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.

Seroprevalence of SARS-CoV-2 infection in pediatric patients in a tertiary care hospital setting.

Globally, cases of children's coronavirus disease 2019 (COVID-19) have been reported since the pandemic started. Most children have an asymptomatic or mild infection. Therefore, the incidence rate of COVID-19 in children might have been underestimated. This study aimed to determine (1) the seroprevalence (and seroconversion rates) of COVID-19, including associated risk factors, in pediatric patients visiting hospitals; and (2) the immunological responses to COVID-19. This was a prospective, cross-sectional study. Patients aged 0-18 years who visited the hospital from September 2020 to February 2022 were included. Demographic, clinical, and laboratory data were reviewed. A total of 1,443 pediatric patients were enrolled. Of these, 323 (22.6%) had a history of COVID-19. In the pre-Delta period, the seroprevalence increased from 4.1% to 70.6% in all included patients and from 0.5% to 10% in patients without a known history of COVID-19 compared with the Delta-Omicron period. The seroconversion rate was 6.8% (19 per 100 person-years) in pediatric patients with COVID-19. Risk factors for COVID-19 seropositivity were respiratory symptoms, being in an outpatient department setting, and infection during the Delta-Omicron period. Exposure to household members with confirmed COVID-19 was a risk factor for seropositivity and seroconversion. Infection during the Delta-Omicron period and testing conducted >2 weeks after the onset of symptoms was associated with spike immunoglobulin (Ig) M and spike and nucleocapsid IgG, respectively. High nucleocapsid IgG levels were associated with pneumonia in pediatric patients with COVID-19. Pediatric patients exposed to household members with COVID-19 and respiratory symptoms should be tested for COVID-19. Nucleocapsid IgG can be used as a surrogate marker to identify patients who may have experienced pneumonia from COVID-19 and as a screening tool for the COVID-19 outbreak, regardless of COVID-19 vaccination status.

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.

DEK::AFF2 Fusion-Associated Squamous Cell Carcinoma: A Case Series with Literature Review on an Emerging and Challenging Entity.

DEK::AFF2 fusion-associated squamous cell carcinoma (DEK::AFF2 SCC), also reported in the literature as low-grade papillary sinonasal (Schneiderian) carcinoma (LGPSC), is a rare, primarily bland-appearing, but locally aggressive neoplasm. Morphologically, these tumors can closely resemble sinonasal papilloma (SP), especially on small or limited biopsy, often leading to misdiagnosis. DEK::AFF2 SCC is devoid of the underlying mutually exclusive EGFR or KRAS driver mutations of SP, suggesting it may represent a distinct unique entity. In this study, we conducted a retrospective search of "unusual" SP reported either as atypical, dysplastic, or suspicious for malignant transformation at our institution in the last 13 years (2010-2023), to identify potential cases of DEK::AFF2 SCC. Of the 201 SP cases during this time period, 30 "unusual" SP cases were identified. On morphologic review of these 30 cases, 6 were worrisome for DEK::AFF2 SCC and were selected for AFF2 immunohistochemical stain (IHC), of which 3 cases were positive. All 3 AFF2 IHC positive cases were also positive for DEK::AFF2 fusion by fluorescence in situ hybridization (FISH), thereby, confirming IHC results. This study highlights that AFF2 IHC can be an invaluable surrogate marker to FISH in identifying DEK::AFF2 SCC in challenging cases to avoid misdiagnosis. Detailed clinical and pathologic data were collected to gain a better understanding of this emerging challenging entity. A literature review was performed to enrich our knowledge of DEK::AFF2 SCC.

Optical coherence tomography characterization of degradation kinetics between second- and third-generation resorbable magnesium scaffold.

This preclinical study aimed to establish optical coherence tomography (OCT)-derived parameters that could be used in the clinical setting for assessing strut degradation in the third-generation drug-eluting resorbable magnesium scaffold (DREAMS-3G), and characterize the comparative degradation profile against its precursor device (MagmarisTM scaffold). Twelve DREAMS-3G and 10 MagmarisTM scaffolds were implanted in juvenile pigs, and OCT images obtained at baseline and follow-up (6 or 12 months). Strut degradation was assessed by planimetric analysis and compared with OCT-derived indices to validate their diagnostic accuracy. A total of 3327 struts of DREAMS-3G and 2995 struts of the MagmarisTM scaffold were delineated by OCT. DREAMS-3G exhibited a significantly higher number of visible struts per analyzed frame at 6 months than the MagmarisTM scaffold, in the absence of significant differences at 12 months. Attenuation index (AtI) analysis indicated DREAMS-3G degradation was less advanced at 6 months but more advanced at 12 months compared to the MagmarisTM scaffold. These OCT-derived indices significantly correlated with the results of the planimetric analysis. The current preclinical study validated OCT indices that may serve as clinical surrogate markers for scaffold degradation. AtI analysis indicated that DREAMS-3G showed less degradation at 6 months but more advanced degradation at 12 months compared to the MagmarisTM scaffold, which corroborates the findings from planimetric analysis.

Association between triglyceride-glucose index and all-cause mortality in patients underwent transcatheter aortic valve replacement

BackgroundsThe prognosis of the triglyceride-glucose (TyG) index, a validated surrogate marker for insulin resistance, in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) remains unknown.MethodsThis study consecutively enrolled patients diagnosed with severe AS who underwent TAVR in a Chinese tertiary hospital from March 2013 to September 2023. Participants were stratified based on the TyG index cut-off value. Cox proportional hazards regression models were utilized to explore the association between the TyG index and all-cause mortality, including an assessment of interactions between the TyG index and various covariates on mortality outcomes.ResultsAmong 1045 patients (mean age 74.7 years, 58.2% male), there was 134 all-cause mortality, resulting in a crude mortality rate of 64.3 per 1000 person-years. Adjusting for age, sex, body mass index, smoking, hypertension, diabetes mellitus, bicuspid aortic valve, atrial fibrillation, Society of Thoracic Surgeons (STS) score, and left ventricular ejection fraction, a per-unit increase in the TyG index was associated with a 41% higher all-cause mortality risk (HR 1.41, 95% CI 1.03–1.93, p = 0.030). Notably, the relationship between the TyG index and all-cause mortality was significantly modified by age (pinteraction = 0.027), sex (pinteraction = 0.007), hypertension (pinteraction = 0.030), and STS score (pinteraction = 0.002).ConclusionsA higher TyG index is significantly associated with an increased risk of all-cause mortality in AS patients after TAVR. These results underscore the importance of considering the TyG index in the prognostic evaluation of AS patients following TAVR.

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

Abstract Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men from the United States (US) and Puerto Rico (PR). In 2024, around 35,250 PCa-related deaths will occur in the US, making PCa the second leading cause of cancer-related mortality in men in the US. In Puerto Rican men, PCa represents the first cause of cancer incidence (38%) and mortality (19%). Metastatic castrate-resistant prostate cancer (mCRPC) remains among the most frequent causes of cancer-related mortality in males. Patients with mCRPC become progressively resistant to androgen deprivation therapy, and the median survival for these patients is around two years. Ortiz-Sanchez et al. (2022) previously reported that the nucleotide excision repair (NER) pathway is dysregulated in the lymphocytes from patients with indolent and aggressive PCa; nevertheless, mCRPC cases were not included in the study design. Therefore, this pilot study aimed to evaluate the DNA repair capacity (DRC) in Puerto Rican men with and without mCRPC through the CometChip assay using lymphocytes as surrogate markers. Variations in mean DRC values were expected among the study groups. DRC measurements through the NER pathway were performed in a cohort of 96 participants, including PCa cases (n=71) and controls (n=25). The mean DRC value for the control group was 17.63%, and for the cases, it was 7.90%. When comparing mCRPC (n=16), non-mCRPC (n=55), and controls, significant differences were observed between the controls and each cancer group. However, no significant differences were found between PCa cases stratified by disease aggressiveness. Currently, we are evaluating the functionality of the homologous recombination repair pathway to gain additional insights into the role of DRC in PCa. Our results represent the first effort to apply a phenotypic assay to evaluate the overall DRC in mCRPC. This may improve patient diagnosis and patient stratification in terms of disease progression. Citation Format: Jaime Matta, Jarline Encarnación-Medina, Gilberto Ruiz-Deya, Valerie Rodriguez-Baez, Carmen Ortiz-Sanchez. DNA repair capacity in metastatic castration-resistant prostate cancer patients using lymphocytes as surrogate markers [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A034.

Competence in Unsustainability Resolution—A New Paradigm

Environmental unsustainability in coupled human–nature systems is accumulating. Yet, there is no accreditation requirement for unsustainability resolution competency in higher education. Thus, a new and complete representation of the pedagogy for unsustainability resolution competence has been induced, using what is already available and working. The nature of unsustainability problems points to collaboration and holism attitudes. Resolution requires social skills, namely participation, perspective taking, and the generation of social capital, and cognitive skills, namely project management, knowledge building, and modeling. Resolution is scaffolded in three successive steps during the collaborative process within a systems approach: (i) collapse complexity; (ii) select a path/trajectory; and (iii) operationalize a plan. The hierarchically cumulative abilities toward unsustainability resolution competence are to source data and information about the coupled human–nature system (SEARCH); simplify the dynamics of the human–nature system (SIMULATE); generate and test alternative paths and end points for the coupled human–nature system (STRATEGIZE); chose a favorable path among the available alternatives (SELECT); operationalize the favorable path into a plan (strategy–program–project) with measurable management and policy objectives (IMPLEMENT); and develop criteria/indicators to monitor and adjust when necessary the implementation of the plan toward system goals (STEER). For each one of these learning objectives, the Bloom’s taxonomy and a progression from behaviorist through cognitivist to constructivist tools apply. The development of mastery requires the comparison and contrast of many similar cases with the same unsustainability problem and project-based learning with specific cases for deep learning. In this way, it is the resolutions of unsustainability in human–nature systems that will be accumulating.

Acetylsalicylic acid alone or in combination with either enoxaparin or unfractionated heparin for postoperative thromboprophylaxis in coronary artery bypass surgery patients. A randomised clinical trial assessing surrogate outcomes

IntroductionCoronary artery bypass graft surgery has considerable effects on patient haemostasis. Heparins as thromboprophylaxis may be beneficial but may also increase the risk of bleeding complications. ObjectivesTo assess the effects of heparins on haemostasis in post-coronary artery bypass graft patients. MethodsAcross one year, we randomised 60 participants scheduled for an elective coronary artery bypass graft-procedure with or without aortic valve replacement. The trial was a prospective, open-label (though blinded for the laboratory), randomised, single-centre trial with three intervention groups (n = 20 in each): group 1 received acetylsalicylic acid, group 2 received subcutaneous low molecular weight heparin and acetylsalicylic acid, and group 3 received intravenous unfractionated heparin and acetylsalicylic acid. Primary outcomes were platelet activation (Multiplate® ASPI-test) and time to clot initiation (TEG® R-time). We secondly assessed several additional Multiplate® and TEG® parameters. ResultsGroup 3 (intravenous unfractionated heparin) compared with group 1 (acetylsalicylic acid alone) showed evidence of 1) increased clot initiation time (R-time + 0.9 min; 95 % CI: +0.4 to +1.4 min; P = 0.009), and 2) decreased 30-min lysis (−1.3 %; 95 % CI: −2.1 to −0.5 %; P = 0.02). The remaining analyses of primary and secondary outcomes showed no evidence of a difference between the three groups. DiscussionIntravenous unfractionated heparins may increase the clot initiation time post-operatively after coronary artery bypass graft surgery and reduce lysis. Otherwise, there seems to be no effect of low molecular weight or unfractionated heparin on haemostatic parameters after coronary artery bypass surgery patients.

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

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. 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. 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. 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. 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.

Next generation yellow fever vaccine induces an equivalent immune and transcriptomic profile to the current vaccine: observations from a phase I randomised clinical trial

Yellow fever (YF), a mosquito-borne acute viral haemorrhagic illness, is endemic to many tropical and subtropical areas of Africa and Central and South America. Vaccination remains the most effective prevention strategy; however, as repeated outbreaks have exhausted vaccine stockpiles, there is a need for improved YF vaccines to meet global demand. A live-attenuated YF vaccine candidate (referred to as vYF) cloned from a YF-17D vaccine (YF-VAX®) sub-strain, adapted for growth in Vero cells cultured in serum-free media, is in clinical development. We report the innate and adaptive immune responses and the transcriptome profile of selected genes induced by vYF. Healthy adults aged 18-60 years were randomised at a 1:1:1:1 ratio to receive one dose of vYF at 4, 5 or 6 Log CCID50 or YF-VAX (reference vaccine), administered subcutaneously in the upper arm (ClinicalTrials.gov identifier: NCT04142086). Blood/serum samples were obtained at scheduled time points through 180 days (D180) post-vaccination. The surrogate endpoints assessed were: serum cytokine/chemokine concentrations, measured by bead-based Multiplex assay; peripheral blood vYF-specific IgG and IgM memory B cell frequencies, measured by FluoroSpot assay; and expression of genes involved in the immune response to YF-17D vaccination by RT-qPCR. There was no increase in any of the cytokine/chemokine concentrations assessed through D14 following vaccination with vYF or YF-VAX, except for a slight increase in IP-10 (CXCL10) levels. The gene expression profiles and kinetics following vaccination with vYF and YF-VAX were similar, inclusive of innate (antiviral responses [type-1 interferon, IFN signal transduction; interferon-stimulated genes], activated dendritic cells, viral sensing pattern recognition receptors) and adaptive (cell division in stimulated CD4+ T cells, B cell and antibody) immune signatures, which peaked at D7 and D14, respectively. Increases in vYF-specific IgG and IgM memory B cell frequencies at D28 and D180 were similar across the study groups. vYF-induced strong innate and adaptive immune responses comparable to those induced by YF-VAX, with similar transcriptomic and kinetic profiles observed. Sanofi.

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.

Profiling of B cells and their subsets by whole blood gene expression analysis versus flow cytometry in multiple sclerosis

We investigated if differentially expressed mRNA targets could be used as surrogate markers for circulating B cells and subsets. In paired blood samples from patients with untreated, anti-CD20-treated, fingolimod-treated, and natalizumab-treated multiple sclerosis, whole blood expression of CD19 correlated with B cell counts determined by flow cytometry, ROR1 with transitional B cells, TCL1A and ZNF727 with naïve B cells, NEXMIF with memory B cells and BCMA with plasmablasts. CD19 expression distinguished patients with B cell repletion and may be used as an alternative to flow cytometry, but NEXMIF was unsuitable for memory B cell monitoring in rituximab-treated patients.

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.