Miracle-dz/UniFAR-FTUs huggingface dataset:
How can multidisciplinary management with remote monitoring improve the outcome of patients with chronic cardiac diseases?

The greatest challenge that we face over the next 20 years is the management of chronic diseases in an aging population. Despite new and more effective pharmacological and nonpharmacological treatments, chronic diseases are a major public health problem in Western industrialized countries, prognosis remains poor and hospitalizations are the major component of healthcare costs. Although the clinical guidelines suggest a combined strategy of using evidence-based drugs and lifestyle modification for secondary prevention of chronic coronary syndrome (CCS) [1] the implementation of these recommendations remains suboptimal. The benefit of exercise training, life style modification, medication adherence, and education are well documented in the literature [2], but it is very difficult to reach their implementation in the life of chronic cardiac patients. Furthermore, aging and presence of multiple comorbidities in these patients limit the achievement of a physical and psychological recovery in the shortened period of the acute care hospitalization. A recent review compared the effectiveness of transitional care services in chronic cardiac patients discharged from the hospital and highlighted that the use of multiple tools improves the patient outcome and adherence [3]. The majority of cardiac patients cannot solve their problems during the brief period (6–8 days) of hospitalization in an acute setting and then to overcome the ‘transitional period’ should undertake a cardiac rehabilitation program [4]. In fact, all chronic patients have complex individual needs, present a progressive decline of their functions and have frequent episodes of serious instabilizations. Moreover, in these patients, there is a vicious circle of inactivity, with reduced effort tolerance and a high risk of depression.
A highly contiguous genome assembly of the bat hawkmoth Hyles vespertilio (Lepidoptera: Sphingidae)

Abstract Background Adapted to different ecological niches, moth species belonging to the Hyles genus exhibit a spectacular diversity of larval color patterns. These species diverged ∼7.5 million years ago, making this rather young genus an interesting system to study a wide range of questions including the process of speciation, ecological adaptation, and adaptive radiation. Results Here we present a high-quality genome assembly of the bat hawkmoth Hyles vespertilio, the first reference genome of a member of the Hyles genus. We generated 51× Pacific Biosciences long reads with an average read length of 8.9 kb. Pacific Biosciences reads longer than 4 kb were assembled into contigs, resulting in a 651.4-Mb assembly consisting of 530 contigs with an N50 value of 7.5 Mb. The circular mitochondrial contig has a length of 15,303 bp. The H. vespertilio genome is very repeat-rich and exhibits a higher repeat content (50.3%) than other Bombycoidea species such as Bombyx mori (45.7%) and Manduca sexta (27.5%). We developed a comprehensive gene annotation workflow to obtain consensus gene models from different evidence including gene projections, protein homology, transcriptome data, and ab initio predictions. The resulting gene annotation is highly complete with 94.5% of BUSCO genes being completely present, which is higher than the BUSCO completeness of the B. mori (92.2%) and M. sexta (90%) annotations. Conclusions Our gene annotation strategy has general applicability to other genomes, and the H. vespertilio genome provides a valuable molecular resource to study a range of questions in this genus, including phylogeny, incomplete lineage sorting, speciation, and hybridization. A genome browser displaying the genome, alignments, and annotations is available at https://genome-public.pks. mpg.de/cgi-bin/hgTracks? db=HLhylVes1.
Characteristics and outcomes in patients with primary intraspinal tumours.

INTRODUCTION We report a retrospective cohort study aimed at presenting data on incidence, patient char-ac-teristics, tumour type, level of pathology, clinical status before and after surgery and complications in patients with surgically treated primary intraspinal tumours (PIST) in Western Denmark. METHODS Population-based data were retrieved from hospital files from 1 January 2010 to 31 December 2015. RESULTS In total, 78 males and 88 females with PIST were included in the study. Incidence per 100,000 persons per year in the population-based cohort was 2.18. The incidence of malignant PIST was 0.14 and the incidence of non-malignant PIST was 2.03. We found 25 extradural tumours, 100 intradural extramedullary tumours and 41 intramedullary tumours. Eleven were malignant and 155 were benign tumours. Schwannoma, meningioma and ependymoma were more common in adults, whereas haemangioblastoma, neurofibroma and epidermoid cysts were seen in 14 paediatric cases. Motor function disturbances were found in 38% of cases. Sensory disturbances were found in 54% of cases, and worsening of sensory functions was the most frequent post-operative sequela. Ataxia and neurogenic bowel/bladder dysfunction seem to constitute the highest risk in cases of intramedullary tumours. Pain was found in 75% of cases and was the most common symptom among all patients with PITS with a 58% improvement after surgery. Complications were recorded in 12% of cases. CONCLUSIONS The incidence of PIST seems to be higher in Western Denmark than in other European studies. PIST are rare in children. FUNDING none. TRIAL REGISTRATION not relevant.
Dynamics of strand slippage in DNA hairpins formed by CAG repeats: roles of sequence parity and trinucleotide interrupts

Abstract DNA trinucleotide repeats (TRs) can exhibit dynamic expansions by integer numbers of trinucleotides that lead to neurodegenerative disorders. Strand slipped hairpins during DNA replication, repair and/or recombination may contribute to TR expansion. Here, we combine single-molecule FRET experiments and molecular dynamics studies to elucidate slipping dynamics and conformations of (CAG)n TR hairpins. We directly resolve slipping by predominantly two CAG units. The slipping kinetics depends on the even/odd repeat parity. The populated states suggest greater stability for 5′-AGCA-3′ tetraloops, compared with alternative 5′-CAG-3′ triloops. To accommodate the tetraloop, even(odd)-numbered repeats have an even(odd) number of hanging bases in the hairpin stem. In particular, a paired-end tetraloop (no hanging TR) is stable in (CAG)n = even, but such situation cannot occur in (CAG)n = odd, where the hairpin is “frustrated’’ and slips back and forth between states with one TR hanging at the 5′ or 3′ end. Trinucleotide interrupts in the repeating CAG pattern associated with altered disease phenotypes select for specific conformers with favorable loop sequences. Molecular dynamics provide atomic-level insight into the loop configurations. Reducing strand slipping in TR hairpins by sequence interruptions at the loop suggests disease-associated variations impact expansion mechanisms at the level of slipped hairpins.
Efficacy of bone marrow mesenchymal stem cell transplantation in animal models of pulmonary fibrosis after exposure to bleomycin: A meta-analysis

Previous studies have demonstrated that bone marrow mesenchymal stem cell (BMSC) transplantation is a promising treatment strategy for pulmonary fibrosis. Although encouraging results have been obtained using animal models of bleomycin (BLM)-induced pulmonary fibrosis, it is evident that transplantation of BMSCs at various time-points after BLM administration has produced different results in terms of treatment efficacy. To shed light on the potential utility of BMSCs for the treatment of lung disease, the present study performed a meta-analysis to estimate the efficacy of BMSCs in animal models of BLM-induced pulmonary fibrosis, and compare early transplantation (BMSCs injected on the same day after administration of BLM) with late transplantation (BMSCs injected on the 14th day after administration of BLM). Relevant studies were retrieved from the MEDLINE, PubMed, Chinese Knowledge Infrastructure and WanFang databases using a comprehensive search approach. A total of 6 studies involving 228 model rats were included. Meta-analysis indicated that early BMSC transplantation was able to prevent or reduce BLM-induced alveolitis and pulmonary fibrosis, while late BMSC transplantation was able to reduce alveolitis, but there was no significant evidence regarding improvement of pulmonary fibrosis. Although BMSC therapy was identified to be generally beneficial in rodent models of BLM-induced pulmonary fibrosis, the efficacy of early transplantation appears to be more satisfactory; overall, the efficacy of transplantation of BMSCs at the acute inflammatory phase was more effective compared with that at the chronic fibrosis stage. Of note, regarding alveolitis and pulmonary fibrosis scores after late transplantation of BMSCs, the sensitivity analysis revealed that the scores were less stable; thus, this result must be interpreted with caution. Furthermore, the quality and methodology of the included studies was comparatively low. Therefore, higher-quality and more rigorous studies are required to validate the results of the present meta-analysis in the future.
Tb1, a Neurotoxin from Tityus bahiensis Scorpion Venom, Induces Epileptic Seizures by Increasing Glutamate Release

Here, we report the neurotoxic effects aroused by the intracerebral injection (in rats) of Tb1, which is a neurotoxin isolated from Tityus bahiensis scorpion venom. Biochemical analyses have demonstrated that this toxin is similar to the gamma toxin from T. serrulatus, which is a β-scorpion toxin that acts on sodium channels, causing the activation process to occur at more hyperpolarized membrane voltages. Male Wistar rats were stereotaxically implanted with intrahippocampal electrodes and cannulas for electroencephalographic recording and the evaluation of amino acid neurotransmitters levels. Treated animals displayed behavioral and electroencephalographic alterations similar to epileptiform activities, such as myoclonus, wet dog shakes, convulsion, strong discharges, neuronal loss, and increased intracerebral levels of glutamate. Scorpion toxins are important pharmacological tools that are widely employed in ion channel dysregulation studies. The current work contributes to the understanding of channelopathies, particularly epilepsy, which may originate, among other events, from dysfunctional sodium channels, which are the main target of the Tb1 toxin.
Mainstream-sidestream wastewater switching promotes anammox nitrogen removal rate in organic-rich, low-temperature streams

ABSTRACT The main issues with mainstream anammox application are loss of bacterial activity by low temperatures and by a high organic content of wastewater. We demonstrate a novel switching method between sidestream and mainstream wastewater. The wastewater flow was switched between sidestream (reject water at >22°C) and mainstream (municipal wastewater at 16.5°C), so that the anammox biomass activity and biomass growth could benefit from sidestream conditions. Real sidestream wastewater (biogas plant effluent) (≈1000 mg NH+ 4-N L−1) and synthetic mainstream (municipal wastewater-like source) (≈100 mg NH+ 4-N) wastewater were used for 20 L biofilm reactor feeding. The highest total nitrogen removal rate (TNRR) of 527 g N m−3 d−1 (average TNRR 180 (±140) g N m−3 d−1) was achieved with sidestream wastewater at a low chemical oxygen demand (COD)/TN ratio of 1.1/1. For reactor feeding with mainstream, the highest TNRR achieved was 61 g N m−3 d−1. Average TNRR for mainstream of 20 (±15) g N m−3 d−1 was low due to a higher COD/N ratio of 3.2/1. The highest TNRR in a batch test was achieved at the COD concentration of 480 mg L−1, reflecting a TNRR of ≈5 mg N g−1 TSS h−1. With a high COD concentration of 2600 mg L−1 (TOC/TN = 8/1), TNRR decreased similarly in both feeds to 1.6 mg N g−1 TSS h−1. The anammox microorganism's genus Candidatus Brocadia enrichment in deammonification biofilm reactor was higher in the mainstream operation (7.6% of all bacteria) than in sidestream operation period (<0.7% of all bacteria). GRAPHICAL ABSTRACT
Emergency Laparoscopic Cholecystectomy: Is Dedicated Hot Gall Bladder List Cost Effective?

Background Acute presentation of gall stone disease is a common emergency. Resource limitation often results in unnecessary long waiting times and repeat hospital admissions. The aim of this study was to investigate if funding a dedicated hot gall bladder list is justified. Methods Patients with acute gall stone related complications between 1st January 2016 and 31st December 2017 were studied. Outcome measures included the number of acute admissions, length of hospital stay (LOS), approximate cost per patient. The length of stay was identified as a critical outcome measure. Results Fourteen hundred and ninety-five (11%) out of 14189 acute surgical admissions were related to gall stone complications. These included acute cholecystitis 576 (39%), biliary colic 485 (32%), pancreatitis 405 (27%) and jaundice 34 (2%). Twelve hundred and twenty-two patients accounted for 1461 admissions. 182 (15%) patients had recurrent admissions (35%) and on average stayed 11.2 days in the hospital compared to 5.8 days for that of single presentation. The cost of emergency LC (£2053) was less than half of elective LC following single emergency admission (£5661) and less than one third of Elective LC following recurrent admissions (£7453). A trust can save £1,891,784 per year by achieving 80% target. The savings can be used to fund a dedicated hot gall bladder list, releasing hospital beds and additional benefit of reducing the workforce days lost to sickness in general. Conclusions Emergency LC is cost effective and savings made for such a service is sufficient to fund a dedicated hot gall bladder list.
The Corpus Callosum and PTSD Severity

Posttraumatic stress disorder (PTSD) is a chronic, debilitating disorder that is associated with neural alterations in multiple brain regions. Neuroimaging studies have largely focused on gray matter abnormalities in PTSD, with less information known about the integrity of white matter tracts. Prior studies of brain white matter in PTSD have produced mixed results, likely due to differences in neuroimaging sequences and clinical variables. This study addressed this gap by examining the microstructural integrity of the corpus callosum, the largest white matter fiber bundle in the brain, using diffusion tensor imaging (DTI). Sixty adult females diagnosed with PTSD with a history of interpersonal violence were compared with 18 trauma-exposed controls. All participants underwent DTI using 1.5 T. MANOVA revealed significantly higher fractional anisotropy (FA; p = .012) in the genu of the corpus callosum (GCC) compared with the trauma-exposed controls. These results suggest the GCC to relate to PTSD symptomatology. Further studies of this mechanism may provide insight into improving treatment and prevention efforts.
Different Routes of Proton Pumps Inhibitors Co-Administration have Significant Impact on Mycophenolate Acid (MPA) Serum Levels in Heart Transplant Recipients

Background Antiproliferative drugs including mycophenolate mofetil (MMF) are widely accepted part of an immunosuppressive therapy following heart transplantation. Proton pump inhibitors (PPIs) are routinely administered after cardiac surgery procedures including transplantation. They may also have impact on mycophenolate acid (MPA) serum levels. Material/Methods There were 30 consecutive patients (28 male and 2 female patients) with a mean age of 45±12 years who were enrolled into this study. MPA serum levels were studied; PPIs were intravenously and orally administered. Results The mean MPA plasma concentrations were statistically significantly different between parenteral group (2.3±1.4 umg/mL) and oral group (3.1±2.2 umg/mL) (P=0.036) before immunosuppressive drug administration (C-0 time). There was a statistically significant different drug concentration at the second sample time C-30 (30 minutes after drug intake) reaching 4.4±2.8 umg/mL versus 7.9±4.5 umg/mL (P<0.05). There was no statistically significant difference in MPA plasma concentration at the 3rd measurement C-120 (10.7±4,9 umg/mL versus 9.8±5 umg/mL) (P=0.3). There is a statistically significant different MMF serum concentration after oral intake and intravenous infusion at C-30 (2.4±1.4 in group 1 versus 3.3±2.5 in group 2, P<0.036) but not at C-120 time interval (8.9±5.0 versus 9.8±5.3 in group 1 and 2, respectively) (P=0.3). Conclusions Our study was the first study that compared different routes of PPI co-administration on MPA serum levels in a transplant recipient group. Our study revealed that the parenteral route of administration only slowed not decreased MPA pharmacokinetics within 120 minutes following MMF administration.
The Structural Determinants Accounting for the Broad Substrate Specificity of the Quorum Quenching Lactonase GcL

Quorum quenching lactonases are enzymes capable of hydrolyzing lactones, including N‐acyl homoserine lactones (AHLs). AHLs are molecules known as signals in bacterial communication dubbed quorum sensing. Bacterial signal disruption by lactonases was previously reported to inhibit behavior regulated by quorum sensing, such as the expression of virulence factors and the formation of biofilms. Herein, we report the enzymatic and structural characterization of a novel lactonase representative from the metallo‐β‐lactamase superfamily, dubbed GcL. GcL is a broad spectrum and highly proficient lactonase, with kcat/KM values in the range of 104 to 106 m−1 s−1. Analysis of free GcL structures and in complex with AHL substrates of different acyl chain length, namely, C4‐AHL and 3‐oxo‐C12‐AHL, allowed their respective binding modes to be elucidated. Structures reveal three subsites in the binding crevice: 1) the small subsite where chemistry is performed on the lactone ring; 2) a hydrophobic ring that accommodates the amide group of AHLs and small acyl chains; and 3) the outer, hydrophilic subsite that extends to the protein surface. Unexpectedly, the absence of structural accommodation for long substrate acyl chains seems to relate to the broad substrate specificity of the enzyme.
Pharmacokinetic Properties of Humanized IgG1 and IgG4 Antibodies in Preclinical Species: Translational Evaluation

Assessment of the factors that regulate antibody exposure–response relationships in the relevant animal models is critical for the design of successful translational strategies from discovery to the clinic. Depending on the specific clinical indication, preclinical development paradigms may require that the efficacy or dosing-related attributes for the existing antibody be assessed in various species when cross-reactivity of the lead antibody to the intended species is justified. Additionally, with the success of monoclonal antibodies for management of various human conditions, a parallel interest in therapeutic use of these novel modalities in various veterinary species has followed. The protective role of neonatal Fc receptor (FcRn) in regulation of IgG homeostasis and clearance is now well recognized and the “nonspecific clearance” of antibodies through bone marrow-derived phagocytic and vascular endothelial cells (via lysosomal processes) is modulated by interactions with FcRn receptors. In this study, we have attempted to examine the PK properties of human IgG antibodies in dog and monkey. These studies establish a translational framework for evaluation of IgG antibody PK properties across species.
Biphasic changes in airway epithelial cell EGF receptor binding and phosphorylation induced by components of hogbarn dust

Abstract Purpose of the study: Workers in enclosed hogbarns experience an increased incidence of airway inflammation and obstructive lung disease, and an aqueous hogbarn dust extract (HDE) induces multiple inflammation-related responses in cultured airway epithelial cells. Epidermal growth factor receptor (EGFR) phosphorylation and activation has been identified as one important mediator of inflammatory cytokine release from these cells. The studies here investigated both early and late phase adaptive changes in EGFR binding properties and subcellular localization induced by exposure of cells to HDE. Materials and Methods: Cell surface EGFRs were quantified as binding to intact cells on ice. EGFR phosphorylation, expression, and localization were assessed with anti-EGFR antibodies and either blotting or confocal microscopy. Results: In BEAS-2B and primary human bronchial epithelial cells, HDE induced decreases in cell surface EGFR binding following both 15-min and 18-h exposures. In contrast, H292 cells exhibited only the 15-min decrease, with binding near the control level at 18 hr. Confocal microscopy showed that the 15-min decrease in binding is due to EGFR endocytosis. Although total EGFR immunoreactivity decreased markedly at 18 hr in confocal microscopy with BEAS-2B cells, immunoblots showed no loss of EGFR protein. HDE stimulated EGFR phosphorylation at both 15 min and 18 hr in BEAS-2B cells and primary cells, but only at 15 min in H292 cells, indicating that the different EGFR binding changes among these cell types is likely related to their different time-dependent changes in phosphorylation. Conclusions: These studies extend the evidence for EGFRs as important cellular targets for components of HDE and they reveal novel patterns of EGFR phosphorylation and binding changes that vary among airway epithelial cell types. The results provide both impetus and convenient assays for identifying the EGFR-activating components and pathways that likely contribute to hogbarn dust-induced lung disease in agricultural workers.
CLIPPERS Spectrum Disorder: A Rare Pediatric Neuroinflammatory Condition

CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is a recently described, rare neuroinflammatory disorder diagnosed by clinical symptoms involving the brain stem with a distinct pattern on neuroimaging and a perivascular T-lymphocyte infiltrate on brain biopsy. It is a condition usually described in adults in the fourth to fifth decade. We report a case of 13-year-old Indian boy who presented with recurrent episodes of ataxia and diplopia with onset at 7 years of age. He was investigated extensively to rule out infective, neoplastic, autoimmune, and demyelinating conditions over a span of 6 years. The diagnosis of CLIPPERS was entertained on the basis of clinico-radio-pathological correlation. Treatment with steroids and steroid-sparing agents, particularly methotrexate, seems to provide a promising outcome. With very few cases in literature so far, reporting of a larger case series with pediatric onset may expand it to CLIPPERS spectrum disorder.