Surrogate Marker Research Articles

Multiple surrogates in the meta-analytic setting for normally distributed endpoints

The identification of good surrogate endpoints is a challenging endeavour. This may, at least partially, be attributable to the fact that most researchers have focused on the identification of a single surrogate endpoint. It is thus implicitly assumed that the treatment effect on the true endpoint (T) can be accurately predicted based on the treatment effect on one surrogate endpoint (S) only. Given the complex nature of many diseases and the different therapeutic pathways in which a treatment can impact T, this assumption may be too optimistic. For example, in oncology, the effect of a treatment often depends on both the treatment’s efficacy and its toxicity. In the present paper, the meta-analytic framework of Buyse et al. (2000) is extended to the setting where multiple S are considered. To cope with potential model convergence issues that often arise in a meta-analytic framework, several simplified model fitting strategies are proposed. Further, simulation studies are conducted to evaluate the properties of the estimated surrogacy metrics, and the new methodology is applied on a case study in schizophrenia. An online Appendix that details how the analyses can be conducted in practice (using the R package Surrogate) is also provided.

Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.

Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.

A case series on endometrial cancer in multipara and their prognostication based on IHC markers

Endometrial carcinoma is one of the leading gynecological malignancies across the globe. With advent of molecular analysis, establishing an accurate treatment plan and improving patient outcome has become eminent. In resource limited settings like India, surrogate IHC markers like hormonal receptor expression are congruous substitutes that aid to accurately predict patient prognosis. In this case series, expression of hormonal receptors in multiparous women and it’s association with patient outcome seen as disease free survival at a span of 2 years was compared. This study opines inclusion of hormonal receptors in evaluation of endometrial carcinoma patients to accurately comment on patient outcome.

Cerebral Infarct Growth: Pathophysiology, Pragmatic Assessment, and Clinical Implications.

Cerebral ischemic injury occurs when blood flow drops below a critical level, resulting in an energy failure. The progressive transformation of hypoperfused viable tissue, the ischemic penumbra, into infarction is a mechanism shared by patients with ischemic stroke if timely reperfusion is not achieved. Yet, the pace at which this transformation occurs, known as the infarct growth rate (IGR), exhibits remarkable heterogeneity among patients, brain regions, and over time, reflecting differences in compensatory collateral flow and ischemic tolerance. We review (1) the pathophysiology of infarct growth, (2) the advantages and pitfalls of different approaches of IGR measurement, (3) research gaps for future studies, and (4) the clinical implications of stroke progressor phenotypes. The estimated average IGR in patients with acute large vessel occlusion stroke is 5.4 mL/h although there is wide variability based on ischemic stroke subtype, occlusion location, presence of collaterals, and patient baseline status. The IGR can be calculated using various pragmatic strategies, mostly either quantifying the extension of the infarct at a particular time and dividing this measure by the time that elapsed from symptom onset to imaging assessment or by using collateral blood flow status as a radiological surrogate marker. The IGR defines a spectrum of clinical stroke phenotypes, often dichotomized into fast and slow progressors. An IGR ≥10 mL/h and the perfusion metric hypoperfusion intensity ratio ≥0.5 are commonly used definitions of fast progressors. A nuanced understanding of the IGR and stroke progressor phenotypes could have clinical implications, including informing prognostication, acute decision-making in peripheral-to-comprehensive transfer patients eligible for thrombectomy, and selection for adjuvant neuroprotective agents.

Circulating levels of Low Density Granulocytes and cell-free DNA as predictors of cardiovascular disease and bone deterioration in SLE patients.

The present work evaluates the predictive value of low-density-granulocytes (LDG) for the development of cardiovascular disease (CVD) and/or bone deterioration (BD) in a six-year prospective study in Systemic Lupus Erythematosus (SLE). Considering the high SLE-LDG capacity to form Neutrophil Extracellular Traps (NETs), circulating levels of total cell-free DNA (cirDNA) and relative amounts of mitochondrial and nuclear DNA (mtDNA and nDNA, respectively) were tested as LDG-associated biomarkers to identify SLE patients at risk of CVD and BD. To this end, the frequency of total blood LDGs, as well as the CD16negCD14neg (nLDG) and CD16posCD14low (pLDG) subsets, was quantified by flow cytometry in 33 controls and 144 SLE patients. Total cirDNA and relative amounts of mitochondrial (mtDNA) and nuclear (nDNA) cell-free DNA were measured by fluorometry or qPCR in plasma from a subgroup of 117 patients and 23 controls at enrolment. Our findings showed increased blood levels of SLE-nLDGs at enrolment associated with prospective CVD development (pCVD) and the presence of BD, thus revealing LDG expansion as a predictor of both comorbidities in SLE progression. The amounts of the different types of circulating DNA analysed were increased in patients, especially those presenting traditional CV-risk factors or subclinical atheromatosis. Similar to nLDGs, the nDNA concentration could predict the development of pCVD in SLE, supporting the quantification of cirDNA levels as a surrogate marker of LDGs in clinical practice.

Association Between Zinc Status and Insulin Resistance/Sensitivity Check Indexes in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is considered the most common metabolic disorder of the pregnancy period. It is characterized by pancreatic beta-cell dysfunction in the setting of chronic insulin resistance. Zinc is a nutrient involved in numerous metabolic processes and shows a relationship with glycometabolic disorders and GDM. The latest data have demonstrated the association of zinc with insulin sensitivity and resistance. The exact role of zinc in the connection with indexes of insulin resistance and insulin sensitivity is still not fully clarified. The aim of the study is to analyze the newly calculated indexes Glu/Zn, Ins/Zn, and HOMA-IR/Zn as surrogate markers to explore the correlation between serum zinc status and some indexes of insulin sensitivity and insulin resistance. The possible role of these indexes as markers of insulin resistance in pregnant women was analyzed too. An ROC analysis demonstrated that HOMA-IR/Zn with AUC 0.989, p < 0.001 (95% CI 0.967–1.000) and Ins/Zn with AUC 0.947, p < 0.001 (95% CI 0.889–1.000) in the GDM group, and only HOMA-IR/Zn index with AUC 0.953, p < 0.001 (95% CI 0.877–1.000) in healthy pregnant women, have good power as markers of insulin resistance in both groups. We speculate that these new ratios could be suitable for the assessment of pregnant women at high risk of insulin resistance development and, probably, for the evaluation of the specific pathophysiologic characteristics of women with GDM.

Development of clinical questions and outcomes on Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters

To develop the clinical questions and outcomes of Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters based on Norms of Formulation and Evaluation for the Clinical Guideline on Acupuncture and Moxibustion released by World Federation of Acupuncture and Moxibustion Societies. Combined the investigation with expert consultation and consensus method, and taken clinicians (members) of Chinese Association of Acupuncture and Moxibustion as the subjects, the clinical questions concerned were collected and the two-round consultation was conducted among expert group by letter. In the first round questionnaire, using the voting method, the relevant clinical questions in intervention measures were collected; and in the second round, with the Delphi method adopted, the importance of clinical questions and outcomes in the investigation was scored. A total of 200 structured clinical questions proposed by 153 clinicians and the clinical experience with 13 kinds of combined therapies involved and fire needling as the key measure were collected. The authority coefficient (Cr) of the Delphi questionnaire was >0.70, and the coefficient of variation for the importance scores of alternative clinical questions and outcomes was 0.06-0.26 and 0.12-0.47, respectively. The top 10 clinical questions and 12 outcomes (6 outcomes referred to the patients either in the acute stage or the post-neuralgia stage) were included, with the importance score of clinical questions>4, the importance score of outcomes>6, and the coefficient of variation ≤0.25. The clinical questions and outcomes of Clinical Practice Guideline of Fire Needling Therapy for Herpes Zosters are formulated, which provides the research basis for the recommendation development of the guideline.

Do sociodemographic and health predictors affect the non-insulin-based insulin resistance index? A cross-sectional study.

Insulin resistance (IR) is considered a risk factor for cardiovascular diseases (CVD). Therefore, early diagnosis of IR is clinically significant for primary and secondary CVD prevention initiatives. In addition, non-insulin metabolic indices may be useful for diagnosing IR. The first objective was to estimate the triglyceride and glucose (TyG) index and the metabolic score for insulin resistance (METS-IR) index values in a local community with high social deprivation and increased cardiovascular risk according to the Systematic Coronary Risk Evaluation scale. The second objective was to identify significant sociodemographic and health predictors for the TyG index and METS-IR index. This cross-sectional study was conducted in the local community of Janów district in eastern Poland and consisted of 2 stages. The 1st stage involved basic research (n = 4,040), while the 2nd stage involved enhanced diagnostics (n = 2,657). Data from the 2nd stage was used for the analyses. Anthropometric and physiological measurements were taken, blood was drawn for laboratory tests, selected sociodemographic and health variables were evaluated, and the TyG index and METS-IR index were calculated. The mean TyG index score in the study group was 8.65 (±0.58), and the mean METS-IR index score was 41.45 (±9.02). Both indices were significantly associated with age, male sex, smoking, and systolic blood pressure (SBP) in a multivariable model. In addition, alcohol consumption and body mass index (BMI) were significantly correlated with the TyG index, whereas education was significantly associated with the METS-IR index. Our results show the association between IR and sociodemographic and health variables in a group with a high social deprivation rate and increased cardiovascular risk. Early detection of cardiometabolic risk is important for both primary and secondary CVD prevention. In primary healthcare, this can be accomplished through surrogate markers of IR.

Abstract 4138332: Lipoprotein (a), Triglyceride-Glucose Index and Incident Atherosclerotic Cardiovascular Disease (ASCVD): Analysis of the UK Biobank

Background: The triglyceride-glucose index (TyG), an inexpensive novel surrogate marker for insulin resistance, and lipoprotein (a) [Lp(a)] are both risk factors for atherosclerotic cardiovascular disease (ASCVD). However, it is uncertain whether TyG modifies the relationship of Lp(a) with incident ASCVD. Objective: To investigate the relationship of Lp(a) and TyG with the risk of incident ASCVD. Methods: We included UK Biobank participants without ASCVD at enrollment. Baseline TyG was calculated as ln[fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. We classified TyG values as high (≥75th percentile) or low (<75th percentile), and Lp(a) levels, in nmol/L, as <125 or ≥125. Participants were then stratified into four groups: Group-1: Low TyG with Lp(a), <125, Group-2: Low TyG with Lp(a) ≥125, Group-3: High TyG with Lp(a) <125, and Group-4: High TyG with Lp(a) ≥125. We used multivariable Cox regression to estimate the risk of ASCVD (a composite of peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) of TyG and Lp(a) adjusted for the other, and in the four combination groups. Results: Eligible participants (N=254,377) had a mean (SD) age of 56.0 (8.1) years, and 53.2% were female. The median follow-up was 14.6 years. In separate models additionally adjusted for cardiovascular risk factors (see Figure legend), the hazard ratio (HR [95% CI]) for ASCVD was 1.18(1.13–1.23) for Lp(a) ≥125 nmol/L (vs. <125 nmol/L), adjusted for TyG, and 1.09(1.05–1.13) for high TyG (vs. low), adjusted for Lp(a). A statistically significant interaction between TyG and Lp(a) was observed in the fully adjusted model (p <0.001). Compared to Group-1 (low TyG with Lp(a) <125nmol/L), the adjusted HR (95% CI) of incident ASCVD in Group-2, -3 and -4 were: 1.07(1.04–1.13), 1.15 (1.09–1.21) and 1.34(1.25–1.44), respectively (Figure). Conclusions: These findings demonstrate that TyG and Lp(a) are associated with incident ASCVD risk independently of each other. Moreover, TyG modified the effect of Lp(a) on ASCVD, suggesting that insulin resistance may amplify the atherogenic, inflammatory, and/or thrombotic effects of Lp(a), thereby further increasing ASCVD risk.

Abstract 4141457: Forms of Childhood Maltreatment and Subclinical Cardiovascular Disease Risk in Black men and women

Background: Exposure to specific forms of childhood maltreatment have been associated with cardiovascular disease (CVD) risk factors and CVD events in adulthood. Heterogenous experiences of childhood maltreatment across race and sex exist, yet there is little evidence regarding these relationships and CVD risk in Black populations. Aims: To investigate the association between various forms of childhood maltreatment (emotional, general, physical, and sexual abuse) and surrogate markers of vascular dysfunction and test whether sex modify these associations. Methods: Forms of childhood maltreatment and indices of vascular function were assessed in a cohort of healthy Black adults without known CVD (n=404) from a large metropolitan southeastern city. Childhood maltreatment was assessed using the Early Trauma Inventory short form (ETISR-SF) consisting of physical, sexual, emotional, and general domains. A trauma severity index score was calculated by summing the indexes for each of the four domains. Higher scores are indicative of higher traumatic life events before age 18 years. Outcomes of central augmentation index (cAIx) corrected for a heart rate of 75 bpm and carotid femoral pulse wave velocity (CfPWV) were measured as indices of wave reflections and arterial stiffness using applanation tonometry (Sphygmocor Inc.), and central pulse pressure (CPP) was calculated as the difference between the aortic systolic and diastolic blood pressures. Associations between each domain and outcomes were assessed using multivariate-adjusted and sex-stratified linear regression models. Results: Mean age of the cohort was 53 + 10.3 years, 61% women. Exposure to emotional [ b = -1.5%, 95%CI: -2.7,-0.3] and physical abuse [ b = -1.3%, 95%CI: -2.5,-0.2] was associated with cAIx overall but not CPP or CfPWV after adjusting for sociodemographic, clinical factors, health behaviors, and depressive symptoms. Significant emotional abuseXsex ( P= 0.014) and physical abuseXsex ( P=< 0.001) interactions were identified for cAIx. Among women, physical abuse was associated with higher cAIx [ b =1.5%, 95%CI: 0.6, 2.4] and among men emotional [ b =-1.6%, 95%CI: -3.2, -0.0] and physical [ b =-1.7%, 95%CI: -3.1, -0.3] abuse was associated with lower cAIx. Conclusions: Exposure to emotional and physical abuse as children was associated with vascular dysfunction; moreover, exposure to physical abuse among women and not men have adverse clinical implications for CVD risk and prospects for enhanced preventive care.

Association of phenylalanine and tyrosine metabolism with mortality and response to nutritional support among patients at nutritional risk: a secondary analysis of the randomized clinical trial EFFORT

BackgroundElevated phenylalanine serum level is a surrogate marker of whole-body proteolysis and has been associated with increased mortality in critically ill patients. Tyrosine is a metabolite of phenylalanine and serves as a precursor of thyroid hormones and catecholamines with important functions in the oxidative stress response among others. Herein, we examined the prognostic significance of phenylalanine, tyrosine, as well as its metabolites nitrotyrosine, L-3,4-dihydroxyphenylalanine (DOPA), and dopamine regarding clinical outcomes and response to nutritional therapy in patients at nutritional risk.MethodsThis is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized controlled trial investigating individualized nutritional support compared to standard care in patients at risk of malnutrition. The primary outcome was 30-day all-cause mortality.ResultsWe analyzed data of 238 patients and found a significant association between low plasma levels of phenylalanine [adjusted HR 2.27 (95% CI 1.29 to 3.00)] and tyrosine [adjusted HR 1.91 (95% CI 1.11 to 3.28)] with increased 30-day mortality. This association persisted over a longer period, extending to 5 years. Additionally, trends indicated elevated mortality rates among patients with low nitrotyrosine and high DOPA and dopamine levels. Patients with high tyrosine levels showed a more pronounced response to nutritional support compared to patients with low tyrosine levels (HR 0.45 versus 1.46, p for interaction = 0.02).ConclusionIn medical inpatients at nutritional risk, low phenylalanine and tyrosine levels were associated with increased short-and long-term mortality and patients with high tyrosine levels showed a more pronounced response to nutritional support. Further research is warranted to gain a deeper understanding of phenylalanine and tyrosine pathways, their association with clinical outcomes in patients at nutritional risk, as well as their response to nutritional therapy.Clinical trial registrationwww.clinicaltrials.gov, identifier NCT02517476.

Logistic organ dysfunction system as an early risk stratification tool after aneurysmal subarachnoid hemorrhage

AbstractAneurysmal subarachnoid hemorrhage (aSAH) not only causes neurological deficits but also influences extracerebral organ functions. The Logistic Organ Dysfunction System (LODS) reliably captures organ dysfunctions and predicts mortality of critically ill patients. This study investigated LODS in the setting of aSAH as a surrogate marker for early brain injury (EBI). Patients with aSAH treated between 2012 and 2020 were retrospectively analyzed. LODS was calculated within 24 h upon admission applying functional parameters for each organ system. The EBI was evaluated based on 1-persistent loss of consciousness, 2-global cerebral edema, and 3-intracranial blood burden. The outcome was assessed with the modified Rankin scale (mRS) at 3-months after ictus (mRS > 2 = unfavorable outcome). A total of 324 patients with a mean age of 55.9 years were included. Severe EBI (EBI grade ≥ 3) was found in 38% (124/324) of patients. Higher LODS score correlated with severe EBI (p < 0.0001) and poor outcome (p < 0.0001). LODS with a cutoff of 7 allowed a reliable discrimination (AUC 78%, p < 0.0001) of patients with severe from those with mild EBI. The LODS-calculation as an early risk stratification and prognostic tool reliably reflected the severity of EBI after aSAH and correlated with outcome.

Hard-to-treat autoimmune hepatitis and primary biliary cholangitis: The dawn of a new era of pharmacological treatment.

Patients with hard-to-treat autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) are defined a posteriori as those who do not show a sufficient response or are intolerant to pharmacological treatments, thus not achieving biochemical surrogate endpoints that are associated with long-term liver-related-event-free survival. The absence of a recently harmonized definition of 'complete biochemical response within 6 months (CBR≤6M)', which is defined as the normalization of serum transaminase and IgG levels below the upper limit of normal (ULN) at ≤6 months after treatment initiation is regarded as hard-to-treat AIH. The implementation of CBR≤6M, in turn, has been facilitating clinical trials, e.g., between azathioprine and mycophenolate mofetil, to reconsider appropriate first-line steroid sparing agents, leading to a reduction in the number of hard-to-treat AIH cases. Regarding PBC, one of the disseminated definitions of hard-to-treat patients is the absence of POISE criteria, which are evaluated at 12 months with serum alkaline phosphatase and bilirubin levels, after the introduction of ursodeoxycholic acid. Hard-to-treat PBC not meeting the POISE criteria has very recently been the target population for the U.S. FDA-approved second-line drugs, elafibranor and seladelpar. In future pharmacological treatment of AIH and PBC, the primary objective for AIH is likely to focus on lowering the number of hard-to-treat patients with personalized steroid sparing treatment regimens. A challenging goal in PBC treatment is the further optimization of treatment surrogate endpoints, even to the stricter ALP normalization, with which an indication of second- or later-line drugs might be expanded, but could ultimately lengthen patients' long-term survival.

BIOM-11. PROGNOSTIC VALUE OF H3K27ME3 AND EZH2 IN ASTROCYTOMA, IDH-MUTANT

Abstract BACKGROUND H3K27 trimethylation (H3K27me3), catalyzed by EZH2, regulates gene expression through epigenetic mechanisms. H3K27me3 is used as a surrogate marker in pathology for diffuse midline glioma, ependymoma. However, the clinical value of H3K27me3 and EZH2 in astrocytoma, IDH-mutant has not been reported. The aim of this study was to evaluate the clinical significance of H3K27me3 and EZH2 in astrocytoma, IDH-mutant. METHODS A total of 30 patients with astrocytoma, IDH-mutant treated at our institute were included. The patients were divided into 2 groups according to the expression of immunohistochemistry (IHC) for H3K27me3. The following factors were analyzed; age, WHO grade, IHC for EZH2, CDKN2A status, ki67-index and extent of resection. The CDKN2A status was diagnosed by IHC for MTAP and was confirmed by NGS-based CGP test in some cases. Kaplan–Meier analysis and Cox regression analysis were performed to analyze overall survival (OS) and progression-free survival (PFS). RESULTS According to WHO classification 2021, astrocytomas were classified as follows: WHO grade2: 20 cases, grade 3: 2 cases, grade 4: 8 cases. Seventeen patients were identified as H3K27me3 positive, while fourteen patients were classified as H3K27me3 negative. The proportion of WHO grade 3 or 4 and ki-67 index were significantly higher in the H3K27me3 positive group (p=0.0011, 0.0036, respectively). OS and PFS were significantly longer in H3K27me3 positive group (p=0.0379, 0.0025). Furthermore, in the analysis of WHO grade 2/3, double-positive expression of H3K27me3 and EZH2 showed significantly shorter PFS and OS than the other group (p=0.0114 and 0.0068, respectively). In Cox regression analysis, H3K27me3 showed the highest likelihood ratio for OS (p=0.01061). CONCLUSIONS In Astrocytoma, IDH-mutant, the H3K27me3 positive group showed poor prognosis than H3K27me3 negative group. In addition, patients with double-positive expression of H3K27me3 and EZH2 demonstrated more unfavorable prognosis. H3K27me3 and EZH2 could be prognostic markers for astrocytoma, IDH-mutant.

IMMU-71. CRANIOENCEPHALIC FUNCTIONAL LYMPHOID UNITS IN GLIOBLASTOMA

Abstract The general accessibility of the brain to immune cells has been a subject of intense debate and reinterpretation within the last decade. While glioblastoma’s brain tumor ecosystem is typically considered immunosuppressed, we report the presence of a tumor-reactive immune cell niche within the cranial bone marrow (CB) situated adjacent to treatment-naive tumors. At time of initial diagnosis, glioblastoma patients underwent clinical and anatomical imaging, which revealed an unexpected co-morbid association between the CB and the tumor. Following this observation, we conducted an extensive experimental study including multiplex immunofluorescence, immunoprofiling, functional assays, and single-cell analysis, which identified an active lymphoid niche within the patient’s CB. CD8+ T cell effector cells residing in this niche exhibited acute and durable antitumor responses, and, compared to cells from the distal bone marrow, showed increased expression of the lymphoid egress marker S1PR1. Single-cell T cell receptor sequencing revealed a rich reservoir of non-exhausted tumor-shared CD8+ T cell clonotypes within the CB lymphoid niche, suggesting re-circulation between the proximal bone and the tumor tissue. These clonotypes were characterized by a high predicted tumor-reactivity, significantly surpassing levels found in blood and distal bone marrow. We discovered the entire developmental spectrum of CD8+ T cells in the CB, indicating that anatomical proximity may play a critical role in the process of early anti-tumor response. Correspondingly, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker, indicating focal association with improved progression-free survival. Our findings support the preservation and further exploitation of these cranioencephalic units to improve clinical care in glioblastoma patients.

A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions.

To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple broadly neutralizing antibody (bNAb) combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs). We demonstrate that subcutaneous infusion of the triple bNAb regimen was well tolerated in pediatric monkeys and resulted in durable systemic and mucosal distribution. Plasma obtained from passively-immunized RMs demonstrated potent HIV-neutralizing and Fc-mediated antiviral effector functions. Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker threshold of >200, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has PT80>200 against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV.

Association between triglyceride glucose-body mass index and depression among US adults: A cross-sectional study

ObjectivesThe triglyceride glucose-body mass index (TyG-BMI) is a well-established surrogate marker for insulin resistance. While an association between insulin resistance and depression has been identified, that between TyG-BMI and depression remains unclear. Therefore, we used data from the National Health and Nutrition Examination Survey (NHANES) database to investigate this. Study designThis cross-sectional study included 9673 adults (aged ≥20 years) from the NHANES in the United States from 2011 to 2020. MethodsDepressive symptoms were assessed using a nine-item version of the Patient Health Questionnaire. The covariates included age, sex, race/ethnicity, marital status, educational level, poverty-income ratio, smoking status, alcohol intake, diabetes status, cardiovascular disease, hypertension, physical activity, high-density lipoprotein, low-density lipoprotein, and total cholesterol. Multivariate logistic regression models, subgroup analyses, and threshold saturation effect analyses were conducted. ResultsAfter adjusting for age, sex, race/ethnicity, marital status, education level, poverty-income ratio, smoking status, drinking status, diabetes status, cardiovascular disease, hypertension, physical activity, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, the threshold saturation effect showed a TyG-BMI inflection point of 174.4. Below the inflection point, a 10-unit increase in TyG-BMI was associated with a 12 % lower prevalence of depression. Above the inflection point, each 10-unit increase in TyG-BMI was associated with a 4 % increase in prevalence of depression. ConclusionsTyG-BMI had a U-shaped relationship with prevalence of depression. There was a significant link between higher TyG-BMI levels and increased prevalence of depression. When the TyG-BMI value was below 174.4, any further increase in TyG-BMI was associated with a significantly lower prevalence of depression.

Correlation Between Serum Copeptin and NTproBNP Levels in Heart Failure

Introduction: Heart Failure is a leading cause of morbidity and mortality worldwide. It is associated with upregulation and dysfunction of the renin-angiotensin aldosterone system, the sympathetic nervous system and the vasopressin system. In heart failure, the levels of vasopressin are elevated and out of sync with the osmotic status. Arginine Vasopressin has a half-life of only 20 minutes and is bound to circulating platelets. Hence, it is not useful as a biomarker. Copeptin, a by-product of vasopressin metabolism has been used as a surrogate marker for Arginine Vasopressin in clinical practice. Thus, our study aims to find the use of copeptin in studying heart failure and its use in predicting severity. We also sought to correlate copeptin with NTproBNP the standard biomarker used in heart failure. Methods: Our study was a single-centre cross-sectional observational study involving 90 admitted heart failure patients over 18 months. NYHA Class was used to assess the severity of heart failure. Copeptin levels were measured using Human Copeptin ELISA Kit. Results: In these patients, elevated levels of copeptin and NTproBNP were found. In patients with higher NYHA Class, a greater rise in serum copeptin and NTproBNP levels was noted. Moreover, a strong positive correlation between NTproBNP and copeptin (rho = 0.7) was found in our study. Conclusion: Our study puts forward copeptin as a simple additional cost-effective biomarker for predicting the severity of heart failure.

The Relationship between Raised Mean Platelet Volume and Severity of Newly Diagnosed Acute Ischaemic Stroke

Introduction and Objective: Stroke is one of the leading causes of mortality and long-term disability throughout the world. Mean platelet volume (MPV), a marker of platelet activation, is calculated and provided by automatic blood cell count equipment during routine complete blood count analysis is a surrogate marker of platelet function and a potential mediator of the association between inflammation and thrombosis. So, to investigate MPV in ischaemic stroke and its role to discriminating more severe stroke from mild one the current study was done. Methods: This observational case control study was carried out in Department of Medicine, Dhaka Medical College Hospital (DMCH) from July 2015 to June 2016. 100 patients with attack of ischaemic stroke who presented within 24 hours of symptoms onset were divided into 2 groups (group-1: mRS score 0-2, and group-2: mRS score 3 or more) based on severity. Severity of ischaemic stroke was assessed by the modified Rankin Scale. At the same time 100 age and sex matched controls were taken. Blood samples were collected from both groups and MPV was measured. The results were statistically compared by SPSS 22.0. Statistical significance was accepted at <0.05. Results: The MPV values were more in case group in comparison to control group (10.88±1.23 vs 10.03±1.03; z score-5.31; p value <0.01). Comparison between the 2 groups revealed that MPV value was higher and more significant in group 2 of cases than group 1(10.15± 0.739 in group 1 versus 11.63± 1.04 in group having 2; z score-7.7, p value <0.001). 6 patients of group 2, who could not overcome the situation and died within 24 hours of admission had MPV value of 12.92±0.30. After controlling the risk profiles associated with ischaemic stroke by means of binary logistic regression model, the effect of MPV in ischaemic stroke remained statistically significant (OR: 4.418, 95% CI 2.468-7.908, p= 0.000). ROC curve was 0.85 and standard error 0.039 (95% CI: 0.779-0.932; p<0.01), ...

Isotretinoin increases non-insulin-based surrogate markers of insulin resistance in acne vulgaris patients

Background Lipid indices, particularly the triglyceride-glucose index (TyG index) and the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio, are simple, reliable, non-insulin-based surrogate markers of insulin resistance that have recently gained prominence. The aim of this study was to evaluate the effect of isotretinoin treatment on surrogate markers of insulin resistance, in particular the TyG index, in patients with acne vulgaris (AV). Materials and methods This retrospective study reviewed the records of 200 patients who received isotretinoin treatment for acne vulgaris at the Department of Dermatology and Venereology between September 2023 and March 2024. Serum fasting glucose, fasting lipid profile [triglyceride (TG), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)] and other biochemical parameters were recorded. Triglyceride-glucose (TyG) index value was calculated with the formula Ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. Pre-treatment values were compared with values after 5 months of treatment. Results TyG index and TG/HDL, TC/HDL, and LDL/HDL ratios all increased statistically significantly (p < 0.001). In addition, a positive correlation was found between pre- and post-treatment TyG index values and pre- and post-treatment TC/HDL, LDL/HDL and TG/HDL ratio values (p < 0.001). Among lipid measurements, triglycerides, total cholesterol, VLDL-C, LDL-C increased statistically significantly (p < 0.001), while HDL-C decreased statistically significantly (p < 0.05). Conclusion The results of this study suggest that isotretinoin treatment may increase insulin resistance in AV patients by increasing surrogate biomarkers of insulin resistance. We also suggest that the TyG index and other lipid indices can be used in treatment follow-up.