Elevated Burden Research Articles

Abstract 14816: PCSK9 Inhibitors Modify Plaque and Reduce Plaque Progression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Elevated coronary plaque burden and high-risk plaque characteristics, such as thin fibrous cap, are associated with an increased risk of adverse cardiovascular events. However, there is limited evidence on the effect of PCSK9 inhibitors (PCSK9i) on changes to plaque burden and composition. Hypothesis: We aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of standard lipid-lowering therapy with vs. without PCSK9i on plaque burden and phenotype. Methods: We searched PubMed, Embase and Cochrane Central for studies that performed serial intravascular imaging comparing patients with vs. without PCKS9i therapy. Two reviewers independently performed study selection, data extraction and assessment of bias. All outcomes were continuous; thus, we computed pooled mean difference (MD) or standardized mean difference (SMD) with 95% confidence intervals (CI). Random-effects models were used. Statistical analysis was performed using Review Manager 5.4.1. Results: We included 1,696 patients from 6 RCTs. The mean follow-up ranged from 36 to 76 weeks. Mean age ranged from 58.4 to 61.8 years; 1,246 (65%) were male; and 368 (21.6%) had previous myocardial infarction. Percent atheroma volume (MD -1.05%; 95% CI -1.32, -0.77%; p<0.001), total atheroma volume (MD -6.33 mm 3 ; 95% CI -10.01,-2.66 mm 3 ; p<0.001), and total lipid index (SMD -0.58; 95% CI -0.90,-0.26; p<0.001) were significantly reduced in patients treated with PCSK9i. The minimum fibrous cap thickness (SMD 0.59; 95% CI 0.26,0.93; p<0.001) was also significantly improved in patients randomized to PCSK9i. Conclusions: Our findings suggests that PCSK9i reduce progression of coronary atherosclerosis and stabilizes plaque, as evidence by favorable changes in percent atheroma volume, total atheroma volume, lipid index of the plaque, and minimal fibrous cap thickness.

Abstract 13051: Profiling CD8+ T Cell Activation in Experimental Models With LDL-R Deficiency and in Patients With Familial Hypercholesteroleamia

Introduction and Hypothesis: Familial Hypercholesterolaemia (FH) is a rare genetic disease characterized by elevated plasma cholesterol levels, xanthomas, overt atherosclerosis and premature cardiovascular death. HoFH and severe HeFH present an elevated inflammatory burden and poorly responsive to therapeutics such as anti-PCSK9 monoclonal antibodies. Therefore, innovative approaches to diagnose the severity of the disease and control the over-activation of the immune-inflammatory response in the arterial wall of FH patients should be studied to improve the management of this genetic disease. Here we profiled the activation of CD8+ T lymphocytes from experimental models and with patients with clinical diagnosis of FH. Methods: Immunophenotypic characterization of T cells from WT and LDLR KO mice was performed in vitro and in vivo coupled to proteomics and WB analysis on isolated T cells. CD8 T cell response in FH patients, carrying mutations in the LDLR gene, was profiled. Results: LDLR mRNA expression increased after in vitro activation of CD8, but not CD4 T cells, suggesting a different regulation of cholesterol homeostasis between T cell subsets. LDLR deficiency mainly affected CD8 T cell activation as demonstrated by reduced in vitro and in vivo proliferation and cytokine production after ovalbumin vaccination of LDL-R KO T cells compared to their wild type counterpart. The addition of LDL to serum free media increased CD8 proliferation in WT but not in KO CD8 T cells. Proteomic and WB analysis showed that this phenotype is the consequence of reduced mTORC1 activation and impaired lysosomal organization. The proliferation of CD8 T cells from FH patients was less pronounced compared to sex- and age-matched controls. In addition, CD8 T cells from FH vaccinated for seasonal influenza were tested in vitro with virus-derived peptides, showing a decreased granzyme production compared to CD8 from vaccinated controls. Conclusions: LDLR plays a critical role in regulating the immunometabolic reprogramming of activated CD8 T cells by fuelling the cholesterol-lysosome-mTORC1 axis. Acknowledgments: This study is supported by a Grant from the Italian Ministry of Health: RF-2019-12370896

Postoperative outcomes, predictors and trends of mortality and morbidity in patients undergoing hip fracture surgery with underlying aortic stenosis: a nationwide inpatient sample analysis

BackgroundHip fractures frequently necessitate hospitalization, especially among patients aged 75 and above who might concurrently suffer from aortic stenosis (AS). This study focuses on postoperative outcomes, potential determinants of morbidity and mortality, as well as evolving trends in patients with AS undergoing surgical repair of hip fractures.MethodsA retrospective analysis of the Nationwide Inpatient Sample from 2008 to 2019 was conducted. Hip fracture cases were identified, and a subgroup with AS was isolated using the ICD-9 and ICD-10 diagnostic codes. We compared baseline characteristics, postoperative in-hospital outcomes and trends in mortality and morbidity between patients with and without AS.ResultsFrom the dataset, 2,834,919 patients with hip fracture were identified on weighted analysis. Of these, 94,270 (3.3%) were found to have concurrent AS. The AS cohort was characterized by higher mean age and elevated burden of cardiovascular comorbidities, such as coronary artery disease, peripheral vascular disease, pulmonary hypertension, congestive heart failure and cardiac arrhythmias. Postoperative mortality following hip fracture surgery was greater in the AS groups compared to non-AS group (3.3% vs 1.57%, p < 0.001). Risk factors such as congestive heart failure (OR, 2.3[CI, 2.1–2.6]), age above 85 years (OR, 3.2[CI, 2.2–4.7]), cardiac arrhythmias (OR, 2.4[CI, 2.2–2.6]), end-stage renal disease (OR, 3.4[CI, 2.7–4.1]), malnutrition (OR, 2.3[CI, 2.1–2.7]) and AS (OR, 1.2[CI, 1.08–1.5] were associated with increased adjusted odds of postoperative mortality. AS was linked to higher adjusted odds of postoperative mortality (OR, 1.2 [CI, 1.1–1.5]) and complications such as acute myocardial infarction (OR, 1.2 [CI, 1.01–1.4]), cardiogenic shock (OR, 2.0[CI, 1.4–2.9]) and acute renal failure (OR, 1.1[CI, 1.02–1.2]). While hospital stay duration was comparable in both groups (average 5 days), the AS group incurred higher costs (mean $50,673 vs $44,607). The presence of acute heart failure in patients with AS and hip fracture significantly increased mortality, hospital stay, and cost. A notable decline in postoperative in-hospital mortality was observed in both groups from 2008–2019 though the rate of major in-hospital complications rose.ConclusionAS significantly influences postoperative in-hospital mortality and complication rates in hip fracture patients. While a reduction in postoperative mortality was observed in both AS and non-AS cohorts, the incidence of major in-hospital complications increased across both groups.

55 The Indirect Effect of Positive Aspects of Caregiving on the Relationship between Dementia Severity and Caregiver Burden

Objective:Caregiver burden tends to worsen as severity of dementia increases, and elevated burden can lead to negative consequences for dementia caregivers. In contrast, positive aspects of caregiving, such as feelings of being useful, needed, or appreciated as a caregiver, are associated with better outcomes. Caregivers reporting fewer positive experiences robustly demonstrate greater burden, suggesting that a lack of positive aspects of caregiving could be a key component of the relationship between dementia severity and burden. This study investigated whether an indirect effect of positive aspects of caregiving would be observed on the association between dementia severity and burden.Participants and Methods:Data were extracted from the medical records of 724 patients enrolled for services at an outpatient memory clinic. Caregiver-care recipient dyads were included based on a clinically supported patient diagnosis on the dementia spectrum following a comprehensive geriatric evaluation and having fully completed assessments from an informal caregiver. Caregivers completed the Zarit Burden Interview (ZBI) and the Positive Aspects of Caregiving (PAC) measures. The Montreal Cognitive Assessment and Mini-Mental State Exam were used to estimate dementia severity, standardized to create a single variable. Multiple potential covariates (e.g., age, gender, education, nature of dyadic relationship) were considered for inclusion in the model. A cross-sectional mediation analysis using the Hayes PROCESS macro explored presence of an indirect effect of PAC on the relationship between dementia severity and ZBI using 5000 bootstrap samples.Results:Of the proposed covariates, only caregiver age was correlated with any of the primary variables; this variable was controlled in subsequent analyses. Significant relationships emerged between dementia severity and ZBI (r=-.12, p&lt;.001), between PAC and ZBI (r=-.23, p&lt;.001), and between dementia severity and PAC (r=-.07, p&lt;.05). An indirect effect of positive aspects of caregiving on the relationship between dementia severity and ZBI was statistically significant (B= .0092, BC 95% CI [.0008, .0185]), accounting for 14.4% of the variance in the model.Conclusions:A small but significant indirect effect of positive aspects of caregiving was observed on the association between dementia severity and burden. Results suggest that as dementia severity worsens, a caregiver who experiences greater positive aspects of caregiving will sustain less burden. Longitudinal examination of these relationships is needed to fully understand causality. Findings may help healthcare providers tailor treatment to alleviate caregiver burden.

DRG2 in macrophages is crucial for initial inflammatory response and protection against Listeria monocytogenes infection

Innate immune response is critical for the control of Listeria monocytogenes infection. Here, we identified developmentally regulated GTP-binding protein 2 (DRG2) in macrophages as a major regulator of the innate immune response against L. monocytogenes infection. Both whole-body DRG2 knockout (KO) mice and macrophage-specific DRG2 KO mice had low levels of IL-6 during early infection and increased susceptibility to L. monocytogenes infection. Following an initial impaired inflammatory response of macrophages upon i.p. L. monocytogenes infection, DRG2−/− mice showed delayed recruitment of neutrophils and monocytes into the peritoneal cavity, which led to elevated bacterial burden, inflammatory cytokine production at a late infection time point, and liver micro-abscesses. DRG2 deficiency decreased the transcriptional activity of NF-κB and impaired the inflammatory response of both bone marrow-derived and peritoneal macrophages upon L. monocytogenes stimulation. Our findings reveal that DRG2 in macrophages is critical for the initial inflammatory response and protection against L. monocytogenes infection.

64 Neuroimaging Evidence of Neurodegenerative Disease in Former Professional American Football Players Who “Fail” Validity Testing: A Case Series

Objective:Former professional American football players have a high relative risk for neurodegenerative diseases like chronic traumatic encephalopathy (CTE). Interpreting low cognitive test scores in this population occasionally is complicated by performance on validity testing. Neuroimaging biomarkers may help inform whether a neurodegenerative disease is present in these situations. We report three cases of retired professional American football players who completed comprehensive neuropsychological testing, but “failed” performance validity tests, and underwent multimodal neuroimaging (structural MRI, Aß-PET, and tau-PET).Participants and Methods:Three cases were identified from the Focused Neuroimaging for the Neurodegenerative Disease Chronic Traumatic Encephalopathy (FIND-CTE) study, an ongoing multimodal imaging study of retired National Football League players with complaints of progressive cognitive decline conducted at Boston University and the UCSF Memory and Aging Center. Participants were relatively young (age range 55-65), had 16 or more years of education, and two identified as Black/African American. Raw neuropsychological test scores were converted to demographically-adjusted z-scores. Testing included standalone (Test of Memory Malingering; TOMM) and embedded (reliable digit span, RDS) performance validity measures. Validity cutoffs were TOMM Trial 2 &lt; 45 and RDS &lt; 7. Structural MRIs were interpreted by trained neurologists. Aß-PET with Florbetapir was used to quantify cortical Aß deposition as global Centiloids (0 = mean cortical signal for a young, cognitively normal, Aß negative individual in their 20s, 100 = mean cortical signal for a patient with mild-to-moderate Alzheimer’s disease dementia). Tau-PET was performed with MK-6240 and first quantified as standardized uptake value ratio (SUVR) map. The SUVR map was then converted to a w-score map representing signal intensity relative to a sample of demographically-matched healthy controls.Results:All performed in the average range on a word reading-based estimate of premorbid intellect. Contribution of Alzheimer’s disease pathology was ruled out in each case based on Centiloids quantifications &lt; 0. All cases scored below cutoff on TOMM Trial 2 (Case #1=43, Case #2=42, Case #3=19) and Case #3 also scored well below RDS cutoff (2). Each case had multiple cognitive scores below expectations (z &lt; -2.0) most consistently in memory, executive function, processing speed domains. For Case #1, MRI revealed mild atrophy in dorsal fronto-parietal and medial temporal lobe (MTL) regions and mild periventricular white matter disease. Tau-PET showed MTL tau burden modestly elevated relative to controls (regional w-score=0.59, 72nd%ile). For Case #2, MRI revealed cortical atrophy, mild hippocampal atrophy, and a microhemorrhage, with no evidence of meaningful tau-PET signal. For Case #3, MRI showed cortical atrophy and severe white matter disease, and tau-PET revealed significantly elevated MTL tau burden relative to controls (w-score=1.90, 97th%ile) as well as focal high signal in the dorsal frontal lobe (overall frontal region w-score=0.64, 74th%ile).Conclusions:Low scores on performance validity tests complicate the interpretation of the severity of cognitive deficits, but do not negate the presence of true cognitive impairment or an underlying neurodegenerative disease. In the rapidly developing era of biomarkers, neuroimaging tools can supplement neuropsychological testing to help inform whether cognitive or behavioral changes are related to a neurodegenerative disease.

2 Computerized Cognitive Practice Effects in Relation to Amyloid and Tau in Preclinical Alzheimer's Disease: Results from a Multi-Site Cohort

AbstractObjective:There is a need to identify scalable cognitive paradigms that are sensitive enough to relate to Alzheimer's disease biomarkers (amyloid and tau) in the preclinical stage. Here, we determine whether initial performance and practice effects on the memory-focused Computerized Cognitive Composite (C3) relate to demographic variables, amyloid status [abnormal (A+), normal (A-)], and regional tau in clinically unimpaired (CU) older adults.Participants and Methods:We examined pre-randomization data from CU older adults screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. We focused on participants who completed the C3 (n=3287), most of whom completed an alternate version of the C3 again approximately 51 days later (n=4141), as well as a subset of preclinical AD participants (i.e., A+ CU) who completed the C3 and tau PET imaging with [18]F-flortaucipir (initial C3: n=354; repeat C3: n=343). C3 initial performance and practice effects were examined in relation to amyloid status (A+, A-) and continuous regional tau burden.Results:Initial C3 performance was associated with amyloid status [B(SE) = -0.075 (0.021), p &lt; 0.001] across all participants, as well as tau burden in the medial temporal lobe (MTL) [B (SE) = -0.728 (0.220), p = 0.001], inferior temporal (IT) cortex [B (SE) = -0.782 (0.264), p = 0.003], and inferior parietal (IP) cortex [B (SE) = -0.721 (0.281), p = 0.011] amongst preclinical AD individuals. Short-term practice effects were also associated with reduced tau burden in MTL [B (SE) = -0.471 (0.202), p = 0.020], IT [B (SE) = -0.640 (0.240), p = 0.008], and IP [B( SE) = - 0.584 (0.255), p = 0.023] amongst preclinical AD participants, but were not associated with amyloid status [B (SE) = -0.018 (0.020), p = 0.348]. Critically, these effects with tau were only detected when baseline performance was accounted for presumably due to opposing influence from both practice effects and regression to the mean effects.Conclusions:This is the first study to show that performance on a brief cognitive battery administered in a multisite context is associated with both amyloid and tau among CU older adults. These findings suggest that computerized assessments may be a cost-effective and scalable approach for early detection efforts. Further, diminished practice effects on memory-based measures are associated with elevated tau burden in preclinical AD, suggesting that high-frequency cognitive testing collected over a short follow-up period may provide additional insights regarding early disease processes than single assessments.

Mercury sources and budget for the Snake River above a hydroelectric reservoir complex

Understanding sources of mercury (Hg) and methylmercury (MeHg) to a water body is critical for management but is often complicated by poorly characterized Hg inputs and in situ processes, such as inorganic Hg methylation. In this study, we determined inorganic Hg and MeHg concentrations and loads (filter-passing and particulate fractions) for a semi-arid 164-kilometer stretch of the Snake River above the Hells Canyon Complex, a Hg-impaired hydroelectric reservoir complex on the Idaho-Oregon border, and used water quality measurements and Hg stable isotope ratios to create a comprehensive Hg source budget for the river. Results show that whereas most of the streamflow to the study reach comes from the main branch of the Snake River (i.e., the upstream watershed), major tributaries within the study reach contribute a greater proportion of inorganic Hg and MeHg loads. Mercury stable-isotope analyses highlight that Hg within the tributaries is predominantly associated with geologic deposits and snowmelt sources, the latter reflecting wet deposition. Surprisingly, irrigation return drains contribute 40–50 % of particulate inorganic Hg loads despite being ≤4.3 % of the overall water budget. Together, tributaries and irrigation return drains account for 97–100 % of the inorganic Hg and streamflow to the study reach, but ~65 % of the MeHg, indicating in-stream and riparian methylation may be an important and previously unrecognized source of MeHg. Streamflow, total suspended solids, dissolved organic carbon, and agricultural land cover were found to be important controls on the mobilization and transport of different Hg species and fractions. This study represents the first fluvial budget for Hg in the Snake River that accounts for particulate and filter-passing Hg species from both major tributaries and irrigation return drains, and expands our understanding of Hg sources and methylation processes within semi-arid environments. This information is critical to inform management decisions related to elevated Hg burdens in biota.

Burden of dengue, leishmaniasis and lymphatic filariasis in India and its states from 1990-2019: Analysis from the Global Burden of Disease study (GBD 2019).

Vector-borne diseases such as dengue, leishmaniasis, and lymphatic filariasis, constitute significant sources of illness, disability, and mortality among the poor and vulnerable in many countries around the world, including India. Based on the global burden of diseases, injuries, and risk factors study 2019, we analyse the burden of dengue, leishmaniasis, and lymphatic filariasis, in India from 1990 to 2019. Over this period, there was a reduction in the burden of lymphatic filariasis and leishmaniasis. Notably, dengue emerged as the most common vector-borne disease, exhibiting high fatality rate above 15 years of age and the highest DALY within 15-49 age group. Additionally, dengue cases surged substantially between 1990 and 2019. Leishmaniasis related mortality and DALY declined in the year 2019 compared to the year 1990, with high mortality and DALY in the 0-49-year-old age group. For lymphatic filariasis, DALY was more pronounce among those in the 15-49-year age group, which underwent reduction in 2019. Males had a higher burden in other vector-borne diseases than females, although females had a slightly elevated dengue burden. These findings highlight the evolving epidemiological trends related to vector-borne diseases in India, over the last three decades and underline the critical significance of sustained efforts for the elimination and control of vector-borne diseases.

Evaluating the potential of matrix metalloproteinase as a diagnostic biomarker in rheumatoid arthritis and periodontitis: A systematic review and meta-analysis.

Matrix metalloproteinases (MMPs) play a crucial role in the pathogenesis of several chronic diseases including rheumatoid arthritis (RA) and periodontitis (PD). RA patients with periodontitis (RA-PD) are associated with elevated inflammatory burden due to increased production of proinflammatory cytokines. Controlling upregulated MMPs activity in these patients may have potential therapeutic effects. Therefore, aim of this study is to address the focused question: "Do RA subjects with concurrent PD have different levels of MMPs in comparison to RA alone, PD alone and HC subjects?" The systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search from 4 electronic databases (EMBASE, Medline, Web of Science, and Cochrane library) and manual search was performed from inception to July 2023. Quality assessment of each article was done using Newcastle-Ottawa Scale. Meta-analyses derived results were summarized as standardized mean difference (SMD) with 95% confidence intervals. A total of 879 articles were extracted. Following screening and full text assessment, 9 studies were included. MMP-1, MMP-3, MMP-8, MMP-9, and MMP-13 were consistently elevated in RA-PD subjects. MMP-8 levels were found to be higher in RA-PD subjects compared with RA alone, PD alone, and HC in 3 studies reporting GCF levels (SMD = 1.2; Z = 2.07; P = .04) and 2 studies reporting serum levels (SMD = 0.87; Z = 4.53; P < .00001). RA-PD group showed significantly higher MMP levels in their serum and GCF compared with HC, RA, and PD alone individuals. MMP-8 may serve as a reliable biomarker in the diagnosis and management of RA-PD subjects.

Deep coverage and quantification of the bone proteome provides enhanced opportunities for new discoveries in skeletal biology and disease.

Dysregulation of cell signaling in chondrocytes and in bone cells, such as osteocytes, osteoblasts, osteoclasts, and an elevated burden of senescent cells in cartilage and bone, are implicated in osteoarthritis (OA). Mass spectrometric analyses provides a crucial molecular tool-kit to understand complex signaling relationships in age-related diseases, such as OA. Here we introduce a novel mass spectrometric workflow to promote proteomic studies of bone. This workflow uses highly specialized steps, including extensive overnight demineralization, pulverization, and incubation for 72 h in 6 M guanidine hydrochloride and EDTA, followed by proteolytic digestion. Analysis on a high-resolution Orbitrap Eclipse and Orbitrap Exploris 480 mass spectrometer using Data-Independent Acquisition (DIA) provides deep coverage of the bone proteome, and preserves post-translational modifications, such as hydroxyproline. A spectral library-free quantification strategy, directDIA, identified and quantified over 2,000 protein groups (with ≥ 2 unique peptides) from calcium-rich bone matrices. Key components identified were proteins of the extracellular matrix (ECM), bone-specific proteins (e.g., secreted protein acidic and cysteine rich, SPARC, and bone sialoprotein 2, IBSP), and signaling proteins (e.g., transforming growth factor beta-2, TGFB2), and lysyl oxidase homolog 2 (LOXL2), an important protein in collagen crosslinking. Post-translational modifications (PTMs) were identified without the need for specific enrichment. This includes collagen hydroxyproline modifications, chemical modifications for collagen self-assembly and network formation. Multiple senescence factors were identified, such as complement component 3 (C3) protein of the complement system and many matrix metalloproteinases, that might be monitored during age-related bone disease progression. Our innovative workflow yields in-depth protein coverage and quantification strategies to discover underlying biological mechanisms of bone aging and to provide tools to monitor therapeutic interventions. These novel tools to monitor the bone proteome open novel horizons to investigate bone-specific diseases, many of which are age-related.

Predictors of Poor Treatment Experience in Cervical Cancer Patients Receiving Definitive Chemoradiation and Brachytherapy Boost: A Prospective Study

Cervical cancer patients experience high overall symptom burden. Here, we analyzed patient reported outcomes (PROs) to identify disease, treatment, or patient-related characteristics that can predict poor treatment experience. Cervical cancer patients treated with definitive chemoradiation (CRT) at a single institution enrolled on a prospective trial evaluating PROs between 2021-2023 were included. Patients received PRO questionnaires at baseline (BL) and 2-7 days after final brachytherapy implant (post-BT). Data was collected using the EORTC-QLQ-C30, which is a validated metric scored on a 4-point Likert scale (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much). Poor treatment experience was defined as low physical function [score >2], significant overall symptom burden [> population mean], or substantial nausea/vomiting (N/V), diarrhea, pain, or fatigue [score >2] after BT. Potential predictors included age, menopause status, stage, radiation field size, BT modality (PDR vs HDR), marital status, high baseline financial toxicity [score >2], depression [score >2], worse social function [score >2] and poor emotional function [score >2]. Logistic regression modeling was performed and p<0.05 were considered significant. A total of 36 patients completed BL and post-BT PRO metrics. Median age was 42 (range, 18-85), 22% (n = 8) of patients had localized disease, 75% (n = 27) had regional disease, and 3% (n = 1) had distant disease. Low BL social function was associated with high symptom burden after BT (HR 12.5, 95% CI 2.3-68.2, p = 0.004), significant N/V (HR 19.0, 95% CI 1.9-191.0, p = 0.012), high rates of fatigue (HR 9.29, 95% CI 1.6-54.8, p = 0.014), and overall poor physical function after treatment (HR 5.67, 95% CI 1.1-30.1, p = 0.042). High BL financial toxicity was predictive of elevated symptom burden after BT (HR 12.0, 95% CI 2.2-66.0, p = 0.004) and substantial fatigue (HR 7.33, 95% CI 1.5-36.7, p = 0.015). Significant depression at BL was also associated with high rates of N/V (HR 9.78, 95% CI 1.4-66.9, p = 0.02). Patient age, menopausal status, disease stage, radiation field size, BT modality, and marital status were not significantly predictive for symptom burden or physical function after treatment. Patients with poor baseline social function, high financial toxicity, and depression are at risk for increased symptom burden. Screening for these factors may provide an opportunity to intervene early and improve patient treatment experience.

Increased Incidence of Liver Metastases in Colorectal Versus Appendiceal Adenocarcinoma Peritonectomy Patients Despite Equivocal Survival.

Colorectal adenocarcinoma (CRAdenoCa) and appendiceal adenocarcinoma (AAdenoCa) are diseases of the same histopathological type that metastasise to the liver and peritoneum. In selected subgroups, peritonectomy and heated intraperitoneal chemotherapy (HIPEC) may be indicated as part of the multimodal treatment plan. However, literature comparing the survival outcomes and preoperative tumour activity and burden of CRAdenoCa and AAdenoCa peritonectomy patients without synchronous liver metastases (sLM) is scarce. Little is also known about the comparative incidence of sLM and metachronous LM (mLM) between CRAdenoCa and AAdenoCa peritonectomy patients. This study aimed to clarify the above. A retrospective cohort study of 684 CRAdenoCa and AAdenoCa primary peritonectomy patients between 2001-2021 was conducted at St George Hospital in Sydney, Australia. Median overall survival (years) was equivocal between CRAdenoCa and AAdenoCa peritonectomy patients (1.7 vs. 1.9, p=0.35). Peritoneal cancer index and preoperative carcinoembryonic antigen (CEA) were significantly elevated (25 vs. 9, p<0.0001 and 7.9 vs. 5, p=0.0080) in AAdenoCa versus CRAdenoCa peritonectomy patients without sLM. The incidence of sLM and mLM was increased in CRAdenoCa peritonectomy patients (24% vs. 3.1%, p<0.0001 and 26% vs. 10%, p=0.0001). This study demonstrates similar survival outcomes between CRAdenoCa and AAdenoCa peritonectomy patients. Despite elevated preoperative tumour burden and biological activity in AAdenoCa patients, CRAdenoCa patients had higher rates of sLM and mLM. Further studies are warranted to validate and identify cellular and molecular targets that increase CRAdenoCa's ability to metastasise to the liver.

Predictors of Nocturnal Hypoxemic Burden in Patients Undergoing Elective Coronary Artery Bypass Grafting Surgery.

Background: Nocturnal hypoxemia has been linked to increased cardiovascular morbidity and mortality. Several common diseases, such as sleep-disordered breathing (SDB), heart failure (HF), obesity, and pulmonary disease, coincide with an elevated nocturnal hypoxemic burden with and without repetitive desaturations. Research question: This study aimed to evaluate the association of relevant common diseases with distinctive metrics of nocturnal hypoxemic burden with and without repetitive desaturations in patients undergoing coronary artery bypass grafting surgery. Study design and methods: In this subanalysis of the prospective observational study, CONSIDER-AF (NCT02877745) portable SDB monitoring was performed on 429 patients with severe coronary artery disease the night before cardiac surgery. Pulse oximetry was used to determine nocturnal hypoxemic burden, as defined by total recording time spent with oxygen saturation levels < 90% (T90). T90 was further characterized as T90 due to intermittent hypoxemia (T90desaturation) and T90 due to nonspecific and noncyclic SpO2-drifts (T90non-specific). Results: Multivariable linear regression analysis identified SDB (apnea-hypopnea-index ≥ 15/h; B [95% CI]: 6.5 [0.4; 12.5], p = 0.036), obesity (8.2 [2.5; 13.9], p = 0.005), and mild-to-moderate chronic obstructive pulmonary disease (COPD, 16.7 [8.5; 25.0], p < 0.001) as significant predictors of an increased nocturnal hypoxemic burden. Diseases such as SDB, obesity and HF were significantly associated with elevated T90desaturation. In contrast, obesity and mild-to-moderate COPD were significant modulators of T90non-specific. Interpretation: SDB and leading causes for SDB, such as obesity and HF, are associated with an increased nocturnal hypoxemic burden with repetitive desaturations. Potential causes for hypoventilation syndromes, such as obesity and mild-to-moderate COPD, are linked to an increased hypoxemic burden without repetitive desaturations. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02877745.

Headache among combat-exposed veterans and service members and its relation to mild traumatic brain injury history and other factors: a LIMBIC-CENC study.

Headache (HA) is a common persistent complaint following mild traumatic brain injury (mTBI), but the association with remote mTBI is not well established, and risk factors are understudied. Determine the relationship of mTBI history and other factors with HA prevalence and impact among combat-exposed current and former service members (SMs). Secondary cross-sectional data analysis from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium prospective longitudinal study. We examined the association of lifetime mTBI history, demographic, military, medical and psychosocial factors with (1) HA prevalence ("lately, have you experienced headaches?") using logistic regression and (2) HA burden via the Headache Impact Test-6 (HIT-6) using linear regression. Each lifetime mTBI was categorized by mechanism (blast-related or not) and setting (combat deployed or not). Participants with non-credible symptom reporting were excluded, leaving N = 1,685 of whom 81% had positive mTBI histories. At a median 10 years since last mTBI, mTBI positive participants had higher HA prevalence (69% overall, 78% if 3 or more mTBIs) and greater HA burden (67% substantial/severe impact) than non-TBI controls (46% prevalence, 54% substantial/severe impact). In covariate-adjusted analysis, HA prevalence was higher with greater number of blast-related mTBIs (OR 1.81; 95% CI 1.48, 2.23), non-blast mTBIs while deployed (OR 1.42; 95% CI 1.14, 1.79), or non-blast mTBIs when not deployed (OR 1.23; 95% CI 1.02, 1.49). HA impact was only higher with blast-related mTBIs. Female identity, younger age, PTSD symptoms, and subjective sleep quality showed effects in both prevalence and impact models, with the largest mean HIT-6 elevation for PTSD symptoms. Additionally, combat deployment duration and depression symptoms were factors for HA prevalence, and Black race and Hispanic/Latino ethnicity were factors for HA impact. In sensitivity analyses, time since last mTBI and early HA onset were both non-significant. The prevalence of HA symptoms among formerly combat-deployed veterans and SMs is higher with more lifetime mTBIs regardless of how remote. Blast-related mTBI raises the risk the most and is uniquely associated with elevated HA burden. Other demographic and potentially modifiable risk factors were identified that may inform clinical care.

Adhesion-regulating molecule 1 (ADRM1) can be a potential biomarker and target for bladder cancer

Adhesion-regulating molecule 1 (ADRM1) has been implicated in tumor development, yet its specific role in bladder cancer (BC) remains undefined. This study aimed to elucidate the function of ADRM1 in BC through a combination of bioinformatics analysis and immunohistochemical analysis (IHC). Utilizing R version 3.6.3 and relevant packages, we analyzed online database data. Validation was conducted through IHC data, approved by the Institutional Ethics Committee (Approval No. K20220830). In both paired and unpaired comparisons, ADRM1 expression was significantly elevated in BC tissues compared to adjacent tissues, as evidenced by the results of TCGA dataset and IHC data. Patients with high ADRM1 expression had statistically worse overall survival than those with low ADRM1 expression in TCGA dataset, GSE32548 dataset, GSE32894 dataset, and IHC data. Functional analysis unveiled enrichment in immune-related pathways, and a robust positive correlation emerged between ADRM1 expression and pivotal immune checkpoints, including CD274, PDCD1, and PDCD1LG2. In tumor microenvironment, samples with the high ADRM1 expression contained statistical higher proportion of CD8 + T cells and Macrophage infiltration. Meanwhile, these high ADRM1-expressing samples displayed elevated tumor mutation burden scores and stemness indices, implying potential benefits from immunotherapy. Patients with low ADRM1 expression were sensitive to cisplatin, docetaxel, vinblastine, mitomycin C, and methotrexate. According to the findings from bioinformatics and IHC analyses, ADRM1 demonstrates prognostic significance for BC patients and holds predictive potential for both immunotherapy and chemotherapy responses. This underscores its role as a biomarker and therapeutic target in BC.

Association of ERCC family mutations with prognosis and immune checkpoint inhibitors response in multiple cancers

The proteins encoded by the excision repair cross-complementing (ERCC) family are pivotal in DNA damage repair and maintaining genome stability. However, the precise role of the ERCC family in tumor prognosis and the effectiveness of immune checkpoint inhibitors (ICI) therapy remain uncertain. This study aimed to explore the connection between ERCC mutations and prognosis as well as the response to ICI. We observed that patients with ERCC mutations exhibited enhanced progression-free survival (PFS) and overall survival (OS) in two independent pan-cancer cohorts. Furthermore, this mutant subgroup showed higher tumor mutation burden (TMB) compared to the wild-type subgroup. Notably, ERCC mutations were associated with better OS (HR 0.54, 95% CI 0.42–0.70; P < 0.001) in pan-cancer patients who underwent ICI therapy (N = 1661). These findings were validated in a separate cohort, where patients in the ERCC mutant subgroup demonstrated improved clinical outcomes (HR 0.56, 95% CI 0.37–0.84; P = 0.03) and higher response rates (51.9% vs. 26.8%) than the wild-type subgroup. Further analysis revealed that patients with ERCC mutations displayed elevated tumor neoantigen burden (TNB) levels and increased infiltration of immune-response cells. Our study suggests that ERCC mutations are linked to enhanced immunogenicity and improved ICI efficacy, thus potentially serving as a biomarker for ICI therapy.

Cardiometabolic predictors of high-risk CCTA phenotype in a diverse patient population

IntroductionLow-attenuation non-calcified plaque (LAP) burden and vascular inflammation by pericoronary adipose tissue (PCAT) measured from coronary CT angiography (CCTA) have shown to be predictors of cardiovascular outcomes. We aimed to investigate the relationships of cardiometabolic risk factors including lipoprotein(a) and epicardial adipose tissue (EAT) with CCTA high-risk imaging biomarkers, LAP and vascular inflammation. MethodsThe patient population consisted of consecutive patients who underwent CCTA for stable chest pain and had a complete cardiometabolic panel including lipoprotein(a). Plaque, PCAT and EAT were measured from CT using semiautomated software. Elevated LAP burden and PCAT attenuation were defined as ≥4% and ≥70.5 HU, respectively. The primary clinical end-point was a composite of myocardial infarction, revascularization or cardiovascular death. ResultsA total of 364 consecutive patients were included (median age 56 years, 64% female); the majority of patients were of Hispanic (60%), and the rest were of non-Hispanic Black (21%), non-Hispanic White (6%) and non-Hispanic Asian (4%) race/ethnicity. The prevalence of elevated LAP burden and PCAT attenuation was 31 and 18%, respectively, while only 8% had obstructive stenosis. There were significant differences in plaque characteristics among different racial/ethnic groups (p<0.001). Lipoprotein(a) correlated with LAP burden in Hispanic patients. Patients with elevated LAP were older, more likely to be have diabetes, hypertension, hyperlipidemia and smoke with higher CAC and EAT volume (all P<0.05). Patients with elevated LAP were more likely to develop the primary clinical outcome (p<0.001) but those with elevated PCAT were not (p=0.797). ConclusionThe prevalence of LAP and PCAT attenuation were 31 and 18%, respectively. Lipoprotein(a) levels correlated with LAP burden in Hispanic patients. Age, male sex, hypertension and hyperlipidemia increased the odds of elevated LAP, which showed prognostic significance.

Tumor microenvironment characterization in colorectal cancer to identify prognostic and immunotherapy genes signature

BackgroundThe tumor microenvironment (TME) plays a crucial role in tumorigenesis, progression, and therapeutic response in many cancers. This study aimed to comprehensively investigate the role of TME in colorectal cancer (CRC) by generating a TMEscore based on gene expression.MethodsThe TME patterns of CRC datasets were investigated, and the TMEscores were calculated. An unsupervised clustering method was used to divide samples into clusters. The associations between TMEscores and clinical features, prognosis, immune score, gene mutations, and immune checkpoint inhibitors were analyzed. A TME signature was constructed using the TMEscore-related genes. The results were validated using external and clinical cohorts.ResultsThe TME pattern landscape was for CRC was examined using 960 samples, and then the TMEscore pattern of CRC datasets was evaluated. Two TMEscore clusters were identified, and the high TMEscore cluster was associated with early-stage CRC and better prognosis in patients with CRC when compared with the low TMEscore clusters. The high TMEscore cluster indicated elevated tumor cell scores and tumor gene mutation burden, and decreased tumor purity, when compared with the low TMEscore cluster. Patients with high TMEscore were more likely to respond to immune checkpoint therapy than those with low TMEscore. A TME signature was constructed using the TMEscore-related genes superimposing the results of two machine learning methods (LASSO and XGBoost algorithms), and a TMEscore-related four-gene signature was established, which had a high predictive value for discriminating patients from different TMEscore clusters. The prognostic value of the TMEscore was validated in two independent cohorts, and the expression of TME signature genes was verified in four external cohorts and clinical samples.ConclusionOur study provides a comprehensive description of TME characteristics in CRC and demonstrates that the TMEscore is a reliable prognostic biomarker and predictive indicator for patients with CRC undergoing immunotherapy.

A major role for CD4+ T cells in driving cytokine release syndrome during CAR T cell therapy

Anti-CD19 chimeric antigen receptor (CAR) Tcell therapy represents a breakthrough for the treatment of B cell malignancies. Yet, it can lead to severe adverse events, including cytokine release syndrome (CRS), which may require urgent clinical management. Whether interpatient variability in CAR Tcell subsets contributes to CRS is unclear. Here, we show that CD4+ CAR Tcells are the main drivers of CRS. Using an immunocompetent model of anti-CD19 CAR Tcell therapy, we report that CD4+, but not CD8+, CAR Tcells elicit physiological CRS-like manifestations associated with the release of inflammatory cytokines. In CAR Tcell-treated patients, CRS occurrence and severity are significantly associated with high absolute values of CD4+ CAR Tcells in the blood. CRS in mice occurs independently of CAR Tcell-derived interferon γ (IFN-γ) but requires elevated tumor burden. Thus, adjusting the CD4:CD8 CAR Tcell ratio to patient tumor load may help mitigate CAR Tcell-associated toxicities.