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ABSTRACT Periprosthetic joint infection (PJI) is the most common and difficult to treat form of arthroplasty failure. While treatment with debridement, antibiotics, and implant retention (DAIR) is preferable to one- or two-stage implant exchange based on morbidity and cost, outcomes are not successful in all cases selected for this management strategy. DAIR is currently recommended when infection is perceived to be in an “acute” phase, based on symptom duration; despite this selection strategy, DAIR failure rates are high. A more objective means of predicting DAIR success could improve patient outcomes by limiting DAIR failures. To explore this possibility, advanced proteomic analysis of sonicate fluid samples from 95 subjects with PJI was performed using proximity extension assay (PEA), with 77 samples additionally undergoing complementary proteomics analysis with liquid chromatography with tandem mass spectrometry (LC-MS/MS). Sparse partial least squares differentiation analysis (sPLS-DA) separated samples from patients who underwent DAIR with known outcomes ( n = 19) into successful or unsuccessful groups, predicting DAIR surgical outcome (area under the curve [AUC]: 1; mean “leave one out” AUC: 0.6). Proteins predictive of DAIR surgical outcome were significantly enriched for the “protein repair” Gene Ontology (GO) pathway ( P -adj = 0.02). Additionally, proteomic signatures associated with symptom duration in PJI categorized samples into short and long symptom duration PJI. In summary, an investigation of 7,261 unique human proteins separated PJI-associated samples based on symptom duration and identified a proteomic profile predictive of DAIR success. IMPORTANCE Chronic infections are generally understood to last months to years, with acute infections lasting days to weeks. The transition from acute to chronic infection is, however, poorly understood. Periprosthetic joint infection (PJI) has been considered more challenging to treat when “chronic” than when “acute.” A surgery preferred for its recovery time and cost—debridement, antibiotics, and implant retention (DAIR)—is recommended for PJI management when symptom duration is short; yet, even in this select patient group, DAIR is associated with a high treatment failure rate. A means to better identify those predicted to have a successful outcome if they undergo DAIR is needed. Here, over 7,000 proteins from human clinical PJI samples were measured and shown to be able to separate samples based on symptom duration. Importantly, a proteomic profile predictive of DAIR success was identified.

Study Design: A panel of 13 clinicians with experience in dermatology and primary care was assembled to review literature regarding the diagnostic workup of scarring and nonscarring alopecias. The literature for review included clinical trials, meta-analyses, systematic reviews, and previously published guidelines from the last 10 years. After review, the panel drafted a list of consensus statements and then voted on these statements using a modified eDelphi method in order to verify the validity and clarity of each statement. Objective: Our objective, as a panel, was to formulate a clear set of guidelines in the workup of various forms of hair loss by a systematic review of clinical data and literature on the matter. Background: Hair loss is a common and frustrating medical concern for patients worldwide and accounts for significant health care utilization and cost. Moreover, hair loss may present as a symptom of an underlying medical condition requiring attention and treatment. Results: After review, the panel reached a total of 22 consensus statements regarding recommendations for diagnostic testing in the setting of hair loss, 17 of those statements focused on nonscarring alopecias, and 5 statements directed toward scarring alopecias. The statements were evaluated by members of the panel and voted on through a modified eDelphi method and discussed in an open forum. Conclusion: The panel’s review revealed that the diagnostic laboratories and/or scalp biopsy should be considered to varying degrees depending on the type of hair loss at presentation. If there is concern for a scarring process, a biopsy should be strongly considered, while serum laboratory work may be of little benefit. In nonscarring alopecias including alopecia areata, telogen effluvium, and androgenetic alopecia, the literature supports ordering certain serologic tests based on the type of hair loss at presentation.

Abstract The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

Abstract Objective Autoimmune encephalitis is a cause of brain inflammation characterized by auto‐antibodies, which target cell surface neuronal proteins and lead to neuronal dysfunction. The most common form is associated with auto‐antibodies to leucine‐rich glioma‐inactivated 1 (LGI1) protein, the presentation of which includes frequent focal seizures. The exact cause of these auto‐antibodies remains unknown, but established predispositions include overrepresented human leukocyte antigen ( HLA ) alleles. Yet, these HLA alleles are themselves common in the healthy ancestry‐matched population. One potential etiological hypothesis is that an environmental trigger, such as the gut microbiome, interacts with a genetically predisposed individual. Methods To investigate this, we studied 42 patients with LGI1‐antibody encephalitis (LGI1‐Ab‐E) and 27 familial/environmentally matched controls, and performed metagenomic shotgun sequencing, to describe the compositional and functional differences in the gut microbiome. Results We observed that LGI1‐Ab‐E gut microbiomes exhibited a significant reduction in the ratio of Firmicutes (or Bacillota) and Bacteroidetes phyla, which is associated with the dosage of HLA susceptibility allele count in patients with LGI1‐Ab‐E. Furthermore, we identified differences in functional gene profiles in the gut microbiome that led to a reduction of neuroinflammatory protective short‐chain fatty acids (SCFAs) in LGI1‐Ab‐E patients. Significance Taken together, our results suggest that a compositional shift in the gut microbiome of LGI1‐Ab‐E associates with a neuroinflammatory state, possibly through the reduction of SCFA production. Our study highlights the potential of the gut microbiome to explain some of the complex condition and unravel etiological questions. Validation studies with greater sample sizes are recommended.

Abstract Dementia with Lewy bodies (DLB), a progressive neurodegenerative disease with heterogeneous clinical presentations, greatly impacts patients, caregivers, and society. Despite its frequency, diagnosing and treating DLB remains challenging. Advances in in vivo biomarker assays reflecting underlying pathology are improving disease identification, diagnostic accuracy, and therapeutic development for biologically targeted, disease‐modifying agents. Consequently, definitions of Alzheimer's disease and Parkinson's disease (PD) have shifted to focus on pathological changes occurring before clinical features, with proposed frameworks for detecting pathological amyloid and tau, neurodegeneration, and other markers (National Institute on Aging‐Alzheimer's Association) and alpha‐synucleinopathy and dopaminergic degeneration (Neuronal α‐synuclein Disease Integrated Staging System, SynNeurGe). The biological frameworks, particularly those related to alpha‐synuclein (α‐synuclein), have sparked debate about unifying DLB and PD under a single pathobiologic disease. This paper discusses the implications of these biological frameworks for the DLB community, addressing topics regarding multiple pathologies and neurochemical systems, clinical heterogeneity, and functional impairment, and exploring the potential impact on clinical trials and care. Highlights DLB is a progressive neurodegenerative disease with varied clinical presentations. Diagnosing and treating DLB remains challenging despite its frequency. Biological frameworks are reshaping Alzheimer's and Parkinson's definitions. In vivo biomarkers are improving DLB identification and diagnostic accuracy. Debate exists regarding unifying DLB and Parkinson's under one pathobiology.

Abstract Background and objective The placenta is crucial for fetal development; altered function is associated with complications and adverse neonatal outcomes. Our goal was to ascertain changes in the placental transcriptome in relation to neonatal outcome and fetal/placental sex. Study design Seventy-two mother-baby dyads were included. Demographic, obstetrical, neonatal, and infant health data were obtained through medical charts. Adverse neonatal outcome was defined as the presence of a pulmonary, cardiac, neurological or other health complication. Bulk RNA-sequencing of placental biopsies was obtained. P-value <0.05 was considered statistically significant. Results Neonates experiencing adverse outcomes were more likely to be premature or have lower birth weights. Analysis of the placental transcriptome revealed a predominant inflammatory profile in pregnancies associated with adverse neonatal outcomes with the top pathways being related to immune and inflammatory responses. Among differently expressed genes (DEGs), 1237 were upregulated and 239 were downregulated in adverse vs no adverse outcomes. Furthermore, sex-specific differences in gene expression were observed and indicated that male and female placentas displayed unique DEGs in association with adverse outcomes. Indeed, no DEG was observed in female placentas when comparing those without vs with adverse neonatal outcomes, as opposed to 1279 DEGs in male placentas, of which 91% were up-regulated in adverse subgroups. Conclusions These findings highlight that inflammatory pathways are upregulated in placentas in association with adverse neonatal outcomes, and showcase the importance of the fetal sex in understanding neonatal health. The placenta provides a unique tool for early identification of high-risk infants rapidly after delivery.

Abstract BACKGROUND Postpartum preeclampsia (PPPE) is a maternal condition characterized by de novo hypertension in the postpartum period with end-organ damage. We investigated the use of perinatal immune changes, through routine complete blood count (CBC), to identify high-risk individuals before PPPE development. METHODS We performed a retrospective matched case-control study of 100 individuals with PPPE, 200 term pregnancies (Ctrl) and 200 antenatal preeclampsia (PE). Detailed demographic, obstetrical, and laboratory data were retrieved from medical records. Statistical analysis was performed using one-way ANOVA, multivariate regression, and paired or unpaired t-tests, as appropriate. RESULTS Individuals who developed PPPE were significantly older and predominantly Black vs Ctrl and PE. Both PE and PPPE had higher pre-pregnancy BMI and increased personal and family history of hypertension/PE vs Ctrl (P < 0.001). Before delivery, individuals who later developed PPPE, had lower total leukocyte counts vs Ctrl (9.61 vs 10.75 × 109/L, P < 0.05) whereas monocytes percentage was elevated (8.07 vs 7.27%, P < 0.01). Comparing the postpartum/antenatal ratio in-between each condition revealed elevated leukocyte ratio in PPPE vs Ctrl (P < 0.001). The Neutrophils ratio was also increased, whereas lymphocytes and monocytes were decreased in PPPE vs both Ctrl and PE. After adjusting for race, maternal age, pre-pregnancy BMI, personal history of PE/HT, and diabetes mellitus, perinatal immune changes were still significantly associated with PPPE. CONCLUSIONS Globally, perinatal immune changes were observed in individuals with a seemingly uncomplicated pregnancy prior to the development of PPPE. This strongly supports that such changes could be used to identify high-risk individuals prior to disease onset.

Abstract P2x purinoreceptor 7 (P2RX7), an ATP-gated ion channel, is known to play pivotal roles in the progression of Alzheimer’s disease (AD), although its cell type-specific pathological mechanisms have yet to be elucidated. Here, we show that genetic deletion of P2rx7 mitigates brain atrophy, tau accumulation and cognitive impairment in PS19 tauopathy mice. Specific deletion of P2rx7 in microglia, but not astrocytes, significantly suppresses tau propagation from the entorhinal cortex to CA1 in the hippocampus, an early event in AD pathology. Single-cell (sc)-RNA sequencing of mouse brains revealed specific P2rx7 expression in microglia, inducing inflammatory changes accompanied by elevated extracellular vesicles (EVs) secretion in PS19 mice. Brain-derived EVs (BDEVs) proteome demonstrated that P2RX7 increases EV cargo loading of tau and mitochondrial molecules in BDEVs from PS19 mice, which was further validated by single-molecule super-resolution. Notably, following the injection of BDEVs isolated from PS19 mice with or without P2rx7 deficiency, the microglial transcriptome of recipient mice revealed enriched DNA-sensing and type II interferon signaling in response to BDEVs from PS19 mice, which was diminished in the group injected with P2rx7-deficient BDEVs. Thus, our results indicate that P2RX7 regulates EV-mediated tau and mitochondrial transfer and inflammatory activation in microglia with increased EV secretion, thereby contributing to tauopathy and neurodegeneration, highlighting the therapeutic potential of targeting the P2RX7-EV axis in AD.

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.

TPS5118 Background: The median overall survival of patients with mCRPC remains under 2 years even with newer therapies. Xaluritamig, an XmAb 2+1 T-cell engager that targets the six-transmembrane epithelial antigen of prostate 1 (STEAP1), facilitates lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. In a first-in-human study, xaluritamig demonstrated encouraging efficacy and a manageable safety profile for patients with mCRPC refractory to standard of care therapies (Kelly WK, et al. Cancer Discov. 2024;14(1):76-89). Methods: XALute is a randomized, multicenter, open-label, phase 3 study to evaluate the efficacy and safety of xaluritamig vs cabazitaxel or second ARDT in men with mCRPC previously treated with taxane chemotherapy. Enrollment in the control arm treatments will be split evenly between cabazitaxel and second ARDT. Stratification factors include LDH ≤ or > 260 IU/L, liver metastases (Y/N), prior prostate-specific membrane antigen radioligand therapy (PSMA-RLT) (Y/N) and the intention to treat with cabazitaxel or ARDT switch. Approximately 675 patients will be enrolled. Participants will be randomly assigned in a 2:1 ratio to xaluritamig monotherapy or standard care. Participants will receive treatment until radiographic disease progression per Prostate Cancer Clinical Trials Working Group 3 (PCWG3), unacceptable toxicity, initiation of other anticancer therapy, withdrawal of consent, death, or end of study as determined by the sponsor. The primary efficacy endpoint is overall survival. The key secondary efficacy endpoint is radiographic progression-free survival per PCWG3 by blinded independent central review. Key inclusion criteria are pathological/cytological confirmation of prostate adenocarcinoma; mCRPC with at least one metastatic lesion; evidence of progressive disease; prior treatment with at least one ARDT; one taxane therapy in the mCRPC setting, and ongoing androgen deprivation with serum testosterone levels (<50 ng/dL or <1.7 nmol/L). Prior treatment with PSMA-RLT, poly ADP-ribosylation inhibitors, and immune checkpoint inhibitors are permitted. Exclusion criteria include prior STEAP1-targeted therapy, any anticancer therapy within 4 weeks prior to first dose of study treatment (not including androgen deprivation therapy), prior PSMA-RLT within 2 months of first dose of study treatment unless less than 2 cycles received, and prior radionuclide therapy (radium-223) within 2 months of first dose of study treatment To mitigate risk of cytokine release syndrome, xaluritamig will be administered with step dosing. Cabazitaxel or second ARDT will be administered according to regional prescribing information. Funded by Amgen Inc. Clinical trial information: NCT06691984 .