Surrogate Marker Research Articles

Association of Disease-Modifying Treatment With Outcome in Patients With Relapsing Multiple Sclerosis and Isolated MRI Activity.

Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome. Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses. A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%. In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred. This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

Expedited program and utilization for anticancer drug approval in China and the United States

Objective: To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021. Methods: Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison. Results: Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions: Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Abstract A034: DNA repair capacity in metastatic castration-resistant prostate cancer patients using lymphocytes as surrogate markers

Abstract A034: DNA repair capacity in metastatic castration-resistant prostate cancer patients using lymphocytes as surrogate markers

Ensemble for evaluating diagnostic efficacy of non-invasive indices in predicting liver fibrosis in untreated hepatitis C virus population

BACKGROUND Hepatitis C virus (HCV) infection progresses through various phases, starting with inflammation and ending with hepatocellular carcinoma. There are several invasive and non-invasive methods to diagnose chronic HCV infection. The invasive methods have their benefits but are linked to morbidity and complications. Thus, it is important to analyze the potential of non-invasive methods as an alternative. Shear wave elastography (SWE) is a non-invasive imaging tool widely validated in clinical and research studies as a surrogate marker of liver fibrosis. Liver fibrosis determination by invasive liver biopsy and non-invasive SWE agree closely in clinical studies and therefore both are gold standards. AIM To analyzed the diagnostic efficacy of non-invasive indices [serum fibronectin, aspartate aminotransferase to platelet ratio index (APRI), alanine aminotransferase ratio (AAR), and fibrosis-4 (FIB-4)] in relation to SWE. We have used an Artificial Intelligence method to predict the severity of liver fibrosis and uncover the complex relationship between non-invasive indices and fibrosis severity. METHODS We have conducted a hospital-based study considering 100 untreated patients detected as HCV positive using a quantitative Real-Time Polymerase Chain Reaction assay. We performed statistical and probabilistic analyses to determine the relationship between non-invasive indices and the severity of fibrosis. We also used standard diagnostic methods to measure the diagnostic accuracy for all the subjects. RESULTS The results of our study showed that fibronectin is a highly accurate diagnostic tool for predicting fibrosis stages (mild, moderate, and severe). This was based on its sensitivity (100%, 92.2%, 96.2%), specificity (96%, 100%, 98.6%), Youden’s index (0.960, 0.922, 0.948), area under receiver operating characteristic curve (0.999, 0.993, 0.922), and Likelihood test (LR+ > 10 and LR- < 0.1). Additionally, our Bayesian Network analysis revealed that fibronectin (> 200), AAR (> 1), APRI (> 3), and FIB-4 (> 4) were all strongly associated with patients who had severe fibrosis, with a 100% probability. CONCLUSION We have found a strong correlation between fibronectin and liver fibrosis progression in HCV patients. Additionally, we observed that the severity of liver fibrosis increases with an increase in the non-invasive indices that we investigated.

Update on Clinical Trial Endpoints in Gene Therapy Trials for Inherited Retinal Diseases

Inherited retinal diseases (IRDs) encompass a wide spectrum of rare conditions characterized by diverse phenotypes associated with hundreds of genetic variations, often leading to progressive visual impairment and profound vision loss. Multiple natural history studies and clinical trials exploring gene therapy for various IRDs are ongoing. Outcomes for ophthalmic trials measure visual changes in three main categories—structural, functional, and patient-focused outcomes. Since IRDs may range from congenital with poor central vision from birth to affecting the peripheral retina initially and progressing insidiously with visual acuity affected late in the disease course, typical outcome measures such as central visual acuity and ocular coherence tomography (OCT) imaging of the macula may not provide adequate representation of therapeutic outcomes including alterations in disease course. Thus, alternative unique outcome measures are necessary to assess loss of peripheral vision, color vision, night vision, and contrast sensitivity in IRDs. These differences have complicated the assessment of clinical outcomes for IRD therapies, and the clinical trials for IRDs have had to design novel specialized endpoints to demonstrate treatment efficacy. As genetic engineering and gene therapy techniques continue to advance with growing investment from industry and accelerated approval tracks for orphan conditions, the clinical trials must continue to improve their assessments to demonstrate safety and efficacy of new gene therapies that aim to come to market. Here, we will provide an overview of the current gene therapy approaches, review various endpoints for measuring visual function, highlight those that are utilized in recent gene therapy trials, and provide an overview of stage 2 and 3 IRD trials through the second quarter of 2024.

Considerations for the design and conduct of pediatric obesity pharmacotherapy clinical trials: Proceedings of expert roundtable meetings.

Anti-obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long-term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs. These barriers can delay the AOM development and evaluation process, increase the cost of performing trials, create challenges in the interpretation of results, influence the generalizability of the findings and present ethical dilemmas. In an effort to address these issues and provide guidance to streamline the process of designing and conducting pediatric AOM clinical trials, relevant key stakeholders convened a series of roundtable meetings to discuss, debate and achieve harmonization on design features. Stakeholder participants included a multidisciplinary group of international pediatric obesity experts, patient (parent) representatives and representatives from academic medicine, key regulatory agencies and industry. Topics of discussion included primary efficacy end-points, secondary end-points, eligibility criteria, trial run-in and follow-up phases, use of active comparators and guidelines for down-titration and/or stopping rules for excessive weight reduction. Consensus recommendations were agreed upon. Regarding end-points, emphasis was placed on moving away from BMI z-score as a primary outcome, incorporating multiple alternative BMI-related outcomes and measuring adiposity/body fat as a prominent secondary end-point. Trial eligibility criteria were carefully considered to maximize generalizability while maintaining safety. The limited value of trial run-in phases was discussed. It was also underscored that designing trials with extended follow-up periods after AOM withdrawal should be avoided owing to ethical issues (including possible psychological harm) related to weight regain without providing the opportunity to access other treatments. The panel emphasized the value of the randomized, placebo-controlled trial but recommended the thoughtful consideration of the use of active comparators in addition to, or instead of, placebo to achieve clinical equipoise when appropriate. Finally, the panel recommended that clinical trial protocols should include clear guidance regarding AOM down-titration to avoid excessive weight reduction when applicable.

Slow growth and short stature in children with attention deficit hyperactivity disorder (ADHD): aretrospective study of 493 children who underwent growth hormone provocation testing at one tertiary paediatric endocrine centre.

We hypothesised that growth hormone (GH) deficiency (GHD) in children with attention deficit hyperactivity disorder (ADHD) is rare. This study aimed to determine any distinct clinical or biochemical parameters, including GH provocation testing, in children with ADHD on psychostimulants or idiopathic short stature (ISS). Retrospective cross-sectional study of children who had GH provocative testing between 1998 and 2013 at one tertiary paediatric endocrine centre. Clinical data included age, sex, anthropometry, pubertal staging, bone age, diagnostic code as per the European Society Paediatric Endocrinology (ESPE), GH provocation test results, thyroid function tests, serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) levels. Four hundred ninety-three subjects underwent GH provocation testing for investigation of short stature to exclude GHD during the study period. Fifty-one children hada diagnosis of ADHD. In the remaining children, the diagnosis was Idiopathic short stature (n=240), GHD +/- hypopituitarism (n=60), and 142 subjects had other causes of short stature. Children with ADHD were older, had higher height and weight SDS and were GH-sufficient. All 51 children with ADHD had a normal serum IGFBP-3, while 20 out of these 51 subjects had a low serum IGF-1. GHD in children with ADHD on psychostimulant medication is rare. GH testing in children with ADHD may not be necessary, particularly if serum IGFBP-3 is in thenormal range. We suggest IGFBP-3 could be used as a surrogate marker of GH sufficiency in children with ADHD. However, this needs to be confirmed with a larger study group.

Alterations in circulating immunoregulatory proteins discriminate poor CD4 T lymphocyte trajectories in people with HIV on suppressive antiretroviral therapy.

It is essential to track immune perturbations related to insufficient CD4 T-cell recovery in PWH on suppressive ART as those with incomplete reconstitution are at a greater risk of non-AIDS-related morbidity and mortality. Several inflammatory soluble mediators have associated with poor immune reconstitution and adverse morbid outcomes in PWH, yet their implementation into routine clinical care to guide management remains inconsistent. Circulating immune checkpoint proteins have been linked to dysregulated immune pathways during suppressive ART and may serve as improved surrogate markers of clinical relevance. Here we investigate soluble lymphocyte-associated immunoregulatory proteins in virally suppressed PWH with no reported co-morbid outcomes and varying CD4 T-cell counts, to reveal underlying pathways that remain perturbed despite ART. This novel signature of immunoregulatory markers pertaining to poor CD4 T-cell trajectories uncover previously overlooked immune checkpoints as important targets for clinical monitoring of PWH in the setting of durable viral suppression by ART.

Changes in urinary output due to concomitant administration of sacubitril/valsartan and atrial natriuretic peptide in patients with heart failure: a multicenter retrospective cohort study

BackgroundSacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that inhibits the degradation of endogenous natriuretic peptides. Therefore, ARNIs may increase the efficacy of human atrial natriuretic peptide (hANP), a drug for acute heart failure, by mediating its pharmacological mechanism. This study was aimed at evaluating the effects of ARNIs on the pharmacological effects of hANP by using surrogate marker, such as urinary output, in patients with heart failure.MethodsIn this multicenter retrospective cohort study, adult patients with heart failure who were taking angiotensin II receptor blockers (ARB) or ARNIs combined with hANP were enrolled. Information on basic characteristics, clinical laboratory data, medical history, and severity of cardiac insufficiency were collected from electronic medical records. The primary outcome was the change in adjusted fluid balance, calculated by IN-volume (mL/day) – OUT-volume (mL/day) / daily hANP dosage (μg).ResultsNinety-two and 62 patients in the ARB + hANP and ARNI + hANP groups, respectively, were eligible for analysis. The adjusted fluid balance in the ARNI + hANP group was significantly lower than that in the ARB + hANP group (p = 0.001). After propensity score matching, 27 patients from each group were included. Similarly, there was a significant reduction in adjusted fluid balance in the ARNI + hANP group after propensity score matching (p = 0.026).ConclusionsThese findings suggest that ARNIs may enhance the efficacy of hANP and the combination of the two may be effective in the treatment of heart failure.

Different pattern of association between body composition parameters and surrogate markers of bone quality, in patients with overweight or obesity

Different pattern of association between body composition parameters and surrogate markers of bone quality, in patients with overweight or obesity

Observational and genetic evidence disagree on the association between loneliness and risk of multiple diseases.

Loneliness-the subjective experience of social disconnection-is now widely regarded as a health risk factor. However, whether the associations between loneliness and multiple diseases are consistent with causal effects remains largely unexplored. Here we combined behavioural, genetic and hospitalization data from the UK Biobank to examine the associations of loneliness with a wide range of non-overlapping diseases. During a median 12.2-year follow-up, loneliness was associated with greater risks in 13 of 14 disease categories and 30 of 56 individual diseases considered. Of the 30 diseases significantly associated with loneliness, 26 had genetic data available for Mendelian randomization (MR) analyses. After Benjamini‒Hochberg correction and multiple sensitivity analyses within the MR framework, non-causal associations were identified between genetic liability to loneliness and 20 out of the 26 specific diseases, including cardiovascular diseases, type 2 diabetes mellitus, obesity, chronic liver diseases, chronic kidney disease, most neurological diseases and the other common diseases. Genetic liability to loneliness was only potentially causally associated with the remaining six diseases. Socioeconomic factors, health behaviours, baseline depressive symptoms and comorbidities largely explained the associations between loneliness and diseases. Overall, our study revealed a dissociation between observational and genetic evidence regarding the associations of loneliness with multiple diseases. These findings suggest that loneliness may serve as a potential surrogate marker rather than a causal risk factor for most diseases tested here.

Impact of propofol versus desflurane anesthesia on postoperative hepatic and renal functions in infants with living-related liver transplantation: a randomized controlled trial

BackgroundThe effects of anesthetics on liver and kidney functions after infantile living-related liver transplantation (LRLT) are unclear. This study aimed to investigate the effects of propofol-based total intravenous anesthesia (TIVA) or desflurane-based inhalation anesthesia on postoperative liver and kidney functions in infant recipients after LRLT and to evaluate hepatic ischemia–reperfusion injury (HIRI).MethodsSeventy-six infants with congenital biliary atresia scheduled for LRLT were randomly divided into two anesthesia maintenance groups: group D with continuous inhalation of desflurane and group P with an infusion of propofol. The primary focus was to assess alterations of liver transaminase and serum creatinine (Scr) levels within the first 7 days after surgery. And the peak aminotransferase level within 72 h post-surgery was used as a surrogate marker for HIRI.ResultsThere were no differences in preoperative hepatic and renal functions between the two groups. Upon the intensive care unit (ICU) arrival, the levels of aspartate aminotransferase (AST, P = 0.001) and alanine aminotransferase (ALT, P = 0.005) in group P were significantly lower than those in group D. These changes persisted until the fourth and sixth days after surgery. The peak AST and ALT levels within 72 h after surgery were also lower in group P than in group D (856 (552, 1221) vs. 1468 (732, 1969) U/L, P = 0.001 (95% CI: 161–777) and 517 (428, 704) vs. 730 (541, 1100) U/L, P = 0.006, (95% CI: 58–366), respectively). Patients in group P had lower levels of Scr upon the ICU arrival and on the first day after surgery, compared to group D (17.8 (15.2, 22.0) vs. 23.0 (20.8, 30.8) μmol/L, P < 0.001 (95% CI: 3.0–8.7) and 17.1 (14.9, 21.0) vs. 20.5 (16.5, 25.3) μmol/L, P = 0.02 (95% CI: 0.0–5.0) respectively). Moreover, the incidence of severe acute kidney injury was significantly lower in group P compared to that in group D (15.8% vs. 39.5%, P = 0.038).ConclusionsPropofol-based TIVA might improve liver and kidney functions after LRLT in infants and reduce the incidence of serious complications, which may be related to the reduction of HIRI. However, further biomarkers will be necessary to prove these associations.

Health expenditure trajectory and gastric cancer incidence in the National Health Insurance Senior Cohort: a nested case-control study

BackgroundGastric cancer is the fourth most common cancer and highly prevalent in South Korea. As one of the predictors of gastric cancer, we focused on health utilization patterns and expenditures, as the surrogate variables of health conditions. This nested case-control study aimed to identify the association between health expenditure trajectory and incidence of gastric cancer.MethodsData from the National Health Insurance Service Senior Cohort of South Korea were used. Individuals diagnosed with gastric cancer (N = 14,873) were matched to a non-diagnosed group (N = 44,619) in a 1:3 ratio using a nested case-control design. A latent class trajectory analysis was performed to identify the patterns of health expenditure among the matched participants. Furthermore, conditional logistic regression analysis was conducted to examine the relationship between healthcare expenditure trajectories and gastric cancer incidence.ResultsSeven distinct health expenditure trajectories for five years were identified; consistently lowest (13.8%), rapidly increasing (5.9%), gradually increasing (13.8%), consistently second-highest (21.4%), middle-low (18.8%), gradually decreasing (13.1%), and consistently highest (13.2%). Compared to the middle-low group, individuals in the rapidly increasing [odds ratio (OR) = 2.11, 95% confidence interval (CI); 1.94–2.30], consistently lowest (OR = 1.40, 95% CI; 1.30–1.51), and gradually increasing (OR = 1.26, 95% CI; 1.17–1.35) groups exhibited a higher risk of developing gastric cancer.ConclusionsOur findings suggest that health expenditure trajectories are predictors of gastric cancer. Potential risk groups can be identified by monitoring health expenditures.

Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy

Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone, suggesting them as insulin resistance loci. Candidate causal genes at these loci were prioritized by fine mapping with directions-of-effect and tissue specificity annotated through analysis of protein coding and expression quantitative trait variation. Directions-of-effect were corroborated in an independent cohort of individuals with directly measured insulin resistance. We highlight two phospholipase encoding genes, PLA2G12A and PLA2G6, which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we implicate the anti-apoptotic gene TNFAIP8 as a sex-dimorphic insulin resistance factor, which acts by increasing visceral adiposity, specifically in females. In summary, our study identifies several candidate modulators of insulin resistance that have the potential to serve as biomarkers and pharmacological targets.

Comparison of Ultrasound Findings Associated with Adverse Fetal, Obstetric, and Neonatal Outcomes in Pregestational Type 1 And Type 2 Diabetes: A Systematic Review.

We aimed to summarize the available evidence examining the association between prenatal ultrasound findings and adverse fetal, obstetric, and neonatal outcomes in pregnancies complicated by type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and to evaluate whether the predictive value of ultrasound findings for adverse outcomes varies between T1DM and T2DM pregnancies. We conducted a systematic review of the existing literature through August 12, 2024. We included articles in English that reported associations between ultrasound findings and fetal, obstetric, and neonatal outcomes in pregnant people with T1DM and T2DM. Two independent reviewers examined articles at the abstract level and, if eligible, at the full-text level; disagreements were adjudicated by a third reviewer. Of the 2,088 unique citations reviewed, 12 studies met the inclusion criteria describing associations between ultrasound findings and fetal, obstetric, and neonatal outcomes among a total of 1,165 pregnant people with T1DM and 489 pregnant people with T2DM. Most studies (10/12) examined the association between ultrasound measures of growth, including estimated fetal weight (EFW) and its individual components, abdominal wall thickness, head circumference to abdominal circumference (HC/AC) ratio, and birthweight, large for gestational age (LGA) or small for gestational age (SGA). Studies did not examine stillbirth, neonatal demise, or maternal outcomes other than cesarean section. This systematic review synthesizes the available literature on ultrasound risk markers of adverse fetal, obstetric, and neonatal outcomes separately in pregnant people with T1DM and T2DM. We identified very few studies that distinguished between pregnant people with T1DM and T2DM, and the majority focused on surrogate outcomes (e.g., LGA, SGA) of morbidity. Our findings highlight the need for further studies investigating these distinct diseases to provide evidence for antenatal management recommendations.

Canadian beach cohort study: protocol of a prospective study to assess the burden of recreational water illness

BackgroundRecreational water activities at beaches are popular among Canadians. However, these activities can increase the risk of recreational water illnesses (RWI) among beachgoers. Few studies have been conducted in Canada to determine the risk of these illnesses. This protocol describes the methodology for a study to determine the risk and burden of RWI due to exposure to fecal pollution at beaches in Canada.MethodsThis study will use a mixed-methods approach, consisting of a prospective cohort study of beachgoers with embedded qualitative research. The cohort study involves recruiting and enrolling participants at public beaches across Canada, ascertaining their water and sand contact exposure status, then following-up after seven days to determine the incidence of acute RWI outcomes. We will test beach water samples each recruitment day for culture-based E. coli, enterococci using rapid molecular methods, and microbial source tracking biomarkers. The study started in 2023 and will continue to 2025 at beaches in British Columbia, Manitoba, Ontario, and Nova Scotia. The target enrollment is 5000 beachgoers. Multilevel logistic regression models will be fitted to examine the relationships between water and sand contact and RWI among beachgoers. We will also examine differences in risks by beachgoer age, gender, and beach location and the influence of fecal indicator bacteria and other water quality parameters on these relationships. Sensitivity analyses will be conducted to examine the impact of various alternative exposure and outcome definitions on these associations. The qualitative research phase will include focus groups with beachgoers and key informant interviews to provide additional contextual insights into the study findings. The study will use an integrated knowledge translation approach.DiscussionInitial implementation of the study at two Toronto, Ontario, beaches in 2023 confirmed that recruitment is feasible and that a high completion rate (80%) can be achieved for the follow-up survey. While recall bias could be a concern for the self-reported RWI outcomes, we will examine the impact of this bias in a negative control analysis. Study findings will inform future recreational water quality guidelines, policies, and risk communication strategies in Canada.

Thrombopoietin Receptor Agonists as Second-Line Treatment in Children With Ongoing Immune Thrombocytopenia

What Is the Issue? Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelets and an increase in bleeding risk; in the pediatric population, the reported incidence rate varies between 2 and 5 per 100,000 children per year. Spontaneous remission may be observed in up to 70% of patients, while 20% of patients may experience severe bleeding symptoms. In children whose ITP does not respond to first-line corticosteroids, IV immunoglobulin (IVIG), or anti-D immunoglobulin, guidelines recommend the use of thrombopoietin receptor agonists (TPO-RAs), i.e., eltrombopag or romiplostim (avatrombopag did not have a marketing authorization and Notice of Compliance at the time that the review was initiated). Rituximab is considered a subsequent-line of therapy. Splenectomy is not usually considered an appropriate treatment option in children. The goal of therapy in pediatric patients with ITP is to reduce bleeding and improve quality of life. Platelet response is considered a valid and appropriate surrogate end point in studies and routine assessment in clinical practice. Children whose ITP does not respond to available first-line drugs may require subsequent treatment with off-label drugs because they do not have access to TPO-RAs. What Did We Do? We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence. A systematic review of the literature identified 5 studies (4 randomized controlled trials [RCTs] and 1 observational study), which were synthesized narratively. The review addressed the following policy questions: In children with ongoing, active ITP, what is the overall body of evidence supporting the use of TPO-RAs and rituximab after failure of first-line therapies? Based on the level and quality of clinical evidence, should TPO-RAs be reimbursed for use earlier in the treatment sequencing for children with ongoing, active ITP, instead of being reimbursed only after a course of rituximab? What Did We Find? Evidence from 2 RCTs (n = 159) suggests that eltrombopag likely increases and maintains platelet response over time, in addition to decreasing the use of rescue medication and clinically significant bleeding compared to placebo, which were considered clinically meaningful outcomes for pediatric patients with ITP. There was a low risk of bias in the studies, but uncertainty was introduced due to the small sample sizes. Evidence from 1 RCT (n = 62) suggests that romiplostim may also increase and maintain platelet response, as well as reduce clinically significant bleeding compared to placebo. However, there was some concern due to a high risk of bias in the studies and uncertainty due to the small sample size, which suggests a need for caution in the interpretation of the findings. The effectiveness of rituximab was inconclusive due to the lack of evidence, as no comparative RCTs could be identified, while the observational study included presented only descriptive comparisons. No evidence was identified in support of trying rituximab before accessing TPO-RAs. What Does This Mean? Given that ITP is rare in children, there is a gap in available relevant evidence, and robust evidence from large RCTs in this patient population are unlikely to be conducted. Jurisdictions may consider requesting an implementation advice panel for use of eltrombopag and romiplostim after failure of first-line therapies in children with ongoing, active ITP.

Variation of C-terminal domain governs RNA polymerase II genomic locations and alternative splicing in eukaryotic transcription

The C-terminal domain of RPB1 (CTD) orchestrates transcription by recruiting regulators to RNA Pol II upon phosphorylation. With CTD driving condensate formation on gene loci, the molecular mechanism behind how CTD-mediated recruitment of transcriptional regulators influences condensates formation remains unclear. Our study unveils that phosphorylation reversibly dissolves phase separation induced by the unphosphorylated CTD. Phosphorylated CTD, upon specific association with transcription regulators, forms distinct condensates from unphosphorylated CTD. Functional studies demonstrate CTD variants with diverse condensation properties exhibit differences in promoter binding and mRNA co-processing in cells. Notably, varying CTD lengths influence the assembly of RNA processing machinery and alternative splicing outcomes, which in turn affects cellular growth, linking the evolution of CTD variation/length with the complexity of splicing from yeast to human. These findings provide compelling evidence for a model wherein post-translational modification enables the transition of functionally specialized condensates, highlighting a co-evolution link between CTD condensation and splicing.

Oculomic stratification of COVID-19 patients' intensive therapy unit admission status and mortality by retinal morphological findings.

To investigate if retinal thickness has predictive utility in COVID-19 outcomes by evaluating the statistical association between retinal thickness using OCT and of COVID-19-related mortality. Secondary outcomes included associations between retinal thickness and length of stay (LoS) in hospital. In this retrospective cohort study, OCT scans from 230 COVID-19 patients admitted to the Intensive Care Unit (ITU) were compared with age and gender-matched patients with pneumonia from before March 2020. Total retinal, GCL + IPL, and RNFL thicknesses were recorded, and analysed with systemic measures collected at the time of admission and mortality outcomes, using linear regression models, Pearson's R correlation, and Principal Component Analysis. Retinal thickness was significantly associated with all-time mortality on follow up in the COVID-19 group (p = 0.015), but not 28-day mortality (p = 0.151). Retinal and GCL + IPL layer thicknesses were both significantly associated with LoS in hospital for COVID-19 patients (p = 0.006 for both), but not for patients with pneumonia (p = 0.706 and 0.989 respectively). RNFL thickness was not associated with LoS in either group (COVID-19 p = 0.097, pneumonia p = 0.692). Retinal thickness associated with LoS in hospital and long-term mortality in COVID-19 patients, suggesting that retinal structure could be a surrogate marker for frailty and predictor of disease severity in this group of patients, but not in patients with pneumonia from other causes.

Omicron COVID-19 immune correlates analysis of a third dose of mRNA-1273 in the COVE trial

In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.