Higher Baseline Research Articles

Survival outcomes of Durvalumab in combination to cisplatin and gemcitabine in advanced biliary tract cancer: real world results from a single Italian institution.

The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a retrospective analysis of its first-line treatment outcomes. We included patients with unresectable, locally advanced, or metastatic BTC treated with cisplatin, gemcitabine plus durvalumab. The primary endpoint was overall survival (OS). 33 patients were enrolled. Median OS was NR and median PFS was 7.6 months, after a median follow up of 13.5 months. The investigator-assessed overall response rate was 34.5 %, with stable disease in 53.0 % of patients. High baseline CEA levels were associated with poor survival. Any grade adverse events (AEs) occurred in 97 % of patients. Immune-related AEs (irAEs) occurred in 16 % (grade >2: 6 %). Presence of TP53 mutation was related to a worse OS, conversely the presence of ARID1A genomic alteration was related to a better PFS. A tendence toward a better OS was found for BRCAness patients which did not reach the statistical significance. On the other hand, BRCAness patients showed significantly higher PFS compared to no BRCAness patients Conclusion: This real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC.

Lipid disturbances induced by psychotropic drugs: clinical and genetic predictors for early worsening of lipid levels and new-onset dyslipidaemia in Swiss psychiatric samples.

Early worsening of plasma lipid levels (EWL; ≥5% change after 1 month) induced by at-risk psychotropic treatments predicts considerable exacerbation of plasma lipid levels and/or dyslipidaemia development in the longer term. We aimed to determine which clinical and genetic risk factors could predict EWL. Predictive values of baseline clinical characteristics and dyslipidaemia-associated single nucleotide polymorphisms (SNPs) on EWL were evaluated in a discovery sample (n = 177) and replicated in two samples from the same cohort (PsyMetab; n1 = 176; n2 = 86). Low baseline levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides, and high baseline levels of high-density lipoprotein cholesterol (HDL-C), were risk factors for early increase in total cholesterol (P = 0.002), LDL-C (P = 0.02) and triglycerides (P = 0.0006), and early decrease in HDL-C (P = 0.04). Adding genetic parameters (n = 17, 18, 19 and 16 SNPs for total cholesterol, LDL-C, HDL-C and triglycerides, respectively) improved areas under the curve for early worsening of total cholesterol (from 0.66 to 0.91), LDL-C (from 0.62 to 0.87), triglycerides (from 0.73 to 0.92) and HDL-C (from 0.69 to 0.89) (P ≤ 0.00003 in discovery sample). The additive value of genetics to predict early worsening of LDL-C levels was confirmed in two replication samples (P ≤ 0.004). In the combined sample (n ≥ 203), adding genetics improved the prediction of new-onset dyslipidaemia for total cholesterol, LDL-C and HDL-C (P ≤ 0.04). Clinical and genetic factors contributed to the prediction of EWL and new-onset dyslipidaemia in three samples of patients who started at-risk psychotropic treatments. Future larger studies should be conducted to refine SNP estimates to be integrated into clinically applicable predictive models.

Influence of Treatment Effect Modifiers in Fabry Disease: A Systematic Literature Review.

Fabry disease (FD) is a rare metabolic disorder which presents with considerable heterogeneity in disease characteristics. Given the absence of interventional studies comparing all available treatments, it is important for indirect treatment comparisons (ITCs) to account for potential treatment effect modifiers (TEMs). This systematic literature review (SLR) aimed to identify patient characteristics that may impact clinical outcomes by analyzing real-world evidence (RWE) in FD. An SLR was conducted according to PRISMA guidelines, with searches performed in the EMBASE, MEDLINE, and Cochrane databases (1946-2022; with a recent update in April 2023). Full-text articles reporting clinical outcomes from RWE studies of pharmacological therapies for the treatment of FD were included. Including studies from the recent SLR update, a total of 119 original studies met the PICOS criteria and 25 studies provided insights into TEMS. Potential TEMs in FD were identified: sex, age, timing of treatment initiation (early/delayed), left ventricular hypertrophy (LVH), estimated glomerular filtration rate (eGFR), proteinuria, presence of anti-drug-antibodies (ADAs) at baseline, and previous enzyme replacement therapy (ERT). In three studies (two including ERT-treated patients and one study of migalastat-treated patients) males showed worse renal outcomes than females. Five studies found that younger patients and those who received initial ERT before the age of 25years had greater reductions in plasma-lysoGb3, as well as more favorable renal, cardiac, and biochemical outcomes. Seven studies identified associations between LVH and reduced eGFR at baseline, along with an increased risk of cardiovascular, renal, and neurological events. In four studies, lower baseline eGFR and proteinuria were associated with faster annual eGFR decline despite ERT; high baseline proteinuria was a significant predictor of renal disease progression. Baseline ADAs were linked to lower eGFR, increased left ventricular mass, and reduced treatment impact on plasma/urine-lysoGb3. Migalastat was effective in treatment-naïve patients, while those previously treated with ERT experienced deteriorations in mean lysoGb3, eGFR, and left ventricular mass. This SLR highlighted several patient characteristics that influence treatment effectiveness in FD. It is important to account for these characteristics in ITCs to ensure unbiased outcomes.

Leveraging local wildlife surveys for robust occupancy trend estimation

Natural resource agencies are frequently tasked with monitoring populations of at-risk species to ensure management activities do not negatively affect the viability of wildlife populations. Typically, these monitoring efforts evaluate trends in a population’s abundance, occupancy, or geographic distribution. Often, surveys provide local information, but results are generally not incorporated into broad-scale monitoring efforts that focus on range-wide population changes due to their variable nature in both spatial extent and effort. We investigated whether aggregating these local (hereafter “variable”) surveys can generate enough statistical power to estimate broad-scale population trends using simulations of declining populations of fishers (Pekaniapennati) over a 10-year time horizon. Our simulations included three population sizes which we refer to as abundant, common, and rare (N0 = 700, 350, and 100 individuals, respectively) with each declining at a rapid and moderate pace (λ = 0.933, and 0.977, respectively). For each population, we simulated variable surveys using an occupancy framework to subsample the population with parameters that mimic combining multiple independent monitoring efforts which vary annually in location, and effort. Regardless of spatial consistency of annual sampling, there was minimal variation in statistical power under both high and low detection probability simulations. However, when sampling effort varied each year, statistical power was lower for most populations and sampling scenarios when compared to consistent sampling effort unless some baseline level of sampling effort was reliably achieved in all years. In many cases, adding low-level consistent baseline sampling to variable surveys resulted in statistical power close to that of consistent sampling efforts. Our results suggest statistical power is driven by annual consistency in the proportion of landscape sampled rather than spatial consistency in sampling locations. This result indicates that current variable surveys could be leveraged and combined to detect population declines for at-risk species at broad-scales if a baseline proportion of landscape is robustly sampled. The level of baseline sampling is highly dependent on population size and magnitudes of population change. In simulations with a common or abundant population experiencing a rapid decline, a baseline survey effort of at least 5% of the landscape in combination with variable surveys resulted in statistical power consistently above the standard threshold of 0.80 for occupancy monitoring. Leveraging existing local efforts to achieve high detection probability and baseline sampling would reduce financial and logistical burdens of broad-scale wildlife monitoring efforts.

Clinical and Preclinical Activity of EGFR Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Harboring BRAF Class 3 Mutations.

Patients with tumors harboring BRAF class 3 mutations lack targeted therapies. These mutations are characterized by low/absent BRAF kinase domain activation and are believed to amplify already active RAS signaling, potentially triggered by receptor tyrosine kinases like EGFR. Two patients with BRAF class 3-mutated metastatic non-small-cell lung cancer (NSCLC) were treated with erlotinib at our Institution after failure of standard therapies. Two cell lines were established from patients with BRAF class 3-mutated NSCLC, and their sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was assessed using EGFR-mutated, BRAF class 1 and 2-mutated, and KRAS-mutated NSCLC cell lines as controls. Patient 1, a 60-year-old male with BRAFD594N-mutated NSCLC, achieved complete response to erlotinib after progression on first- and second-line chemotherapy. Patient 2, a 60-year-old female with BRAFD594G-mutated NSCLC, achieved partial response to erlotinib after progression on first-line chemoimmunotherapy. High baseline phosphorylated EGFR values and reduced EGFR activation following erlotinib were observed in BRAF class 3-mutated and EGFR-mutated cell lines, but not in BRAF class 1-mutated, BRAF class 2-mutated, or KRAS-mutated lines. Erlotinib inhibited 2-dimensional growth in BRAF class 3-mutated cell lines (IC50 6.33 and 7.11 µM) and in the BRAF class 2-mutated cell line (IC50 5.51 µM), albeit at higher concentrations than in EGFR-mutated lines, whereas it showed no effect on BRAF class 1-mutated (IC50, >25 µM) or KRAS-mutated (IC50, >25 µM) lines. These findings were corroborated by 3-dimensional and sphere formation assays. In the Cancer Cell Line Encyclopedia, BRAF class 3-mutated NSCLC cell lines showed greater sensitivity to EGFR-TKIs compared with BRAF class 2-mutated and KRAS-mutated lines. BRAF class 3 mutations in NSCLC may identify a novel targetable population sensitive to EGFR-TKIs.

High-dose Vitamin-B6 reduces sensory over-responsivity.

Sensory reactivity differences are experienced by between 5% and 15% of the population, often taking the form of sensory over-responsivity (SOR), in which sensory stimuli are experienced as unusually intense and everyday function is affected. A potential mechanism underlying over-responsivity is an imbalance between neural excitation and inhibition in which inhibitory influences are relatively weakened. Therefore, interventions that boost neural inhibition or reduce neural excitation may reduce SOR; Vitamin-B6 is the coenzyme for the conversion of excitatory glutamate to inhibitory gamma-aminobutyric acid (GABA), and in animal models, it both increases the concentration of GABA and reduces glutamate. To discover whether taking a high dose of Vitamin-B6 reduces SOR and other aspects of sensory reactivity. We recruited 300 adults (249 females) from the general population who completed the Sensory Processing 3-Dimensions Scale (SP-3D) first at baseline, and again following randomisation to either 1 month's supplementation with 100 mg Vitamin-B6, or one of two control conditions (1000 µg Vitamin-B12 or placebo). To focus on individuals who experience SOR, we analysed the effects of supplementation only on individuals with high baseline SOR scores (above the 87th percentile). In individuals with SOR at baseline, Vitamin-B6 selectively reduced SOR compared to both placebo and Vitamin-B12. We also found that Vitamin-B6 selectively reduced postural disorder in individuals with high scores on this subscale at baseline, but there were no effects on the four remaining SP-3D subscales. Clinical trials and mechanistic studies should now be conducted in autism, attention deficit hyperactivity disorder and other groups with SOR.

Effects of Baseline Blood Zinc Levels on the Humoral Immune Response After COVID-19 mRNA Vaccination: A Prospective Study in a Japanese Population

Background/Objectives: Although the protective effects of zinc against COVID-19 are documented, its impact on COVID-19 vaccine immunogenicity remains unknown. Methods: We conducted a prospective study involving a cohort of 79 Japanese individuals (aged 21–56 years; comprising three subcohorts) and measured their serum zinc levels pre-vaccination and anti-SARS-CoV-2 IgM/IgG levels pre- and post-vaccination over 4 months. Results: Serum zinc concentrations ranged between 74–140 and 64–113 μg/dL in male and female individuals, respectively, with one male and 11 female participants exhibiting subclinical zinc deficiency (60–80 μg/dL). Mixed models for antibody titers, accounting for the subcohorts, repeat measurements, and covariates (e.g., vaccine type, sex, age, height, steroid use, medical history, smoking and drinking habits, perceived stress, and sleep disturbances) showed positive effects of zinc on IgM (p = 0.012) and IgG (p = 0.013) in 45 female individuals with 255 observations. However, a similar association was not found in the 34 male participants with 162 observations. This discrepancy may be attributed to one participant being included in the subcohort with frequent repeat measurements (10 repeats in 4 months). COVID-19 mRNA vaccine immunogenicity was enhanced in the participants with high baseline blood zinc levels within the reference range. Conclusions: Our findings underscore the relevance of maintaining adequate zinc levels before vaccination, which can be achieved through a balanced diet and healthy lifestyle choices.

Patterns of Adherence to Home Blood Pressure Monitoring Among Older Adults With Ischemic Heart Disease: An Analysis From the RESILIENT Trial of Mobile Health Cardiac Rehabilitation.

Hypertension (HTN) is common and represents a major modifiable risk factor for ischemic heart disease in older adults. While home blood pressure monitoring (HBPM) is important in HTN management, patterns of HBPM engagement in older adults undergoing mobile health cardiac rehabilitation (mHealth-CR) are unknown. We aimed to identify patterns of adherence to HBPM in a cohort of older adults undergoing mHealth-CR to optimize HBPM use in the future. We used interim data from the ongoing Rehabilitation using Mobile Health for Older Adults with Ischemic Heart Disease in the Home Setting (RESILIENT) randomized trial, in which intervention arm participants (adults≥65years with ischemic heart disease) were instructed to monitor blood pressure (BP) at least weekly. Engagement groups were determined by latent class analysis and compared using ANOVA or Chi-Square tests. Longitudinal mixed effect modeling determined the associations between weekly HBPM and baseline covariates including uncontrolled HTN, obesity, diabetes, depression, alcohol, and tobacco use. Of the 111 participants, the mean age was 71.9±5.6years, and 83% had HTN. Over the 12-week study, mean HBPM engagement was 2.3±2.3d/wk. We observed 3 distinct patterns of engagement: high engagement (22%), gradual decline (10%), and sustained baseline engagement (68%). HBPM adherence decreased in two of the engagement groups over time. Of the covariates tested, only depression was associated with weekly HBPM after adjusting for relevant covariates (OR 9.09, P =.03). In this older adult cohort undergoing mHealth-CR, we found three main engagement groups with declining engagement over time in two of the three groups. These patterns can inform future mHealth-CR interventions.

Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) is one of the fastest-growing cancers worldwide, lacking established causal factors or validated early diagnostics. Human endogenous retroviruses (HERVs), comprising 8% of human genomes, have potential as PTC biomarkers due to their comparably high baseline expression in healthy thyroid tissues, indicating homeostatic roles. However, HERV regions are often overlooked in genome-wide association studies because of their highly repetitive nature, low sequence coverage, and decreased sequencing quality. Using targeted whole-genome sequence analysis in conjunction with high sequencing depth to overcome methodological limitations, we identified associations of specific HERV variants with PTC. Analyzing WGS data from 138 patients with PTC generated through The Cancer Genome Atlas project and 2015 control samples from the 1000 Genomes Project, we examined the mutational variation in HERVs within a 20 kb radius of known cancer predisposition genes (CPGs) differentially expressed in PTC. We discovered 15 common and 13 rare germline HERV variants near or within 20 CPGs that distinguish patients with PTC from healthy controls. We identified intragenic–intronic HERV variants within RYR2, LRP1B, FN1, MET, TCRVB, UNC5D, TRPM3, CNTN5, CD70, RYR1, RUNX1, CRLF2, and PCDH1X, and three variants downstream of SERPINA1 and RUNX1T1. Sanger sequencing analyses of 20 thyroid and 5 non-thyroid cancer cell lines confirmed associations with PTC, particularly for MSTA HERV-L variant rs200077102 within the FN1 gene and HERV-L MLT1A LTR variant rs78588384 within the CNTN5 gene. Variant rs78588384, in particular, was shown in our analyses to be located within a POL2 binding site regulating an alternative transcript of CNTN5. In addition, we identified 16 variants that modified the poly(A) region in Alu elements, potentially altering the potential to retrotranspose. In conclusion, this study serves as a proof-of-concept for targeted variant analysis of HERV regions and establishes a basis for further exploration of HERVs in thyroid cancer development.

Cardiorespiratory Stability in Critically Ill Preterm Infants following Dexmedetomidine Initiation.

This study aimed to evaluate cardiorespiratory status in preterm infants receiving dexmedetomidine using high-resolution physiologic data. We analyzed preterm infants with continuous heart rate (HR) and oxygen saturation (SpO2) data for 24 hours preceding and 48 hours following dexmedetomidine initiation. Invasive arterial blood pressure (ABP), when available, was analyzed. In 100 infants with a mean gestational age of 28 weeks and high baseline illness severity, mean HR decreased from 152 to 141 beats per minute while mean SpO2 increased from 91 to 93% in the 48 hours after dexmedetomidine initiation (p < 0.01). In 57 infants with continuous ABP monitoring, mean ABP increased from 40 to 42 mm Hg (p = 0.01). Vasoactive-inotropic support increased before and after initiation. We observed cardiorespiratory changes in critically ill preterm infants following dexmedetomidine initiation; mean HR decreased and mean SpO2 increased in the 48 hours after initiation. In a subset, mean ABP increased along with vasoactive-inotropic support. · Limited evidence exists on the acute cardiorespiratory effects of dexmedetomidine in preterm infants.. · Evaluation of continuous HR, blood pressure, and oxygenation from two centers provides useful data.. · Dexmedetomidine consistently decreased the HR of preterm infants.. · Dexmedetomidine initiation during critical illness complicated the interpretation of physiologic effects.. · Oxygenation stabilized after initiation during invasive mechanical ventilation..

Prognostic importance of baseline and changes in serum uric acid for macro/microvascular and mortality outcomes in individuals with type 2 diabetes: The Rio de Janeiro type 2 diabetes cohort

AimsTo investigate the associations between baseline/changes in serum uric acid (sUA) and the risks for cardiovascular/microvascular outcomes and mortality in a type 2 diabetes cohort. MethodsBaseline sUA was measured in 685 individuals, and 463 had a second sUA measurement during follow-up; sUA was analyzed as a continuous variable and categorized into sex-specific tertile subgroups and low/high levels (>4.5 mg/dl women; >5.5 mg/dl men). The risks associated with baseline sUA and its changes were examined by Cox analyses for all outcomes. ResultsMedian follow up was 10.7 years, there were 173 major cardiovascular events (MACEs), 268 all-cause deaths, 127 microalbuminuria, 104 renal failure, 160 retinopathy and 178 peripheral neuropathy outcomes. Baseline sUA was predictor of all outcomes, except all-cause mortality and retinopathy. In tertile and high/low sUA analyses, the hazard ratios (HRs) varied from 1.6 (microalbuminuria development) to 2.4 (MACEs; cardiovascular mortality). There was interaction with sex for MACEs, an increased risk was observed in women (HR: 2.6), but not in men (HR: 1.2). Changes in sUA were associated with the renal failure (HR: 2.4). ConclusionsIn a prospective cohort, high baseline sUA was a predictor of cardiovascular, renal and peripheral neuropathy. However, sUA changes were only predictor of renal failure.

The load of hepatitis B virus reduces the immune checkpoint inhibitors efficiency in hepatocellular carcinoma patients.

Chronic viral infection may lead to an immunosuppressive microenvironment, whereas the association between virus-related indicators and treatment response in hepatocellular carcinoma(HCC) patients undergoing immune checkpoint inhibitors(ICIs) therapy remains a topic of debate. We aim to investigate the influence of hepatitis virus on the ICI efficiency in HCC patients through a meta-analysis. We searched PubMed, Cochrane Library, Embase, and Web of Science until 14 July 2024 to identify cohort studies involving ICIs treatments in HCC patients. We extracted data from the literature related to hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, baseline HBV load, and antiviral therapy. Overall survival (OS) and progression-free survival (PFS) were considered as the primary endpoints, while objective response rate (ORR) was regarded as a secondary endpoint. We included 55 cohort studies published between 2019 and 2024, involving a patient population of 7180 individuals. Summarized hazard ratio (HR) comparing HBV infection with non-HBV infection in the context of ICIs therapy revealed no significant association between HBV infection and either mortality risk or progression risk with the pooled HR for OS of 1.04(95%CI: 0.93-1.16, P=0.483) and the pooled HR for PFS of 1.07(95%CI:0.96-1.20, P=0.342). HBV infected patients with HCC may have better tumor response than non-HBV infected patients receiving ICIs with the combined relative risk(RR) for ORR was 1.94 (95%CI: 1.12-3.38, P=0.002). High baseline HBV load is associated with poor survival outcomes in patients with HCC who receive ICIs with the pooled HR for OS was 1.74 (95%CI: 1.27-2.37, P=0.001), thereby antiviral therapy has the potential to significantly enhance prognostic outcomes with the pooled HR for OS was 0.24 (95% CI: 0.14-0.42 P<0.001) and the pooled HR for PFS was 0.54 (95% CI: 0.33-0.89 P=0.014). In individuals with HCC who received ICIs, there was no notable link found between HBV or HCV infection and prognosis. However, HBV infection showed a connection with improved tumor response. A higher initial HBV load is linked to worse survival results in HCC patients undergoing ICIs treatment and antiviral therapy can significantly improve its prognosis.

The combination of CSF neurofilament light chain and glial fibrillary acidic protein improves the prediction of long-term confirmed disability worsening in multiple sclerosis

Our objective was to evaluate the individual and combined prognostic attributes of baseline serum and CSF measurements of Neurofilament light chain (sNfL, cNfL) and glial fibrillary acidic protein (sGFAP, cGFAP) on long term clinical outcomes in MS. In this retrospective single center study, patients with serum and CSF stored at first MS presentation and > 15-years of follow-up were analyzed. NfL and GFAP were quantified from cryopreserved samples using a digital immunoassay and analyzed as predictors of confirmed disability worsening (CDW). Sixty patients (70% female) underwent baseline tandem CSF and serum sampling and were followed for a mean of 17.8 years (SD 2.5). 32 developed CDW. By logistic regression, while sNfL cNfL and cGFAP showed prognostic merit (AUC 0.72, 0.70, 0.62 respectively), sGFAP did not (AUC 0.5). The combination of cNfL and cGFAP improved CDW prediction compared to either measure considered in isolation (AUC 0.72). The optimal predictive cut-off for CDW (Youden’s index) for cNfL was 596 pg/mL and for cGFAP was 8160 pg/mL. Kaplan–Meier analysis of the cutoff-defined ‘high-high’ and ‘low-low’ combined cNfL and cGFAP groupings improved prediction of CDW compared to either marker individually (Hazard ratio 4.5 (95% CI 2.7–18.3), Logrank P < 0.0001). Cox Proportional Hazards regression demonstrated that high baseline cNfL and cGFAP were independently prognostic of subsequent CDW after adjusting for baseline age, sex, EDSS score and subsequent treatment exposure. Each unit increase in Ln(cNfL) and Ln(cGFAP) was respectively associated with an additional hazard of 2.36 (95% CI 1.12–5.52) and 2.26 (95% CI 1.03–5.21). CSF NfL and GFAP are independently prognostic of long-term clinical worsening in MS, and may represent a complementary pairing.

Response-Adaptive Surgical Timing in neoadjuvant immunotherapy demonstrates enhanced pathologic treatment response in Head and Neck Squamous Cell Carcinoma.

We evaluated whether IDO-inhibitor BMS986205 (IDOi) + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable HNSCC. We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response. Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 PO daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by HPV status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after nivolumab in both arms. Non-responders underwent surgical resection, while responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing. Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (p=0.909). Treatment was well-tolerated with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDO-inhibitor augmented rates of pTR in patients with high baseline IDO RNA expression (p<0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus non-responders (p=0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-g expression in the HPV- cohort correlated with response. HPV+ cohort found B-cell and CAF signatures predictive of response/non-response. Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.

Examining interactions between baseline expectancy beliefs and task values on weekly motivation in an introductory statistics course

Situated expectancy-value theory is one of the most prominent theories for examining students’ motivational beliefs, suggesting that both students’ expectancy beliefs and task values are antecedents of important academic outcomes. Further, interactions between expectancy beliefs and task values often exist and suggest critical theoretical considerations. In this study, we examined how the interaction between students’ baseline expectancy beliefs and task values (utility, attainment, interest, and cost) predicts weekly motivational beliefs in an introductory statistics course for psychology majors in the United States (N = 145) using an intensive longitudinal design. Using multilevel modeling, we found interaction effects of expectancy beliefs x attainment value on weekly competence and cost, expectancy beliefs x anticipated cost on weekly value, expectancy beliefs x interest value on weekly cost. Results suggested that having high baseline value, or low cost, may be unable to buffer against low expectancy beliefs. Theoretical and practical implications are discussed.

Safety of oral immunotherapy for cashew nut and peanut allergy in children - a retrospective single-centre study.

Oral immunotherapy (OIT) is increasingly used for the treatment of childhood food allergies, with limited data available on cashew nut OIT. This real-life study investigated the safety and feasibility of cashew nut OIT, comparing it with peanut OIT, with a focus on the up-dosing process. We analysed cashew nut (n = 24) and peanut (n = 38) OIT cases with treatment initiated between 2018 and 2022 at the University Children's Hospital Basel. All patients who commenced therapy within this time frame were enrolled without prior selection. Two different starting protocols were used. Within the up-dosing protocol, the nut intake was incrementally increased by 20-30% every 2 weeks until reaching a maintenance dose of 1 g of nut protein. After consuming the maintenance dose regularly for 18-24 months, a second oral food challenge was performed. Patients who passed this challenge were considered desensitised. The safety of the therapy was evaluated based on the severity of adverse reactions during the up-dosing phase. Symptom severity was evaluated using the validated ordinal food allergy severity scale (o-FASS-5). Over the study period, 33% of cashew nut-allergic and 63% of peanut-allergic patients experienced mild to moderate allergic reactions. Severe allergic reactions occurred in five peanut-allergic children with high baseline allergen-specific IgE levels. Six patients with peanut, and none with cashew nut OIT, discontinued the therapy due to adverse reactions. The mean duration to reach the maintenance phase was longer for children with asthma or another food allergy. Among children who already underwent the second oral food challenge, desensitisation was achieved in 91% (11 out of 12) of cashew nut- and 73% (11 out of 15) of peanut-allergic patients. Cashew nut OIT had a low severity of adverse reactions and was generally well-tolerated. However, patient characteristics influenced side effect risk and treatment duration, emphasising the need for individualised OIT strategies.

Association between serum intact parathyroid hormone and survival in dialysis patients.

To examine the relationship between serum intact parathyroid hormone (iPTH) levels and survival in maintenance dialysis patients. We retrospectively reviewed the data of patients who began and continued dialysis from January 2013 to December 2022. Patients were categorized based on their baseline and time-averaged (TA) iPTH levels into three groups: low (iPTH < 150pg/ml), medium (150 ≤ iPTH < 300pg/ml), and high (iPTH ≥ 300pg/ml). We utilized the Kaplan-Meier method to assess survival differences, the Cox proportional hazards regression model to identify risk factors impacting adverse outcomes and the restricted cubic spline model to evaluate the association between iPTH levels and the all-cause mortality. We included a total of 1023 participants, comprising 524 hemodialysis and 499 peritoneal dialysis. Kaplan-Meier analysis showed that high baseline group had higher survival and low baseline group had poorer survival, compared with medium baseline group, respectively (χ2 = 44.974, P < 0.001). The three TA groups showed similar results (χ2 = 67.316, P < 0.001). Multivariate COX regression analysis showed that low TA iPTH was an independent risk factor for all-cause death (hazard ratio [HR] = 1.655, 95% CI 1.159-2.365, P = 0.006). The restricted cubic spline model revealed an L-shaped connection between TA iPTH level and the all-cause mortality with an inflection point of 193pg/ml. The survival for maintenance dialysis patients varies significantly based on their baseline and time-averaged iPTH levels, with time-averaged iPTH emerges as an independent risk factor for all-cause death in these patients.

Evaluating Meaningful Changes in Patient-Reported Outcome Measurement Information System-Fatigue Scores from Three Phase 3 Clinical Trials of Sarilumab for Patients With Rheumatoid Arthritis.

The aim of this study was to evaluate changes in fatigue measured by Patient-Reported Outcome Measurement Information System (PROMIS)-Fatigue scores in patients with rheumatoid arthritis (RA) who received sarilumab and to assess the proportion of patients achieving clinically meaningful change. Data from three phase 3 randomized controlled trials of patients with RA who received sarilumab-MOBILITY, TARGET, and MONARCH-were evaluated. The 10 RA-relevant items from the 13-item Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue were scored in the PROMIS T score metric. Mean changes in 10-item PROMIS-Fatigue T score (PROMIS-Fatigue 10a) were compared, proportions of patients reporting meaningful within-person change thresholds were assessed, and results were visualized using empirical cumulative distribution function (eCDF) curves. Patients with RA reported high baseline fatigue. Using PROMIS-Fatigue 10a, at week 24, patients receiving 150 or 200 mg sarilumab every other week in MOBILITY and TARGET had rapidly and significantly improved mean levels of fatigue compared to those who received placebo. When compared to patients who received adalimumab in MONARCH, patients who received sarilumab had a trend toward increased improvement. eCDF curves showed separation between active treatment versus placebo with both sarilumab doses and across the score range for improvement. Higher proportions of patients reported three-, five-, and seven-point improvements in PROMIS-Fatigue scores in groups who received active treatment. Substantial proportions of patients with RA who received sarilumab reported meaningful change in fatigue measured by PROMIS-Fatigue 10a over time. This study demonstrates the ability to convert FACIT-Fatigue score onto the PROMIS T score metric, the rapid reduction in fatigue with biologic therapies, and the use of novel eCDF curves to show individual patient-level change.

Effectiveness of a tertiary specialist obsessive–compulsive disorder (OCD) service in improving clinical outcomes for patients with treatment-resistant/complex OCD

Abstract Introduction: Obsessive-compulsive disorder (OCD) is a chronic condition that can result in significant distress and impaired quality of life (QoL). This retrospective cohort study investigates the effectiveness of individually tailored pharmacotherapy, exposure and response prevention (ERP), and socioeconomic and family interventions on clinical outcomes at a specialist clinic focused on treatment-resistant/complex OCD. Methods: Patients with treatment-resistant/complex OCD treated at the Institute of Mental Health OCD clinic, Singapore, between January 2015 and March 2019 were invited. The interventions included pharmacotherapy and 12–60 intensive cognitive behavioural therapy/ERP sessions. Interventions also targeted socio-occupational dysfunction and family accommodation. Y-BOCS and Q-LES-Q-SF scales were administered pre- and post-treatment. Linear regression and one-way analysis of variance were used for data analysis. Results: Overall, there was a significant reduction in Y-BOCS score of 9.2 (P = 0.000) and an improvement in Q-LES-Q-SF score of 11.6 (P = 0.000). Of 70 participants, 35 (50%), 12 (17%), and 23 (33%) achieved full, partial, and no treatment response, respectively. Improvement in OCD symptoms was associated with lower baseline Y-BOCS scores and being married. Improvement in QoL was associated with higher baseline Q-LES-Q-SF scores. Conclusion: Interventions at the clinic improved OCD symptoms and QoL in patients with treatment-resistant/complex OCD, likely due to the simultaneous socio-occupational support services available.

Abstract 4137243: Dynamic changes of pericoronary fat attenuation index predicting changes of coronary plaque burden

Background: Percent atheroma volume (PAV) is a validated index of coronary plaque burden, linking to adverse cardiac events. Meanwhile, pericoronary fat attenuation index (FAI) on coronary computed tomography angiography (CCTA) image is a novel prognostic marker of coronary inflammation. Research Questions: It is unknown the impact of coronary inflammation (i.e., FAI) on the progression of coronary PAV in patients at an increased risk of adverse cardiac events. Methods: Patients with type 2 diabetes mellitus (T2DM) who underwent at least two clinically indicated CCTA examinations (time interval &gt; 1 year) at our center were potentially eligible for enrollment. Eligible patients presented with more than one study plaque, defined as non-obstructive stenosis at baseline and not being intervened during serial CCTA. Longitudinal CCTA images were assessed for FAI and compositional plaque characteristics (e.g., PAV) using dedicated post-processing softwares. The relationships between changes in FAI and progression of compositional PAV were examined using the logistic and linear regression analysis. Results: A total of 204 T2DM patients (mean age, 61.2 ± 9.3 years; male, 68.1%) with 366 study plaques were enrolled. All patients were treated with statins, and their time interval between longitudinal CCTAs was 14.1 (12.9, 17.6) months. Compared with patients with improved coronary inflammation (ΔFAI ≤ 0), those with deteriorated coronary inflammation (ΔFAI &gt; 0) had lower high density lipoprotein cholesterol and baseline FAI, whereas higher blood pressure (all p &lt; 0.05). Meanwhile, compared to patients with ΔFAI ≤ 0, those with ΔFAI &gt; 0 had more Δoverall and Δnon-calcified PAV (all p &lt; 0.05). Importantly, these findings were consistent in a dedicated propensity score matching analysis. In logistic regression analysis, ΔFAI &gt; 0 was associated with annual progression of overall PAV and non-calcified PAV, whereas ΔFAI ≤ 0 associated with annual regression of overall PAV and non-calcified PAV after adjusting for cardiac risk factors, baseline PAV and medications (all p &lt; 0.05). Similarly, in linear regression analysis, changes of FAI were independently positively associated with annual changes of overall PAV (β=0.545, p&lt; 0.001) and non-calcified PAV (β=0.461, p&lt; 0.001) (Figure 1). Conclusion: In this longitudinal CCTA study, changes of coronary inflammation are closely correlated with changes of overall and non-calcified PAV among T2DM patients treated with statins.