Citations

INTRODUCTION: A Model for End-Stage Liver Disease-lactate (MELD-LA) score is an independent predictor of inpatient mortality and organ failure validated in more than 8,600 patients across diverse settings. However, its utility in sepsis, particularly when combined with lactate clearance (LA clearance), has not been fully evaluated. In this study, we examined the dynamic role of MELD-LA with 24-hour LA clearance as a predictor of 30-day mortality in critically ill patients with cirrhosis and sepsis. METHODS: We analyzed cirrhosis patients with sepsis admitted to the intensive care unit (ICU) in a large US healthcare system (20 hospitals) from 2014 to 2022, examining MELD-LA and LA clearance within 24 hours as predictors of 30-day mortality. We externally validated our findings in the Asian Pacific Association for the Study of the Liver-acute-on-chronic liver failure Research Consortium, a multinational Asian cohort (31 centers) from 2009 to 2019. RESULTS: A total of 3,879 cirrhosis patients with sepsis were admitted to the ICU (43.2% female, 20.5% Hispanic, 12.4% on dialysis; mean initial LA 4.5 mmol/L, MELD 20.8, MELD-LA 17.6). Survivors showed a median lactate change of −1.04 (35% clearance) compared with −0.4 (12%) for nonsurvivors. LA clearance within 24 hours was influenced by the presenting MELD-LA. In the North American cohort, ≥35% LA clearance was associated with improved 30-day survival (odds ratio 0.41, 95% CI 0.31–0.53; P < 0.001). Similarly, in the Asian Pacific Association for the Study of the Liver cohort (n = 1,259), ≥35% clearance was linked to a 60% reduction in mortality (odds ratio 0.42, 95% CI 0.28–0.62; P < 0.001). When stratified by LA clearance, patients with LA clearance of ≥35% had a higher percentage of early administration of resuscitative measures than those with LA clearance of < 10% especially regarding early antibiotic administration (82.5% vs 67.6%; P value <0.001). DISCUSSION: Early reduction in initial LA by one-third predicts 30-day mortality and may indicate treatment response in cirrhosis patients with sepsis in the ICU. Combining MELD-LA and LA clearance early enables better risk stratification and informs management.

ABSTRACT Musculoskeletal infection (MSKI) remains a major problem after trauma and elective orthopedic surgery. Chronic MSKI is related to the formation of biofilm, which impairs diagnosis and effective treatments. Therefore, to understand and communicate global standards and best practices, the 2025 International Consensus Meeting (ICM) on MSKI created a Biofilm Section to address crucial aspects of biofilm biology pertaining to its mechanisms of drug resistance and immune evasion, and potential approaches to overcome them. This featured a 2‐year process, with final voting and discussion on May 8–10, 2025, in Istanbul, Turkey. This Consensus Article is the effort of the Biofilm Basic Mechanisms Workgroup, which interpreted the results on ICM questions related to (1) the infectious microenvironment; (2) appropriate inocula in preclinical research; (3) biofilm behavior in infected tissues; and (4) synergy within biofilms and with other comorbidities. Collectively, we find that this field has the necessary research tools to discover the pathophysiology of orthopedic implant‐associated biofilm development and maturation, perform clinically relevant studies in animal models, and elucidate mechanisms that allow opportunistic infections in compromised tissues and patients with other health issues.

Abstract Bone marrow is the primary immune organ responsible for stem cell maintenance and hematopoiesis. However, the contribution of the bone marrow niche for the generation of adaptive immune responses is less well-understood. We therefore assessed the capacity of virus antigen-specific CD8 T cells to be generated and expanded in bone marrow following acute neurotropic virus infection. Intracranial infection with the neurotropic Theiler’s Murine Encephalomyelitis Virus (TMEV) results in an acute infection in the C57BL/6 mouse which is cleared within 4 weeks post infection due to the generation of an antigen-specific CD8 T cell response against the immunodominant epitope VP2 121-130 . We determined that 1-10% of CD8 T cells present in the femoral, and sternal bone marrow were virus antigen-specific 5-7 days after intracranial TMEV infection. We determined that antigen-specific CD8 T cells were generated in the bone marrow with similar kinetics to that of conventional responses in the secondary lymphoid organs. Importantly, continuous treatment with FTY720, which sequesters T cells outside of the blood, did not eliminate antigen-specific CD8 T cells in the bone marrow compartment indicating generation within the bone marrow niche. Similarly, injection of Poly I:C admixed with fluorescently labeled ovalbumin into the brain generated a similar antigen-specific CD8 T cell response in the bone marrow indicating these responses occur following various brain insults. This model also identified the likely antigen presenting cell (APC) responsible for scavenging antigens from the brain and trafficking into the bone marrow as a migratory myeloid-derived APC. Moreover, following clearance of TMEV infection, CD8 T cells in the bone marrow established durable memory. Antigen-specific memory CD8 T cells in the bone marrow reactivated and expanded upon cognate antigen reencounter. Antigen-specific reactivation of memory CD8 T cells within the bone marrow caused a concurrent increase in Lineage-, Sca-1+, c-Kit+ (LSK) and CD11b+ MHCII+ myeloid cells. This increase in the LSKs and myeloid cells in the bone marrow niche was abrogated with CD8 T cell depletion. We conclude that brain viral infections induce in situ effector and memory T cell responses within the bone marrow compartment. Memory recall CD8 T cell responses induce niche dysregulation by expanding LSK cells and lead to an influx of MHCII+ myeloid cells. Our data pave the way for crucial studies of bone marrow resident antigen-specific CD8 T cells in health and diseases.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722

Abstract Background Alzheimer's disease (AD) exhibits significant genetic heterogeneity, with no single model fully explaining its inheritance pattern. Structural variants (SVs) may contribute to the missing heritability of AD, particularly in disease pathology and familial AD, which remain largely unexplored. Method Structural variants (SVs) were analyzed in unrelated 1,162 individuals from the ROSMAP study (687 cognitively normal (CN), 475 AD patients), as well as 197 Non‐Hispanic White (NHW) families (926 individuals, 58.5% with AD) and 214 Caribbean Hispanic (CH) families (1,340 individuals, 59.17% with AD). Large insertions and deletions were identified using Manta, Absinthe, and MELT from whole‐genome sequencing, supplemented by Sniffles2 and external SV call sets. This approach generated a unified VCF file containing 45,251 insertions and 76,566 deletions. After filtering for missingness rate and allele counts, a total of 9,290 insertions and 9,529 deletions were retained for analysis. Genome‐wide SV analyses were performed with AD‐related metrics in ROSMAP, adjusting for age, sex, and principal components, and validated in an independent ADSP replication cohort comprising 29,055 unrelated individuals (17,110 CN and 11,945 AD patients). Result We identified nine SVs (one insertion and eight deletions) segregating in AD families. An insertion near PDCD10 in NHW families reached genome‐wide significance ( p <5×10 ‐8 ) for AD risk in the replication cohort. Two deletions in KIF26B and SPHKAP were found in both CH and NHW families, while five appeared only in NHW and one in CH. All eight deletions showed genome‐wide significance for AD risk. SV GWAS on AD pathologies in ROSMAP revealed an insertion in INPP4B with the strongest association to global brain pathology (β=0.19; p = 2.32×10 ‐5 ), also linked to pathological AD, diffuse plaques, and Braak staging. A deletion near ADGRB1 (β=1.53; p = 5.05×10 ‐6 ) was associated with neuritic plaques, and another near ARMC2 (β=1.66; p = 2.17×10 ‐6 ) was linked to diffuse plaques. All three SVs associated with AD ( p <5×10 ‐6 ) in replication. Conclusion Our findings reveal numerous SVs segregating in familial AD across both CH and NHW families, as well as additional SVs linked to sporadic AD. Prioritizing these SVs based on their potential effects on gene function and expression will provide deeper insight into their contributions to both familial and sporadic AD.

Abstract Context Adult growth hormone (GH) deficiency (GHD) is characterized by metabolic abnormalities caused by insufficient GH production. Lonapegsomatropin, a prodrug administered once weekly, was designed to provide sustained release of unmodified somatropin to reduce the burden of daily somatropin injections. Objective This work aimed to evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD. Methods The foresiGHt trial was a multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and active-controlled (open-label) trial (NCT04615273) conducted at 116 centers in North America, Europe, and Asia-Pacific. The trial randomly assigned and dosed 259 adults with GHD. Participants were randomly assigned 1:1:1 to receive once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin for 38 weeks. The primary efficacy end point was change from baseline in trunk percent fat at week 38. Secondary efficacy end points included change from baseline in trunk fat mass and total body lean mass. Results At week 38, lonapegsomatropin significantly reduced trunk percent fat (−1.68% vs +0.37%; least squares [LS] mean difference −2.04%; P &lt; .001), increased total body lean mass (+1.60 kg vs −0.11 kg; LS mean difference 1.70 kg; P &lt; .0001), and reduced trunk fat mass (−0.48 kg vs +0.22 kg; LS mean difference −0.70 kg; P = .0053) vs placebo. The safety and tolerability profile of lonapegsomatropin was comparable to somatropin. Conclusion The foresiGHt trial met its primary efficacy end point by demonstrating superiority of lonapegsomatropin vs placebo with similar safety and tolerability, supporting its potential as a once-weekly treatment option for adults with GHD.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Abstract Introduction: Although current clinical treatment approaches targeting Bruton Tyrosine Kinase (BTK) and BCL2, either as monotherapy or in combination are highly effective in chronic lymphocytic leukemia (CLL), CLL remains incurable. Identifying novel drugs that are potent and effective in the relapsed/refractory (RR) setting remains an unmet need. Methods: Utilizing the CellTiter-Glo 2.0 Cell Viability Assay, we have developed a preclinical drug screening platform which allows conducting drug sensitivity profiling of primary peripheral blood mononuclear cells (PBMCs) collected from CLL patients to a panel of drugs, in the presence and/or absence of bone marrow stromal cells (BMSCs). This unique system mimics the in vivo stromal microenvironment in CLL and enables testing of multiple drug responses in primary patient samples, particularly when leukemic cell numbers are low. In this study, we employed this high throughput drug screening platform to profile drug sensitivity in CLL B cells after disease progression on a BTK inhibitor (BTKi) to a panel of 12 drugs, including inhibitors of BCL2 (venetoclax and LP-118 [Newave]), AXL (TP-0903), histone deacetylase (panobinostat and belinostat), p53 (eprenetapopt and idasanutlin), proteasome (carfizomib) and Type III Receptor Tyrosine Kinase (crenolanib), next generation BTKi (LP-168 [Newave]), as well as a novel anti-cancer drug transcriptional chemical inducer of proximity (TCIP1) and the natural green tea extract (GTE) product Sunphenon 90D (Taiyo International). After 24-hour drug exposure, leukemic cell viability was measured, killing curves and IC50 levels generated and calculated by nonlinear curve regression in GraphPad Prism. Results: Using the Mayo Clinic CLL Database and the Mayo Clinic CLL Tissue Bank, we identified 47 patients with RR CLL, all of whom experienced disease progressionon a BTKi (35 ibrutinib +/- CD20 antibody, 10 acalabrutinib +/- CD20 antibody, 2 other). Median age at BTKi initiation was 64 years (range, 41-82), and 36 (77%) were male. IGHV status was unmutated in 44 (94%) patients, FISH at diagnosis showed del17p in 11 (27%), del11q in 6 (15%), +12 in 5 (12%), del13q in 12 (30%), and not detected in 6 (15%) patients. TP53 mutation was seen in 13 (32%) patients at the start of BTKi therapy. Median number of lines of CLL therapy prior to start of BTKi was 2 (range, 0–8); 13 patients received BTKi as their first-line therapy. Our drug screening results showed definite responses to all tested drugs based on dose range generated killing curves and IC50 levels for 30 RR CLL patient samples, though results varied. Among 12 drugs tested, LP-118 (0.1nM), venetoclax (2.6nM), carfizomib (2.2nM), TP-0903 (116.2nM), crenolanib (1769nM), and TCIP1 (1805nM) demonstrated the highest killing effects, while the remaining generated killing but at higher doses: belinostat (6800nM), eprenetapopt (4500nM), idasanutlin (4900nM), LP-168 (7500nM) and GTE (55.6uM). We also observed that RR CLL cohort exhibited significantly increased drug resistance to most of the tested drugs in the presence of BMSCs with corresponding increases in IC50s (with vs. without BMSCs, fold-change respectively): LP-118 3.92-fold, venetoclax 1.98-fold, carfilzomib 2.58-fold, TP-0903 1.65-fold, panobinostat 204.23-fold, TCIP1 1.91-fold, crenolanib 1.31-fold, idasanutlin 1.69-fold, belinostat 6.14-fold, LP-168 1.29-fold, eprenetapopt 3.44-fold and GTE 1.08-fold (11 out of 12 with p-values &lt;0.05 except for GTE which was not significant, Mann-Whitney U test). We found that even for three drugs with the strongest killing effect based on IC50 levels (LP-118, venetoclax, carfilzomib), their killing effects were significantly reduced in the presence of BMSC (p=0.0002, 0.0002, and &lt;0.0001, respectively). Conclusions: Our results highlight the spectrum of currently available drugs that show promise for therapeutic use in patients with RR CLL who experience disease progression on BTKi. The killing impact was still seen, albeit diminished, even in the presence of BMSC. Our ongoing work will be to associate the drug profiles with each patient's clinical history, as well as to the comprehensive genetic and epigenetic features of the CLL B cell clone.

BACKGROUND: Although obesity and insulin resistance (IR) are established risk factors for left heart dysfunction, their clinical impact in group 1 pulmonary hypertension (PH) remains unclear. We sought to determine the impact of excess adiposity versus IR on biventricular hemodynamic and functional reserve in group 1 PH. METHODS: Homeostasis model of insulin resistance and adiposity indices (body mass index [BMI], fat mass, waist circumference) were measured among group 1 patients with PH recruited to PVDOMICS (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Functional capacity, and dynamic pulmonary capillary wedge pressure (PCWP) and right atrial pressure responses were compared stratified by obesity (BMI≥30 kg/m 2 ) and IR status (HOMA-IR≥2.6) using repeated-measure mixed models. RESULTS: Among patients with group 1 PH (n=418), 158 (38%) had BMI≥30 kg/m 2 (94 [60%] of whom had IR), and 260 (62%) had BMI<30 kg/m 2 (74 [28%] of whom had IR). Among those with waist circumference measurement (n=375), 287 (77%) had excess adiposity by elevated waist/height ratio, with 214 (57%) having elevated waist circumference. Patients with obesity had worse quality of life, exercise capacity and left heart remodeling, along with higher resting/dynamic PCWP, right atrial pressure and cardiac output ( P <0.0001 for all). Higher PCWP response with obesity persisted after adjusting for IR (IR-adjusted PCWP+2.5 mm Hg [95% CI, +1.4 to +3.6]; P <0.0001). All adiposity indices were consistently associated with PCWP response, but IR was not. Similar associations were observed between adiposity indices with higher right atrial pressure and cardiac output. Greater visceral adiposity as measured by body shape index (hazard ratio, 2.01 [95% CI, 1.16–3.47]; P =0.01) or weight-adjusted waist index (hazard ratio, 1.64 [95% CI, 1.10–2.46]; P =0.01) was associated with worse survival. CONCLUSIONS: Excess adiposity is common in group 1 PH, occurring in 4 out of 5 patients by the more sensitive waist/height ratio, in contrast to only 2 out of 5 patients having obesity by traditional BMI criteria. Excess adiposity is associated with higher biventricular filling pressures, cardiac output demand, worse functional status and reduced survival. These data support trials of adipose-reducing therapies in patients with group 1 PH and excess adiposity.

ABSTRACT Background We recently published the first real‐world multicenter and multi‐institutional study of cisplatin, gemcitabine, and durvalumab in patients with advanced biliary tract cancer (BTC). Here we present an expanded patient cohort with an increased sample size and longer median follow‐up. Methods The study population included patients with advanced BTC, who received cisplatin/gemcitabine plus durvalumab at 55 centers across 12 countries in Europe, the United States, and Asia. The primary endpoints of the study were progression‐free survival (PFS) and overall survival (OS). Secondary endpoints were overall response rate (ORR) and safety. Results Overall, 1358 patients were enrolled. Median PFS was 7.6 months (95% CI: 7.2–8.1), and median OS was 15.6 months (95% CI: 14.8–16.5). ORR was 35.6%, and DCR was 82.7%. Any grade AEs occurred in 1213 patients (89.3%). Grade 3–4 AEs occurred in 597 patients (43.2%). The rate of immune‐related AEs (irAE) was 20.3%. Grade 3–4 irAE occurred in 3.0% of patients. At the multivariate analysis for OS, normal albumin level (HR 0.68, 95% CI 0.57–0.81, p < 0.0001), CEA levels within normal ranges (HR 0.68, 95% CI 0.57–0.82, p < 0.0001), NLR < 3 (HR 0.62, 95% CI 0.52–0.74, p < 0.0001), ECOG PS 0 (HR 0.51, 95% CI 0.42–0.61, p < 0.0001), and prior surgery (HR 0.80, 95% CI 0.65–0.99, p = 0.036) were positive prognostic factors. Conclusion The updated findings, derived from an expanded cohort, further support the adoption of durvalumab in combination with gemcitabine and cisplatin in routine clinical practice, reinforcing the efficacy and safety outcomes demonstrated in the phase III TOPAZ‐1 trial.