Surrogate Marker Research Articles

Association of Serum M2BPGi Levels with Nutritional Status (Using CONUT score) in Hepatitis C Virus Related Compensated Liver Cirrhosis Patients

Abstract Background Protein-energy malnutrition (PEM), which is one of the most common complications seen in LC patients and associated with high morbidity and mortality. So, predicting the presence of PEM and providing appropriate nutritional support help improve the prognosis of those patients. Mac-2-binding protein glycosylation isomer (M2BPGi) was recently identified as a serum glycobiomarker for liver fibrosis. However, the relationship between M2BPGi and malnutrition in patients with chronic liver disease (CLD) is unclear. Aim of the Work The aim of this study is to evaluate the role of serum M2BPGi levels as a surrogate marker for malnutrition in HCV related cirrhotic patients, correlated with CONUT score as the nutritional status marker. Patients and Methods This is a Cross-sectional - Analytic study that included patients with chronic HCV infection and normal control group selected from patients attending to Hepatology Outpatient Clinics at Ain Shams University Hospital. This study was carried out from 30 patients (child A) attending to Hepatology Outpatient Clinics at Ain Shams University Hospital and 30 healthy individuals as a control. Results The M2BPGi levels increased with CONUT score. The correlation coefficient between M2BPGi and CONUT score was r = 0.315 (p = 0.05), indicating a positive weak correlation between M2BPGi and CONUT score. The cut-off for M2BPGi to predict CONUT low vs. moderate was 1.43 with a sensitivity 93.33% and specificity 100% when AUC =0.9 and CONUT moderate vs. severe was 1.7 with a sensitivity 91.67% and specificity 100% when AUC =0.9. Conclusion We found that there is correlation between M2BPGi and CONUT score and both can be useful as a marker for malnutrition in HCV related cirrhotic patients cut of point

P-521 Inter-individual variation in gonadotoxicity in female childhood cancer survivors – a genome-wide association study: results from the PanCareLIFE study

Abstract Study question To identify new variants associated with alkylating agent (AA) induced gonadotoxicity among adult female childhood cancer survivors (CCS) using a genome-wide association study approach (GWAS). Summary answer Upon meta-analysis of two independent cohorts, the variant rs78861946 was associated with lower AMH levels in CCS, but not separately in the smaller replication cohort. What is known already Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Study design, size, duration A genome-wide association study (GWAS) approach was used to discover new variants associated with AA-induced gonadotoxicity among adult female CCS. The discovery cohort included adult female CCS from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, CNS, total body irradiation, or stem cell transplantation. Results were replicated in the USA-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years) and combined in a meta-analysis. Participants/materials, setting, methods Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in both the discovery and replication cohort. A GWAS was performed using a linear regression model adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study. Main results and the role of chance Three genome-wide significant (<5.0x10E-8 ) and 16 genome-wide suggestive (<5.0x10E-6 ) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0 × 10E−6 ), and biological relevance, 15 SNPs were selected for replication in the independent replication cohort of the St. Jude Lifetime Cohort. None of the SNPs were statistically significantly associated with AMH levels in this smaller cohort. A meta-analysis indicated thatrs78861946 was associated at borderline genome-wide statistical significance (reference/effect allele: C/T;EAF: 0.04, Beta (SE): −0.484 (0.091), p-value= 9.39 × 10E−8). While the sample size of both the discovery and replication cohorts are large for CCS cohorts, they are very small compared to GWASs in the general population. The limited power is likely one of the reasons the identified SNPs were not statistically significant in our replication cohort of SJLIFE. Limitations, reasons for caution While AMH is a valuable surrogate marker for ovarian reserve, it remains a proxy for ovarian reserve and low AMH levels may still coincide with fertility potential and pregnancy. Wider implications of the findings Identification of risk-contributing variants such as rs78861946 may prove useful to better identify patients who are specifically susceptible for alkylating agent-induced gonadal toxicity. Future polygenic risk scores may aid individualized counselling regarding the treatment-related risk of gonadotoxicity and fertility preservation options for female childhood cancer survivors. Trial registration number not applicable

Increased expression of formyl peptide receptor-1 by basophils from patients with mastocytosis

BackgroundSymptoms in patients with systemic mastocytosis (SM) are associated with an increase in mast cell burden and release of mast cell-derived mediators. The most frequent presentation of SM is indolent (ISM), with moderate symptoms and prognosis. Basophil numbers in these patients are generally normal. However, when examining basophil activation in patients with ISM, we noted an abnormal response to N-formylmethione-leucyl-phenylalanine (fMLP). ObjectiveTo compare basophil responsiveness to fMLP and anti-IgE in healthy volunteers and patients with ISM and relate findings to fMLP receptor (FPR) expression. MethodsBasophils isolated from peripheral blood of fifteen patients with ISM and fourteen healthy volunteers were stimulated with fMLP or anti-IgE. CD63 expression to assess basophil activation and expression of FPRs were assessed by flow cytometry. ResultsBaseline expression of CD63 on basophils was similar between healthy volunteers and patients with ISM. fMLP induced higher expression of CD63 on basophils from patients with ISM, while responses to anti-IgE were similar between groups. Basophils from patients with ISM also had higher fMLP1 receptor (FPR1) expression, while FPR2 and FPR3 were not detected. fMLP blocked the binding of anti-FPR1 antibody to FPR1, consistent with the conclusion that fMLP signals through FPR1. ConclusionsFMLP-induced basophil activation is higher in patients with ISM which is associated with an increase in FPR1 expression. Further investigation is needed to determine why FPR1 expression is elevated, whether such expression might serve as an additional surrogate marker in the diagnosis of ISM, and whether enhanced responses of basophils to fMPL might have some relationship to unexplained episodes of mediator release.

Futility Interim Analysis Based on Probability of Success Using a Surrogate Endpoint.

In clinical trials with time-to-event data, the evaluation of treatment efficacy can be a long and complex process, especially when considering long-term primary endpoints. Using surrogate endpoints to correlate the primary endpoint has become a common practice to accelerate decision-making. Moreover, the ethical need to minimize sample size and the practical need to optimize available resources have encouraged the scientific community to develop methodologies that leverage historical data. Relying on the general theory of group sequential design and using a Bayesian framework, the methodology described in this paper exploits a documented historical relationship between a clinical "final" endpoint and a surrogate endpoint to build an informative prior for the primary endpoint, using surrogate data from an early interim analysis of the clinical trial. The predictive probability of success of the trial is then used to define a futility-stopping rule. The methodology demonstrates substantial enhancements in trial operating characteristics when there is a good agreement between current and historical data. Furthermore, incorporating a robust approach that combines the surrogate prior with a vague component mitigates the impact of the minor prior-data conflicts while maintaining acceptable performance even in the presence of significant prior-data conflicts. The proposed methodology was applied to design a Phase III clinical trial in metastatic colorectal cancer, with overall survival as the primary endpoint and progression-free survival as the surrogate endpoint.

Cancer Therapy, Gonadal Function, and Fertility Preservation: Narrative Review.

Fertility preservation was designed to help young patients overcome complications of cancer treatments, but its effectiveness is unknown. We sought to investigate how often patients with cancer are offered fertility preservation and if patients offered fertility preservation are more likely to have offspring. We searched Embase (through 2022) and PubMed (through 2022). Our broad computerized search strategy was built upon using the keywords "chemotherapy," "radiation," and "fertility." The search took place on December 1, 2022. We included randomized and observational studies and excluded reviews and case reports/series. Eighty-five articles that answered at least one of the research questions were included. Studies assessing fertoprotective therapies often rely on surrogate markers for fertility. Multiple factors affect these markers of fertility. The median premature ovarian failure rate among the intervention group was 18% (IQR, 12%-20%), and among the control group, it was 25% (IQR, 19%-33%). Five of 11 studies reported a significant benefit from fertoprotective therapy. Pregnancies occurred in a median of 21% (IQR, 6%-52%) of patients in the intervention group and 11% (IQR, 7-44) of patients in the control group, with three of seven studies reporting a higher percentage of pregnancies among the intervention group. We reviewed the literature on several questions surrounding fertility preservation and found that there is limited and low-quality research on these therapies in cancer. Hence, there is a strong need for studies, especially randomized studies, that follow patients with cancer who undergo fertility preservation and assess outcomes in which patients are most interested.

Salivary uric acid dynamics are associated with stress response hormones among African Americans in an urban sample

Acute physiological responses to psychosocial stressors are a potential pathway underlying racial disparities in stress-related illnesses. Uric acid (UA) is a potent antioxidant that has been linked to disparities in stress-related illnesses, and recent research has shown that UA is responsive to acute social stress. However, an examination of the relationships between the purinergic system and other commonly measured stress systems is lacking. Here, we measure and characterize associations of salivary uric acid (sUA) with markers of hypothalamic-pituitary-adrenal (HPA) axis activation, sympathetic-adreno-medullar (SAM) axis activation, and acute inflammation. A community sample of 103 African Americans (33 male, 70 female) completed the Trier Social Stress Test to induce social-evaluative threat. Passive drool collected before, during, and after the stressor task provided salivary reactivity measures of UA (sUA), cortisol, dehydroepiandrosterone sulfate (DHEAS), salivary alpha amylase (sAA – a surrogate marker of SAM activity) and C-reactive protein (sCRP). Multiple regressions revealed that total activation of cortisol, DHEAS, and sCRP were each positively associated with higher total activation of sUA. Additionally, DHEAS reactivity was positively associated with sUA reactivity. Relationships between HPA-axis markers and sUA were especially observed among younger and male participants. Overall, findings suggest potential coordination of stress systems with sUA in response to acute stress, which may further the contributions of biological stress processes to racial health disparities.

Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States: A comparative study of accelerated approvals.

Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross-sectional study, we considered 23 indications of cancer drugs that received accelerated approval by the US Food and Drug Administration (FDA) but were subsequently withdrawn as of April 2023. Our investigation extended to assessing the regulatory status of these accelerated approvals in the European Union (EU) and Japan, examining relevant regulatory documents and identifying factors contributing to the withdrawal in the United States. Comparing regions, we found that for 52% (12/23) and 30% (7/23) of withdrawn accelerated approvals in the United States, sponsors had also sought marketing authorization from the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), respectively. As of the April 30, 2023 study cutoff date, 83% (10/12) of drug-indication pairs remained approved by the EMA, while the PMDA retained 100% (7/7). For these indications, the time from FDA withdrawal until the study cutoff date ranged from 0.23 years to 11.45 years for EMA approvals (median: 1.28 years) and 1.10 years to 11.45 years for PMDA approvals (median: 3.22 years). These findings highlight substantial regulatory discrepancies concerning cancer drugs with unconfirmed benefits. Addressing these discrepancies may involve requiring pharmaceutical companies to confirm clinical benefits using more robust end points and fostering international harmonization in regulators' assessment.

Clinical Outcomes of Metabolic Surgery on Diuretic Use in Patients with Heart Failure

The beneficial impacts of metabolic surgery (MS) on patients with heart failure (HF) are incompletely characterized. We aimed to describe the cardiac and metabolic effects of MS in patients with HF and hypothesized that patients with HF would experience both improved metabolic and HF profiles using glycemic control and diuretic dependency as surrogate markers. In this single-center, university-affiliated academic study in the United States, a review of 2,342 hospital records of patients who underwent MS (2017 to 2023) identified 63 patients with a medical history of HF. Preoperative characteristics, 30-day outcomes, and up to 2-year biometric and metabolic outcomes, medication usage, and emergency department utilization were collected. At 24 months, mean body mass index change was -16 kg/m2 (p <0.001) that corresponded to a mean percentage total body weight loss of 29% (p <0.001). Weight loss was accompanied by significant reductions in hemoglobin A1c (p <0.001) and a 65% decrease in diuretic use at 24 months after surgery (p <0.001). Similarly, emergency visits for cardiac conditions (p = 0.06) and intravenous diuresis (p = 0.07) trended favorably at 1 year after surgery compared with 1 year before surgery but were not statistically significant. In conclusion, in patients with HF who were carefully selected, MS appears to provide significant reduction in oral diuretic dependency, and metabolic improvements with trends toward lower rates of emergency department utilization.

Semaglutide Concurrently Improves Vascular and Liver Indices in Patients With Type 2 Diabetes and Fatty Liver Disease.

The cardiovascular benefits of semaglutide are established; however, its effects on surrogate vascular markers and liver function are not known. To investigate the effects of semaglutide on vascular, endothelial, and liver function in patients with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). Overall, 75 consecutive subjects with T2DM and NAFLD were enrolled: 50 patients received semaglutide 1 mg (treatment group) and 25 patients received dipeptidyl peptidase 4 inhibitors (control group). All patients underwent a clinical, vascular, and hepatic examination with Fibroscan elastography at 4 and 12 months after inclusion in the study. Treatment with semaglutide resulted in a reduction of Controlled Attenuation Parameter (CAP) score, E fibrosis score, NAFLD fibrosis score, Fibrosis-4 (FIB-4) score and perfused boundary region (PBR) at 4 and at 12 months (P < .05), contrary to controls. Patients treated with semaglutide showed a greater decrease of central systolic blood pressure (SBP) (-6% vs -4%, P = .048 and -11% vs -9%, P = .039), augmentation index (AIx) (-59% vs -52%, P = .041 and -70% vs -57%, P = .022), and pulse wave velocity (PWV) (-6% vs -3.5%, P = .019 and -12% vs -10%, P = .036) at 4 and at 12 months, respectively. In all patients, ΔPWV and ΔPBR were correlated with a corresponding reduction of CAP, E fibrosis, NAFLD fibrosis, and FIB-4 scores. Twelve-month treatment with semaglutide simultaneously improves arterial stiffness, endothelial function, and liver steatosis and fibrosis in patients with T2DM and NAFLD.

Six-minute walk test as clinical end point in cardiomyopathy clinical trials, including ATTR-CM: a systematic literature review.

Aim: The six-minute walk test (6MWT) is acommon measure of functional capacity in patients with heart failure (HF). Primary clinical study end points in cardiomyopathy (CM) trials, including transthyretin-mediated amyloidosis with CM (ATTR-CM), are often limited to hospitalization and mortality. Objective: To investigate the relationship between the 6MWT and hospitalization or mortality in CM, including ATTR-CM. Method: A PRISMA-guided systematic literature review was conducted using search terms for CM, 6MWT, hospitalization and mortality. Results: Forty-one studies were identified that reported 6MWT data and hospitalization or mortality data for patients with CM. The data suggest that a greater 6MWT distance is associated with a reduced risk of hospitalization or mortality in CM. Conclusion: The 6MWT is an accepted alternative end point in CM trials, including ATTR-CM.

Clinical trial designs to assess treatment effects on glomerular filtration rate decline

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPAREG-Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end-of-treatment (chronic effect in a standard randomized trial design) with GFR change calculated from randomization to end-of-wash-out, or GFR change from treatment specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73m2 /year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73m2 /year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73m2 /year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73m2 /year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.

Dynamics of Liver Stiffness Measurement and Clinical Course of Primary Biliary Cholangitis

Background & aimsIn primary biliary cholangitis (PBC), static liver stiffness measurement (LSM) has proven prognostic value. However, the added prognostic value of LSM time course in this disease remains uncertain. MethodsWe conducted an international retrospective cohort study among PBC patients treated with ursodeoxycholic acid (UDCA) and followed by vibration-controlled transient elastography (VCTE) between 2003 and 2022. Using joint modeling, the association of LSM trajectory and the incidence of serious clinical events (SCE), defined as cirrhosis complications, liver transplantation (LT) or death, was quantified using the hazard ratio (HR) and its confidence interval (CI). ResultsA total of 6,362 LSMs were performed in 3,078 patients (2,007 on UDCA alone; 13% with cirrhosis), in whom 316 SCE occurred over 14,445 person-years (median follow-up, 4.2 years; incidence rate, 21.9 per 1,000 person-years). LSM progressed in 59% of patients (mean 0.39 kPa/year). After adjusting for prognostic factors at baseline, including LSM, any relative change in LSM was associated with a significant variation in SCE risk (p<0.001). For example, the adjusted HRs (95% CI) associated with a 20% annual variation in LSM were 2.13 (1.89 – 2.45) for the increase and 0.40 (0.33 – 0.46) for the decrease. The association between LSM trajectory and SCE risk persisted regardless of treatment response or duration, when patients with cirrhosis were excluded, and when only death or LT was considered. ConclusionsTracking longitudinal changes in LSM using VCTE provides valuable insights into PBC prognosis, offering a robust predictive measure for the risk of SCE. LSM could be used as a clinically relevant surrogate endpoint in PBC clinical trials.

Increased Spironolactone Dosing in Acute Heart Failure Alters Potassium Homeostasis but Does not Enhance Decongestion

The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) clinical trial found no improvements in natriuretic peptide levels or clinical congestion when spironolactone 100 mg/day for 96 hours was used in addition to usual treatment for acute heart failure. We performed a post hoc analysis of ATHENA-HF to determine whether spironolactone treatment induced any detectable pharmacodynamic effects and whether patients with potentially greater aldosterone activity experienced additional decongestion. Trial subjects previously treated with spironolactone were excluded. We first examined for changes in renal potassium handling. Using the baseline serum potassium level as a surrogate marker of spironolactone activity, we then divided each treatment arm into tertiles of baseline serum potassium and explored for differences in laboratory and clinical congestion outcomes. Among spironolactone-naïve patients, the change in serum potassium did not differ after 24 hours or 48 hours but was significantly greater with spironolactone treatment compared to placebo at 72 hours (0.23 ± 0.55 vs 0.03 ± 0.60 mEq/L; P = 0.042) and 96 hours (0.32 ± 0.51 vs 0.13 ± 0.72 mEq/L; P = 0.046). Potassium supplementation was similar at treatment start and at 24 hours, but spironolactone-treated patients required substantially less potassium replacement at 48 hours (24% vs 36%; P = 0.048), 72 hours (21% vs 37%; P = 0.013), and 96 hours (11% vs 38%; P < 0.001). When the treatment arms were divided into tertiles of baseline serum potassium, there were no differences in the 96-hour log N-terminal pro-B-type natriuretic peptide levels, net fluid loss, urine output, or dyspnea relief in any of the potassium groups, with no effect modification by treatment exposure. Spironolactone 100 mg/day for 96 hours in patients receiving intravenous loop diuresis for acute heart failure has no clear added decongestive ability but does meaningfully limit potassium wasting.

Quantitative Activity-Induced Manganese-Enhanced Magnetic Resonance Imaging: Principles, Applications, and Limitations

Accurate identification of regions that show activity changes in response to functional expression is necessary to understand the mechanisms underlying functional expression in the brain. Quantitative activity-induced manganese-enhanced magnetic resonance imaging (qAIM-MRI) is a noninvasive whole-brain activity history imaging method used for this purpose. Notably, qAIM-MRI is a pseudo-Ca2+ imaging method that uses Mn2+ as a surrogate marker for Ca2+. In this paper, I describe the principles, applications, and limitations of qAIM-MRI.

Adenoma detection rate and tolerability of two ultra-low volume bowel preparations in screening: a noninferiority randomized controlled trial

The adenoma detection rate (ADR), recognized as a surrogate marker for colorectal cancer incidence and mortality reduction, is closely linked to the efficacy of bowel cleansing. However, there is a dearth of evidence examining the impact on ADR when employing two distinct very low-dose bowel cleansing products. This study sought to compare ADR in a fecal immunochemical occult blood testing (iFOBT) based organized screening program by utilizing 1L polyethylene glycol plus ascorbate (1L-PEGA) versus magnesium citrate plus picosulphate (SPMC), both administered in a split-dose regimen. We conducted a comparative, parallel, randomized, noninferiority, and low-intervention clinical trial, the study targeted individuals from a population colorectal cancer screening program aged 50-69 with a positive iFOBT result scheduled for a work-up colonoscopy in the morning. Participants were randomized to either 1L-PEGA or SPMC for bowel cleansing. Main outcome was ADR. Secondary outcomes were bowel preparation quality, individuals' safety, tolerability and satisfaction. A total of 1,002 subjects were included, 501 in each group. There were no differences between groups with respect to pooled ADR (SPMC, 56.5% [52.1-60.8]; 1L-PEGA, 53.7% [49.3-58.0]; RR 0.95 [0.85-1.06]); therefore, SPMC demonstrated noninferiority in ADR compared to 1L-PEGA (difference, 2.8%; 2-sided 95% lower confidence limit (LCL), -3.4). In addition, there were no significant differences in mean lesions regardless of size and location between arms. Bowel preparation favored 1L-PEGA (96.2% vs. 89.2%; p<0.001) whereas SPMC exhibited significantly higher safety and tolerability, as evidenced by fewer non-serious treatment-emergent adverse events CONCLUSIONS: SPMC emerged as a noninferior laxative compared to 1L-PEGA concerning ADR. Despite the superior bowel preparation quality associated with 1L-PEGA, the safety, tolerability and overall satisfaction of participants were higher with SPMC. This trial was registered at ClinicalTrials.gov (EudraCT: 2019-003186-18) on March 18, 2019.

Non-invasive pulse arrival time is associated with cardiac index in pediatric heart transplant patients with normal ejection fraction

Objective. Cardiac Index (CI) is a key physiologic parameter to ensure end organ perfusion in the pediatric intensive care unit (PICU). Determination of CI requires invasive cardiac measurements and is not routinely done at the PICU bedside. To date, there is no gold standard non-invasive means to determine CI. This study aims to use a novel non-invasive methodology, based on routine continuous physiologic data, called Pulse Arrival Time (PAT) as a surrogate for CI in patients with normal Ejection Fraction (EF). Approach. Electrocardiogram (ECG) and photoplethysmogram (PPG) signals were collected from beside monitors at a sampling frequency of 250 samples per second. Continuous PAT, derived from the ECG and PPG waveforms was averaged per patient. Pearson’s correlation coefficient was calculated between PAT and CI, PAT and heart rate (HR), and PAT and EF. Main Results. Twenty patients underwent right heart cardiac catheterization. The mean age of patients was 11.7 ± 5.4 years old, ranging from 11 months old to 19 years old, the median age was 13.4 years old. HR in this cohort was 93.8 ± 17.0 beats per minute. The average EF was 54.4 ± 9.6%. The average CI was 3.51 ± 0.72 l min−1 m−2, with ranging from 2.6 to 4.77 l min−1 m−2. The average PAT was 0.31 ± 0.12 s. Pearson correlation analysis showed a positive correlation between PAT and CI (0.57, p < 0.01). Pearson correlation between HR and CI, and correlation between EF and CI was 0.22 (p = 0.35) and 0.03 (p = 0.23) respectively. The correlation between PAT, when indexed by HR (i.e. PAT × HR), and CI minimally improved to 0.58 (p < 0.01). Significance. This pilot study demonstrates that PAT may serve as a valuable surrogate marker for CI at the bedside, as a non-invasive and continuous modality in the PICU. The use of PAT in clinical practice remains to be thoroughly investigated.

Associations between Supper Timing and Mortality from Cardiovascular Disease among People with and without Hypertension.

Less is known about the impact of supper time on cardiovascular disease (CVD) risk among hypertensives and nonhypertensives. We aimed to explore this issue in a cohort study. We analyzed the data of 72,658 participants (15,386 hypertensives and 57,272 nonhypertensives) aged 40-79 years without a history of CVD at baseline (1988-1990) under the Japan Collaborative Cohort study. Supper time was assessed based on self-reported questionnaires categorized as before 17:00, between 17:00 and 20:00, after 20:00, irregular supper time, and reference supper time (17:00-20:00). Hazard ratios (HRs) and 95% confidence intervals (95% CI) of CVD mortality were calculated according to supper time after adjustment for potential confounders, stratified by hypertensive status and age group (＜65 and ≥ 65 years). During a median of 19.4 years of follow-up, 4,850 CVD deaths were recorded. Compared with the reference time, the risk of CVD mortality was higher for irregular supper time for the total population, either hypertensives or nonhypertensives, more specifically hypertensives aged ≥ 65 years; the multivariable HR (95% CI) of CVD mortality in the total population was 1.28 (1.11-1.50, P＜0.01). The supper time of ＞20:00 tended to be associated with the higher risk only for hypertensives; the multivariable HR was 1.39 (0.98-1.96, P=0.06). Irregular supper time was associated with an increased risk of CVD mortality. Supper timing could be a surrogate marker for CVD risk.

Negative LDL-C levels with Detectable Apolipoprotein B: Surrogate Markers of Atherosclerotic Disease and Cardiac Event Risk

Negative LDL-C levels with Detectable Apolipoprotein B: Surrogate Markers of Atherosclerotic Disease and Cardiac Event Risk

Ocrelizumab Alters Cytotoxic Lymphocyte Function While Reducing EBV-Specific CD8+ T-Cell Proliferation in Patients With Multiple Sclerosis.

The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment. In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8+ T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8+ T and NK lymphocytes as surrogate markers of anti-EBV activity. We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8+ T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8+ T-cell proliferation in response to EBV antigenic peptides. Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8+ and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.

Intracranial pulse pressure amplitude as an indicator of intracranial compliance: observations in symptomatic children with Chiari malformation type I.

Reduced intracranial compliance (ICC) may be an important factor in the pathophysiology of Chiari malformation type I (CM-I). However, direct measurement of ICC is controversial because of its invasiveness, particularly in children. Instead, ICC may be estimated from continuous measurements of intracranial pressure (ICP), where the metric mean wave amplitude (MWA) has been found to be more useful as a surrogate marker of ICC than mean ICP. This observational study investigated the distribution of MWA and mean ICP in symptomatic children with CM-I, as well as their association with clinical and radiological findings. From a consecutive series of children treated for CM-I at a single institution between 2006 and 2023, the authors analyzed ICP scores in those who underwent an overnight preoperative ICP recording in which MWA was calculated. Clinical and radiological data were retrieved from the patient records. Thirty-seven children (mean age 12.4 ± 3.6 years) with symptomatic CM-I were identified. From the overnight ICP measurements, the average MWA was 5.2 ± 1.3 mm Hg: 56% of children had an abnormal MWA (> 5 mm Hg) and 33% had a borderline MWA (4-5 mm Hg). In contrast, the average mean ICP was 9.7 ± 4.1 mm Hg: 8% of children had an abnormal mean ICP (> 15 mm Hg) and 41% had a borderline mean ICP (10-15 mm Hg). Thus, more children were found to have an abnormal MWA than an abnormal mean ICP (p < 0.001). MWA was significantly higher in the subgroup of children with medullary compression in the foramen magnum, as seen on MRI, than in those without (5.6 ± 1.0 mm Hg vs 4.7 ± 1.4 mm Hg, p = 0.03), whereas a similar difference was not observed for mean ICP (9.9 ± 4.6 mm Hg vs 9.7 ± 3.7 mm Hg, p = 0.889). In this cohort of symptomatic children with CM-I, MWA was more frequently abnormal than mean ICP, with a clinically significant discrepancy in half of the patients. Moreover, MWA was significantly higher in patients with medullary compression. Based on these findings, the authors' interpretation is that in children with CM-I, the ICC may be reduced, as indicated by increased MWA, even though the mean ICP is within normal thresholds.