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We surveyed low-income, ethnically diverse consumers regarding their attitudes towards providers' use of electronic health information exchange (HIE) and consumer use of HIE through personal health records (PHRs). Amongst respondents (n = 214), 48% had an annual household income below $15,000 and 62% spoke a language other than English at home. A majority indicated that they supported providers' use of HIE (61%). Support for providers' use of HIE was independently associated with consumer willingness to permit health care providers other than their primary care doctor to view their electronic medical record information (odds ratio (OR) = 2.92, 95% confidence interval (CI) = 1.31-6.50) and beliefs that electronic health record use would improve quality of care (OR = 2.70, 95% CI = 1.18-6.18). Seventy-eight percent would potentially use PHRs. Potential PHR use was independently associated with Internet usage rates, (OR = 4.46, 95% CI = 1.77-11.22), belief that PHR use would improve their understanding of their own healthcare (OR = 3.12, 95% CI = 1.27-7.67) and comfort with sharing PHR data with their primary care doctor (OR = 2.79, 95% CI = 1.09-7.11). Low-income, ethnically diverse consumers affected by interoperable health information technology (IT) initiatives largely support using PHRs and HIE, provided these systems demonstrate benefits and address the privacy and security of their electronic health information. Although we found interest in PHRs comparable or higher than nationally representative populations, support for HIE was lower, and thus efforts will need to be made to engage low-income and ethnically diverse consumers to participate in interoperable health IT initiatives. [ABSTRACT FROM AUTHOR]

Heparan sulfate (HS) is an important component of the kidney anionic filtration barrier, the glomerular basement membrane (GBM). HS chains attached to proteoglycan protein cores are modified by sulfotransferases in a highly ordered series of biosynthetic steps resulting in immense structural diversity due to negatively charged sulfate modifications. 3-O-sulfation is the least abundant modification generated by a family of seven isoforms but creates the most highly sulfated HS domains. We analyzed the kidney phenotypes in the Hs3st3a1, Hs3st3b1 and Hs3st6 -knockout (KO) mice, the isoforms enriched in kidney podocytes. Individual KO mice show no overt kidney phenotype, although Hs3st3b1 kidneys were smaller than wildtype (WT). Furthermore, Hs3st3a1 -/- ; Hs3st3b1 -/- double knockout (DKO) kidneys were smaller but also had a reduction in glomerular size relative to wildtype (WT). Mass spectrometry analysis of kidney HS showed reduced 3-O-sulfation in Hs3st3a1 -/- and Hs3st3b1 -/- , but not in Hs3st6 -/- kidneys. Glomerular HS showed reduced HS staining and reduced ligand-and-carbohydrate engagement (LACE) assay, a tool that detects changes in binding of growth factor receptor-ligand complexes to HS. Interestingly, DKO mice have increased levels of blood urea nitrogen, although no differences were detected in urinary levels of albumin, creatinine and nephrin. Finally, transmission electron microscopy showed irregular and thickened GBM and podocyte foot process effacement in the DKO compared to WT. Together, our data suggest that loss of 3-O-HS domains disrupts the kidney glomerular architecture without affecting the glomerular filtration barrier and overall kidney function., Competing Interests: Declaration of competing interest JL is a founder and chief scientific officer for Glycan Therapeutics Corp. Other authors declare no competing interest., (Published by Elsevier B.V.)

The use of topical antimicrobials in wound healing presents challenges like risk of drug resistance and toxicity to local tissue. Simvastatin (SIM), a lipid-lowering agent which reduces the risk of cardiovascular events, is repurposed for its pleiotropic effect in wound healing. A bioactive bioadhesive polymer-based film forming spray (FFS) formulation of SIM was designed using chitosan, collagen, hyaluronic acid and optimised by employing the DoE approach. Optimised formulation demonstrated moderate viscosity (12.5 ± 0.3 cP), rapid film formation (231 ± 5.6 s), flexibility, tensile strength and sustained drug release (T80 - time for 80% drug release - 9.05 ± 0.7 h). Scanning electron microscopy (SEM) verified uniformly dispersed drug within the composite polymer matrix. SIM FFS demonstrated antimicrobial activity against gram positive and gram negative bacteria. In vivo excision wound model studies in mice affirmed the beneficent role of bioactive polymers and the efficacy of SIM FFS in wound contraction and closure, tissue remodelling and re-epithelization in comparison to standard antimicrobial preparation. Cytokines TNF- alpha, IL-6 were downregulated and IL-10 was upregulated. Biochemical markers; hydroxyproline, hexosamine and histopathology were consistent with wound contraction observed. This is an exploratory effort in repurposing SIM for wound healing in a novel dosage form, underscoring its potential as an alternative to conventional topical antimicrobials.

Heparan sulfate (HS) regulation of FGFR function, which is essential for salivary gland (SG) development, is determined by the immense structural diversity of sulfated HS domains. 3-O-sulfotransferases generate highly 3-O-sulfated HS domains (3-O-HS), and Hs3st3a1 and Hs3st3b1 are enriched in myoepithelial cells (MECs) that produce basement membrane (BM) and are a growth factor signaling hub. Hs3st3a1;Hs3st3b1 double-knockout (DKO) mice generated to investigate 3-O-HS regulation of MEC function and growth factor signaling show loss of specific highly 3-O-HS and increased FGF/FGFR complex binding to HS. During development, this increases FGFR-, BM- and MEC-related gene expression, while in adult, it reduces MECs, increases BM and disrupts acinar polarity, resulting in salivary hypofunction. Defined 3-O-HS added to FGFR pulldown assays and primary organ cultures modulates FGFR signaling to regulate MEC BM synthesis, which is critical for secretory unit homeostasis and acinar function. Understanding how sulfated HS regulates development will inform the use of HS mimetics in organ regeneration., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: We conducted a preliminary phase I, dose-escalating, safety, and tolerability trial in the population of patients with acute intracerebral hemorrhage (ICH) by using human allogeneic bone marrow-derived mesenchymal stem/stromal cells., Methods: Eligibility criteria included nontraumatic supratentorial hematoma less than 60 mL and Glasgow Coma Scale score greater than 5. All patients were monitored in the neurosciences intensive care unit for safety and tolerability of mesenchymal stem/stromal cell infusion and adverse events. We also explored the use of cytokines as biomarkers to assess responsiveness to the cell therapy. We screened 140 patients, enrolling 9 who met eligibility criteria into three dose groups: 0.5 million cells/kg, 1 million cells/kg, and 2 million cells/kg., Results: Intravenous administration of allogeneic bone marrow-derived mesenchymal stem/stromal cells to treat patients with acute ICH is feasible and safe., Conclusions: Future larger randomized, placebo-controlled ICH studies are necessary to validate this study and establish the effectiveness of this therapeutic approach in the treatment of patients with ICH., (© 2023. The Author(s).)

Working memory is an executive function that orchestrates the use of limited amounts of information, referred to as working memory capacity, in cognitive functions. Cannabis exposure impairs working memory in humans; however, it is unclear whether Cannabis facilitates or impairs rodent working memory and working memory capacity. The conflicting literature in rodent models may be at least partly because of the use of drug exposure paradigms that do not closely mirror patterns of human Cannabis use. Here, we used an incidental memory capacity paradigm where a novelty preference is assessed after a short delay in spontaneous recognition-based tests. Either object or odor-based stimuli were used in test variations with sets of identical [identical stimuli test (IST)] and different [different stimuli test (DST)] stimuli (three or six) for low-memory and high-memory loads, respectively. Additionally, we developed a human-machine hybrid behavioral quantification approach which supplements stopwatch-based scoring with supervised machine learning-based classification. After validating the spontaneous IST and DST in male rats, 6-item test versions with the hybrid quantification method were used to evaluate the impact of acute exposure to high-Δ 9 -tetrahydrocannabinol (THC) or high-CBD Cannabis smoke on novelty preference. Under control conditions, male rats showed novelty preference in all test variations. We found that high-THC, but not high-CBD, Cannabis smoke exposure impaired novelty preference for objects under a high-memory load. Odor-based recognition deficits were seen under both low-memory and high-memory loads only following high-THC smoke exposure. Ultimately, these data show that Cannabis smoke exposure impacts incidental memory capacity of male rats in a memory load-dependent, and stimuli-specific manner., Competing Interests: R.B.L. is a member of the Scientific Advisory Board for Shackleford Pharma Inc.; however, this company had no input into this research study. All other authors declare no competing financial interests., (Copyright © 2023 Barnard et al.)

Background: Patents and exclusive rights on reference biologics contribute to the emergence of biosimilars. Regulatory bodies, such as the Food and Drug Administration (FDA), World Health Organization (WHO), and EMA (European Medicines Agency) for assessing clinical safety, effectiveness, and consequences between biosimilars and reference medications, have established guidelines. Since generic small molecules from reference can be easily swapped, biosimilars cannot be used interchangeably and may not always indicate interchangeability due to highly restrictive properties. It can be replaced with a reference without the healthcare provider's help under the interchangeability context., Objective: The purpose of our study is to analyze and compare evidence-based clinical safety, therapeutic potential, and importance (outcomes) of several biosimilars with their references along with clinical uses in chronic diseases., Methods: Through a comprehensive systemic literature review of more than 100 articles involving medicinally important drugs whose bio-similarity works optimally, safety-efficacy parameters have been analyzed. Analysis of biosimilar usage, approval, and safety-efficacy aspects are majorly focused upon herein in this review., Results: From this systemic review, it can be stated that the majority of biosimilars are clinically and statistically equivalent to their originators. As biosimilars have good safety-efficacy aspects with lower prices, their utilization can be more encouraged, which was already done by the FDA with the establishment of a public online database entitled "Purple Book," which includes all information regarding biological drugs., Conclusion: To conclude, we suggest widespread use of high-grade biosimilars in clinical practice, maybe via changing, exchanging, or switching, with appropriate clinical monitoring and pharmacovigilance to improve patient accessibility to modern medicines, as it provides similar efficacy and safety parameters across all the accumulated clinical trials and studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: 1.5 Tesla (1.5T) remain a significant field strength for brain imaging worldwide. Recent computer simulations and clinical studies at 3T MRI have suggested that dynamic susceptibility contrast (DSC) MRI using a 30° flip angle ("low-FA") with model-based leakage correction and no gadolinium-based contrast agent (GBCA) preload provides equivalent relative cerebral blood volume (rCBV) measurements to the reference-standard acquisition using a single-dose GBCA preload with a 60° flip angle ("intermediate-FA") and model-based leakage correction. However, it remains unclear whether this holds true at 1.5T. The purpose of this study was to test this at 1.5T in human high-grade glioma (HGG) patients., Methods: This was a single-institution cross-sectional study of patients who had undergone 1.5T MRI for HGG. DSC-MRI consisted of gradient-echo echo-planar imaging (GRE-EPI) with a low-FA without preload (30°/P-); this then subsequently served as a preload for the standard intermediate-FA acquisition (60°/P+). Both normalized (nrCBV) and standardized relative cerebral blood volumes (srCBV) were calculated using model-based leakage correction (C+) with IBNeuro™ software. Whole-enhancing lesion mean and median nrCBV and srCBV from the low- and intermediate-FA methods were compared using the Pearson's, Spearman's and intraclass correlation coefficients (ICC)., Results: Twenty-three HGG patients composing a total of 31 scans were analyzed. The Pearson and Spearman correlations and ICCs between the 30°/P-/C+ and 60°/P+/C+ acquisitions demonstrated high correlations for both mean and median nrCBV and srCBV., Conclusion: Our study provides preliminary evidence that for HGG patients at 1.5T MRI, a low FA, no preload DSC-MRI acquisition can be an appealing alternative to the reference standard higher FA acquisition that utilizes a preload., Competing Interests: Author KS was employed IQ-AI Ltd and Imaging Biometrics LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shiroishi, Weinert, Cen, Varghese, Dondlinger, Prah, Mendoza, Nazemi, Ameli, Amini, Shohas, Chen, Bigjahan, Zada, Chen, Neman-Ebrahim, Chang, Chow, Fan, Yang, Attenello, Ye, Kim, Patel, Lerner, Acharya, Hu, Quarles, Boxerman, Wu and Schmainda.)

HS3ST1 is a genetic risk gene associated with Alzheimer's disease (AD) and overexpressed in patients, but how it contributes to the disease progression is unknown. We report the analysis of brain heparan sulfate (HS) from AD and other tauopathies using a LC-MS/MS method. A specific 3- O -sulfated HS displayed sevenfold increase in the AD group ( n = 14, P < 0.0005). Analysis of the HS modified by recombinant sulfotransferases and HS from genetic knockout mice revealed that the specific 3- O -sulfated HS is made by 3- O -sulfotransferase isoform 1 (3-OST-1), which is encoded by the HS3ST1 gene. A synthetic tetradecasaccharide (14-mer) carrying the specific 3- O -sulfated domain displayed stronger inhibition for tau internalization than a 14-mer without the domain, suggesting that the 3- O -sulfated HS is used in tau cellular uptake. Our findings suggest that the overexpression of HS3ST1 gene may enhance the spread of tau pathology, uncovering a previously unidentified therapeutic target for AD.

Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Multiple Sclerosis, Hereditary Spastic Paraplegia, and Amyotrophic Lateral Sclerosis have emerged as the most dreaded diseases due to a lack of precise diagnostic tools and efficient therapies. Despite the fact that the contributing factors of NDs are still unidentified, mounting evidence indicates the possibility that genetic and cellular changes may lead to the significant production of abnormally misfolded proteins. These misfolded proteins lead to damaging effects thereby causing neurodegeneration. The association between Neurite outgrowth factor (Nogo) with neurological diseases and other peripheral diseases is coming into play. Three isoforms of Nogo have been identified Nogo-A, Nogo-B and Nogo-C. Among these, Nogo-A is mainly responsible for neurological diseases as it is localized in the CNS (Central Nervous System), whereas Nogo-B and Nogo-C are responsible for other diseases such as colitis, lung, intestinal injury, etc. Nogo-A, a membrane protein, had first been described as a CNS-specific inhibitor of axonal regeneration. Several recent studies have revealed the role of Nogo-A proteins and their receptors in modulating neurite outgrowth, branching, and precursor migration during nervous system development. It may also modulate or affect the inhibition of growth during the developmental processes of the CNS. Information about the effects of other ligands of Nogo protein on the CNS are yet to be discovered however several pieces of evidence have suggested that it may also influence the neuronal maturation of CNS and targeting Nogo-A could prove to be beneficial in several neurodegenerative diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Neurotrophin receptors (NTRs) were significantly upregulated in myoepithelial cells (MECs) post-IR, and single cell RNAseq revealed that MECs pericytes, and duct cells are the main sources of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) induces expression of MEC genes during development, and upregulation of NTRs in adult MECs is associated with stress-induced plasticity and morphological abnormalities in IR human glands. As MECs are epithelial progenitors after gland damage and are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially impedes the ability of the gland to regenerate., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Our aim was to assess the acceptability and feasibility of iCare HOME tonometer (HT) and Virtual Field (VF) devices in the home monitoring of glaucoma., Design: Prospective feasibility and acceptability study., Subjects: Twenty patients (39 eyes) with primary open-angle glaucoma, open-angle glaucoma, ocular hypertension, or suspected glaucoma., Methods: Patients were trained and instructed to bring 2 devices home for 1 week and use the HT 4 times/day for 4 days and the VF 3 times total., Main Outcome Measures: For acceptability, we conducted satisfaction surveys and semistructured, qualitative interviews with a thematic analysis. Feasibility was assessed by device usage and quality of tests., Results: Most patients (73.7%) felt that the HT was easy to use, and 100% of them found the HT useful. All patients (100%) felt that VF was easy to use, and 94.4% of them found the VF useful. All patients (100%) obtained acceptable intraocular pressure and completed a VF test at home. We identified 4 key themes, with 33 subthemes. The key themes include the following: (1) advantages of home monitoring; (2) difficulties with home monitoring; (3) future considerations in home monitoring; and (4) the experience of patients with glaucoma., Conclusions: The HT and VF were acceptable and feasible in a small cohort of motivated subjects. Patients were able to perform these tests proficiently at home, and they were generally enthused to obtain more data about their intraocular health, as it allowed them a heightened sense of security and insight about their chronic disease, as well as a reduction in foreseeable barriers to care. Home monitoring may also improve upon glaucoma care by enhancing patient empowerment and fostering community bonds. The VF should be further evaluated to ensure validity., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

A cancerous tumour termed hepatocellular carcinoma (HCC) is characterized by inflammation and subsequently followed by end-stage liver disease and necrosis of the liver. The liver's continuous exposure to microorganisms and toxic molecules affects the immune response because normal tissue requires some immune tolerance to be safeguarded from damage. Several innate immune cells are involved in this process of immune system activation which includes dendritic cells, macrophages, and natural killer cells. The liver is an immunologic organ with vast quantities of innate and innate-like immune cells subjected to several antigens (bacteria, fungal or viral) through the gut-liver axis. Tumour-induced immune system engagement may be encouraged or suppressed through innate immunological systems, which are recognized promoters of liver disease development in pre-HCC conditions such as fibrosis or cirrhosis, ultimately resulting in HCC. Immune-based treatments containing several classes of drugs have transformed the treatment of several types of cancers in recent times. The effectiveness of such immunotherapies relies on intricate interactions between lymphocytes, tumour cells, and neighbouring cells. Even though immunotherapy therapy has already reported to possess potential effect to treat HCC, a clear understanding of the crosstalk between innate and adaptive immune cell pathways still need to be clearly understood for better exploitation of the same. The identification of predictive biomarkers, understanding the progression of the disease, and the invention of more efficient combinational treatments are the major challenges in HCC immunotherapy. The functions and therapeutic significance of innate immune cells, which have been widely implicated in HCC, in addition to the interplay between innate and adaptive immune responses during the pathogenesis, have been explored in the current review., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Mixed data exist regarding the association between hyperglycemia and functional outcome after acute ischemic stroke when accounting for the impact of leptomeningeal collateral flow. We sought to determine whether collateral status modifies the association between treatment group and functional outcome in a subset of patients with large vessel occlusion enrolled in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial., Methods: In this post-hoc analysis, we analyzed patients enrolled into the SHINE trial with anterior circulation large vessel occlusion who underwent imaging with CT angiography prior to glucose control treatment group assignment. The primary analysis assessed the degree to which collateral status modified the effect between treatment group and functional outcome as defined by the 90-day modified Rankin Scale score. Logistic regression was used to model the data, with adjustments made for thrombectomy status, age, post-perfusion thrombolysis in cerebral infarction (TICI) score, tissue plasminogen activator (tPA) use, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Five SHINE trial centers contributed data for this analysis. Statistical significance was defined as a p-value < 0.05., Results: Among the 1151 patients in the SHINE trial, 57 with angiographic data were included in this sub-analysis, of whom 19 had poor collaterals and 38 had good collaterals. While collateral status had no effect (p = 0.855) on the association between glucose control treatment group and functional outcome, patients with good collaterals were more likely to have a favorable functional outcome (p = 0.001, OR 5.02; 95% CI 1.37-16.0)., Conclusions: In a post-hoc analysis using a subset of patients with angiographic data enrolled in the SHINE trial, collateral status did not modify the association between glucose control treatment group and functional outcome. However, consistent with prior studies, there was a significant association between good collateral status and favorable outcome in patients with large vessel occlusion stroke., Trial Registration: ClinicalTrials.gov Identifier is NCT01369069. Registration date is June 8, 2011., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Selecting a medicine has a significant impact on the quality of therapy including efficacy and safety. P-glycoprotein and CYP3A4 share several common substrates known as bi-substrates. Both play major role in the pharmacokinetics and pharmacodynamics when over or under expressed., Objective: The study aimed to assess the Drug-Drug Interaction (DDI) related to P-glycoprotein (P-gp) and Cytochrome P450-3A4 (CYP3A4), to predict their clinical outcomes and also to discover prospective predictors of pDDIs., Methods: The subjects in this retrospective study ranged in age from 18 to 95 years with polypharmacy prescriptions. Information was gathered through patient medical records. Based on Micromedex and previous literature studies, medications prescribed to the patients were observed for pDDIs according to risk rating scale for drug interactions., Results: A total of 504 patients (160 males and 344 females) were included in the study. The mean of pDDI seen in the patients was 1.66 ± 1.48 and total 825 pDDIs were discovered. The factors significantly associated with having ≥1 pDDIs included: taking ≥5 medicines (OR 1.747), increased age (OR 1.026) increased comorbidities (OR 1.73)., Conclusion: In prescriptions, a considerable number of probable DDI were discovered. Therefore, careful selection of drugs and identification of mechanisms for DDI is needed to lower the frequency of pDDI., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Objectives: To assess the prognostic value of positron emission tomography (PET) imaging in patients undergoing evaluation for known or suspected cardiac sarcoidosis (CS) while not on active immunotherapy., Background: Previous studies have attempted to identify the value of PET imaging to aid in risk stratification of patients with CS, however, most cohorts have included patients currently on immunosuppression, which may confound scan results by suppressing positive findings., Methods: We retrospectively analyzed 197 patients not on immunosuppression who underwent 18 F-fluorodeoxyglucose (FDG) PET scans for evaluation of known or suspected CS. The primary endpoint of the study was time to ventricular arrhythmia (VT/VF), or death. Candidate predictors were identified by univariable Cox proportional hazards regression. Independent predictors were identified by performing multivariable Cox regression with stepwise forward selection., Results: Median follow-up time was 531 [IQR 309, 748] days. 41 patients met the primary endpoint. After stepwise forward selection, left ventricular ejection fraction (LVEF) (HR 0.98, 95% CI 0.96-0.99, P = 0.02), history of VT/VF (HR 4.19, 95% CI 2.15-8.17, P < 0.001), and summed rest score (SRS) (HR 1.06, 95% CI 1.02-1.12, P = 0.01) were predictive of the primary endpoint. Quantitative and qualitative measures of FDG uptake on PET were not predictive of clinical events., Conclusions: Among untreated patients who underwent PET scans to evaluate known or suspected CS, LVEF, history of VT/VF, and SRS were associated with adverse clinical outcomes., (© 2021. American Society of Nuclear Cardiology.)

Introduction: Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term., Methods: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions., Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe., Discussion: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection., Key Points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations., Competing Interests: All authors state that they have no relationships/activities/interests to disclose related to the content of this submission. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury, will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular, and genetic levels: the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis, and regeneration, and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.

Type-2 diabetes mellitus (T2DM) is a chronic immuno-inflammatory and metabolic disease characterized by hyperglycemia and insulin resistance with corresponding hyperinsulinemia. On the other hand, Alzheimer's disease (AD) is a neurodegenerative disease involving cognitive impairment, neuronal dysfunction, and memory loss. Several recently published literatures suggest a causal relationship between T2DM and AD. In this review, we have discussed several potential mechanisms underlying diabetes-induced cognitive impairment which include, abnormal insulin signaling, amyloid-β accumulation, oxidative stress, immuno-inflammation, mitochondrial dysfunction, advanced glycation end products, acetylcholinesterase and butyrylcholinesterase, advanced lipid peroxidation products, and apolipoprotein E. All these interconnected mechanisms may act either individually or synergistically which eventually leads to neurodegeneration and AD., Competing Interests: The authors have no conflict of interest to report., (© 2022 – The authors. Published by IOS Press.)

Purpose of Review: The purpose of this review is to discuss clinical trials involving glycemic control in hospitalized stroke patients and to review oral medications used in glycemic control. GLP-1 agonists, which have some preliminary studies in ischemic stroke, will also be reviewed., Recent Findings: Until recently, glycemic control targets in hospitalized stroke patients remained unclear. The SHINE (Stroke Hyperglycemia Insulin Network Effort) trial demonstrated no significant difference between aggressive versus standard of care glycemic control in the acute ischemic stroke patient. Although SHINE demonstrated a lack of statistical difference in glycemic control targets, many questions remain including glycemic control in patients with other stroke types (SAH, ICH). The role of non-insulin-based medications in glycemic control for hospitalized stroke patients remains unclear and presents an opportunity for further research. Finally, GLP-1 agonists present an interesting area of research for acute ischemic stroke., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Medical advancements in oncology and critical care during the past 2 decades have led to more patients with cancer being admitted to intensive care units. This article discusses the most common reasons for intensive care unit admission and factors associated with mortality among patients with cancer. It also reviews the multiple benefits of palliative care services in caring for critically ill patients with cancer and opportunities for critical care nurses working with these patients., (©2021 American Association of Critical-Care Nurses.)

Heparan sulfate 3-O-sulfotransferases generate highly sulfated but rare 3-O-sulfated heparan sulfate (HS) epitopes on cell surfaces and in the extracellular matrix. Previous ex vivo experiments suggested functional redundancy exists among the family of seven enzymes but that Hs3st3a1 and Hs3st3b1 sulfated HS increases epithelial FGFR signaling and morphogenesis. Single-cell RNAseq analysis of control SMGs identifies increased expression of Hs3st3a1 and Hs3st3b1 in endbud and myoepithelial cells, both of which are progenitor cells during development and regeneration. To analyze their in vivo functions, we generated both Hs3st3a1 -/- and Hs3st3b1 -/- single knockout mice, which are viable and fertile. Salivary glands from both mice have impaired fetal epithelial morphogenesis when cultured with FGF10. Hs3st3b1 -/- mice have reduced intact SMG branching morphogenesis and reduced 3-O-sulfated HS in the basement membrane. Analysis of HS biosynthetic enzyme transcription highlighted some compensatory changes in sulfotransferases expression early in development. The overall glycosaminoglycan composition of adult control and KO mice were similar, although HS disaccharide analysis showed increased N- and non-sulfated disaccharides in Hs3st3a1 -/- HS. Analysis of adult KO gland function revealed normal secretory innervation, but without stimulation there was an increase in frequency of drinking behavior in both KO mice, suggesting basal salivary hypofunction, possibly due to myoepithelial dysfunction. Understanding how 3-O-sulfation regulates myoepithelial progenitor function will be important to manipulate HS-binding growth factors to enhance tissue function and regeneration., (Published by Elsevier B.V.)

Background: Diabetes and malnutrition are common in patients with kidney failure. We aimed to evaluate the postprandial glucose response to oral nutritional supplement drinks (ONSs) in patients with diabetes undergoing hemodialysis treatment., Methods: A randomized, single-blind crossover study was conducted in patients with diabetes, and requiring chronic hemodialysis. Patients consumed either a renal-specific ONS, macronutrient-matched ONS, or standard ONS on 3 separate study days, during dialysis, following an overnight fast. Blood was collected before and 15, 30, 45, 60, 90, 120, and 180 minutes post ingestion. Mean net incremental area under the curve (iAUC) and peak incremental blood glucose concentration were compared across conditions, using analyses of variance., Results: Consumption of the renal-specific ONS resulted in the lowest mean net iAUC (87.9 ± 169.0 mmol/L per 3 hours) compared with macronutrient-matched (188.0 ± 127.5 mmol/L per 3 hours) and standard ONS (199.5 ± 169.2 mmol/L per 3 hours) (F 2,30 = 5.115, P = 0.012, partial n 2 = 0.254). Pairwise comparisons demonstrated a mean difference of 100.1 mmol/L per 3 hours (95% CI, -2.8 to 202.9) in mean iAUC between the renal-specific ONS and macronutrient-matched ONS (P = 0.058). Peak blood glucose concentration, corrected for baseline, was significantly lower after the renal-specific ONS (1.40 ± 1.0 mmol/L) compared with both macronutrient-matched (2.02 ± 0.71 mmol/L, P = 0.036) and standard ONS (2.3 ± 1.06 mmol/L, P = 0.017)., Conclusion: A renal-specific ONS elicits a lower postprandial glucose response than either macronutrient-matched ONS or standard ONS in patients with diabetes during hemodialysis., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Introduction: Right ventricular failure (RVF) after left ventricular assist device (LVAD) placement is associated with worse outcomes. We hypothesized that decreased right ventricular (RV) ejection fraction (EF) as well as qualitative assessments of RV function and dilation, as assessed by first pass radionuclide angiography (FPRNA), are associated with an increased risk of RVF following LVAD implantation., Methods: We retrospectively identified 46 patients from 1/2008 to 11/2017 that underwent FPRNA and LVAD implantation. RVF was defined as requiring inotropes for greater than 14 days after LVAD implantation or requiring a right ventricular assist device. FPRNA-derived variables of RV performance and structure were compared between those that did and did not have RVF post implant. Statistical analyses were performed with Mann-Whitney U tests for ordinal and continuous variables. Fisher's exact tests and Pearson's χ 2 tests were used for categorical variables., Results: Eight patients developed RVF after device implantation. The average RV EF on FPRNA was 41.45% in those that did not develop RVF and 40.13% in those that did (P = 0.787). RV dilation (P = 0.896) and global RV function (P = 0.827) by FPRNA were not statistically different between the two groups., Conclusion: In patients that required FPRNA for further assessment of RV function prior to LVAD implantation, decreased RV EF, RV dilation and global RV function on FPRNA were not associated with an increased risk of RVF.

Background: Although N13-ammonia has favorable properties among FDA approved radiotracers, complexity of implementation has limited its use. We describe the initial patient experience of N13-ammonia PET imaging using a compact N13-ammonia production system., Methods: N13 was produced using the ION-12SC, a 12MeV, 10uA superconducting minimally shielded cyclotron, and reduced to N13-ammonia in an automated multi-use purification unit. Patients were power injected with 9.3 ± 1.1 mCi (344.1 ± 40.7 MBq) of N13-ammonia for rest imaging, and 18.8 ± 0.9 mCi (695.6 ± 33.3 MBq) of N13-ammonia was injected at peak hyperemia for stress testing. Images were interpreted for relative perfusion, left ventricular volumes/function, blood flow quantification, and scored for image quality., Results: In total 97 patients underwent 98 N13-ammonia PET scans (32 rest only/65 rest-stress/1 stress only). Image quality was 91.8% good or excellent. None were poor/non-diagnostic. Study durations were acceptable. Tracer related radiation dosimetry to patients was 0.7 ± 0.1 mSv (rest only), and 2.1 ± 0.1 mSv (rest-stress)., Conclusion: Clinical N13-ammonia production by the Ionetix ION-12SC delivers high quality myocardial PET perfusion images in a rapid protocol.

Background: Solid organ transplant (SOT) recipients are considered to be "vulnerable" to COVID-19 infection due to immunosuppression. To date, there are no studies that compared the disease severity of COVID-19 in SOT recipients with nontransplant patients., Methods: In this case-control study, we compared the outcomes of COVID-19 between SOT recipients and their matched nontransplant controls. The cases were all adult SOT recipients (N = 41) from our academic health center who were diagnosed with COVID-19 between March 10, 2020 and May 15, 2020 using positive reverse transcriptase polymerase chain reaction for SARS-CoV2. The controls (N = 121) were matched on age (±5 y), race, and admission status (hospital or outpatient). The primary outcome was death and secondary outcomes were severe disease, intubation and renal replacement therapy (RRT)., Results: Median age of SOT recipients (9 heart, 3 lung, 16 kidney, 8 liver, and 5 dual organ) was 60 y, 80% were male and 67% were Black. Severe disease adjusted risk of death was similar in both the groups (hazard ratio = 0.84 [0.32-2.20]). Severity of COVID-19 and intubation were similar, but the RRT use was higher in SOT (odds ratio = 5.32 [1.26, 22.42]) compared to non-SOT COVID-19 patients. Among SOT recipients, COVID-19-related treatment with hydroxychloroquine (HCQ) was associated with 10-fold higher hazard of death compared to without HCQ (hazard ratio = 10.62 [1.24-91.09])., Conclusions: Although African Americans constituted one-tenth of all SOT in our center, they represented two-thirds of COVID-19 cases. Despite high RRT use in SOT recipients, the severe disease and short-term death were similar in both groups. HCQ for the treatment of COVID-19 among SOT recipients was associated with high mortality and therefore, its role as a treatment modality requires further scrutiny., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Salivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis.

Purpose: A phase I clinical trial was designed to test the feasibility and toxicity of administering high-dose spatially fractionated radiation therapy to magnetic resonance imaging (MRI)-defined prostate tumor volumes, in addition to standard treatment., Methods and Materials: We enrolled 25 men with favorable to high-risk prostate cancer and 1 to 3 suspicious multiparametric MRI (mpMRI) gross tumor volumes (GTVs). The mpMRI-GTVs were treated on day 1 with 12 to 14 Gy via dose cylinders using a lattice extreme ablative dose technique. The entire prostate, along with the proximal seminal vesicles, was then treated to 76 Gy at 2 Gy/fraction. For some high-risk patients, the distal seminal vesicles and pelvic lymph nodes received 56 Gy at 1.47 Gy/fraction concurrently in 38 fractions. The total dose to the lattice extreme ablative dose cylinder volume(s) was 88 to 90 Gy (112-123 Gy in 2.0 Gy equivalents, assuming an α-to-β ratio of 3)., Results: Dosimetric parameters were satisfactorily met. Median follow-up was 66 months. There were no grade 3 acute/subacute genitourinary or gastrointestinal adverse events. Maximum late genitourinary toxicity was grade 1 in 15 (60%), grade 2 in 4 (16%), and grade 4 in 1 (4%; sepsis after a posttreatment transurethral resection). Maximum late gastrointestinal toxicity was grade 1 in 11 (44%) and grade 2 in 4 (16%). Two patients experienced biochemical failure., Conclusions: External beam radiation therapy delivered with an upfront spatially fractionated, stereotactic high-dose mpMRI-GTV boost is feasible and was not associated with any unexpected events. The technique is now part of a follow-up phase II randomized trial., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to describe our experience with fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET/CT) in diagnosing left ventricular assist device (LVAD) infections and perform a meta-analysis of published studies to determine overall diagnostic accuracy., Background: Device-related infections are a common complication of LVADs and are linked to worse outcomes. Diagnosis of LVAD infections remains challenging. FDG PET/CT has demonstrated good diagnostic accuracy in several other infectious conditions., Methods: This was a single-center, retrospective case series of FDG PET/CT scans in suspected LVAD infection between September 2015 and February 2018. A systematic review of PubMed from database inception through March 2018 was also conducted to identify additional studies., Results: Nineteen FDG PET/CT scans were identified for the retrospective case series. The systematic review identified an additional 3 publications, for a total of 4 studies involving 119 scans assessing diagnostic performance. Axial (n = 36) and centrifugal (n = 83) flow LVADs were represented. Pooled sensitivity was 92% (95% confidence interval [CI]: 82% to 97%) and specificity was 83% (95% CI: 24% to 99%) for FDG PET/CT in diagnosing LVAD infections. Summary receiver-operating characteristic curve analysis demonstrated an AUC of 0.94 (95% CI: 0.91 to 0.95)., Conclusions: FDG PET/CT for suspected LVAD infections demonstrates good diagnostic accuracy, with overall high sensitivity but variable specificity., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Anticoagulation risks in older adult, long-term care patients are known to be high, especially in those with frequent transitions between care environments. Introduction of collaborative practice agreements (CPA) in specific settings is encouraged in the United States and has provided an additional option for the care of medically challenging patients. The aim of this study was to investigate the time in therapeutic range (TTR) in a Medicare Part A sponsored long-term care environment managed by pharmacists through a collaborative practice agreement in South-Central Appalachia. A retrospective review of all warfarin patient admissions from a large long-term care pharmacy's anticoagulant clinic was conducted for residents over an 18-month period. For all patients (n = 104), the overall TTR was 46.7% (INR 43% in range). Average management duration was 19.5 days per patient. Further studies are required to optimize CPA and transition strategies for complex, advanced age warfarin patients.

Objective: To determine the prevalence and predictors of receiving a smoking cessation medication prescription at discharge., Methods: Retrospective analysis of ongoing Human Studies Committee-approved clinical trial data at large tertiary care center, The University of Kansas Medical Center. Patients included were smokers over 18, either Spanish or English speaking, those admitted between October 1, 2016 through May 31, 2018. Other eligibility criteria include access to a telephone or mobile phone, not currently be pregnant or breastfeeding, have no significant co-morbidity that precludes participation (acute, life-threatening illness, and communication barriers such as tracheal tube or altered mental status). Those included in this analysis were those randomized into the trial who expressed interest in receiving a smoking cessation medication prescription at discharge., Results: Two hundred fourteen patients were recommended a prescription by their smoking cessation counselor, 88 patients (41.12%) were approved a prescription at discharge. Out of those approved, 50.70 (14.05 SD) was the average age, 12.84 (8.47 SD) was the average number of cigarettes used per day, 47 patients (53.41%) were White, 49 patients (55.68%) were admitted through the emergency department, 55 patients (62.50%) had used smoking cessation medication in the past, 49 patients (55.68%) had used inpatient smoking cessation, 36 patients (40.91%) had Medicaid. A binary logistic regression determined to show insurance status (P = 0.042) and use of inpatient smoking cessation medication use (P < 0.001) as statistically significant predictors of receiving a prescription at discharge., Conclusion: It was determined that among the population recommended for medication, 41.12% actually received a prescription at discharge. The variables of "health insurance status" and "use of inpatient smoking cessation medication" demonstrated to be predictors of receiving a prescription. It is important to further study this as many patients rely on a prescription to afford these medications that are useful in a quit attempt., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Cell transplantation of autologous adult biopsies, grown ex vivo as epithelial organoids or expanded as spheroids, are proposed treatments to regenerate damaged branching organs. However, it is not clear whether transplantation of adult organoids or spheroids alone is sufficient to initiate a fetal-like program of branching morphogenesis in which coordinated branching of multiple cell types including nerves, mesenchyme and blood vessels occurs. Yet this is an essential concept for the regeneration of branching organs such as lung, pancreas, and lacrimal and salivary glands. Here, we used factors identified from fetal organogenesis to maintain and expand adult murine and human epithelial salivary gland progenitors in non-adherent spheroid cultures, called salispheres. These factors stimulated critical developmental pathways, and increased expression of epithelial progenitor markers such as Keratin5, Keratin14, FGFR2b and KIT. Moreover, physical recombination of adult salispheres in a laminin-111 extracellular matrix with fetal salivary mesenchyme, containing endothelial and neuronal cells, only induced branching morphogenesis when neurturin, a neurotrophic factor, was added to the matrix. Neurturin was essential to improve neuronal survival, axon outgrowth, innervation of the salispheres, and resulted in the formation of branching structures with a proximal-distal axis that mimicked fetal branching morphogenesis, thus recapitulating organogenesis. Epithelial progenitors were also maintained, and developmental differentiation programs were initiated, showing that the fetal microenvironment provides a template for adult epithelial progenitors to initiate branching and differentiation. Further delineation of secreted and physical cues from the fetal niche will be useful to develop novel regenerative therapies that instruct adult salispheres to resume a developmental-like program in vitro and to regenerate branching organs in vivo., (Published by Elsevier Ltd.)

Background: Non-Hispanic Black (NHB) men are at an increased risk for aggressive prostate cancer (PCa), making active surveillance (AS) potentially less optimal in this population. This concern has not been explored in other minority populations-specifically, Hispanic/Latino men. We recently found that Mexican-American men demonstrate an increased risk of PCa-specific mortality, and we hypothesized that they may also be at risk for an adverse outcome on AS., Methods: Using the Surveillance, Epidemiology, and End Results (SEER) program, we extracted a population-based cohort of men diagnosed from 2004 to 2013 with localized or regional PCa, who had ≤2 cores of only Grade Group (GG) 1 cancer, and underwent radical prostatectomy (RP) with available biopsy and surgical pathology results. We measured discovery of high-risk PCa at RP and collected socioeconomic status (SES) data across different racial/ethnic groups. We defined aggressive tumors as either an upgrade to GG 3 or higher (GG3+) cancer or non-organ-confined disease (≥pT3a or N1). Univariate and multivariate logistic regression models were developed to assess the association between racial/ethnic categories and the previously mentioned adverse oncologic outcomes both with and without adjusting for SES factors., Results: NHB and Mexican-American men were significantly more likely to have aggressive PCa, following RP. In multivariable logistic regression adjusting for SES factors and relative to non-Hispanic White (NHW) men, Mexican-American men had at increased odds of upgrading to GG3+ (OR 1.67; 95% CI [1.00-2.90]). NHB men were more likely to have non-organ-confined disease (OR 1.34; 95% CI [1.06-1.69]), while Mexican-American men had a similar risk to NHW men., Conclusion: Among individuals with low-risk PCa and eligible for AS, Mexican-American and NHB men are at an increased risk of harboring more aggressive disease at RP. This novel finding among Mexican-Americans deserves further evaluation.

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10 -3 ) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10 -8 ) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

Head and neck cancer patients treated with irradiation often present irreversible salivary gland hypofunction for which no conventional treatment exists. We recently showed that recombinant neurturin, a neurotrophic factor, improves epithelial regeneration of mouse salivary glands in ex vivo culture after irradiation by reducing apoptosis of parasympathetic neurons. Parasympathetic innervation is essential to maintain progenitor cells during gland development and for regeneration of adult glands. Here, we investigated whether a neurturin-expressing adenovirus could be used for gene therapy in vivo to protect parasympathetic neurons and prevent gland hypofunction after irradiation. First, ex vivo fetal salivary gland culture was used to compare the neurturin adenovirus with recombinant neurturin, showing they both improve growth after irradiation by reducing neuronal apoptosis and increasing innervation. Then, the neurturin adenovirus was delivered to mouse salivary glands in vivo , 24 hr before irradiation, and compared with a control adenovirus. The control-treated glands have ∼50% reduction in salivary flow 60 days post-irradiation, whereas neurturin-treated glands have similar flow to nonirradiated glands. Further, markers of parasympathetic function, including vesicular acetylcholine transporter, decreased with irradiation, but not with neurturin treatment. Our findings suggest that in vivo neurturin gene therapy prior to irradiation protects parasympathetic function and prevents irradiation-induced hypofunction.

Background: Few studies focus on prostate cancer (PCa) outcomes in Hispanic/Latino men. Our study explores whether Hispanic/Latino subgroups demonstrate significantly different prostate cancer-specific mortality (PCSM) relative to Non-Hispanic White (NHW) and Non-Hispanic Black (NHB) men., Methods: We extracted a population-based cohort of men diagnosed with local-regional PCa from 2000-2013 (n= 486,865). PCSM was measured in racial/ethnic groups: NHW (n=352,886), NHB (n= 70,983), Hispanic/Latino (n= 40,462), and Asian American/Pacific Islander (n= 22,534). PCSM was also measured in Hispanic/Latino subgroups: Mexican (n= 8,077), Puerto Rican (n= 1,284), South or Central American (n= 3,021), Cuban (n= 788), and Dominican (n= 300). We conducted univariable and multivariable analyses (MVA) to compare risk for PCSM., Results: Compared to NHW men, results showed worse outcomes for NHB men with similar outcomes for Hispanic/Latino men. In MVA with NHW men as a reference, NHB (HR= 1.15, p <0.001) men had significantly worse PCSM and Hispanic/Latino (HR= 1.02, p = 0.534) men did not show a significant difference. In a second MVA, Puerto Rican (HR= 1.71, p <0.001) and Mexican (HR= 1.21, p = 0.008) men had significantly higher PCSM. With NHB men as a reference, the MVA showed Puerto Rican (HR= 1.50, p = 0.006) men with higher PCSM and Mexican (HR= 1.08, p = 0.307) men with no significant difference., Conclusions: Our findings indicate previously unknown disparities in PCSM for Puerto Rican and Mexican American men., Competing Interests: CONFLICTS OF INTEREST All authors had no conflicts of interest related to this study.

Objectives: This study sought to determine whether Holter-based parameters of heart rate variability (HRV) are independently associated with incident heart failure among older adults in the CHS (Cardiovascular Health Study) as evidenced by an improvement in the predictive power of the Health Aging and Body Composition Heart Failure (Health ABC) score., Background: Abnormal HRV, a marker of autonomic dysfunction, has been associated with multiple adverse cardiovascular outcomes but not the development of congestive heart failure (CHF)., Methods: Asymptomatic CHS participants with interpretable 24-h baseline Holter recordings were included (n = 1,401). HRV measures and premature ventricular contraction (PVC) counts were compared between participants with (n = 260) and without (n = 1,141) incident CHF on follow-up. Significantly different parameters between groups were added to the components of the Health ABC score, a validated CHF prediction tool, using stepwise Cox regression., Results: The final model included components of the Health ABC score, In PVC counts (adjusted hazard ratio [aHR]: 1.12; 95% confidence interval [CI]: 1.07 to 1.19; p < 0.001) and the following HRV measures: abnormal heart rate turbulence onset (aHR: 1.52; 95% CI: 1.11 to 2.08; p = 0.009), short-term fractal scaling exponent (aHR: 0.27; 95% CI: 0.14 to 0.53; p < 0.001), in very low frequency power (aHR: 1.28; 95% CI: 1.02 to 1.60; p = 0.037), and coefficient of variance of N-N intervals (aHR: 0.94; 95% CI: 0.90 to 0.99; p = 0.009). The C-statistic for the final model was significantly improved over the Health ABC model alone (0.77 vs. 0.73; p = 0.0002)., Conclusions: Abnormal HRV parameters were significantly and independently associated with incident CHF in asymptomatic, older adults. When combined with increased PVCs, HRV improved the predictive power of the Health ABC score., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Epithelial-mesenchymal interactions involve fundamental communication between tissues during organogenesis and are primarily regulated by growth factors and extracellular matrix. It is unclear whether RNA-containing exosomes are mobile genetic signals regulating epithelial-mesenchymal interactions. Here we identify that exosomes loaded with mesenchyme-specific mature microRNA contribute mobile genetic signals from mesenchyme to epithelium. The mature mesenchymal miR-133b-3p, loaded into exosomes, was transported from mesenchyme to the salivary epithelium, which did not express primary miR-133b-3p. Knockdown of miR-133b-3p in culture decreased endbud morphogenesis, reduced proliferation of epithelial KIT + progenitors, and increased expression of a target gene, Disco-interacting protein 2 homolog B (Dip2b). DIP2B, which is involved in DNA methylation, was localized with 5-methylcytosine in the prophase nucleus of a subset of KIT + progenitors during mitosis. In summary, exosomal transport of miR-133b-3p from mesenchyme to epithelium decreases DIP2B, which may function as an epigenetic regulator of genes responsible for KIT + progenitor expansion during organogenesis., (Published by Elsevier Inc.)

Radiotherapy for head and neck cancer often has undesirable effects on salivary glands that lead to xerostomia or severe dry mouth, which can increase oral infections. Our goal is to engineer functional, three-dimensional (3D) salivary gland neotissue for autologous implantation to provide permanent relief. An immediate need exists to obtain autologous adult progenitor cells as the use of embryonic and induced pluripotent stem cells potentially pose serious risks such as teratogenicity and immunogenic rejection. Here, we report an expandable population of primary salivary human stem/progenitor cells (hS/PCs) that can be reproducibly and scalably isolated and propagated from tissue biopsies. These cells have increased expression of progenitor markers (K5, K14, MYC, ETV4, ETV5) compared with differentiation markers of the parotid gland (acinar: MIST1/BHLHA15 and AMY1A; ductal: K19 and TFCP2L1). Isolated hS/PCs grown in suspension formed primary and secondary spheres and could be maintained in long-term 3D hydrogel culture. When grown in a customized 3D modular hyaluronate-based hydrogel system modified with bioactive basement membrane-derived peptides, levels of progenitor markers, indices of proliferation, and viability of hS/PCs were enhanced. When appropriate microenvironmental cues were provided in a controlled manner in 3D, such as stimulation with β-adrenergic and cholinergic agonists, hS/PCs differentiated into an acinar-like lineage, needed for saliva production. We conclude that the stem/progenitor potential of adult hS/PCs isolated without antigenic sorting or clonal expansion in suspension, combined with their ability to differentiate into specialized salivary cell lineages in a human-compatible culture system, makes them ideal for use in 3D bioengineered salivary gland applications. Stem Cells Translational Medicine 2017;6:110-120., (© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Branching morphogenesis is a fundamental process in the development of diverse epithelial organs such as the lung, kidney, liver, pancreas, prostate, salivary, lacrimal and mammary glands. A unifying theme during organogenesis is the importance of epithelial cell interactions with the extracellular matrix (ECM) and growth factors (GFs). The diverse developmental mechanisms giving rise to these epithelial organs involve many organ-specific GFs, but a unifying paradigm during organogenesis is the regulation of GF activity by heparan sulfates (HS) on the cell surface and in the ECM. This primarily involves the interactions of GFs with the sulfated side-chains of HS proteoglycans. HS is one of the most diverse biopolymers and modulates GF binding and signaling at the cell surface and in the ECM of all tissues. Here, we review what is known about how HS regulates branching morphogenesis of epithelial organs with emphasis on the developing salivary gland, which is a classic model to investigate epithelial-ECM interactions. We also address the structure, biosynthesis, turnover and function of HS during organogenesis. Understanding the regulatory mechanisms that control HS dynamics may aid in the development of therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine., (Published by Elsevier B.V.)

Background: Pityriasis lichenoides (PL) is a dermatologic disorder that manifests in either the acute (pityriasis lichenoides et varioliformis acuta) or the chronic form (pityriasis lichenoides chronica, also known as parapsoriasis chronica). Traditional first-line therapy consists of corticosteroids or antibiotics; however, these treatments are often accompanied with multiple side effects and may be ineffective., Objective: The goal of this study was to review the use of phototherapy for treating PL in the pediatric population., Materials and Methods: We performed a systematic review of the literature in the National Library of Medicine's PubMed database and the SCOPUS database discussing phototherapy for treatment of PL in the pediatric population. The following search terms were used: 'pityriasis lichenoides', 'pityriasis lichenoides chronica', 'pityriasis lichenoides et varioliformis acuta', and 'febrile ulceronecrotic Mucha-Habermann disease'., Results: The systematic search and screening of articles resulted in 14 articles including a total of 64 patients with PL treated with phototherapy. Three different modalities were utilized, with five studies using broadband ultraviolet B (BB-UVB) radiation, nine studies utilizing narrowband UVB (NB-UVB), and two studies employing psoralen with ultraviolet A (PUVA) therapy. Overall, the use of BB-UVB had an initial clearance rate of 89.6 % with 23.1 % recurrence, whereas NB-UVB cleared 73 % of the lesions with no recurrence, and PUVA therapy initially cleared 83 % of the lesions with 60 % recurrence. The side-effect profiles were similar and revealed limited toxicity., Conclusion: Phototherapy shows promising results and a favorable side-effect profile in the treatment of PL. Ultimately, large randomized controlled trials are needed to determine optimal treatments.

Accurate dose calculation and treatment delivery is essential for total body irradiation (TBI). In an effort to verify the accuracy of TBI dose calculation at our institution, we evaluated both the Varian Eclipse AAA and Acuros algorithms to predict dose distributions at an extended source-to-surface distance (SSD) of 400 cm. Measurements were compared to calculated values for a 6 MV beam in physical and virtual phantoms at 400 cm SSD using open beams for both 5 × 5 and 40 × 40cm2 field sizes. Inline and crossline profiles were acquired at equivalent depths of 5 cm, 10 cm, and 20 cm. Depth-dose curves were acquired using EBT2 film and an ion chamber for both field sizes. Finally, a RANDO phantom was used to simulate an actual TBI treatment. At this extended SSD, care must be taken using the planning system as there is good relative agreement between measured and calculated profiles for both algorithms, but there are deviations in terms of the absolute dose. Acuros has better agreement than AAA in the penumbra region.

Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found that deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation, and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons, and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus, K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To demonstrate the use of aggregated and de-identified electronic health record (EHR) data for multivariate post-marketing pharmacosurveillance in a case study of azathioprine (AZA)., Methods: Using aggregated, standardized, normalized, and de-identified, population-level data from the Explore platform (Explorys, Inc.) we searched over 10 million individuals, of which 14,580 were prescribed AZA based on RxNorm drug orders. Based on logical observation identifiers names and codes (LOINC) and vital sign data, we examined the following side effects: anemia, cell lysis, fever, hepatotoxicity, hypertension, nephrotoxicity, neutropenia, and neutrophilia. Patients prescribed AZA were compared to patients prescribed one of 11 other anti-rheumatologic drugs to determine the relative risk of side effect pairs., Results: Compared to AZA case report trends, hepatotoxicity (marked by elevated transaminases or elevated bilirubin) did not occur as an isolated event more frequently in patients prescribed AZA than other anti-rheumatic agents. While neutropenia occurred in 24% of patients (RR 1.15, 95% CI 1.07-1.23), neutrophilia was also frequent (45%) and increased in patients prescribed AZA (RR 1.28, 95% CI 1.22-1.34). After constructing a pairwise side effect network, neutropenia had no dependencies. A reduced risk of neutropenia was found in patients with co-existing elevations in total bilirubin or liver transaminases, supporting classic clinical knowledge that agranulocytosis is a largely unpredictable phenomenon. Rounding errors propagated in the statistically de-identified datasets for cohorts as small as 40 patients only contributed marginally to the calculated risk., Conclusion: Our work demonstrates that aggregated, standardized, normalized and de-identified population level EHR data can provide both sufficient insight and statistical power to detect potential patterns of medication side effect associations, serving as a multivariate and generalizable approach to post-marketing drug surveillance., (Copyright © 2013 Elsevier Inc. All rights reserved.)