Phase separation dynamics in wetting ridges of polymer surfaces swollen with oils of different viscosities.

When drops are placed on a sufficiently soft surface, the drop surface tension drives an out of plane deformation around the contact line (i.e., a wetting ridge). For soft elastomeric surfaces that are swollen with a liquid, capillarity from a drop can induce a phase separation in the wetting ridge. Using confocal microscopy, we study the dynamics of phase separation at the wetting ridge of glycerol drops on silicone elastomers, which are swollen with silicone oils of varying viscosity (i.e., molecular weight). We show that the viscosity of the swelling oil plays a large role in the oil separation size and separation rate. For networks swollen to near their maximum swelling (i.e., saturated), lower viscosity oil separates more and separates faster at early times compared to larger viscosity oil. During late-stage wetting, the growth rate of the separation is a function of viscosity and swelling ratio, which can be described by a simple diffusive model and a defined wetting ridge geometry. In this late-stage wetting, the higher viscosity oil evidently grows faster, likely because it is further from reaching equilibrium. Interestingly, the separated oil phase region grows with a nearly constant, geometrically similar shape. Understanding how phase separation occurs on swollen substrates should provide information on how to control drop spreading, sliding, adhesion, or friction on such surfaces.

Wetting on silicone surfaces.

Silicone is frequently used as a model system to investigate and tune wetting on soft materials. Silicone is biocompatible and shows excellent thermal, chemical, and UV stability. Moreover, the mechanical properties of the surface can be easily varied by several orders of magnitude in a controlled manner. Polydimethylsiloxane (PDMS) is a popular choice for coating applications such as lubrication, self-cleaning, and drag reduction, facilitated by low surface energy. Aiming to understand the underlying interactions and forces, motivated numerous and detailed investigations of the static and dynamic wetting behavior of drops on PDMS-based surfaces. Here, we recognize the three most prevalent PDMS surface variants, namely liquid-infused (SLIPS/LIS), elastomeric, and liquid-like (SOCAL) surfaces. To understand, optimize, and tune the wetting properties of these PDMS surfaces, we review and compare their similarities and differences by discussing (i) the chemical and molecular structure, and (ii) the static and dynamic wetting behavior. We also provide (iii) an overview of methods and techniques to characterize PDMS-based surfaces and their wetting behavior. The static and dynamic wetting ridge is given particular attention, as it dominates energy dissipation, adhesion, and friction of sliding drops and influences the durability of the surfaces. We also discuss special features such as cloaking and wetting-induced phase separation. Key challenges and opportunities of these three surface variants are outlined.

Collimonas rhizosphaerae sp. nov., a novel species isolated from the beech rhizosphere.

Bacterial strain H4R21T was isolated from beech rhizosphere soil sampled in the forest experimental site of Montiers (Meuse, France). It effectively weathers minerals, hydrolyses chitin and produces quorum sensing signal molecules. The strain is aerobic and Gram-stain-negative. Phylogenetic analysis based on its 16S rRNA gene sequence indicated that strain H4R21T belongs to the genus Collimonas with high sequence similarity to C. arenae Ter10T (99.38 %), C. fungivorans Ter6T(98.97 %), C. pratensis Ter91T (98.76 %), C. humicola RLT1W51T (98.46 %) and C. silvisoli RXD178 T (98.46 %), but less than 98 % similarity to other strains of the genus Collimonas. The predominant quinone in H4R21T is ubiquinone-8 (Q8). The major polar lipids are diphosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and lipid. The major fatty acids identified were C12 : 0, C12:0 3-OH, C16  :  0 and C17:0 cyclo. The digital DNA G+C content of the genomic DNA was 59.5 mol%. Furthermore, the strain could be clearly distinguished from its closely related type strains by a combination of phylogenomic and in silico DNA-DNA hybridization results, and phenotypic characteristics. Therefore, strain H4R21T represents a novel species within the genus Collimonas, for which the name Collimonas rhizosphaerae sp. nov. is proposed, with strain H4R21T (=CFBP 9203T=DSM 117599T) as the type strain.

Dupilumab-associated hypereosinophilia in severe asthma.

Dupilumab has been associated with adverse reactions including symptomatic hypereosinophilia. This study reports the incidence of dupilumab-related eosinophilia and adverse reactions in severe asthma patients at an Australian tertiary centre. https://bit.ly/3JgZ5Ya.

Controlling Anti-Penetration Performance by Post-Grafting of Fluorinated Alkyl Chains onto Polystyrene-block-poly(vinyl methyl siloxane).

Polydimethylsiloxane (PDMS) has been widely used as a surface coating material, which has been reported to possess dynamic omniphobicity to a wide range of both polar and nonpolar solvents due to its high segmental flexibility and mobility. However, such high flexibility and mobility also enable penetration of small molecules into PDMS coatings, which alter the chemical and physical properties of the coating layers. To improve the anti-penetration properties of PDMS, a series of fluorinated alkyl segments are grafted to a diblock copolymer of polystyrene-block-poly(vinyl methyl siloxane) (PS-b-PVMS) using thiol-ene click reactions. This article reports the chemical characterization of these model fluorosilicone block copolymers and uses fluorescence measurements to investigate the dye penetration characteristics of polymer thin films. The introduction of longer fluorinated alkyl chains can gradually increase the anti-penetration properties as the time to reach the maximum fluorescence intensity (tpeak) gradually increases from 11 s of PS-b-PVMS to more than 1000 s of PS-b-P(n-C6F13-VMS). The improvement of anti-penetration properties is attributed to stronger inter-/intrachain interactions, phase segregation of ordered fluorinated side chains, and enhanced hydrophobicity caused by the grafting of fluorinated alkyl chains.

In vitro activity of omadacycline against clinical isolates of Nocardia.

Nocardiosis typically requires a prolonged treatment duration of ≥6 months and initial combination therapy with 2-3 antibiotics. First-line regimens for nocardiosis are associated with considerable toxicity; therefore, alternative therapies are needed. Omadacycline is an aminomethylcycline with broad antimicrobial activity whose in vitro activity against Nocardia species has not been formally assessed. The in vitro potency of omadacycline was evaluated against 300 Nocardia clinical isolates by broth microdilution. The most common Nocardia species tested were N. cyriacigeorgica (21%), N. nova (20%), and N. farcinica (12%). The most common specimens were respiratory (178 isolates, 59%) and wound (57 isolates, 19%). Omadacycline minimum inhibitory concentrations (MICs) across all Nocardia species ranged from 0.06 µg/mL to 8 µg/mL, with an MIC50 of 2 µg/mL and MIC90 of 4 µg/mL. The lowest MICs were found among N. paucivorans (MIC50 = 0.25 µg/mL, MIC90 = 0.25 µg/mL), N. asiatica (MIC50 = 0.25 µg/mL, MIC90 = 1 µg/mL), N. abscessus complex (MIC50 = 0.5 µg/mL, MIC90 = 1 µg/mL), N. beijingensis (MIC50 = 0.5 µg/mL, MIC90 = 2 µg/mL), and N. otitidiscaviarum (MIC50 = 1 µg/mL, MIC90 = 2 µg/mL). The highest MICs were found among N. farcinica (MIC50 = 4 µg/mL, MIC90 = 8 µg/mL). In vitro potency differed by species among Nocardia clinical isolates. Further studies are warranted to evaluate the potential clinical utility of omadacycline for nocardiosis.

Virtual Shape-Editing of Patient-Specific Vascular Models Using Regularized Kelvinlets.

OBJECTIVE: Cardiovascular diseases, and the interventions performed to treat them, can lead to changes in the shape of patient vasculatures and their hemodynamics. Computational modeling and simulations of patient-specific vascular networks are increasingly used to quantify these hemodynamic changes, but they require modifying the shapes of the models. Existing methods to modify these shapes include editing 2D lumen contours prescribed along vessel centerlines and deforming meshes with geometry-based approaches. However, these methods can require extensive by-hand prescription of the desired shapes and often do not work robustly across a range of vascular anatomies. To overcome these limitations, we develop techniques to modify vascular models using physics-based principles that can automatically generate smooth deformations and readily apply them across different vascular anatomies. METHODS: We adapt Regularized Kelvinlets, analytical solutions to linear elastostatics, to perform elastic shape-editing of vascular models. The Kelvinlets are packaged into three methods that allow us to artificially create aneurysms, stenoses, and tortuosity. RESULTS: Our methods are able to generate such geometric changes across a wide range of vascular anatomies. We demonstrate their capabilities by creating sets of aneurysms, stenoses, and tortuosities with varying shapes and sizes on multiple patient-specific models. CONCLUSION: Our Kelvinlet-based deformers allow us to edit the shape of vascular models, regardless of their anatomical locations, and parametrically vary the size of the geometric changes. SIGNIFICANCE: These methods will enable researchers to more easily perform virtual-surgery-like deformations, computationally explore the impact of vascular shape on patient hemodynamics, and generate synthetic geometries for data-driven research.

Development and Validation of a Multivariable Nomogram Predictive of Post-Nephroureterectomy Renal Function.

BACKGROUND AND OBJECTIVE: The timing of perioperative nephrotoxic chemotherapy for upper tract urothelial carcinoma (UTUC) remains controversial and strongly depends on predicted platinum eligibility after radical nephroureterectomy (RNU). The study objective was to develop and validate a multivariable nomogram to predict estimated glomerular filtration rate (eGFR) following RNU. METHODS: This was a multi-institutional retrospective study of patients with UTUC treated with RNU from 2000 to 2020 at seven high-volume referral centers. Use of adjuvant chemotherapy was risk-stratified. Patients were retrospectively randomly allocated 2:1 to discovery and validation cohorts. Discovery data were used to identify independent factors associated with GFR at 1-3 mo after RNU on linear regression, and backward selection was applied for model construction. Accuracy was defined as the percentage of predicted eGFR results within 30% of the corresponding observed eGFR. KEY FINDINGS AND LIMITATIONS: We included 1100 patients, of whom 733 were in the discovery and 367 were in the validation cohort. Multivariable predictors of postoperative eGFR decline included advanced age (odds ratio [OR] -0.18, 95% confidence interval [CI] -0.28 to -0.08), diabetes (OR -2.38, 95% CI -4.64 to -0.11), and hypertension (OR -2.24, 95% CI -4.16 to -0.32). Factors associated with favorable postoperative eGFR included larger tumor size (OR 10.57, 95% CI 7.4-13.74 for tumors >5 cm vs ≤2 cm) and preoperative eGFR (OR 0.44, 95% CI 0.39-0.49). A composite nomogram predicted postoperative eGFR with good accuracy in both the discovery (80.5%) and validation (78.6%) cohorts. Limitations include exclusion of patients who received neoadjuvant chemotherapy. CONCLUSIONS: A nomogram that incorporates ubiquitous preoperative clinical variables can predict post-RNU eGFR and was validated with an independent cohort. PATIENT SUMMARY: We developed a tool that uses patient data to predict eligibility for chemotherapy after surgery to remove the kidney and ureter in patients with cancer in the upper urinary tract.

Can We Use Lung Function Thresholds and Respiratory Symptoms to Identify Pre-Chronic Obstructive Pulmonary Disease? A Prospective, Population-based Cohort Study.

Rationale: The term "pre-chronic obstructive pulmonary disease" ("pre-COPD") refers to individuals at high risk of developing COPD who do not meet conventional spirometric criteria for airflow obstruction. New approaches to identifying these individuals are needed, particularly in younger populations. Objectives: To determine whether lung function thresholds and respiratory symptoms can be used to identify individuals at risk of developing COPD. Methods: The Tasmanian Longitudinal Health Study comprises a population-based cohort first studied in 1968 (at age 7 yr). Respiratory symptoms, pre- and post-bronchodilator (BD) spirometry, diffusing capacity, and static lung volumes were measured in a subgroup at age 45, and the incidence of COPD was assessed at age 53. For each lung function measure, z-scores were calculated using Global Lung Function Initiative references. The optimal threshold for best discrimination of COPD incidence was determined by the unweighted Youden index. Measurements and Main Results: Among 801 participants who did not have COPD at age 45, the optimal threshold for COPD incidence by age 53 was pre-BD FEV1/FVC z-score less than -1.264, corresponding to the lowest 10th percentile. Those below this threshold had a 36-fold increased risk of developing COPD over an 8-year follow-up period (risk ratio, 35.8; 95% confidence interval, 8.88 to 144), corresponding to a risk difference of 16.4% (95% confidence interval, 3.7 to 67.4). The sensitivity was 88%, and the specificity was 87%. Positive and negative likelihood ratios were 6.79 and 0.14, respectively. Respiratory symptoms, post-BD spirometry, diffusing capacity, and static lung volumes did not improve on the classification achieved by pre-BD FEV1/FVC alone. Conclusions: This is the first study, to our knowledge, to evaluate the discriminatory accuracy of spirometry, diffusing capacity, and static lung volume thresholds for COPD incidence in middle-aged adults. Our findings support the inclusion of pre-BD spirometry in the physiological definition of pre-COPD and indicate that pre-BD FEV1/FVC at the 10th percentile accurately identifies individuals at high risk of developing COPD in community-based settings.

Cough in Children and Adults: Diagnosis, Assessment and Management (CICADA). Summary of an updated position statement on chronic cough in Australia.

INTRODUCTION: Cough is the most common symptom leading to medical consultation. Chronic cough results in significant health care costs, impairs quality of life, and may indicate the presence of a serious underlying condition. Here, we present a summary of an updated position statement on cough management in the clinical consultation. MAIN RECOMMENDATIONS: Assessment of children and adults requires a focused history of chronic cough to identify any red flag cough pointers that may indicate an underlying disease. Further assessment with examination should include a chest x-ray and spirometry (when age > 6 years). Separate paediatric and adult diagnostic management algorithms should be followed. Management of the underlying condition(s) should follow specific disease guidelines, as well as address adverse environmental exposures and patient/carer concerns. First Nations adults and children should be considered a high risk group. The full statement from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia for managing chronic cough is available at https://lungfoundation.com.au/resources/cicada-full-position-statement. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: Algorithms for assessment and diagnosis of adult and paediatric chronic cough are recommended. High quality evidence supports the use of child-specific chronic cough management algorithms to improve clinical outcomes, but none exist in adults. Red flags that indicate serious underlying conditions requiring investigation or referral should be identified. Early and effective treatment of chronic wet/productive cough in children is critical. Culturally specific strategies for facilitating the management of chronic cough in First Nations populations should be adopted. If the chronic cough does not resolve or is unexplained, the patient should be referred to a respiratory specialist or cough clinic.

Dosimetric predictors for genitourinary toxicity in MR-guided stereotactic body radiation therapy (SBRT): Substructure with fraction-wise analysis.

BACKGROUND: MR-guided radiation therapy (MRgRT) systems provide superior soft tissue contrast than x-ray based systems and can acquire real-time cine for treatment gating. These features allow treatment planning margins to be reduced, allowing for improved critical structure sparing and reduced treatment toxicity. Despite this improvement, genitourinary (GU) toxicity continues to affect many patients. PURPOSE: (1) To identify dosimetric predictors, potentially in combination with clinical parameters, of GU toxicity following SBRT by leveraging MRgRT to accurately monitor daily dose, beyond predicted dose calculated during planning. (2) Improve awareness of toxicity-sensitive bladder substructures, specifically the trigone and urethra. METHODS: Sixty-nine prostate cancer patients (NCT04384770 clinical trial) were treated on a ViewRay MRIdian MRgRT system, with 40 Gy prescribed to 95% of the PTV in over five fractions. Overall, 17 (24.6%) prostate patients reported acute grade 2 GU toxicity. The CTV, PTV, bladder, bladder wall, trigone, urethra, rectum, and rectal wall were contoured on the planning and daily treatment MRIs. Planning and daily treatment DVHs (0.1 Gy increments), organ doses (min, max, mean), and organ volumes were recorded. Daily dose was estimated by transferring the planning dose distributions to the daily MRI based on the daily setup alignment. Patients were partitioned into a training (55) and testing set (14). Dose features were pre-filtered using a t-test followed by maximum relevance minimum redundancy (MRMR) algorithm. Logistic regression was investigated with regularization to select dosimetric predictors. Specifically, two approaches: time-group least absolute shrinkage and selection (LASSO), and interactive grouped greedy algorithm (IGA) were investigated. Shared features across the planning and five treatment fractions were grouped to encourage consistency and stability. The conventional flat non-temporally grouped LASSO was also evaluated to provide a solid benchmark. After feature selection, a final logistic regression model was trained. Dosimetric regression models were compared to a clinical regression model with only clinical parameters (age, baseline IPSS, prostate gland size, ADT usage, etc.) and a hybrid model, combining the best performing dosimetric features with the clinical parameters, was evaluated. Final model performance was evaluated on the testing set using accuracy, sensitivity, and specificity determined by the optimal threshold of the training set. RESULTS: IGA had the best testing performance with an accuracy/sensitivity/specificity of 0.79/0.67/0.82, selecting 12 groups covering the bladder (V19.8 Gy, V20.5 Gy), bladder wall (19.7 Gy), trigone (15.9, 18.2, 43.3 Gy), urethra (V41.4 Gy, V41.7 Gy), CTV (V41.9 Gy), rectum (V8.5 Gy), and rectal wall (1.2, 44.1 Gy) dose features. Absolute bladder V19.8 Gy and V20.5 Gy were the most important features, followed by relative trigone 15.9  and 18.2 Gy. Inclusion of clinical parameters in the hybrid model with IGA did not significantly change regression performance. CONCLUSION: Overall, IGA feature selection resulted in the best GU toxicity prediction performance. This exploratory study demonstrated the feasibility of identification and analysis of dosimetric toxicity predictors with awareness to sensitive substructures and daily dose to potentially provide consistent and stable dosimetric metrics to guide treatment planning. Further patient accruement is warranted to further assess dosimetric predictor and perform validation.

A genetically encoded protein tag for control and quantitative imaging of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has been successful for hematological malignancies. Still, a lack of efficacy and potential toxicities have slowed its application for other indications. Furthermore, CAR T cells undergo dynamic expansion and contraction in vivo that cannot be easily predicted or controlled. Therefore, the safety and utility of such therapies could be enhanced by engineered mechanisms that engender reversible control and quantitative monitoring. Here, we use a genetic tag based on the enzyme Escherichia coli dihydrofolate reductase (eDHFR), and derivatives of trimethoprim (TMP) to modulate and monitor CAR expression and T cell activity. We fused eDHFR to the CAR C terminus, allowing regulation with TMP-based proteolysis-targeting chimeric small molecules (PROTACs). Fusion of eDHFR to the CAR does not interfere with cell signaling or its cytotoxic function, and the addition of TMP-based PROTACs results in a reversible and dose-dependent inhibition of CAR activity via the proteosome. We show the regulation of CAR expression in vivo and demonstrate imaging of the cells with TMP radiotracers. In vitro immunogenicity assays using primary human immune cells and overlapping peptide fragments of eDHFR showed no memory immune repertoire for eDHFR. Overall, this translationally-orientied approach allows for temporal monitoring and image-guided control of cell-based therapies.

27-year trends in incidence rates for testis cancer across a large statewide registry.

PURPOSE: To review 27-years of testicular cancer (TC) incidence data (1990-2017) within the state of Pennsylvania to better define incidence, geographic distribution, and trends over time. METHODS: The Pennsylvania Cancer Registry was reviewed for statewide and component county age-adjusted TC incidence rates and stage distribution. We reported annual percent changes (APCs) in age-adjusted rates. Maps plotting county-level incidence rates across the state in five-year time intervals were created. RESULTS: In Pennsylvania, 9,933 TC cases were recorded between 1990-2017. Over two-thirds of patients were < 40 years of age and 95% were White. Approximately 89% presented as local and regional disease. Age-adjusted annual rates of total TC increased from 4.80 to 7.20 patients per 100,000 with an APC of 0.94 (95% Confidence Interval (CI) = (0.59, 1.29), P < 0.01) over the study interval. Annual rates of local disease increased from 3.20 to 5.00 patients per 100,000 with an APC of 1.07 (95% CI = (0.67, 1.46), P < 0.01). Annual rates of distant disease were stable and ranged from 0.50 to 0.80 patients per 100,000 with an APC of 0.69 (95% CI = (-0.02, 1.40), P = 0.06). Geospatial investigation noted increased incidence in urban centers. CONCLUSIONS: Although TC is rare, incidence is rising. Rates of TC in Pennsylvania almost doubled over the past two decades. Fortunately, this rising trend is primarily attributed to increases in local and regional disease. Counties with higher incidence rates cluster in urban centers which may reflect exposure risk, access to care, or reporting bias.

Effectiveness and Safety of Antiobesity Medications in Patients With Obesity and Inflammatory Bowel Disease.

INTRODUCTION: Limited data exist evaluating antiobesity medications (AOM) in patients with inflammatory bowel disease (IBD). METHODS: We performed a case-control study evaluating the effectiveness and safety of AOM in patients with IBD with obesity, matched to non-IBD controls. RESULTS: After 12 months, the case (n = 36) and control (n = 36) groups achieved similar percent total body weight loss of -6.9 ± 8.3 and -8.1 ± 7.0 (P = 0.30), respectively. Side effect profiles were similar between groups. Seven patients experienced an IBD flare, all managed medically. DISCUSSION: AOM use in patients with IBD demonstrated similar effectiveness and safety when compared with that observed in the non-IBD population.

Rapid model-guided design of organ-scale synthetic vasculature for biomanufacturing.

Our ability to produce human-scale bio-manufactured organs is critically limited by the need for vascularization and perfusion. For tissues of variable size and shape, including arbitrarily complex geometries, designing and printing vasculature capable of adequate perfusion has posed a major hurdle. Here, we introduce a model-driven design pipeline combining accelerated optimization methods for fast synthetic vascular tree generation and computational hemodynamics models. We demonstrate rapid generation, simulation, and 3D printing of synthetic vasculature in complex geometries, from small tissue constructs to organ scale networks. We introduce key algorithmic advances that all together accelerate synthetic vascular generation by more than 230 -fold compared to standard methods and enable their use in arbitrarily complex shapes through localized implicit functions. Furthermore, we provide techniques for joining vascular trees into watertight networks suitable for hemodynamic CFD and 3D fabrication. We demonstrate that organ-scale vascular network models can be generated in silico within minutes and can be used to perfuse engineered and anatomic models including a bioreactor, annulus, bi-ventricular heart, and gyrus. We further show that this flexible pipeline can be applied to two common modes of bioprinting with free-form reversible embedding of suspended hydrogels and writing into soft matter. Our synthetic vascular tree generation pipeline enables rapid, scalable vascular model generation and fluid analysis for bio-manufactured tissues necessary for future scale up and production.

Visualizing Penetration of Fluorescent Dye through Polymer Coatings.

Understanding how small molecules penetrate and contaminate polymer films is of vital importance for developing protective coatings for a wide range of applications. To this end, rhodamine B fluorescent dye is visualized diffusing through polystyrene-polydimethylsiloxane block copolymer (BCP) coatings using confocal microscopy. The intensity of dye inside the coatings grows and decays non-monotonically, which is likely due to a combination of dye molecule transport occurring concurrently in different directions. An empirical fitting equation allows for comparing the contamination rates between copolymers, demonstrating that dye penetration is related to the chemical makeup and configuration of the BCPs. This work shows that confocal microscopy can be a useful tool to visualize the transport of a fluorophore in space and time through a coating.

Capillary detachment of a microparticle from a liquid-liquid interface.

The attachment and detachment of microparticles at a liquid-liquid interface are common in many material systems, from Pickering emulsions and colloidal assemblies to capillary suspensions. Properties of these systems rely on how the particles interact with the liquid-liquid interface, including the detachment process. In this study, we simultaneously measure the capillary detachment force of a microparticle from a liquid-liquid interface and visualize the shape of the meniscus by combining colloidal probe microscopy and confocal microscopy. The capillary behavior is studied on both untreated (hydrophilic) and fluorinated (hydrophobic) glass microparticles. The measured force data show good agreement with theoretical calculations based on the extracted geometric parameters from confocal images of the capillary bridge. It is also evident that contact line pinning is an important aspect of detachment for both untreated and fluorinated particles.

Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer.

Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3caH1047R mouse model expressing one or two R26-Pik3caH1047R alleles in a urothelium-specific manner was generated. Pik3caH1047R functionality was confirmed by quantifying Akt phosphorylation, and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. While at 6 months, Pik3caH1047R mice developed increased urothelial thickness and nuclear atypia, progressive disease was not observed at 12 months. Immunohistochemistry showed urothelium maintained luminal differentiation characterized by high forkhead box A1 (Foxa1) and peroxisome proliferator-activated receptor γ expression. Surprisingly, Pik3caH1047R mice subjected to low-dose carcinogen exposure [N-butyl-N-(4-hydroxybutyl)nitrosamine] exhibited no significant differences after exposure relative to mice without exposure. Furthermore, single-sample gene set enrichment analysis of invasive human tumors showed those with mutant PIK3CA did not exhibit significantly increased phosphatidylinositol 3-kinase/AKT pathway activity compared with wild-type PIK3CA tumors. Overall, these data suggest that Pik3caH1047R can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.

Childhood body mass index trajectories and asthma and allergies: A systematic review.

BACKGROUND: Previous systematic reviews have focused on associations between single time point measures of Body Mass Index (BMI) and asthma and allergic diseases. As BMI changes dynamically during childhood, examination of associations between longitudinal trajectories in BMI and allergic diseases is needed to fully understand the nature of these relationships. OBJECTIVE: To systematically synthesise the association between BMI trajectories in childhood (0-18 years) and allergic diseases (asthma, eczema, allergic rhinitis, or food allergies outcomes). DESIGN: We conducted a systematic review following the PRISMA guidelines, and two independent reviewers assessed the study quality using the ROBINS-E and GRADE tools. A narrative synthesis was performed as the statistical heterogeneity did not allow a meta-analysis. DATA SOURCES: A search was performed on PubMed and EMBASE databases on 4th January 2023. ELIGIBILITY CRITERIA: Longitudinal cohort studies assessing the associations between childhood BMI trajectories and allergic diseases were included. RESULTS: Eleven studies met the inclusion criteria with a total of 37,690 participants between 0 and 53 years of age. Ten studies examined asthma outcomes, three assessed association with allergic rhinitis, two assessed eczema, and one assessed food allergy. High heterogeneity and high risk of bias were observed. Overall, the quality of evidence was very low. Nevertheless, two consistent findings were identified: (1) a persistently high BMI between 6 and 10 years of age may be associated with an increased risk of asthma at 18 years and (2) a rapid increase in BMI in the first 2 years of life may be associated with subsequent asthma. CONCLUSIONS: Maintaining a normal BMI trajectory during childhood may reduce the risk of asthma. Future research that adequately addresses confounding and includes longer-term follow-up is needed. Moreover, additional studies examining potential associations with eczema, food allergies, and allergic rhinitis outcomes are needed.

Sequence-based diagnostics and precision medicine in bacterial and viral infections: from bench to bedside.

PURPOSE OF REVIEW: Nucleic acid sequence-based organism identification plays an important role in the diagnosis and management of transplant and cancer-associated infectious diseases. Here, we provide a high-level overview of advanced sequencing technologies, discuss test performance, and highlight unmet research needs with a focus on immunocompromised hosts. RECENT FINDINGS: Next-generation sequencing (NGS) technologies are powerful tools with a growing role in managing immunocompromised patients with suspected infection. Targeted NGS (tNGS) can identify pathogens directly from patient specimens, especially for mixed samples, and has been used to detect resistance mutations in transplant-related viruses (e.g. CMV). Whole-genome sequencing (WGS) is increasingly used for outbreak investigations and infection control. Metagenomic NGS (mNGS) is useful for hypothesis-free testing and can simultaneously assess pathogens and host response to infection. SUMMARY: NGS testing increases diagnostic yield relative to standard culture and Sanger sequencing but may be limited by high cost, turnaround times, and detection of unexpected organisms or commensals of uncertain significance. Close collaboration with the clinical microbiology laboratory and infectious diseases is recommended when NGS testing is considered. Additional research is required to understand which immunocompromised patients are most likely to benefit from NGS testing, and when testing should ideally be performed.