Novel approaches to increase synaptic resilience as potential treatments for Alzheimer's disease.

A significant proportion of brains with Alzheimer's disease pathology are obtained from patients that were cognitively normal, suggesting that differences within the brains of these individuals made them resilient to the disease. Here, we describe recent approaches that specifically increase synaptic resilience, as loss of synapses is considered to be the first change in the brains of Alzheimer's patients. We start by discussing studies showing benefit from increased expression of neurotrophic factors and protective genes. Methods that effectively make dendritic spines stronger, specifically by acting through actin network proteins, scaffolding proteins and inhibition of phosphatases are described next. Importantly, the therapeutic strategies presented in this review tackle Alzheimer's disease not by targeting plaques and tangles, but instead by making synapses resilient to the pathology associated with Alzheimer's disease, which has tremendous potential.

HCMV UL8 interaction with ß-catenin and DVL2 regulates viral reactivation in CD34+ hematopoietic progenitor cells.

IMPORTANCE: CD34+ hematopoietic progenitor cells (HPCs) are an important cellular reservoir for latent human cytomegalovirus (HCMV). Several HCMV genes are expressed during latency that are involved with the maintenance of the viral genome in CD34+ HPC. However, little is known about the process of viral reactivation in these cells. Here, we describe a viral protein, pUL8, and its interaction and stabilization with members of the Wnt/ß-catenin pathway as an important component of viral reactivation. We further define that pUL8 and ß-catenin interact with DVL2 via a PDZ-binding domain, and loss of UL8 interaction with ß-catenin-DVL2 restricts viral reactivation. Our findings will be instrumental in understanding the molecular processes involved in HCMV reactivation in order to design new antiviral therapeutics.

Endothelial Glycocalyx Degradation Patterns in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome: A Single Center Retrospective Observational Study.

BACKGROUND: Sepsis-associated destruction of the pulmonary microvascular endothelial glycocalyx (EGCX) creates a vulnerable endothelial surface, contributing to the development of acute respiratory distress syndrome (ARDS). Constituents of the EGCX shed into circulation, glycosaminoglycans and proteoglycans, may serve as biomarkers of endothelial dysfunction. We sought to define the patterns of plasma EGCX degradation products in children with sepsis-associated pediatric ARDS (PARDS), and test their association with clinical outcomes. METHODS: We retrospectively analyzed a prospective cohort (2018-2020) of children (≥1 month to <18 years of age) receiving invasive mechanical ventilation for acute respiratory failure for ≥72 h. Children with and without sepsis-associated PARDS were selected from the parent cohort and compared. Blood was collected at time of enrollment. Plasma glycosaminoglycan disaccharide class (heparan sulfate, chondroitin sulfate, and hyaluronan) and sulfation subtypes (heparan sulfate and chondroitin sulfate) were quantified using liquid chromatography tandem mass spectrometry. Plasma proteoglycans (syndecan-1) were measured through an immunoassay. RESULTS: Among the 39 mechanically ventilated children (29 with and 10 without sepsis-associated PARDS), sepsis-associated PARDS patients demonstrated higher levels of heparan sulfate (median 639 ng/mL [interquartile range, IQR 421-902] vs 311 [IQR 228-461]) and syndecan-1 (median 146 ng/mL [IQR 32-315] vs 8 [IQR 8-50]), both p = 0.01. Heparan sulfate subtype analysis demonstrated greater proportions of N-sulfated disaccharide levels among children with sepsis-associated PARDS (p = 0.01). Increasing N-sulfated disaccharide levels by quartile were associated with severe PARDS (n = 9/29) with the highest quartile including >60% of the severe PARDS patients (test for trend, p = 0.04). Higher total heparan sulfate and N-sulfated disaccharide levels were independently associated with fewer 28-day ventilator-free days in children with sepsis-associated PARDS (all p < 0.05). CONCLUSIONS: Children with sepsis-associated PARDS exhibited higher plasma levels of heparan sulfate disaccharides and syndecan-1, suggesting that EGCX degradation biomarkers may provide insights into endothelial dysfunction and PARDS pathobiology.

Human cytomegalovirus blocks canonical TGFß signaling during lytic infection to limit induction of type I interferons.

Human cytomegalovirus (HCMV) microRNAs (miRNAs) significantly rewire host signaling pathways to support the viral lifecycle and regulate host cell responses. Here we show that SMAD3 expression is regulated by HCMV miR-UL22A and contributes to the IRF7-mediated induction of type I IFNs and IFN-stimulated genes (ISGs) in human fibroblasts. Addition of exogenous TGFß interferes with the replication of a miR-UL22A mutant virus in a SMAD3-dependent manner in wild type fibroblasts, but not in cells lacking IRF7, indicating that downregulation of SMAD3 expression to limit IFN induction is important for efficient lytic replication. These findings uncover a novel interplay between SMAD3 and innate immunity during HCMV infection and highlight the role of viral miRNAs in modulating these responses.

Cefepime-induced neurotoxicity: systematic review.

BACKGROUND: Cefepime-induced neurotoxicity (CIN) has been well acknowledged among clinicians, although there are no clear diagnostic criteria or specific laboratory testing to help with its diagnosis. We aimed to summarize the existing evidence regarding CIN and provide future agendas for research. METHODS: Following the PRISMA Extension for Scoping Reviews, we searched MEDLINE and Embase for all peer-reviewed articles using keywords including 'cefepime', 'neurotoxicity', 'encephalopathy' and 'seizure', from their inception to 20 January 2022. RESULTS: We included 92 articles, including 23 observational studies and 69 cases from case reports and case series, in the systematic review. Among 119 patients with CIN, 23.5% were in the ICU at the time of diagnosis and nearly 90% of the cases showed renal dysfunction.Cefepime overdoses were described in 41%. The median latency period of developing CIN from cefepime initiation was 4 days, and about 12% developed CIN during empirical treatment. CIN patients commonly manifested altered mental status (93%), myoclonus (37%) and non-convulsive seizure epilepticus (28%). A serum cefepime trough level of >20 mg/L would put patients at risk for CIN. CIN-related symptoms were ameliorated in 97.5% by dose reduction or discontinuation of cefepime, with median time to improvement of 3 days. No CIN-associated deaths were reported. CONCLUSIONS: This systematic review summarizes the current evidence and characteristics of CIN. In the current situation where there are no CIN diagnostic criteria and the drug monitoring platform is not routinely available, candidates for cefepime should be carefully selected. Also, based on these findings, it needs to be appropriately dosed to avoid the development of CIN.

Machine learning for prediction of bronchopulmonary dysplasia-free survival among very preterm infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is one of the most common and serious sequelae of prematurity. Prompt diagnosis using prediction tools is crucial for early intervention and prevention of further adverse effects. This study aims to develop a BPD-free survival prediction tool based on the concept of the developmental origin of BPD with machine learning. METHODS: Datasets comprising perinatal factors and early postnatal respiratory support were used for initial model development, followed by combining the two models into a final ensemble model using logistic regression. Simulation of clinical scenarios was performed. RESULTS: Data from 689 infants were included in the study. We randomly selected data from 80% of infants for model development and used the remaining 20% for validation. The performance of the final model was assessed by receiver operating characteristics which showed 0.921 (95% CI: 0.899-0.943) and 0.899 (95% CI: 0.848-0.949) for the training and the validation datasets, respectively. Simulation data suggests that extubating to CPAP is superior to NIPPV in BPD-free survival. Additionally, successful extubation may be defined as no reintubation for 9 days following initial extubation. CONCLUSIONS: Machine learning-based BPD prediction based on perinatal features and respiratory data may have clinical applicability to promote early targeted intervention in high-risk infants.

Novel Pharmacological Nonopioid Therapies in Chronic Pain.

PURPOSE OF REVIEW: Opioid use and abuse has led to a worldwide opioid epidemic. And while opioids are clinically useful when appropriately indicated, they are associated with a wide range of dangerous side effects and whether they are effective at treating or eliminating chronic pain is controversial. There has long been a need for the development of nonopioid alternative treatments for patients that live in pain, and until recently, only a few effective treatments were available. Today, there are a wide range of nonopioid treatments available including NSAIDs, acetaminophen, corticosteroids, nerve blocks, SSRIs, neurostimulators, and anticonvulsants. However, these treatments are still not entirely effective at treating pain, which has sparked a new exploration of novel nonopioid pharmacotherapies. RECENT FINDINGS: This manuscript will outline the most recent trends in novel nonopioid pharmacotherapy development including tramadol/dexketoprofen, TrkA inhibitors, tapentadol, opioid agonists, Nektar 181, TRV 130, ßarrestin2, bisphosphonates, antibodies, sodium channel blockers, NMDA antagonists, TRP receptors, transdermal vitamin D, AAK1 kinase inhibition, calcitonin gene-related peptide (CGRP), TRPV4 antagonists, cholecystokinin, delta opioid receptor, neurokinin, and gene therapy. The pharmacotherapies discussed in this manuscript outline promising opioid alternatives which can change the future of chronic pain treatment.

Discharge materials provided to patients with kidney stones in the emergency department may be a source of misinformation.

INTRODUCTION: Renal colic is commonly seen in the emergency department (ED), where the focus is on diagnosis and symptom control. Educational materials are sometimes provided upon discharge, however, no standard content has been established. We characterized the educational materials given to patients reporting to EDs in different regions across the U.S. for symptomatic kidney stones, specifically evaluating disease-specific information, symptom management, prevention strategies including dietary recommendations (DRs), and patient follow up plans. MATERIALS AND METHODS: Generic discharge instructions for patients presenting to EDs with renal colic were obtained from community hospitals and academic medical centers between October 2016 and November 2017. Hospitals were called directly. If the same discharge instructions were used by more than one hospital, each was included in our analysis. We assessed the different types of information provided with a focus on stone prevention and DRs by characterizing them into specific nutritional categories. RESULTS: Of 266 hospitals contacted, 79 provided discharge instructions. Of these, 51 (65%) provided some information on diet. While most recommended higher fluid intake, almost 40% endorsed unnecessary fluid restrictions. Recommendations to reduce protein and oxalate intake were common, but erroneous information for both was given. Nearly 1 in 5 EDs recommended lower calcium intake. Less than 30% of EDs mentioned that stones can have different composition or causes. Less than 30% referenced consultation with a registered dietitian nutritionist (RDN) or that dietary approaches to stone prevention are optimally individualized. Only 9 summaries recommended urologic follow up. CONCLUSIONS: Many ED discharge materials contain DRs for stone prevention. These recommendations can be inaccurate and/or inappropriate. Advice on diet and stone prevention is more appropriately addressed in the outpatient setting when more data (stone composition, serum and urine parameters) and expert consultants are available.

Capillary Flow Resistors: Local and Global Resistors.

The use of capillary systems in space and biotechnology applications requires the regulation of the capillary flow velocity. It has been observed that constricted sections act as flow resistors. In this work, we also show that enlarged sections temporarily reduce the velocity of the flow. In this work, the theory of the dynamics of capillary flows passing through a constricted or an enlarged channel section is presented. It is demonstrated that the physics of a capillary flow in a channel with a constriction or an enlargement is different and that a constriction acts as a global flow resistor and an enlargement as a local flow resistor. The theoretical results are checked against experimental approaches.

Same sibling marrow following cord allogeneic transplantation as therapy for second relapse acute promyelocytic leukemia in a pediatric patient.

Optimal therapy for relapsed APL in pediatric patients is controversial. Allogeneic HSCT is an alternative, with event-free survival of 70-75%. We report a pediatric patient with APL who relapsed 28 months after CBT from her sibling and then was treated with BMT from the same donor. Bone marrow was selected for higher cell dose, donor availability, and partial donor chimerism. Persistent molecular remission was achieved, currently at 65 months after BMT. This case suggests the potential role of GVL activity in APL and illustrates the use of different cell sources from the same donor in allogeneic transplantation for pediatric patients.

Secondary organic aerosol from aqueous reactions of green leaf volatiles with organic triplet excited states and singlet molecular oxygen.

Vegetation emits a class of oxygenated hydrocarbons--the green leaf volatiles (GLVs)--under stress or damage. Under foggy conditions GLVs might be a source of secondary organic aerosol (SOA) via aqueous reactions with hydroxyl radical (OH), singlet oxygen ((1)O2*), and excited triplet states ((3)C*). To examine this, we determined the aqueous kinetics and SOA mass yields for reactions of (3)C* and (1)O2* with five GLVs: methyl jasmonate (MeJa), methyl salicylate (MeSa), cis-3-hexenyl acetate (HxAc), cis-3-hexen-1-ol (HxO), and 2-methyl-3-butene-2-ol (MBO). Second-order rate constants with (3)C* and (1)O2* range from (0.13-22) × 10(8) M(-1) s(-1) and (8.2-60) × 10(5) M(-1) s(-1) at 298 K, respectively. Rate constants with (3)C* are independent of temperature, while values with (1)O2* show significant temperature dependence (Ea = 20-96 kJ mol(-1)). Aqueous SOA mass yields for oxidation by (3)C* are (84 ± 7)%, (80 ± 9)%, and (38 ± 18)%, for MeJa, MeSa, and HxAc, respectively; we did not measure yields for other conditions because of slow kinetics. The aqueous production of SOA from GLVs is dominated by (3)C* and OH reactions, which form low volatility products at a rate that is approximately half that from the parallel gas-phase reactions of GLVs.

Structural Insight into Geranylgeranyl Diphosphate Synthase (GGDPS) for Cancer Therapy.

Geranylgeranyl diphosphate synthase (GGDPS), the source of the isoprenoid donor in protein geranylgeranylation reactions, has become an attractive target for anticancer therapy due to the reliance of cancers on geranylgeranylated proteins. Current GGDPS inhibitor development focuses on optimizing the drug-target enzyme interactions of nitrogen-containing bisphosphonate-based drugs. To advance GGDPS inhibitor development, understanding the enzyme structure, active site, and ligand/product interactions is essential. Here we provide a comprehensive structure-focused review of GGDPS. We reviewed available yeast and human GGDPS structures and then used AlphaFold modeling to complete unsolved structural aspects of these models. We delineate the elements of higher-order structure formation, product-substrate binding, the electrostatic surface, and small-molecule inhibitor binding. With the rise of structure-based drug design, the information provided here will serve as a valuable tool for rationally optimizing inhibitor selectivity and effectiveness.

Progressive Encephalopathy With New Pulmonary Opacities in an Immunocompromised Host.

A 48-year-old man with history of recent travel to central Mexico and immunosuppression sought treatment with a 1-month-long history of progressive headache, fatigue, word-finding difficulties, and night sweats. The patient had a history of end-stage renal disease; he had undergone a kidney transplantation 7 years prior with good graft function with immunosuppression with tacrolimus, everolimus, and low-dose prednisone. At an outside hospital, he recently had been treated with empiric antibiotics for meningitis, but these were discontinued given the low suspicion for a bacterial cause. After discharge, he continued to have headaches, limited oral intake, persistent nausea, urinary frequency, and falls, prompting him to seek treatment at the ED. Physical examination findings were benign aside from disorientation. Laboratory workup was significant for hyponatremia of 122 mM, creatinine of 1.4 mg/dL (baseline, 1.4-1.5 mg/dL), WBC count of 7.2 109/L, hemoglobin of 13 g/dL, and platelet count of 349 109/L. Neither tacrolimus nor everolimus levels were supratherapeutic.

The risk of new heart failure associated with protease inhibitor: Systematic scoping review.

BACKGROUND: Protease inhibitors (PIs) have contributed to the long-term survival of persons with human immunodeficiency virus (PHIV). While there is a concern linking protease inhibitors to an increased risk of heart failure (HF), the evidence linking protease inhibitors and heart failure has been uncertain. METHODS: Following the PRISMA Extension for Scoping Reviews, we searched MEDLINE and EMBASE for peer-reviewed articles using keywords including "protease inhibitor," "heart failure," and "human immunodeficiency virus" from their inception to December 21, 2022. RESULTS: Five articles, including three observational studies and two randomized controlled trials, were included in the review. While protease inhibitors seem to be associated with atherosclerotic cardiovascular disease through their effects on metabolic markers, there is scarce evidence suggesting a direct association between protease inhibitors and heart failure. Although one study showed a possible correlation between protease inhibitor use and lower left ventricular ejection fraction and increased heart failure admission, the results were subject to confounders, and participants had poor medication adherence. CONCLUSION: Although current data are conflicting, there could be an association between PIs and HF in PHIV. Future prospective studies are warranted to evaluate the incidence of heart failure stratified on the generation of PIs and with adjustment for other metabolic risk factors.

Hamartoma of mature cardiac myocytes: systematic review.

BACKGROUND: While primary cardiac tumors are rare, it has been increasingly recognized due to improvement in screening measures. However, the hamartoma of mature cardiac myocytes has been underrecognized compared to other cardiac tumors, such as cardiac myxomas and papillary fibroelastomas, and is still potentially associated with critical consequences such as sudden death. This systematic review aims to summarize the evidence regarding the hamartoma of mature cardiac myocytes and characterize the presentations and symptoms for clinicians. METHODS: Following the PRISMA statement, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including "hamartoma of mature cardiac myocytes" from their inception to January 2, 2023. RESULTS: We included 25 articles, including 34 cases, in this systematic review. Patients with hamartoma of mature cardiac myocytes commonly presented with nonspecific symptoms such as dyspnea (35.3%), although a few presented with sudden death and syncope. The left ventricle was the common site of origin (41.2%), followed by the right atrium and ventricle. Surgery was commonly pursued for diagnosis and treatment, while a few required cardiac transplants (8.8%), and 29.4% were diagnosed with autopsy or expired. CONCLUSION: Hamartoma of mature cardiac myocytes is a potentially underrecognized primary cardiac tumor associated with treatable yet potentially critical consequences. Given the challenges of differentiating it from malignancy such as angiosarcoma, multimodal imaging needs to be utilized to pursue a diagnosis. Future studies are warranted to develop a noninvasive diagnosis mode for cardiac tumor.

Environmental life cycle impacts of small wastewater treatment plants: Design recommendations for impact mitigation.

The objective of this study was to quantify potential mitigation of environmental impacts from the operation and construction of wastewater treatment plants (WWTP) from implementing specific design recommendations. The study investigated small WWTPs, many of which are serving slow growing or declining populations. Life Cycle Assessment methodology was used to evaluate and compare the inventory and environmental impacts of nine small WWTP case studies. Detailed inventory data was collected from the facilities' engineering design plans and utility bills. One recommended practice was to avoid significant overdesign by planning for no lower than a 75% capacity utilization by the facilities' end-of-life. A theoretical correction to a 75% capacity utilization was estimated to mitigate 0.4% of lifetime electricity usage and 1% of secondary process concrete for every 1% reduction in design average flow rate. Relatedly, a 0.4% mitigation in the Carcinogenic and Global Warming impacts could be achieved for every 1% reduction in design average flow toward a 75% capacity utilization. Other suggested practices were focused on conveyance, namely, to minimize non-process facility area and to use polyvinyl chloride pipe instead of ductile iron pipe where possible. The latter practice was estimated to mitigate between 1.1 and 4.8% of the Carcinogenic impact in the nine case studies.

Optogenetic Manipulations of Amygdala Neurons Modulate Spinal Nociceptive Processing and Behavior Under Normal Conditions and in an Arthritis Pain Model.

The amygdala is an important neural substrate for the emotional-affective dimension of pain and modulation of pain. The central nucleus (CeA) serves major amygdala output functions and receives nociceptive and affected-related information from the spino-parabrachial and lateral-basolateral amygdala (LA-BLA) networks. The CeA is a major site of extra-hypothalamic expression of corticotropin releasing factor (CRF, also known as corticotropin releasing hormone, CRH), and amygdala CRF neurons form widespread projections to target regions involved in behavioral and descending pain modulation. Here we explored the effects of modulating amygdala neurons on nociceptive processing in the spinal cord and on pain-like behaviors, using optogenetic activation or silencing of BLA to CeA projections and CeA-CRF neurons under normal conditions and in an acute pain model. Extracellular single unit recordings were made from spinal dorsal horn wide dynamic range (WDR) neurons, which respond more strongly to noxious than innocuous mechanical stimuli, in normal and arthritic adult rats (5-6 h postinduction of a kaolin/carrageenan-monoarthritis in the left knee). For optogenetic activation or silencing of CRF neurons, a Cre-inducible viral vector (DIO-AAV) encoding channelrhodopsin 2 (ChR2) or enhanced Natronomonas pharaonis halorhodopsin (eNpHR3.0) was injected stereotaxically into the right CeA of transgenic Crh-Cre rats. For optogenetic activation or silencing of BLA axon terminals in the CeA, a viral vector (AAV) encoding ChR2 or eNpHR3.0 under the control of the CaMKII promoter was injected stereotaxically into the right BLA of Sprague-Dawley rats. For wireless optical stimulation of ChR2 or eNpHR3.0 expressing CeA-CRF neurons or BLA-CeA axon terminals, an LED optic fiber was stereotaxically implanted into the right CeA. Optical activation of CeA-CRF neurons or of BLA axon terminals in the CeA increased the evoked responses of spinal WDR neurons and induced pain-like behaviors (hypersensitivity and vocalizations) under normal condition. Conversely, optical silencing of CeA-CRF neurons or of BLA axon terminals in the CeA decreased the evoked responses of spinal WDR neurons and vocalizations, but not hypersensitivity, in the arthritis pain model. These findings suggest that the amygdala can drive the activity of spinal cord neurons and pain-like behaviors under normal conditions and in a pain model.

A Systematic Review of the Potential Implication of Infectious Agents in Myasthenia Gravis.

Background: Myasthenia gravis (MG) is an autoimmune disorder of unknown etiology in most patients, in which autoantibodies target components of neuromuscular junctions and impair nerve to muscle transmission. Objective: To provide a synthesis of the evidence examining infectious agents associated with the onset of MG. Hypothesis: We hypothesized that microbes play a pathogenic role in the initiation of MG. For clinical cases, the onset of clinical signs is used as a proxy for the true onset of autoimmunity. Methods: We searched PubMed and Web of Science. Papers captured through database searching (n = 827) were assessed, yielding a total of 42 publications meeting the inclusion and exclusion criteria. An additional 6 papers were retrieved from the reference lists of relevant articles. For each pathogen, an integrated metric of evidence (IME) value, from minus 8 to plus 8, was computed based on study design, quality of data, confidence of infectious disease diagnosis, likelihood of a causal link between the pathogen and MG, confidence of MG diagnosis, and the number of infected patients. Negative IME values corresponded to studies providing evidence against a role for microbes as triggers of MG. Results: One hundred and sixty-nine myasthenic patients infected with 21 different pathogens were documented. Epstein-Barr virus (median = 4.71), human papillomavirus (median = 4.35), and poliovirus (median = 4.29) demonstrated the highest IME values. The total median IME was 2.63 (mean = 2.53; range -3.79-5.25), suggesting a general lack of evidence for a causal link. Conclusions: There was a notable absence of mechanistic studies designed to answer this question directly. The question of the pathogenic contribution of microbes to MG remains open.