dementia. In 3295 with tau PET, tau severity increased with amyloid and clinical stage and showed complex associations with age. Within each clinical stage, the full spectrum of amyloid and tau PET severity was observed. DISCUSSION PET‐based staging revealed heterogeneous amyloid and tau burden along the clinical continuum. Highlights PET‐based staging is feasible across multiple cohorts and PET tracers. There is heterogeneity in amyloid and tau severity across the clinical spectrum. The frequency of amyloid and tau PET severity increased with clinical severity. The likelihood of tau PET severity differed by age, amyloid, and clinical severity.

Background Deep brain stimulation (DBS) has been investigated for patients with drug-resistant epilepsy who are not candidates for resective surgery. Because different types of epilepsy involve distinct brain networks, numerous DBS targets have been explored, yet a comprehensive synthesis is lacking. Methods To provide a comprehensive overview of this expanding literature, we conducted a systematic review of studies for DBS in epilepsy, including case series, prospective and retrospective studies. We collected data on surgical targets, individual disease characteristics, outcomes and precise electrode placements. DBS electrode coordinates were gathered into a common template space and related to clinical outcomes. Results We included 124 studies, corresponding to 1210 patients and 20 distinct surgical targets. While the anterior (ANT) and centromedian (CM) nuclei of the thalamus remain the most studied, we also review less commonly used targets that show promise for specific forms of epilepsy and may warrant further investigation. Substantial variability in targeting strategies and electrode placement was observed within each of the target regions. Importantly, significant relationships between stimulation location and outcomes were identified for ANT-DBS and CM-DBS. For ANT-DBS, shorter distance to the mammillothalamic tract junction was associated with greater seizure reduction on both study-level and patient-level analyses (r=−0.55, p<0.001 and r=−0.51, p<0.001, respectively). For CM-DBS, localisation effects may be dependent on the form of epilepsy, with stimulation of the parvocellular CM being associated with better outcomes in generalised epilepsy. Conclusions Our results emphasise the importance of accurate targeting in DBS for epilepsy. Our database and atlas of DBS targets are made publicly available, potentially serving further meta-analytical work. PROSPERO registration number CRD420250649304.

Abstract Background Critical illness is a risk factor for carnitine deficiency. Carnitine deficiency may result in serious medical complications and poor clinical outcomes. This study aimed to identify the prevalence and potential predictors of carnitine deficiency. Methods This was a descriptive cross‐sectional study conducted in a convenience sample of 144 critically ill adults admitted to a surgical or cardiovascular intensive care unit at the University of Utah Hospital, with serum carnitine levels measured from January 1, 2022, to December 31, 2024. Binary and multivariable logistic regression models were constructed to explore potential predictors of carnitine deficiency, which was defined as a free serum carnitine level <36 µmol/L. Results The mean age of patients was 56.5 years; 41.7% of the sample had carnitine deficiency. For each unit decrease in body mass index, the odds of developing carnitine deficiency increased by 5% compared with maintaining normal free carnitine status (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.9–0.99). Those prescribed continuous renal replacement therapy were 2.43 times more likely to develop carnitine deficiency than those not on continuous renal replacement therapy (OR, 2.43; 95% CI, 1.12–5.25). Conclusion A high proportion of our study population had carnitine deficiency. Continuous renal replacement therapy and a lower body mass index were significant predictors in the multivariable model. Female sex and a history of chronic kidney disease may warrant further exploration based on significance in the univariable analysis.