Surrogate Marker Research Articles

Evaluating time-to-event surrogates for time-to-event true endpoints: an information-theoretic approach based on causal inference.

Putative surrogate endpoints must undergo a rigorous statistical evaluation before they can be used in clinical trials. Numerous frameworks have been introduced for this purpose. In this study, we extend the scope of the information-theoretic causal-inference approach to encompass scenarios where both outcomes are time-to-event endpoints, using the flexibility provided by D-vine copulas. We evaluate the quality of the putative surrogate using the individual causal association (ICA)-a measure based on the mutual information between the individual causal treatment effects. However, in spite of its appealing mathematical properties, the ICA may be ill defined for composite endpoints. Therefore, we also propose an alternative rank-based metric for assessing the ICA. Due to the fundamental problem of causal inference, the joint distribution of all potential outcomes is only partially identifiable and, consequently, the ICA cannot be estimated without strong unverifiable assumptions. This is addressed by a formal sensitivity analysis that is summarized by the so-called intervals of ignorance and uncertainty. The frequentist properties of these intervals are discussed in detail. Finally, the proposed methods are illustrated with an analysis of pooled data from two advanced colorectal cancer trials. The newly developed techniques have been implemented in the R package Surrogate.

Neutrophil extracellular traps as an important part of the pathogenesis of chronic rhinosinusitis without polyps

Background. Chronic sinusitis occurs in the Russian Federation in 16.4±10.89% of the population and has a great impact on the quality of life of patients. The inflammatory process underlying this pathology is often resistant to conservative treatment and causes surgical intervention. The study of the role of neutrophil extracellular traps as an important part of the immune response, as well as the capabilities of drugs capable of influencing the processes of netosis, is an important and relevant area of modern research. Aim. Studying the role of NETs in the pathogenesis of CRS without polyps, assessing the effect of azoximer bromide on the metabolism of NETs in patients with CRS. Materials and methods. The study included 82 patients diagnosed with chronic rhinosinusitis (average age 37±12 years), and 40 healthy volunteers (average age 34±10 years). Patients with CRS were treated with surgery and a course of azoximer bromide, the severity of the disease did not differ in patients. Nasal secretions and venous blood were analyzed in all study participants with the determination of surrogate markers of neutrophil extracellular traps – myeloperoxidase complexes with DNA and the detection of double-stranded DNA (Quant Pico Green dsDNA kit). In patients who received azoximer bromide, the material was taken twice – before the start of treatment and 10 days after the course of treatment. Results. In patients with CRS, the amount of NETs in nasal secretions and venous blood is higher compared to the control group (p0.05). The use of azoximer bromide in CRS outside of exacerbation reduces the activity of NETosis processes with intranasal use of the drug not only in the area of inflammation (reduction of NET in nasal secretions); p0.05, but also at the general level (decrease NETs in venous blood); p0.05. Conclusion. An increase in the amount of NETs in nasal flushes and venous blood in patients with CRS without exacerbation compared with the control group may indicate a likely pathological role of NETosis processes, and an increase in the amount of NETs in the blood of patients with CRS without exacerbation compared with the control group indicates the systemic effect of a local inflammatory process in the mucous membrane of the nasal cavity and paranasal sinuses.

Association between type III collagen degradation and local tissue damage of a single joint

ObjectiveThe development of disease-modifying drugs is limited by OA's heterogeneity and the challenge of defining clinical endpoints. Serological biomarkers are considered potential surrogate endpoints, but their contribution from single joints to systemic levels in OA patients is unclear. In this exploratory study we longitudinally assessed systemic biomarker levels' response to tissue damage and healing before and after surgery in patients undergoing knee or hip joint replacement revision for aseptic failure. Patients with chronic pain associated with a prior hip or knee arthroplasty, but not receiving revision surgery were included as control. MethodThe serological biomarker of MMP mediated type III collagen degradation C3M, associated with synovial tissue degradation, was measured at baseline before revision surgery, after revision surgery and at a 6-month follow-up in 48 patients with aseptic loosening of a knee or hip prosthesis and in 18 patients with chronic pain from a hip or knee prosthesis. Longitudinal changes in biomarkers were modeled using linear mixed models. ResultsNo differences between the aseptic loosening and chronic pain groups were observed at baseline. Revision surgery in the aseptic loosening group led to a swift increase in C3M, which normalized within 2–3 months. No changes in biomarker level were observed in chronic pain patients over three months. ConclusionThese findings suggest that tissue damage in a single joint significantly impacts systemic biomarker levels and underscores the relevance of systemic biomarkers in assessing local tissue remodeling.

Association of triglyceride-glucose index with diabetes or prediabetes in Chinese hypertensive patients: A retrospective cohort study.

Insulin resistance is a key factor in diabetes development. This study aimed to investigate the association between baseline triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, and the onset of hyperglycemia in Chinese individuals with hypertension. Using the Rich Healthcare Group database, this retrospective cohort study included 28,687 hypertensive individuals without preexisting diabetes. A wide range of demographic information and baseline biochemical indicators was collected and rigorously analyzed. This study utilized the Cox proportional hazards model and smooth curve fitting to explore the link between TyG index and the risk of developing hyperglycemia. The robustness of the findings was validated by sensitivity and subgroup analyses. During longitudinal monitoring of hypertensive patients in our retrospective cohort study, we observed that 5.31% (1524/28,687) progressed to diabetes, while 21.66% (4620/21,326) developed prediabetes. After adjusting for confounding variables, a statistically significant positive association was observed between the TyG index and the risk of hyperglycemia. Subgroup and sensitivity analyses further supported these findings, demonstrating consistent outcomes and reinforcing the robustness of our conclusions. The TyG index, which is significantly linked to hyperglycemia in hypertensives, can aid early risk identification and intervention.

Global longitudinal strain is a surrogate marker for time constant of isovolumic relaxation in post-Fontan operation patients with single right ventricle and preserved ejection fraction.

The time constant of isovolumic relaxation is an established index of ventricular relaxation, a major component of diastolic function, even in a single right ventricle. However, the specific echocardiographic parameters for estimating diastolic dysfunction are insufficient for a single right ventricle. This study aimed to investigate the echocardiographic indices associated with time constant of isovolumic relaxation in post-Fontan operation patients with a single right ventricle. We included 39 patients with hypoplastic left heart syndrome after Fontan operation with an ejection fraction ≥45% and preserved valve function. First, the correlation between echocardiographic parameters and time constant of isovolumic relaxation was examined, and partial correlation coefficients were calculated using age and heart rate as covariates. Next, univariate regression analysis was performed using time constant of isovolumic relaxation as the objective variable and echocardiographic parameters as independent variables, followed by multivariate regression analysis incorporating parameters with p < 0.10. Among the echocardiographic parameters, global longitudinal strain correlated most strongly with time constant of isovolumic relaxation (r = 0.778, p < 0.001). This was consistent with the partial correlation coefficients (r = 0.707, p < 0.001). Using stepwise multivariate regression analysis, only global longitudinal strain was found to be an independent predictor of time constant of isovolumic relaxation (adjusted R2 = 0.551). Global longitudinal strain could be used as a surrogate marker of time constant of isovolumic relaxation, an invasive indicator of relaxation impairment, in post-Fontan operation patients with a single right ventricle, preserved ejection fraction, and valve function.

Calprotectin as a marker of disease activity in spondyloarthritis

Introduction: Spondyloarthritis is a group of arthritic diseases that classically manifest as inflammation of the sacroiliac and limb joints, as well as the axial skeleton. Microscopic bowel inflammation is identifiable in over 50% of these patients. Calprotectin measured in the serum and stool is an emerging surrogate marker of disease activity and/or bowel inflammation in spondyloarthritis. Objective: This article aims to review published literature to determine the accuracy of serum and faecal calprotectin levels for use in monitoring bowel inflammation and spondyloarthritis disease activity. Methods: Boolean operator strategy was used to search two databases (Embase and PubMed) and 52 relevant articles were identified. Duplicate results were eliminated, inclusion and exclusion criteria were applied. Results: Ten studies met the inclusion criteria and were summarized and analyzed. The EBL Validity questionnaire was applied to determine study quality. All research articles found calprotectin to be elevated in spondyloarthritis patients when compared to controls. Faecal calprotectin was superior in detecting disease activity and correlated with disease activity questionnaires, radiology and endoscopy results. Only one study assessed the effect of treatment on calprotectin and its correlation to bowel inflammation. Conclusion: Faecal calprotectin shows promise as a surrogate marker for disease activity and bowel inflammation in spondyloarthritis. Future studies should focus on the effect of treatment on faecal calprotectin and whether some treatments are better at preventing the progression of bowel inflammation in addition to treating spondyloarthritis. Supplementary investigations are needed to identify whether faecal calprotectin is useful as a marker of disease activity in response to treatment.

Selective neuronal expression of progranulin is sufficient to provide neuroprotective and anti-inflammatory effects after traumatic brain injury

Progranulin (PGRN), which is produced in neurons and microglia, is a neurotrophic and anti-inflammatory glycoprotein. Human loss-of-function mutations cause frontotemporal dementia, and PGRN knockout (KO) mice are a model for dementia. In addition, PGRN KO mice exhibit severe phenotypes in models of traumatic or ischemic central nervous system (CNS) disorders, including traumatic brain injury (TBI). It is unknown whether restoration of progranulin expression in neurons (and not in microglia) might be sufficient to prevent excessive TBI-evoked brain damage. To address this question, we generated mice with Nestin-Cre-driven murine PGRN expression in a PGRN KO line (PGRN-KONestinGrn) to rescue PGRN in neurons. PGRN expression analysis in primary CNS cell cultures from naïve mice and in (non-) injured brain tissue from PGRN-KONestinGrn revealed expression of PGRN in neurons but not in microglia. After experimental TBI, examination of the structural brain damage at 5 days post-injury (dpi) showed that the TBI-induced loss of brain tissue and hippocampal neurons was exacerbated in PGRN-KOGrnflfl mice (PGRN knockout with the mGrn fl-STOP-fl allele, Cre-negative), as expected, whereas the tissue damage in PGRN-KONestinGrn mice was similar to that in PGRN-WT mice. Analysis of CD68+ immunofluorescent microglia and Cd68 mRNA expression showed that excessive microglial activation was rescued in PGRN-KONestinGrn mice, and the correlation of brain injury with Cd68 expression suggested that Cd68 was a surrogate marker for excessive brain injury caused by PGRN deficiency. The results show that restoring neuronal PGRN expression was sufficient to rescue the exacerbated neuropathology of TBI caused by PGRN deficiency, even in the absence of microglial PGRN. Hence, endogenous microglial PGRN expression was not essential for the neuroprotective or anti-inflammatory effects of PGRN after TBI in this study.Graphical

Nuclear DUX4 immunohistochemistry is a highly sensitive and specific marker for the presence of CIC::DUX4 fusion in CIC-rearranged sarcomas: a study of 48 molecularly confirmed cases.

CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms. Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic smallround cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion. DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

Altered Surrogate Markers of Inflammation in Perinatal HIV-Exposed Children with Caries.

Dental caries is associated with immunologic response, yet its association with hematologic parameters and inflammatory markers is unclear. This study aimed to examine the relationship between some surrogate markers of inflammation and dental caries in the context of perinatal exposure to human immunodeficiency virus (HIV). This cross-sectional study involved 2 groups of children aged 4 to 11 y who were (1) HIV exposed but uninfected (HEU) and (2) HIV unexposed/uninfected (HUU) and recruited from HIV pediatric and child outpatient clinics, respectively, at a tertiary health facility in Nigeria. Medical records were reviewed, and trained dentists conducted oral and dental examinations. Five milliliters of EDTA blood was obtained and used for CD4 and CD8 and complete blood analysis, from which other inflammatory markers such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), systemic inflammatory index (SII), CD4/CD8 ratio were calculated using referenced formulas. In total, 245 (125 HEU and 120 HUU) children with a mean (standard deviation) age of 7 (2) y were included in this study. No differences in caries experience were observed in both groups of children (38 children [16%] were caries affected; 19 [16%] and 19 [15%] from the HEU and HUU groups, respectively). Examining the relationship between studied inflammatory markers and caries showed that leucocyte counts were slightly lower in caries-affected children compared with their caries-free counterparts (P = 0.05). Lower levels of neutrophils (P = 0.04) and higher levels of lymphocytes (P = 0.02) were associated with caries prevalence. Although not significant, NLR, PLR, and SII were lower in caries-affected children. Caries is associated with leucocytes and some of its subsets in both groups of children and independent of perinatal HIV exposure, highlighting the potential of evaluating inflammatory markers in caries prevention, treatment, and research. This study provides evidence that a relationship exists between dental caries, HIV exposure, and inflammation using affordable methods and advocates the inclusion of these markers in caries care in resource-limited settings.

Myopia and systemic manifestation of tissue hyperlaxity: A population-based cross-sectional study.

Whether non-syndromic connective tissue hyperlaxity is associated with myopia is unknown. The aim of this study was to examine the association between systemic signs of tissue hyperlaxity and myopia among adolescents. Included were adolescents assessed before mandatory military service at the age of 16-18 years between 2011 and 2022. Diagnoses of hernias, pes planus, genu varus, genu valgum, and scoliosis, as well as joint injuries were used as surrogate markers for tissue hyperlaxity. The prevalence of these events among adolescents with myopia was evaluated and compared to the non-myopic population. Included were 920 806 adolescents. The mean age was 17.4 ± 1.4 years and 58.6% were men. Myopia was diagnosed in 290 759 adolescents (31.6%) and high myopia in 24 069 adolescents (2.6%). The prevalence of hernias was higher among adolescents with myopia, (2.76%, 95% confidence interval (95% CI): 2.69%-2.82% vs. 2.60%, 95% CI: 2.57%-2.65%), as were pes planus (14.92%, 95% CI: 14.79-15.05 vs. 13.51%, 95% CI: 13.42-13.59) and scoliosis (9.14%, 95% CI: 9.03-9.24 vs. 7.69%, 95%CI: 7.62-7.76). The prevalence of joint injuries was clinically similar between groups (less than 0.1% difference for ankle, shoulder, and knee injuries), as were genu varum and genu valgum (0.66%, 95%CI: 0.64%-0.69% vs. 0.68%, 95% CI: 0.66-0.70, respectively). Adjusted for possible confounders results remained consistent. Among a large sample of Israeli adolescents, those with myopia had a higher prevalence of hernias, pes planus, and scoliosis. These results could suggest a propensity for systemic conditions related to tissue laxity among myopic adolescents.

Predictive role of cardiopulmonary bypass exposure indexed to body surface area on postoperative organ dysfunction: a retrospective cohort study.

Long cardiopulmonary bypass times are associated with adverse postoperative outcomes and increased healthcare resource use. It is likely that this effect is pronounced in smaller patients. Previous studies have been criticized for not taking into consideration that prolonged bypass times are often due to higher complexity. The purpose of this study was to investigate the relationship between bypass index (bypass time/body surface area) and adverse postoperative events. Single-centre, retrospective cohort study including 2413 patients undergoing cardiac surgery on cardiopulmonary bypass from June 2018 to April 2020. Length of hospital stay, as surrogate marker of postoperative morbidity, was selected as primary outcome. The strength of association between bypass index and the primary outcome was assessed with linear regression analysis. Secondary outcomes included new onset renal, pulmonary or cardiac rhythm dysfunction. The predictive value of bypass index was assessed with linear regression analysis; univariate and multiple regression were used to assess the strength of association between Bi and the secondary outcomes. Bypass index was predictive for length of stay at univariate (Relative Risk (RR): 1.004, P < 0.001) and at multivariable (RR: 1.003, P < 0.001) analysis. The association between bypass index and new renal (mean difference: 14.1 min/m2, P < 0.001) and cardiac rhythm dysfunction (mean difference: 12.6 min/m2) was significant. This was not true of postoperative lung dysfunction (mean difference: -1.5 min/m2, P = 0.293). Bypass index, calculated as total bypass time/patient body surface area, is predictive of postoperative morbidity and resource utilization after cardiac surgery on pump.

7867 Treatment-Related Changes in Total Hip Bone Mineral Density and Fracture Risk Reduction for Drugs With Different Mechanisms of Action: The FNIH-ASBMR-SABRE Project

Abstract Disclosure: T. Vilaca: None. M.T. Schini: None. A.R. Thompson: None. E. Vittinghoff: None. L. Lui: None. S.K. Ewing: None. D.C. Bauer: None. D.M. Black: None. M. Bouxsein: None. R. Eastell: Consulting Fee; Self; Immunodiagnostic Systems, CL Bio, CureTeQ, Biocon, Takeda, UCB. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Osteolabs. Speaker; Self; Pharmacosmos, Alexion Pharmaceuticals, Inc., Amgen Inc, UCB. Introduction: To date, trials of new anti-osteoporosis therapies have used fractures as primary endpoints. In the FNIH-ASBMR-SABRE project, we posited that the treatment-related change in total hip BMD (THBMD) could be used as a surrogate endpoint for fractures in future clinical trials of new osteoporosis therapies. To demonstrate this, we compiled a large dataset of individual patient data (IPD) from randomized trials and showed a strong association between the change in THBMD at 24 months and reduction in fracture risk. To further explore the use of THBMD as a surrogate endpoint, here we examine whether the association is robust across drugs with different mechanisms of action. Methods: We used IDP (n&amp;gt;120,000 participants) from 22 randomized, placebo-controlled, double-blind trials of osteoporosis medications (17 anti-resorptive, 3 PTH analogs, 1 odanacatib, and 1 romosozumab). We calculated the treatment-related difference (active-placebo) in mean % change in THBMD at 12, 18, and 24 months for each trial. We determined the treatment-related fracture risk reductions for the entire follow-up period, using logistic regression for radiologic vertebral fractures and Cox regression for all clinical fractures (a combination of non-vertebral and clinical vertebral fractures). We used meta-regression to estimate the study-level association (r2) between treatment-related differences in THBMD changes and fracture risk reduction, including only the 17 trials of anti-resorptive drugs and then using the entire set of 22 trials. Since there were only 3 trials of anabolic drugs, we did not perform separate analyses for the anabolic trials. Results: The r2 values were similar between all trials and antiresorptive trials only for both fracture outcomes at all time points. Specifically, for vertebral fractures, the r2 was 0.59 vs 0.70 at 12 mo, 0.69 vs 0.74 at 18 mo, and 0.73 vs 0.78 at 24 mo for all trials vs anti-resorptive trials only. For all clinical fractures, the r2 was 0.46 vs 0.51 at 12 mo, 0.64 vs 0.60 at 18 mo, and 0.71 vs 0.65 at 24 mo for all trials vs anti-resorptive trials only. Conclusion: These results demonstrate that the associations between treatment-related changes in THBMD and fracture risk reductions are robust across anti-osteoporosis therapies with varying mechanisms of action. We conclude that the treatment-related difference in THBMD change would predict fracture reduction equally well for drugs with different mechanisms of action. Presentation: 6/2/2024

7718 Dysregulated BCAA catabolism and insulin secretory response in the early stages of insulin resistance in mature adolescents

Abstract Disclosure: A. Basin: None. Q. Wang: None. H. Hong: None. O. Ilkayeva: None. M. Muehlbauer: None. D. Hsia: None. D.A. D'Alessio: None. C.B. Newgard: None. M. Freemark: None. P. Gumus Balikcioglu: None. Objective: We recently showed that surrogate markers of insulin resistance (IR) and insulin secretion are differentially associated with branched-chain amino acids (BCAAs) and their catabolites the branched-chain ketoacids (BCKAs). In this longitudinal study, we determined if baseline levels of BCAAs, BCKAs or the BCKA/BCAA ratio are associated with changes in IR, insulin secretion, and insulin secretion adjusted for IR after a one year follow up in adolescents aged 18-21 yr without Type 2 diabetes. Methods: We performed frequently sampled oral glucose tolerance tests (OGTT) at baseline and one year follow up in 10 adolescents with normal weight and 10 adolescents without Type 2 diabetes but with overweight/obesity and mild IR. After an overnight fast of 8-12 hours, participants had fasting blood samples drawn and consumed 1.75 g/kg, to a maximum of 75 g glucose solution as the initiation of an OGTT. Glucose (G) and insulin (I) were measured at times -15, 0, 10, 15, 30, 45, 60, 90, 120, and 180 minutes. Plasma metabolomic profiles were obtained at time 0. HOMA-IR, Matsuda Index, AUC glucose, AUC insulin, insulinogenic index (IGI) and disposition index (DI) at 15 and 30 min were calculated. % Body fat was measured by TANITA. Results: At one year follow up groups were comparable in age, sex, race, ethnicity and pubertal status. Participants with overweight/obesity had higher BMI (22.5±1.3 vs 36.2±9.7), BF% (16.8±8.4 vs 37.9±10.2), leptin, and diastolic blood pressure than lean participants. They were also more insulin resistant as evidenced by higher HOMA-IR . AUC glucose,AUC insulin, and IGI were comparable across groups, as were fasting BCAA levels and BCKA/BCAA ratio. As with baseline levels, follow-up BCAA levels correlated positively with AUC insulin, HOMA-IR, and IGI at 30 min and negatively with totaland HMW-adiponectin, and Matsuda Index, but did not correlate with BMI or % body fat. Likewise at follow up, BCKAs correlated negatively with total and HMW-adiponectin and did not correlate with Matsuda Index, or HOMA-IR. In association models adjusted for baseline age, sex, and BMI, higher baseline levels of the BCKA, α-keto-β-methylvalerate (KMV, isoleucine catabolite), and a higher BCKA/BCAA ratio were associated with a relative reduction in acute insulin secretion as reflected in a reduction in 15 min IGI at 1 year follow up. Conclusions: In this cohort of adolescents without Type 2 diabetes and with varying degrees of adiposity and insulin sensitivity, we identified KMV as a marker associated with a subsequent reduction in acute glucose-stimulated insulin secretion at one year follow up.These findings suggest that dysregulated BCAA catabolism is associated with loss of compensatory insulin secretion in the face of IR and may play a role in progression to impaired glucose tolerance and development of Type 2 diabetes. Presentation: 6/1/2024

Stereologic consequences of iatrogenic collapse: The morphology of adenocarcinoma in situ overlaps with invasive patterns. Proposal for a necessary modified classification of pulmonary adenocarcinomas

Recognizing non-invasive growth patterns is necessary for correct diagnosis, invasive size determination and pT-stage in resected non-small cell lung carcinoma. Due to iatrogenic collapse after resection, the distinction between adenocarcinoma in-situ (AIS) and invasive adenocarcinoma may be difficult. The aim of this study is to investigate the complex morphology of non-mucinous non-invasive patterns of AIS in resection specimen with iatrogenic collapse, and to relate this to follow-up.The effects of iatrogenic collapse on the morphology of collapsed AIS were simulated in a mathematical model. Three dimensional related criteria applied in a modified classification, using also cytokeratin 7 and elastin as additional stains, in two independent retrospective cohorts of primary pulmonary adenocarcinomas ≤3 cm resection specimen with available follow-up information.The model demonstrated that infolding of alveolar walls occurs during iatrogenic collapse and lead to a significant increase in tumor cell heights in maximal collapse areas, compared to less collapsed areas. The morphology of infolded AIS overlaps with patterns described as papillary and acinar adenocarcinoma according to the WHO classification, necessitating an adaptation.The modified classification incorporates recognition of iatrogenic and biologic collapse, tangential cutting effect true invasion and surrogate markers of invasion i.e. grey zone, covering a multilayering falling short of micropapillary, cribriform and solid alveolar filling growth. The use of elastin and CK7 staining aids in the morphologic recognition of iatrogenic collapsed AIS and the distinction from invasive adenocarcinoma. Out of a total of 70 resection specimens 1 case was originally classified as AIS and 9 were reclassified as iatrogenic collapsed AIS. Patients with collapsed AIS showed a 100 % recurrence-free survival after a mean follow-up time of 69.5 months.With the current WHO classification, AIS is overdiagnosed as invasive adenocarcinoma due to infolding. The modified classification facilitates the diagnosis of AIS.

Calf circumference was negatively associated with all-cause mortality among the Chinese centenarians: a prospective study with a 5-year follow-up

BackgroundSarcopenia is an aging-related disorder characterized by a loss of muscle mass and function. Calf circumference (CC) is a useful surrogate marker of muscle mass and function. This prospective study was designed to investigate the association between CC and all-cause mortality during a follow-up for 5 years in the Chinese centenarians.MethodsThe China Hainan Centenarian Cohort Study (CHCCS) is conducted in 18 cities and counties of Hainan, China.ResultsAll 231 centenarians had a mean age of 103.03 years. Survival participants had a longer CC and were often living alone compared with others (P<0.05 for all). Multivariate Cox regression models showed that CC was negatively associated with all-cause mortality (P < 0.05 for all). Participants with a longer CC had a lower mortality risk compared with others [Exp(β): 0.918; 95%confidence interval: 0.863–0.977]. Participants with a longer CC had a lower mortality risk whether they were males or females and lived with family members or alone.ConclusionCC was negatively associated with all-cause mortality and could be an indicator of future mortality among the Chinese centenarians. Further researches should focus on preventing a decline in the CC in order to promote human longevity.

Surrogate Immunohistochemical Markers of Proliferation and Embryonic Stem Cells in Distinguishing Ameloblastoma from Ameloblastic Carcinoma

PurposeThe current study aimed to investigate the use of surrogate immunohistochemical (IHC) markers of proliferation and stem cells to distinguish ameloblastoma (AB) from ameloblastic carcinoma (AC).MethodsThe study assessed a total of 29 ACs, 6 ABs that transformed into ACs, and a control cohort of 20 ABs. The demographics and clinicopathologic details of the included cases of AC were recorded. The Ki-67 proliferation index was scored through automated methods with the QuPath open-source software platform. For SOX2, OCT4 and Glypican-3 IHC, each case was scored using a proportion of positivity score combined with an intensity score to produce a total score.ResultsAll cases of AC showed a relatively high median proliferation index of 41.7%, with statistically significant higher scores compared to ABs. ABs that transformed into ACs had similar median proliferation scores to the control cohort of ABs. Most cases of AC showed some degree of SOX2 expression, with 58.6% showing high expression. OCT4 expression was not seen in any case of AC. GPC-3 expression in ACs was limited, with high expression in 17.2% of ACs. Primary ACs showed higher median proliferation scores and degrees of SOX2 and GPC-3 expression than secondary cases. Regarding SOX2, OCT4 and GPC-3 IHC expression, no statistically significant differences existed between the cohort of ABs and ACs.ConclusionKi-67 IHC as a proliferation marker, particularly when assessed via automated methods, was helpful in distinguishing AC from AB cases. In contrast to other studies, surrogate IHC markers of embryonic stem cells, SOX2, OCT4 and GPC-3, were unreliable in distinguishing the two entities.

Non-Alcoholic Fatty Liver Disease and Its Association with Kidney and Cardiovascular Outcomes in Moderate to Advanced Chronic Kidney Disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) has emerged as a potential indicator for cardio-metabolic risk. However, clinical implications of NAFLD in patients with chronic kidney disease (CKD) are still elusive. We investigated to explore the association between NAFLD and adverse clinical outcomes among patients with CKD. Methods: In this national population-based retrospective cohort study, we analyzed 816,857 individuals who underwent National Health Insurance Service health examinations and had an estimated glomerular filtration rate of 15–59 mL/min/1.73 m2. The main predictor was the fatty liver index (FLI), a surrogate marker for NAFLD. The primary outcome was a composite cardiovascular or kidney events, which were examined combined or separately. Results: During a median follow-up of 7.7 (IQR, 6.4–9.6) years, the composite outcome events occurred in 74,266 (9.1%) individuals. Among these, there were 55,525 (6.8%) cardiovascular events and 22,961 (2.8%) kidney events, respectively. Compared to FLI of <30, the hazard ratio (HRs; 95% confidence intervals [CIs]) for the composite outcome were 1.16 (1.14–1.18) and 1.30 (1.26–1.33) for the FLIs of 30–59 and ≥60, respectively. The corresponding HRs for cardiovascular events were 1.21 (95% CI, 1.18–1.23) and 1.36 (95% CI, 1.31–1.40), respectively. Furthermore, FLIs of 30–59 and ≥60 were associated with an 11% (HR, 1.11; 95% CI, 1.07–1.15) and 24% (HR, 1.24; 95% CI, 1.17–1.30) increased risk of kidney events, respectively. Conclusions: NAFLD was associated with higher risk of adverse clinical outcomes in individuals with CKD. These findings suggest that NAFLD, as assessed by the FLI, can serve as a predictor of cardiovascular and kidney events in CKD population.

Continuous digital cough monitoring during 6-month pulmonary tuberculosis treatment

IntroductionThe recent advances in digital and wearable technologies with artificial intelligence (AI) enable the use of continuous cough monitoring (CCM) to objectively monitor symptoms as surrogate markers of treatment efficacy in pulmonary tuberculosis (PTB). The objectives of this study are to describe the evolution of cough during PTB treatment in adult and to assess the feasibility of community-based CCM.MethodsWe prospectively enrolled PTB adult participants upon treatment initiation. Participants’ coughs were continuously monitored during 6 months with a smartphone loaded with an app able to detect cough by using an AI algorithm.ResultsTwenty-two participants were included. The median age was 28.5 (IQR: 22–42) and 62% were male. The median cough per hour (medCPH) was 11.0 (IQR: 7.0–27.0) at week 1. By the end of the intensive phase of PTB treatment at week 8, the medCPH was 3.5 (IQR: 1.5–7.0), which was significantly lower than the medCPH at week 1 (p=0.002). At week 26 (end of treatment), the medCPH was 1.0 (IQR: 1.0–2.5). The adherence to CCM was high during the first 13 weeks of PTB treatment and then waned over time. The adherence was similar during daytime and nighttime.ConclusionCough counts rapidly drop during the intensive phase of PTB treatment and then slowly decrease to a low baseline level by the end of the treatment. Community-based CCM using digital technology is feasible in low resource settings but requires evaluation of alternative approaches to overcome adherence issues and technical limitations (mobile internet and electricity availability).

Group sequential testing of a treatment effect using a surrogate marker.

The identification of surrogate markers is motivated by their potential to make decisions sooner about a treatment effect. However, few methods have been developed to actually use a surrogate marker to test for a treatment effect in a future study. Most existing methods consider combining surrogate marker and primary outcome information to test for a treatment effect, rely on fully parametric methods where strict parametric assumptions are made about the relationship between the surrogate and the outcome, and/or assume the surrogate marker is measured at only a single time point. Recent work has proposed a nonparametric test for a treatment effect using only surrogate marker information measured at a single time point by borrowing information learned from a prior study where both the surrogate and primary outcome were measured. In this paper, we utilize this nonparametric test and propose group sequential procedures that allow for early stopping of treatment effect testing in a setting where the surrogate marker is measured repeatedly over time. We derive the properties of the correlated surrogate-based nonparametric test statistics at multiple time points and compute stopping boundaries that allow for early stopping for a significant treatment effect, or for futility. We examine the performance of our proposed test using a simulation study and illustrate the method using data from two distinct AIDS clinical trials.

Effects of aerobic training on cardiopulmonary fitness in patients with long COVID-19: a randomized controlled trial

BackgroundLong COVID-19 is characterized by systemic deterioration of the entire body, leading to significant physical and mental disorders. Exercise training has the potential to improve persistent symptoms and cardiopulmonary functions.MethodThis was a single-center, randomized, controlled trial. Twenty-four patients aged 18 to 75 years who had a history of SARS-CoV-2 infection and long COVID symptoms. Patients were randomly allocated in a 1:1 ratio to receive either a 4-week exercise training program or an attention control group. The training group participated in 12 supervised aerobic sessions on a cycling ergometer over 4 weeks. The outcomes were to assess the impact of a 4-week aerobic exercise on the persistent symptoms and cardiopulmonary fitness, the surrogate endpoints of COVID-19 recovery and cardiopulmonary health.ResultsAfter the 4-week intervention, significant reductions were observed in the total number of symptoms in the training group. Specifically, 67.8% of patients in the training group exhibited reduced or completely resolved symptoms, in comparison to 16.7% in the control group (P = 0.013). After adjusting for gender, significant improvements in the training group were observed for exercise time (Pgroup*time = 0.028), maximum load (Pgroup*time = 0.01), and peak VO2 (Pgroup*time = 0.001), as well as O2 pulse (Pgroup*time = 0.042) and maximum heart rate (Pgroup*time = 0.007). The score of Short Form-12, depression, anxiety, perceived stress, and insomnia did not show significant changes between groups (Pgroup*time > 0.05).ConclusionA supervised aerobic training program has the potential to alleviate persistent symptoms and improve exercise tolerance in patients with long COVID-19. Further research is necessary to confirm these effects in a large population. This intervention could be easily implemented in non-hospital settings, potentially benefiting a broader range of individuals.Trial registration numberClinicalTrials.gov NCT05961462. Registered on July 25, 2023.