Citations

ABSTRACT Knowledge of Treponema pallidum subspecies pallidum ( TPA ) outer membrane protein (OMP) sequence variability is essential for understanding spirochete proliferation within endemic populations as well as design of a globally effective syphilis vaccine. Our group has identified extracellular loops (ECLs) of TPA BamA (TP0326) and members of the FadL family (TP0548, TP0856, TP0858, TP0859, and TP0865) as potential components of a multivalent vaccine cocktail. As part of a consortium to explore TPA strain diversity, we mapped the variability of BamA and FadL orthologs in 186 TPA strains from Malawi, China and Colombia onto predicted 3D structures. The 186 genomes fell into eight subclades (five Nichols-, three SS14-lineage) with substantial geographic restriction. Single nucleotide variants accounted for the large majority of proteoforms, with variability notably higher within the Nichols-lineage strains. Most mutations were in regions of the proteins predicted to be extracellular and harboring B cell epitopes. We observed a striking difference in the degree of variability between the six OMPs, suggesting that these proteins are following divergent evolutionary paths. Concatenation of OMP sequences recapitulated the phylogenetic structure of the TPA strains, effectively segregating within clades and largely clustering by subclades. Lastly, we noted that BamA and FadL candidate ECL vaccinogens previously shown to elicit antibodies that kill treponemes during in vitro cultivation are well conserved. Taken as a whole, our study establishes a structural-phylogenetic approach for analyzing the forces shaping the host-pathogen interface in syphilis within endemic populations while informing selection of vaccine targets. IMPORTANCE Syphilis remains a major global health concern, reinforcing the need for a safe and effective vaccine. Understanding the variability of TPA OMPs is essential for tracking pathogen evolution and informing vaccine design. Here, we analyzed the variability of six TPA OMPs in 186 strains from Malawi, China, and Colombia, identifying protein-specific evolutionary patterns. Most mutations were localized in extracellular regions and, notably, appeared to correlate with the phylogenetic structure of TPA . Despite OMP heterogeneity, several candidate vaccinogens remained highly conserved, reinforcing their potential as globally effective vaccine targets. Our study establishes a structural-phylogenetic framework for dissecting the forces shaping the host-spirochete interface within endemic populations and provides a foundation for designing a globally effective syphilis vaccine.

AbstractINTRODUCTIONSelf‐reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear.METHODSWe analyzed 394 genetic‐FTD patients and 279 controls from the ALLFTD consortium, assessing annual neuropsychological performance and MRI‐based cortical thickness. Clinical characteristics and cortical thickness were compared between sexes. We used the residuals of linear regression models, which predict each participant's cognitive and behavioral performance levels relative to cortical thickness, as a proxy for reserve. We then modeled sex differences in longitudinal trajectories with linear mixed‐effects models.RESULTSSymptomatic females with genetic FTD had lower frontal cortical thickness than males, and the C9orf72 subgroup showed lower‐than‐expected frontal cortical thickness for a given level of executive functioning. Differences in cognitive reserve between sexes peaked near symptom onset but diminished thereafter.DISCUSSIONFemales with genetic FTD showed higher cognitive reserve than males, suggesting that self‐reported sex modulates resilience to frontotemporal neurodegeneration.Highlights Females with genetic FTD showed higher cognitive reserve than males. Those differences were particularly pronounced in the C9orf72 and GRN subgroups. The higher cognitive reserve in females declined as the disease progressed.

Abstract The International League Against Epilepsy (ILAE) has updated the operational classification of epileptic seizures, building upon the framework established in 2017. This revision, informed by the implementation experience, involved a working group appointed by the ILAE Executive Committee. Comprising 37 members from all ILAE regions, the group utilized a modified Delphi process, requiring a consensus threshold of more than two thirds for any proposal. Following public comments, the Executive Committee appointed seven additional experts to the revision task force to address and incorporate the issues raised, as appropriate. The updated classification maintains four main seizure classes: Focal, Generalized, Unknown (whether focal or generalized), and Unclassified. Taxonomic rules distinguish classifiers, which are considered to reflect biological classes and directly impact clinical management, from descriptors, which indicate other important seizure characteristics. Focal seizures and those of unknown origin are further classified by the patient's state of consciousness (impaired or preserved) during the seizure, defined operationally through clinical assessment of awareness and responsiveness. If the state of consciousness is undetermined, the seizure is classified under the parent term, that is, the main seizure class (focal seizure or seizure of unknown origin). Generalized seizures are grouped into absence seizures, generalized tonic–clonic seizures, and other generalized seizures, now including recognition of negative myoclonus as a seizure type. Seizures are described in the basic version as with or without observable manifestations, whereas an expanded version utilizes the chronological sequence of seizure semiology. This updated classification comprises four main classes and 21 seizure types. Special emphasis was placed on ensuring translatability into languages beyond English. Its aim is to establish a common language for all health care professionals involved in epilepsy care, from resource‐limited areas to highly specialized centers, and to provide accessible terms for patients and caregivers.

Study Design Systematic Review. Objective To assess the current literature regarding the accuracy of different imaging modalities and criteria used to assess lumbar fusion, and their correlation with surgical direct observation as the current Gold Standard. Methods Following PRISMA guidelines, we conducted a comprehensive search of PubMed, Embase, Google Scholar, and Cochrane Library, studies were included if they focused on patients with a prior history of lumbar interbody fusion and at least 1 year of radiographic follow-up. The review assessed the sensitivity, specificity, and accuracy of different imaging techniques, and their correlation with surgical findings. Results Thirteen studies (1989-2019) were reviewed, including 715 patients, common imaging modalities included plain radiographs (53.8%), Computed Tomography (CT) (69.2%), and dynamic radiographs (30.7%). CT appeared as the most utilized modality post-2006. There was substantial variability in diagnostic accuracy, with CT showing high variability in sensitivity and specificity. Descriptive criteria for fusion were widely used, but interobserver agreement was generally low. Conclusion The review highlights a lack of standardized criteria for assessing lumbar fusion. Despite advancements in imaging techniques, the variability in diagnostic parameters suggests a need for consensus and multicentric studies to stablish reliable, universal criteria for evaluating fusion success.

Abstract Background: Bladder cancer patients with lower socioeconomic status (SES) often present with more aggressive disease and face poor outcomes, likely due to complex interactions with risk factors linked to lower SES. However, little is known about the effect of low SES on bladder tumor biology at the molecular level. This study sought to characterize better the impact of low SES on the bladder tumor microenvironment. Methods: This is a retrospective analysis of 93 patients (63 male and 30 female) ranging from age 33 to 92 presenting to the University of Arizona Cancer Center with bladder cancer from 2016-2023. Each patient's neighborhood level of SES was scored using the Area Deprivation Index on a scale of 1-100, with 1 representing the highest SES and 100 the least. These patients were then split into tertile 1: 1-33 (T1: N=16), tertile 2: 34-67 (T2: N=43), and tertile 3: 68-100 (T3: N=34), and each patient’s tumor microenvironment and mutational landscape was characterized and compared utilizing NGS (592, NextSeq; WES, NovaSeq) and WTS Sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Statistical significance was determined using chi-square and Mann-Whitney U (p<0.05). Results: Our study had no significant difference between age, sex, and race between the three tertiles. Hispanic ethnicity was significantly higher in T3 (26.5%) when compared to T2 (7%) and T1 (0%), p=0.013. The frequency of TMB-H (>10 mutations/megabase) was significantly lower in T3 (15.6%) when compared to T2 (51.2%, p=0.02) and T1 (50%, p=0.01). There was significantly less T cell CD8+ infiltration in tertile 3 (0.02%) when compared to T2 (0.43%, p=0.04) and T1 (0.37%, p=0.08), and less dendritic cell infiltration in T3 (0%) when compared to T2 (0.1%, p=0.13) and T1 (0.64%, p=0.008). T regulatory cells were lower in T3 (1.37%) compared to T2 (2.13%, p=0.09) and T3 (2.02%, p=0.24). IHC-PD-L1 and gene expression for immune checkpoint genes, MHC-Class I, and MHC-Class II did not vary significantly between tertiles. KMT2C-mt was highest in T2 (21.1%) compared to T1 (3.12%, p=0.03) and T3 (6.67%). There was no other significant differences in mutation prevalence between the three tertiles. Discussion: In our study, lower SES bladder cancer patients had a lower amount of CD8+ cells, dendritic cell infiltration, and a low frequency of TMB-H, indicating a lower level of adaptive immune response present in the tumor microenvironment. Lower levels of adaptive immune activity have been associated with more aggressive tumor behavior and worse outcomes in bladder cancer patients. These findings provide a partial explanation of the molecular mechanisms underlying the poor prognosis observed in low SES patients with bladder cancer. Larger-scale studies exploring the impact of SES on tumor biology are essential as they hold significant therapeutic and preventive implications. Citation Format: Tom Marco, Kenneth Barker, Jesse Ritter, Numaan Mahmood, Rishab Srivastava, Amith Rao, Isaac Zarif, Ricardo Estrada Mendizabal, Sachin Deshmukh, Edgar Tapia, Jose Guillen-Rodriguez, Juan Chipollini, Alejandro Recio-Boiles. The effects of socioeconomic deprivation on the tumor microenvironment of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7392.

Study Design: Analysis of prospectively collected data. Objective: To assess if systemic illness severity affects cervical spondylotic myelopathy (CSM) surgery outcomes. Summary of Background Data: It remains unclear if CSM patients with poor physical status/severe systemic illness benefit as much from surgery as those in good condition. Methods: Using the Quality Outcomes Database CSM cohort and the American Association of Anesthesiology (ASA) grade as a surrogate for illness burden, we compared patients with (ASA 3–4) and without (ASA 1–2) severe systemic illness, including rates of readmission and 24-month minimal clinically important differences (MCID) achievement for patient-reported outcomes (PROs)—numerical rating score (NRS) arm and neck pain, neck pain-related disability (NDI), and quality of life (EQ-5D). Results: Of 1141 CSM patients, 1062 had ASA grades recorded. Of these 1062 patients, 70.2% had a 2-year follow-up for mJOA, and 81%–84% had a follow-up for NRS arm and neck, NDI, and EQ-5D. Five hundred twenty-one patients (49.1%) had mild (ASA 1–2) and 541 (50.9%) had severe systemic illness (ASA 3–4). The severe disease cohort was older (63.3±11.0 vs. 57.4±11.7), had higher BMI (31.4±7.0 vs. 28.9±5.6), had more comorbidities (diabetes, coronary artery disease, depression), and had less independent ambulation (71.3% vs. 90.6%) ( P <0.05). At baseline, severe disease patients had worse NRS arm (5.2±3.5 vs. 4.7±3.4) and neck (5.5±3.2 vs. 5.1±3.3) pain, NDI (40.5±20.1 vs. 36.8±21.0), and EQ-5D (0.53±0.22 vs. 0.59±0.22) scores ( P <0.05). Perioperatively, the severe disease cohort had longer hospitalizations (2.4±2.6 vs. 1.7±2.0 days) and increased nonhome discharges (17% vs. 5%) ( P <0.05). The severe disease cohort had higher 90-day readmissions (7.6% vs. 2.5%), including surgery-related (3.7% vs. 1.5%) and non–surgery-related reasons (3.9% vs. 1.0%) ( P <0.05). On multivariate analysis, increased ASA grade was significantly associated with 90-day readmissions (OR: 2.55 per 1-grade increase, 95% CI: 1.38–4.83). However, both severe and mild disease cohorts had similarly high rates of achieving 2-year MCID for mJOA (67.5% vs. 66.0%), NRS arm (72.0% vs. 74.1%), neck (69.5% vs. 69.4%) pain, NDI (63.1% vs. 68.1%), and EQ-5D (67.9% vs. 66.9%) ( P >0.05). Conclusion: Patients with severe systemic illness (higher ASA) have worse baseline PROs and higher 90-day readmissions. However, they achieve similar MCID rates for mJOA and all measured PROs 2 years postoperatively.

Background Severe alcohol-associated hepatitis (sAH) is a life-threatening condition with high mortality, where corticosteroid use is the only treatment that has shown short-term benefits. Pentoxifylline, an anti-tumour necrosis factor-alpha agent, has been proposed for its potential to improve outcomes, especially in patients with acute kidney injury (AKI). We aimed to evaluate the impact of pentoxifylline on mortality in patients with sAH and AKI in a well-characterised global cohort. Methods We conducted a retrospective, registry-based study including patients meeting the National Institute on Alcohol Abuse and Alcoholism clinical criteria for sAH and AKI. Mortality was the primary endpoint, with liver transplantation as a competing risk. Statistical analysis included Cox regression and Kaplan-Meier survival estimates. Results We included 525 patients from 20 centres across eight countries. The median age was 48 years, with 26.1% females, and 76.9% had a history of cirrhosis. Multivariable Cox regression models showed that pentoxifylline use was not associated with survival (HR 1.20, 95% CI 0.85 to 1.69, p=0.291). Factors associated with mortality included age (HR 1.23, 95% CI 1.10 to 1.36, p<0.001), Model for End-Stage Liver Disease score at admission (HR 1.06, 95% CI 1.04 to 1.08, p<0.001) and renal replacement therapy use (HR 1.39, 95% CI 1.05 to 1.84, p=0.019). The main causes of death were multiple organ failure (42%), infections (10%), oesophageal varices bleeding (7%) and renal failure (6%). Conclusion Pentoxifylline showed no significant benefit on mortality in patients with sAH and AKI. Further studies are needed to refine treatment strategies for this high-risk group.

Abstract Background The Global Leadership Initiative on Malnutrition (GLIM) introduced an approach for malnutrition diagnosis in 2019 that comprised screening followed by assessment of three phenotypic criteria (weight loss, low body mass index [BMI], and low muscle mass) and two etiologic criteria (reduced food intake/assimilation and inflammation/disease burden). This planned update reconsiders the GLIM framework based on published knowledge and experience over the past 5 years. Methods A working group ( n = 43 members) conducted a literature search spanning 2019–2024 using the keywords “Global Leadership Initiative on Malnutrition or GLIM.” Prior GLIM guidance activities for using the criteria on muscle mass and inflammation were reviewed. Successive rounds of revision and review were used to achieve consensus. Results More than 400 scientific reports were published in peer‐reviewed journals, forming the basis of 10 systematic reviews, some including meta‐analyses of GLIM validity that indicate strong construct and predictive validity. Limitations and future priorities are discussed. Working group findings suggest that assessment of low muscle mass should be guided by experience and available technological resources. Clinical judgment may suffice to evaluate the inflammation/disease burden etiologic criterion. No revisions of the weight loss, low BMI, or reduced food intake/assimilation criteria are suggested. After two rounds of review and revision, the working group secured 100% agreement with the conclusions reported in the 5‐year update. Conclusion Ongoing initiatives target priorities that include malnutrition risk screening procedures, GLIM adaptation to the intensive care setting, assessment in support of the reduced food intake/assimilation criterion, and determination of malnutrition in obesity.

BACKGROUND: Data registries lack a definitive classification system that distinguishes different locations of colon cancer from one another. OBJECTIVE: To establish an international consensus on the definition of primary colon cancer segment locations. DESIGN: Between December 2022 and June 2023, Delphi survey study was conducted to seek opinions from relevant international experts and eventually develop a consensus definition of each colon cancer segment. SETTING: Three-round online-based Delphi survey study. INTERVENTIONS: Online survey included 17 questions. In the first two rounds, participating experts were asked to rank each statement on a scale of 1–9 (9 is the most relevant). Consensus statements and definitions were revised according to results, obtaining a consensus score of 7–9. During the third round and online meeting, definitions and statements reached a moderate or high consensus(above 4 in more than 70% of participants) were included. MAIN OUTCOME AND MEASURE: Primary goal of our project was focused on precisely localizing the specific segment affected by primary colon cancer, rather than to identify surgical treatment or type of resection needed for particular segment. RESULTS: The first round included 331 experts, 301 (91%) completed the second round, and 295 (98%) completed the final round. Experts strongly supported the use of a “10 cm rule” to describe colon cancer sites at the flexures and anatomical landmarks for other segments. Regarding the definition of rectosigmoid cancer, experts from America and Europe reached a high consensus that the term rectosigmoid as a colon cancer location must be abolished in contrast to experts from Asia. Description of cancers overlapping segments achieved a consensus of 64%. LIMITATIONS: Subjective decisions are based on individual expert clinical experience. CONCLUSIONS: This Delphi survey, the first internationally conducted consensus study, achieved a remarkable level of consensus among a panel of global experts. Ambiguity still exists regarding overlapping lesions. See Video Abstract .

Mitral regurgitation (MR) in lung transplant (LTx) recipients is a rare but complex cardiopulmonary phenomenon. The overlap between symptoms of MR and post-LTx complications, such as primary graft dysfunction, complicates its diagnosis and management. This systematic review aims to characterize the incidence, pathophysiology, presentation, and management of MR in LTx patients. We conducted a literature search in PubMed, Web of Science, Scopus, and Embase. The search yielded 133 studies, of which 11 were included. Data regarding MR development, clinical presentation, echocardiographic findings, and management strategies were extracted and analyzed. Perioperative MR, occurring during or immediately post-LTx, was frequently attributed to the systolic anterior motion of the mitral valve (MV) occurring in the setting of hypovolemia and/or inotrope usage. Later postoperative MR, on the other hand, was associated with reverse ventricular remodeling and mitral annular dilation, although some variability in the literature was present. Preexisting MR or ventricular dysfunction, elongated MV leaflets, and bilateral LTx procedure appeared to be risk factors for MR development. Management was dependent on the timing of MR and its pathophysiology, where systolic anterior motion–related MR was treated with medical therapy, whereas postoperative MR often required MV interventions. In conclusion, the diagnosis of MR in LTx patients is complicated by its symptomatic overlap with other post-LTx complications. Echocardiographic monitoring in patients with preexisting MR, regardless of severity, is essential for early identification and management. Further research is needed to better understand the underlying mechanisms and refine management strategies for MR in this population.