Respiratory Interventions, Hospital Utilization, and Clinical Outcomes of Persons with COPD and COVID-19.

Purpose: Coronavirus disease 2019 (COVID-19) impacted outcomes of persons with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). This study investigated the differences in respiratory interventions, hospital utilization, smoking status, and 30-day readmission in those with COPD and COVID-19 based on hospital survival status. Methods: A retrospective cross-sectional study was conducted from February 2020 to October 2020 and included persons with COPD and COVID-19 infection. We examined respiratory interventions, hospital utilization and outcomes, and 30-day hospital readmission. Chi-square test analysis was used to assess categorical variables, and t-test or Mann-Whitney was used to analyze continuous data based on normality. Results: Ninety persons were included in the study, 78 (87%) were survivors. The most common comorbidity was hypertension 71 (78.9%) (p = 0.003). Twenty-two (24%) persons were intubated, from whom 12 (15%) survived (p < 0.001). There were 25 (32.1%) and 12 (100%), (p < 0.001) persons who required an ICU admission from the survivor and non-survivor groups, respectively. Among the survivor group, fifteen (19%) persons required 30-day hospital readmission. Conclusion: Persons with COPD and COVID-19 had a lower mortality rate (13%) compared to other studies in the early pandemic phase. Non-survivors had increased ICU utilization, endotracheal intubation, and more frequent application of volume control mode. Discharging survivors to long-term acute care facilities may reduce 30-day hospital readmissions.

Hippocampal neurobiology and function in an aged mouse model of TDP-43 proteinopathy in an APP/PSEN1 background.

Aging is a major risk factor for Alzheimer's disease (AD), the most common cause of dementia worldwide. TDP-43 proteinopathy is reported to be associated with AD pathology is almost 50% of cases. Our exploratory study examined near end-stage (28 months old) mice selectively driving expression of human TDP-43 in the hippocampus and cortex in an APP/PSEN1 background. We hypothesized that hippocampal neuropathology caused by ß-amyloidosis with TDP-43 proteinopathy induced in this model, resembling the pathology seen in AD cases, manifest with changes in resting state functional connectivity. In vivo magnetic resonance imaging and post-mortem histology were performed on four genotypes: wild type, APP/PSEN1, Camk2a/TDP-43, and Camk2a/TDP-43/APP/PSEN1. Our results revealed loss of functional coupling in hippocampus and amygdala that was associated with severe neuronal loss in dentate gyrus of Camk2a/TDP-43/APP/PSEN1 mice compared to APP/PSEN1 and wild type mice. The loss of cells was accompanied by high background of ß-amyloid plaques with sparse phosphorylated TDP-43 pathology. The survival rate was also reduced in Camk2a/TDP-43/APP/PSEN1 mice compared to other groups. This end-of-life study provides exploratory data to reach a better understanding of the role of TDP-43 hippocampal neuropathology in diseases with co-pathologies of TDP-43 proteinopathy and ß-amyloidosis such as AD and limbic predominant age-related TDP-43 encephalopathy (LATE).

Antimicrobial stewardship through telemedicine and its impact on multi-drug resistance.

INTRODUCTION: Telemedicine technologies are increasingly being incorporated into infectious disease practice. We aimed to demonstrate the impact of antimicrobial stewardship through telemedicine on bacterial resistance rates. METHODS: We conducted a quasi-experimental study in a 220-bed hospital in southern Brazil. An antimicrobial stewardship program incorporating the use of telemedicine was implemented. Resistance and antimicrobial consumption rates were determined and analysed using a segmented regression model. RESULTS: After the intervention, the rate of appropriate antimicrobial prescription increased from 51.4% at baseline to 81.4%. Significant reductions in the consumption of fluoroquinolones (level change, ß = -0.80; P < 0.01; trend change, ß = -0.01; P = 0.98), first-generation cephalosporins (level change, ß = -0.91; P < 0.01; trend change, ß = +0.01; P = 0.96), vancomycin (level change, ß = -0.47; P = 0.04; trend change, ß = +0.17; P = 0.66) and polymyxins (level change, ß = -0.15; P = 0.56; trend change, ß = -1.75; P < 0.01) were identified. There was an increase in the consumption of amoxicillin + clavulanate (level change, ß = +0.84; P < 0.01; trend change, ß = +0.14; P = 0.41) and cefuroxime (level change, ß = +0.21; P = 0.17; trend change, ß = +0.66; P = 0.02). A significant decrease in the rate of carbapenem-resistant Acinetobacter spp. isolation (level change, ß = +0.66; P = 0.01; trend change, ß = -1.26; P < 0.01) was observed. CONCLUSIONS: Telemedicine, which provides a tool for decision support and immediate access to experienced specialists, can promote better antibiotic selection and reductions in bacterial resistance.

TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics.

Transactive response DNA-binding protein of 43 kDa (TDP-43) functions as a heterogeneous nuclear ribonucleoprotein and is the major pathological protein in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). TDP-43 pathology may also be present as a comorbidity in approximately 20-50% of sporadic Alzheimer's disease cases. In a mouse model of MND, full-length TDP-43 increases association with the mitochondria and blocking the TDP-43/mitochondria interaction ameliorates motor dysfunction. Utilizing a proteomics screen, several mitochondrial TDP-43-interacting partners were identified, including voltage-gated anion channel 1 (VDAC1) and prohibitin 2 (PHB2), a crucial mitophagy receptor. Overexpression of TDP-43 led to an increase in PHB2 whereas TDP-43 knockdown reduced PHB2 expression in cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP), an inducer of mitophagy. These results suggest that TDP-43 expression contributes to metabolism and mitochondrial function however we show no change in bioenergetics when TDP-43 is overexpressed and knocked down in HEK293T cells. Furthermore, the fusion protein mitofusin 2 (MFN2) interacts in complex with TDP-43 and selective expression of human TDP-43 in the hippocampus and cortex induced an age-dependent change in Mfn2 expression. Mitochondria morphology is altered in 9-month-old mice selectively expressing TDP-43 in an APP/PS1 background compared with APP/PS1 littermates. We further confirmed TDP-43 localization to the mitochondria using immunogold labeled TDP-43 transmission electron microscopy (TEM) and mitochondrial isolation methods There was no increase in full-length TDP-43 localized to the mitochondria in APP/PS1 mice compared to wild-type (littermates); however, using C- and N-terminal-specific TDP-43 antibodies, the N-terminal (27 kDa, N27) and C-terminal (30 kDa, C30) fragments of TDP-43 are greatly enriched in mitochondrial fractions. In addition, when the mitochondrial peptidase (PMPCA) is overexpressed there is an increase in the N-terminal fragment (N27). These results suggest that TDP-43 processing may contribute to metabolism and mitochondrial function.

TDP-43 expression influences amyloidß plaque deposition and tau aggregation.

Although the main focus in Alzheimer's disease (AD) has been an investigation of mechanisms causing Aß plaque deposition and tau tangle formation, recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic cases. Furthermore, elevated phosphorylated TDP-43 has been associated with more severe AD pathology. Therefore, we hypothesized that TDP-43 may regulate amyloid-beta precursor protein (APP) trafficking and tau phosphorylation/aggregation. In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1ΔE9). In our model, increased TDP-43 was related to increased tau aggregation as evidenced by thioflavin S-positive phosphorylated tau, which may implicate TDP-43 expression in pre-tangle formation. In addition, there was increased endosomal/lysosomal localization of APP and reduced Aß plaque formation with increased TDP-43. Furthermore, there was decreased calcineurin with elevated TDP-43 expression. Since calcineurin is a phosphatase for TDP-43, the decreased calcineurin expression may be one mechanism leading to an increase in accumulation of diffuse phosphorylated TDP-43 in the hippocampus and cortex. We further show that when TDP-43 is knocked down there is an increase in calcineurin. In our model of selective TDP-43 overexpression in an APP/PSEN1 background, we show that TDP-43 decreases Aß plaque deposition while increasing abnormal tau aggregation. These observations indicate that TDP-43 may play a role in regulating APP trafficking and tau aggregation. Our data suggest that TDP-43 could be a putative target for therapeutic intervention in AD affecting both Aß plaque formation and tauopathy.

Opioid-like compound exerts anti-fibrotic activity via decreased hepatic stellate cell activation and inflammation.

Hepatic fibrosis is characterized by excess type I collagen deposition and exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic animal models, which can be accompanied by deleterious side effects. Additionally, opioid neurotransmission is upregulated in patients with inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal) and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does not show significant opioid receptor antagonism. To delineate the potential hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal could modulate activation of hepatic stellate cells (HSCs), primary effector cells that secrete type I collagen and inflammatory mediators during liver injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth muscle α-actin, a marker of HSC activation, mRNA and protein expression. Despite decreased collagen mRNA expression, both compounds increased intracellular collagen protein expression; however, inhibition of collagen secretion was observed. To address a possible mechanism for suppressed collagen secretion or retention of intracellular collagen, endoplasmic (ER) protein expression and matrix metalloproteinase (MMP) activity were examined. While no change in ER protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was dramatically increased. In an acute LPS inflammatory injury animal model, JKB-119 treatment decreased liver injury (ALT), plasma TNFα and PMN liver infiltration. Overall, these results suggest that JKB-119 can directly inhibit HSC activation attributed to anti-inflammatory activity and may, therefore, attenuate inflammation associated with HSC activation and liver disease.

Influence of beta-Endorphin on anxious behavior in mice: interaction with EtOH.

RATIONALE: The opioid peptide beta-endorphin (beta-E) is synthesized by the pro-opiomelanocortin gene in response to environmental stressors and alcohol administration and is implicated in the behavioral sequelae associated with these stimuli. OBJECTIVES: We sought to determine the influence of beta-E on the stress response by evaluating basal measures of anxiety as well as on EtOH-induced anxiolytic behavior using transgenic mice that differ with respect to beta-E. METHODS: Anxious behavior was evaluated for male and female heterozygous, wild-type, and beta-E knockout mice using the Light-Dark Box and Plus Maze assays. Subsequent tests evaluated behavior 20 min after administration of intraperitoneal saline or EtOH (0.5, 1.0, and 1.5 g/kg). RESULTS: We observed a direct relationship between beta-E levels and the percentage of entries into open arms of the Plus Maze as well as the time spent in either the open arms or the light compartment of the Light-Dark box during basal conditions, suggesting that this peptide normally inhibits anxious behavior. However, mice lacking beta-E demonstrated an exaggerated anxiolytic response to EtOH in these assays. CONCLUSIONS: These data suggest that beta-E moderates the response to stressful stimuli and supports the hypothesis that this peptide influences the behavioral effects of EtOH.

Optimal stoichiometric designs of ATP-producing systems as determined by an evolutionary algorithm.

The design of metabolic pathways is thought to be the result of an optimization process such that the structure of contemporary metabolic routes maximizes a particular objective function. Recently, it has been shown that some essential stoichiometric properties of glycolysis can be explained on the basis of the requirement for a high ATP production rate. Because the number of stoichiometrically feasible designs increases strongly with the number of reactions involved, a systematic analysis of all the possibilities turns out to be inaccessible beyond a certain system size. We present, therefore, an alternative approach to compute in a more efficient way the optimal design of glycolysis interacting with an external ATP-consuming reaction. The algorithm is based on the laws of evolution by natural selection, and may be viewed as a particular version of evolutionary algorithms. The following conclusions are derived: (a) evolutionary algorithms are very useful search strategies in determining optimal stoichiometries of metabolic pathways. (b) Essential topological features of the glycolytic network may be explained on the basis of flux optimization. (c) There is a strong interrelation between the optimal stoichiometries and the thermodynamic and kinetic properties of the participating reactions. (d) Some subsequences of reactions in optimal pathways are strongly conserved at variation of system parameters, which may be understood by applying principles of metabolic control analysis.

Kinetic and thermodynamic principles determining the structural design of ATP-producing systems.

It is theoretically analysed whether the structural design of ATP-producing pathways, in particular the design of glycolysis, may be explained by optimization principles. On the basis of kinetic and thermodynamic principles conclusions are derived concerning the stoichiometry of these pathways in states of high ATP production rates. One of the extensions to previous investigations is that the concentrations of the adenine nucleotides are taken into account as variable quantities. This necessitates the consideration of an interaction of the ATP-producing system I with an external ATP-consuming system II. A great variety of pathways is studied which differ in the number and location of ATP-consuming reactions, ATP-producing reactions and reactions involving inorganic phosphate. The corresponding number of possible pathways may be calculated in an explicit manner as a function of the number of those reactions which do not couple to ATP or inorganic phosphate. The kinetics of the individual reactions are described by linear or bilinear functions of reactant concentrations and all rate equations are expressed in terms of equilibrium constants and characteristic times. A thermo-dynamical analysis of the two coupled systems yields upper and lower limits for the concentration of ATP and an explicit expression for the maximal difference between the number of ATP-producing and ATP-consuming reactions of system I. The following results of the optimization are obtained. (i) The ATP production rate always increases if the ATP-producing reactions as well as those reactions characterized by an uptake of inorganic phosphate are shifted as far as possible towards the end of system I. (ii) Explicit conditions for the optimal location of the ATP-consuming reactions are presented. The results are discussed in the context of characteristic times as well as in terms of enzyme kinetic parameters. (iii) For two sets of characteristic times the resulting stoichiometries and their corresponding steady-state fluxes are investigated in detail. One of these stoichiometries shows a close correspondence to contemporary standard glycolysis. (iv) It is shown that most possible pathways result in a very low steady-state flux, that is, the optimal stoichiometry is characterized by a significant selective advantage. (v) The standard free energy profile of a pathway with an optimal stoichiometry is discussed. It differs significantly from the free energy profiles of nonoptimized pathways.

Eversion of the tunica vaginalis for prophylaxis of testicular torsion recurrences.

After direct orchiopexy with punctiform suture fixation for prophylaxis of testicular torsion recurrence, at worst recurrent torsion may result in complete loss of the testis. Clinical and animal experience makes it appear more effective and reliable to prevent recurrent testicular torsion by eversion of the tunica vaginalis with extensive superficial adherence of the testicular integuments. We present the early and late results in 35 patients who underwent 46 eversion orchiopexies with a primary and definitive salvage rate of 87.5% and no case of recurrent testicular torsion.

Intracavity absorption spectroscopy with a Nd(3+)-doped fiber laser.

A broadband Nd(3+)-doped fiber laser has been operated in an external cavity by pumping with an Ar(+)-ion laser. The emission spectrum of the fiber laser shows high sensitivity to intracavity absorption. The equivalent absorber path length is 15 km; with a loss-reduced setup that includes pumping by a diode laser this path length is 150 km. The spectrum of atmospheric absorption in the range from 1.065 to 1.145 microm has been recorded by stepwise tuning of the 0.3-nm-wide laser emission band by an intracavity prism.