A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants.

The receptor tyrosine kinase FGFR3 is frequently mutated in bladder cancer and is a validated therapeutic target. Although pan-FGFR tyrosine kinase inhibitors (TKI) have shown clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapeutics can offer superior selectivity than TKIs, conventional ligand-blocking antibodies are usually ineffective inhibitors of constitutively active receptor tyrosine kinases. Furthermore, the existence of multiple oncogenic variants of FGFR3 presents an additional challenge for antibody-mediated blockade. Here, we developed a tetravalent FGFR3×FGFR3 bispecific antibody that inhibited FGFR3 point mutants and fusion proteins more effectively than any of the conventional FGFR3 antibodies that we produced. Each arm of the bispecific antibody contacted two distinct epitopes of FGFR3 through a cis mode of binding. The antibody blocked dimerization of the most common FGFR3 oncogenic variant (S249C extracellular domain mutation) and inhibited the function of FGFR3 variants that are resistant to pan-FGFR TKIs. The antibody was highly effective in suppressing growth of FGFR3-driven tumor models, providing efficacy comparable to that of the FDA-approved TKI erdafitinib. Thus, this bispecific antibody may provide an effective approach for broad and highly selective inhibition of oncogenic FGFR3 variants. Significance: Development of a bispecific antibody that broadly inhibits gain-of-function FGFR3 variants provides a therapeutic strategy to target tumors with oncogenic FGFR3 point mutations and fusions, a particularly difficult case for antibody blockade.

Test-Retest Reliability of the Verran Professional Governance Scale©.

Background and Purpose: Stability testing, conducted using a test-retest protocol, measures an instrument's reliability by evaluating the consistency of participant responses to survey questions with repeated testing within a short interval. No studies have measured the stability of the Verran Professional Governance Scale© (VPGS). The purpose of this study was to evaluate the test-retest reliability of the VPGS. Methods: Volunteers from a parent study using the VPGS were sent a link to a retest version of the survey 14 days after taking the initial survey with a reminder email sent 5 days after the first request. Item-level and subscale comparisons were made between participants' initial and retest responses using intraclass correlation coefficients (ICCs) applying a two-way random-effects model. Results: VPGS subscales had ICC scores of 0.71 for decision-making, 0.73 for collateral relationships, and 0.86 for professional obligation. Conclusions: Findings suggest that the VPGS demonstrates test-retest reliability. Future research should evaluate the instrument's responsiveness.

Exploring the relationships between pathogen-specific prenatal infections requiring inpatient admission and domains of offspring behaviour at age 5.

BACKGROUND: Research exploring the relationship between prenatal infection and child behavioural outcomes would benefit from further studies utilising full-population samples with the scale to investigate specific infections and to employ robust designs. We tested the association among several common infections requiring inpatient admission during and after pregnancy with a range of childhood behavioural outcomes, to determine whether any negative impact was specific to the period of foetal development. METHODS: The sample included all mother-offspring pairs from the Australian state of New South Wales (NSW) for whom the child commenced their first year of full-time schooling in 2009 (~age 5 years; n = 77,302 offspring), with records linked across four health administrative data sets including the NSW perinatal data collection (PDC), the NSW admitted patient data collection (APDC) and the NSW component of the 2009 Australian Early Development Census (AEDC). Multivariable linear regression was used to test associations between a number of infections requiring inpatient admission during and after pregnancy with a range of teacher assessed behavioural outcomes. RESULTS: Associations specific to the prenatal period were only found for streptococcus A although this would need to be reproduced in external samples given the low prevalence. Otherwise, 12 out of 15 selected infections either showed no association prenatally or also demonstrated associations in the 12 months after pregnancy. For example, prenatal hepatitis C, influenza and urinary E. coli infections were associated with lower scores of several domains of childhood behaviour, but even stronger associations were found when these same maternal infections occurred after pregnancy. CONCLUSIONS: The prenatal infections we tested appeared not to impact childhood behaviour by altering foetal neurodevelopment. Rather, the strong associations we found among infections occurring during and after pregnancy point to either residual socioeconomic/lifestyle factors or a shared familial/genetic liability between infections and behavioural problems.

An agricultural digital twin for mandarins demonstrates the potential for individualized agriculture.

A digital twin is a digital representation that closely resembles or replicates a real world object by combining interdisciplinary knowledge and advanced technologies. Digital twins have been applied to various fields, including to the agricultural field. Given big data and systematic data management, digital twins can be used for predicting future outcomes. In this study, we endeavor to create an agricultural digital twin using mandarins as a model crop. We employ an Open API to aggregate data from various sources across Jeju Island, covering an area of approximately 185,000 hectares. The collected data are visualized and analyzed at regional, inter-orchard, and intra-orchard scales. We observe that the intra-orchard analysis explains the variation of fruit quality substantially more than the inter-orchard analysis. Our data visualization and analysis, incorporating statistical models and machine learning algorithms, demonstrate the potential use of agricultural digital twins in the future, particularly in the context of micro-precision and individualized agriculture. This concept extends the current management practices based on data-driven decisions, and it offers a glimpse into the future of individualized agriculture by enabling customized treatment for plants, akin to personalized medicine for humans.

Emergency Department Volumes After State-Wide Lockdown Orders Across the United States During the COVID-19 Pandemic: COVID-19 lockdown and emergency volume.

OBJECTIVE: The objective of this study was to describe changes in emergency department volumes after statewide lockdown in a network of hospitals across the United States during the COVID-19 global pandemic. METHODS: A retrospective study was performed utilizing data on daily volumes across multiple emergency departments from a centralized data warehouse from a private for-profit hospital system during the COVID-19 pandemic. The mean daily volumes of 148 emergency departments were evaluated across 16 states in relation to each state's governmental statewide lockdown orders. Comparisons of the same period in the prior year were evaluated for percent changes in volumes. We also compared pre-lockdown to post-lockdown volumes. A separate analysis was made for the pediatric ED volumes. RESULTS: The 2020 post-lockdown volumes compared to the same 2019 dates revealed a mean percent change of -43.09%. The overall post-lockdown volumes compared to the pre-lockdown volumes had a mean percent change of -45.00%. The pediatric data revealed a greater mean percentage change in volumes of -71.52% (post-lockdown compared to 2019) and -69.03% (post-lockdown compared to pre-lockdown). CONCLUSIONS: This study found an overall decrease in volumes among 148 emergency departments across 16 states when compared to the comparable period pre-global pandemic.

Early allogeneic immune modulation after establishment of donor hematopoietic cell-induced mixed chimerism in a nonhuman primate kidney transplant model.

Background: Mixed lymphohematopoietic chimerism is a proven strategy for achieving operational transplant tolerance, though the underlying immunologic mechanisms are incompletely understood. Methods: A post-transplant, non-myeloablative, tomotherapy-based total lymphoid (TLI) irradiation protocol combined with anti-thymocyte globulin and T cell co-stimulatory blockade (belatacept) induction was applied to a 3-5 MHC antigen mismatched rhesus macaque kidney and hematopoietic cell transplant model. Mechanistic investigations of early (60 days post-transplant) allogeneic immune modulation induced by mixed chimerism were conducted. Results: Chimeric animals demonstrated expansion of circulating and graft-infiltrating CD4+CD25+Foxp3+ regulatory T cells (Tregs), as well as increased differentiation of allo-protective CD8+ T cell phenotypes compared to naïve and non-chimeric animals. In vitro mixed lymphocyte reaction (MLR) responses and donor-specific antibody production were suppressed in animals with mixed chimerism. PD-1 upregulation was observed among CD8+ T effector memory (CD28-CD95+) subsets in chimeric hosts only. PD-1 blockade in donor-specific functional assays augmented MLR and cytotoxic responses and was associated with increased intracellular granzyme B and extracellular IFN-γ production. Conclusions: These studies demonstrated that donor immune cell engraftment was associated with early immunomodulation via mechanisms of homeostatic expansion of Tregs and early PD-1 upregulation among CD8+ T effector memory cells. These responses may contribute to TLI-based mixed chimerism-induced allogenic tolerance.

Strategies to Improve the Utilization and Function of DCD Livers.

Despite the increased usage of livers from donation after circulatory death (DCD) donors in the last decade, many patients remaining on the waitlist who need a liver transplant. Recent efforts have focused on maximizing the utilization and outcomes of these allografts using advances in machine perfusion technology and other perioperative strategies such as normothermic regional perfusion (NRP). In addition to the standard donor and recipient matching that is required with DCD donation, new data regarding the impact of graft steatosis, extensive European experience with NRP, and the increasing use of normothermic and hypothermic machine perfusion have shown immense potential in increasing DCD organ overall utilization and improved outcomes. These techniques, along with viability testing of extended criteria donors, have generated early promising data to consider the use of higher-risk donor organs and more widespread adoption of these techniques in the United States. This review explores the most recent international literature regarding strategies to optimize the utilization and outcomes of DCD liver allografts, including donor-recipient matching, perioperative strategies including NRP versus rapid controlled DCD recovery, viability assessment of discarded livers, and postoperative strategies including machine perfusion versus pharmacologic interventions.

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.

ShinyCore: An R/Shiny program for establishing core collection based on single nucleotide polymorphism data.

BACKGROUND: Managing and investigating all available genetic resources are challenging. As an alternative, breeders and researchers use core collection-a representative subset of the entire collection. A good core is characterized by high genetic diversity and low repetitiveness. Among the several available software, GenoCore uses a coverage criterion that does not require computationally expensive distance-based metrics. RESULTS: ShinyCore is a new method to select a core collection through two phases. The first phase uses the coverage criterion to quickly attain a fixed coverage, and the second phase uses a newly devised score (referred to as the rarity score) to further enhance diversity. It can attain a fixed coverage faster than a currently available algorithm devised for the coverage criterion, so it will benefit users who have big data. ShinyCore attains the minimum coverage specified by a user faster than GenoCore, and it then seeks to add entries with the rarest allele for each marker. Therefore, measures of genetic diversity and distance can be improved. CONCLUSION: Although GenoCore is a fast algorithm, its implementation is difficult for those unfamiliar with R, ShinyCore can be easily implemented in Shiny with RStudio and an interactive web applet is available for those who are not familiar with programming languages.

Peritoneal dialysis in the setting of acute brain injury: an underappreciated modality.

INTRODUCTION: Dialysis is complicated in the setting of acute brain injury (ABI) due to several factors including acute solute shifts, acid base changes, need for anticoagulation, and changes in intracranial pressure. For these reasons, continuous renal replacement therapy (CRRT) is often the chosen modality for renal replacement needs in these patients. Peritoneal dialysis (PD) is less discussed but shares many of the benefits often attributed to CRRT. We describe, from both nephrology and neurosurgical perspectives, a case successfully managed with PD. CASE: A 25-year-old male with history of end-stage kidney disease (ESKD) secondary to focal segmental glomerulosclerosis on continuous cycling PD for 5 years presented to the hospital with headache and altered mental status. Initial imaging revealed a large intraventricular hemorrhage extending to the fourth ventricle. He underwent an emergent right depressive hemicraniectomy and clot evacuation. Post-operative imaging revealed worsening cerebral edema, intraventricular hemorrhage, and hydrocephalus. The decision was made to continue PD, noting that it retains many of the benefits of CRRT (which it is in fact, a form of) which he tolerated well until the need for a percutaneous gastrostomy tube arose. He was transiently transitioned to hemodialysis but returned to PD once his gastrostomy healed. He continued PD for 1 year without complication and eventually received a kidney transplant. DISCUSSION: In managing patients with ABI undergoing dialysis, a number of considerations must be undertaken including avoidance of hypotension to maintain cerebral perfusion pressure and minimize ischemia reperfusion injury, avoidance of anticoagulants that can precipitate or worsen bleeding, the potential for cerebral edema due to rapid solute clearance and osmotic dissipation of therapeutic hypernatremia, and the mitigation of intracellular acidosis from bicarbonate delivery. Although underutilized, PD may potentially serve as a viable option for dialysis in the setting of ABI as demonstrated by the case presented.

CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival.

Costimulation blockade using belatacept results in improved renal function after kidney transplant as well as decreased likelihood of death/graft loss and reduced cardiovascular risk; however, higher rates and grades of acute rejection have prevented its widespread clinical adoption. Treatment with belatacept blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while leaving CTLA-4 mediated coinhibitory signals intact. Here we test a novel domain antibody directed at CD28 (anti-CD28 dAb (BMS-931699)) in a non-human primate kidney transplant model. Sixteen macaques underwent native nephrectomy and received life-sustaining renal allotransplantation from an MHC-mismatched donor. Animals were treated with belatacept alone, anti-CD28 dAb alone, or anti-CD28 dAb plus clinically relevant maintenance (MMF, Steroids) and induction therapy with either anti-IL-2R or T cell depletion. Treatment with anti-CD28 dAb extended survival compared to belatacept monotherapy (MST 187 vs. 29 days, p=0.07). The combination of anti-CD28 dAb and conventional immunosuppression further prolonged survival to MST ∼270 days. Animals maintained protective immunity with no significant infectious issues. These data demonstrate CD28-directed therapy is a safe and effective next-generation costimulatory blockade strategy with a demonstrated survival benefit and presumed advantage over belatacept by maintaining intact CTLA-4 coinhibitory signaling.

Estimating the impact of environmental management on strawberry yield using publicly available agricultural data in South Korea.

Advanced information and communication technologies (ICTs) have made data collection more efficient for agricultural studies. Using publicly available database in South Korea, we estimated the relationship between the management of air temperature and relative humidity and the strawberry yield during two harvest seasons. Longitudinal data of multiple greenhouses were merged and processed, and mixed-effects models were applied to account both observed and unobserved factors across the greenhouses. The averages of air temperature and relative humidity inside each greenhouse do not take volatility of the time-varying variables into consideration, so we assessed the management of each greenhouse by the percent of time that air temperature between 15 °C and 20 °C (denoted as T%) and the percent of time that relative humidity between 0% and 50% (denoted by H%). The statistical models estimated that the strawberry yield decreases with respect to the number of days since harvest began and the rate of decrease is slower when T% and H% are higher. This study used large-scale multilocation data to provide the practical suggestion that air temperature and relative humidity should be maintained within the optimal ranges to mitigate the loss of strawberry yield especially at the later phase of a harvest season.

Development and validation of a machine learning-based tool to predict autism among children.

Autism is a lifelong condition for which intervention must occur as early as possible to improve social functioning. Thus, there is great interest in improving our ability to diagnose autism as early as possible. We take a novel approach to this challenge by combining machine learning with maternal and infant health administrative data to construct a prediction model capable of predicting autism disorder (defined as ICD10 84.0) in the general population. The sample included all mother-offspring pairs from the Australian state of New South Wales (NSW) between January 2003 and December 2005 (n = 262,650 offspring), linked across three health administrative data sets including the NSW perinatal data collection (PDC); the NSW admitted patient data collection (APDC) and the NSW mental health ambulatory data collection (MHADC). Our most successful model was able to predict autism disorder with an area under the receiver operating curve of 0.73, with the strongest risk factors for diagnoses found to include offspring gender, maternal age at birth, delivery analgesia, maternal prenatal tobacco disorders, and low 5-min APGAR score. Our findings indicate that the combination of machine learning and routinely collected admin data, with further refinement and increased accuracy than achieved by us, may play a role in the early detection of autism disorders.

Pediatric Surgery from the Roads Less Traveled: Challenges, Communication, and Collaboration from a Community Nonteaching Hospital.

Unique challenges face pediatric surgeons at community-based nonteaching hospitals. Communication and collaboration among and between healthcare providers, hospital administrators, and quaternary referral programs is crucial for the success of these smaller hospitals as they care for children.

Incremental healthcare cost burden in patients with atrial flutter only.

Background: Limited information is available on the costs related to atrial flutter only. This study provides a comprehensive estimate of the cost in patients with atrial flutter only versus matched patients without any atrial arrhythmia. Methods: Patients over 20 years of age with a minimum of one inpatient or two outpatient diagnosis codes for atrial flutter in 2005 and a minimum of 12 months of continuous enrollment pre- and post-index were identified using the MarketScan Commercial and Medicare databases. Atrial flutter patients were propensity matched to patients without atrial arrhythmias. Total costs for each patient for 12 months post-index were calculated. National cost was estimated using the projected prevalence of atrial flutter for 2010. Results: A total of 1,042 patients with atrial flutter only were successfully matched with comparison patients. For atrial flutter patients compared to matched controls without atrial arrhythmias, total mean annual cost per patient was 81% higher ($23,008 vs. $12,717) and mean annual inpatient expenditure was 214% higher ($8,518 vs. $2,713). When applied to national atrial flutter prevalence data, total incremental cost burden was estimated to be $687.9 million per year more than patients without atrial arrhythmias, primarily due to cardiovascular specific expenditure ($377 million, 55% of total) with 58% ($218.5 million) of the increased inpatient expenditure due to cardiovascular specific admissions and $159 million (23%) for atrial flutter specific care. Sex-related differences were also present in atrial flutter only patients. Conclusion: Although atrial flutter-only patients are less prevalent than atrial fibrillation patients, the national incremental cost burden in atrial flutter is substantial on a per-patient level.

Prediction of strawberry yield based on receptacle detection and Bayesian inference.

The receptacle of strawberry is a more direct part than the flower for predicting yield as they eventually become fruits. Thus, we tried to predict the yield by combining an AI technique for receptacle detection in images and statistical analysis on the relationship between the number of receptacles detected and the strawberry yield over a period of time. Five major cultivars were cultivated to consider the cultivar characteristics and environmental factors for two years were collected to consider the climate difference. Faster R-CNN based object detector was used to estimate the number of receptacles per strawberry plant in given two-dimensional images, which achieved a mAP of 0.6587 for our dataset. However, not all receptacles appear on the two-dimensional images, and Bayesian analysis was used to model the uncertainty associated with the number of receptacles missed by the AI. After estimating the probability of fruiting per receptacle, prediction models for the total strawberry yield at the end of harvest season were evaluated. Even though the detection accuracy was not perfect, the results indicated that counting the receptacles by object detection and estimating the probability of fruiting per receptacle by Bayesian modeling are more useful for predicting the total yield per plant than knowing its cumulative yield during the first month.

Management of Latent Tuberculosis Infection.

This JAMA Insights Clinical Update examines treatment recommendations and therapy options among adults with latent tuberculosis infection.

Nodular regenerative hyperplasia and liver transplantation: a systematic review.

Nodular regenerative hyperplasia (NRH) is a primary disease of the liver that may cause noncirrhotic portal hypertension. Common causes include autoimmune, hematologic, immune deficiency, and myeloproliferative disorders. Given the limited data regarding the development of NRH in contemporary immunosuppressive protocols and the occurrence of NRH post-liver transplantation, we systematically reviewed NRH as it pertains to liver transplantation. We performed a comprehensive search for NRH and transplantation. Nineteen studies were identified with relevant data for NRH as an indication for a liver transplant. Thirteen studies were identified with relevant data pertaining to NRH development after liver transplant. Pooled analysis revealed 0.9% of liver transplant recipients had NRH. A total of 113 patients identified with NRH underwent liver transplantation. Most series report transplants done after the failure of endoscopic banding and TIPS management of portal hypertension. Reported 5-year graft and patient survival ranged from 73%-78% and 73%-90%. The pooled incidence of NRH after liver transplant for all indications was 2.9% and caused complications of portal hypertension. Complications related to portal hypertension secondary to NRH are a rare indication for a liver transplant. NRH can develop at any time after liver transplantation often without an identifiable cause, which may lead to portal hypertension requiring treatment or even re-transplantation.