Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional connectivity changes and their relationship with clinical disability and white matter integrity in patients with relapsing–remitting multiple sclerosis

Background and objective: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor imaging, and clinical impairments. Methods: Thirty relapsing–remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with General-Linear-Model and corrected for multiple comparisons. Results: Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. Conclusions: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities.
Sources and level of income among individuals with multiple sclerosis compared to the general population: A nationwide population-based study

Introduction: Multiple sclerosis (MS) is associated with reduced work capacity, but there is limited knowledge about MS patients’ sources of income. Objectives: The purpose of this study was to elucidate MS patients’ earnings and social benefits compared to those of the general population. Methods: From nationwide registers of all residents in Sweden aged 21–64 years in 2010 (n=5,291,764), those with an MS diagnosis (n=13,979) were compared to a propensity score matched reference group (n=69,895). Descriptive statistics and regression models were used to estimate the percentage difference between the MS patients and the matched references regarding the following annual incomes: earnings, disability pension, sickness absence, disability allowance, unemployment compensation and social assistance. Results: Both MS patients and the matched references received most of their income from earnings followed by disability pension and sickness absence. MS patients that were diagnosed in 2010 had 15% lower earnings than the matched references, while MS patients diagnosed before 2005 had 38% lower earnings. Corresponding figures regarding summed social benefits were 33% and 130% higher for MS patients, respectively. Conclusion: The results indicate that MS patients are overrepresented, in relative and absolute terms, regarding health-related benefits and have lower levels of earnings. However, the redistributing welfare systems appear to financially compensate the MS patients considerably.
Reconsidering outdoor temperature and cognition in multiple sclerosis

Background: Research in multiple sclerosis (MS) suggests warmer weather plays a role in disease manifestation. Objective: This work sought to replicate the finding that warmer outdoor temperatures are significantly associated with poorer cognition in MS. Methods: Associations between outdoor temperature and cognition were examined in three studies with a total of 263 patients with MS. Results: Contrary to previous research, no significant relationship was found between cognitive performance and outdoor temperature in MS. Conclusions: The results of the current work underscore the need to better understand if, when, and how cognitive performance may be influenced by seasonal variables in MS.
Multicenter Study of Isavuconazole MIC Distributions and Epidemiological Cutoff Values for Aspergillus spp. for the CLSI M38-A2 Broth Microdilution Method

ABSTRACT Epidemiological cutoff values (ECVs) were established for the new triazole isavuconazole and Aspergillus species wild-type (WT) MIC distributions (organisms in a species-drug combination with no detectable acquired resistance mechanisms) that were defined with 855 Aspergillus fumigatus, 444 A. flavus, 106 A. nidulans, 207 A. niger, 384 A. terreus, and 75 A. versicolor species complex isolates; 22 Aspergillus section Usti isolates were also included. CLSI broth microdilution MIC data gathered in Europe, India, Mexico, and the United States were aggregated to statistically define ECVs. ECVs were 1 μg/ml for the A. fumigatus species complex, 1 μg/ml for the A. flavus species complex, 0.25 μg/ml for the A. nidulans species complex, 4 μg/ml for the A. niger species complex, 1 μg/ml for the A. terreus species complex, and 1 μg/ml for the A. versicolor species complex; due to the small number of isolates, an ECV was not proposed for Aspergillus section Usti. These ECVs may aid in detecting non-WT isolates with reduced susceptibility to isavuconazole due to cyp51A (an A. fumigatus species complex resistance mechanism among the triazoles) or other mutations.
Complete Sequence of pJIE143, a pir-Type Plasmid Carrying ISEcp1-blaCTX-M-15 from an Escherichia coli ST131 Isolate

ABSTRACT pJIE143 (34 kb), from an Escherichia coli ST131 isolate, carries blaCTX-M-15 but could not be typed using the standard PCR-based replicon-typing primer set. Complete sequencing revealed a backbone with similarity to IncX plasmids, including a pir-like gene encoding a π-like replication protein and iterons related to those of other IncX plasmids. The 2.971-kb ISEcp1-blaCTX-M-15-orf477Δ transposition unit often found within Tn2 is inserted just beyond the end of pir, flanked by 5-bp direct repeats.
Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial

Background: Mobility impairment is a common disability in MS and negatively impacts patients’ lives. Objective: Evaluate the effect of prolonged-release (PR) fampridine (extended-release dalfampridine in the United States) on self-assessed walking disability, dynamic/static balance and safety in patients with MS. Methods: MOBILE was a randomised, double-blind, exploratory, placebo-controlled trial. Patients with progressive/relapsing-remitting MS and Expanded Disability Status Scale score of 4.0–7.0 were treated with PR-fampridine or placebo twice daily for 24 weeks. Efficacy endpoints included change from baseline in the 12-item MS Walking Scale (MSWS-12), Timed Up and Go (TUG) test and Berg Balance Scale (BBS). Results: 132 patients were randomised at 24 sites in six countries. PR-fampridine therapy resulted in greater median improvements from baseline in MSWS-12 score, TUG speed and BBS total score versus placebo over 24 weeks. A higher proportion of patients receiving PR-fampridine versus placebo experienced significant improvements at MSWS-12 improvement thresholds ⩾7 (p = 0.0275), ⩾8 (p = 0.0153) and ⩾9 points (p = 0.0088) and TUG speed thresholds ⩾10% (p = 0.0021) and ⩾15% (p = 0.0262). PR-fampridine was well tolerated. Conclusions: PR-fampridine therapy resulted in early and sustained improvements in broad measures of walking and balance over six months.
Review: Cardiopulmonary Toxicity of Adoptive Immunotherapy

ABSTRACT Adoptive immunotherapy, the administration of interleukin-2 (IL-2) and interleukin-2 activated cells, leads to tumor regression in some patients with advanced cancer. Although this new therapeutic modality offers hope for the future, at present, a multitude of toxicities limit the total dose and duration of therapy. Among the toxic side effects a purported third space or vascular leak syndrome is the most serious. In this review, we detail the evidence for a third space syndrome (peripheral edema, ascites, oliguria, elevated' serum creatinine levels) and cardiopulmonary dysfunction (hypotension, respiratory distress, pulmonary edema, hypoxemia) with adoptive immunotherapy in human and animal studies. We conclude that IL-2 administration is associated with increased pulmonary microvascular permeability, infiltration of the lung parenchyma with large esterase negative lymphoid cells, hypoxemia, systemic hypotension, positive fluid balance and, in animals, transient pulmonary hypertension. These abnormalities do not seem to be caused by IL-2 directly; the causes may be mediated by IL-2 activated lymphocytes or other IL-2 activated cellular mediators.
Chronic Thromboembolic Pulmonary Hypertension: Diagnosis and Treatment

Pulmonary hypertension can be difficult to suspect on the basis of physical examination. It is particularly difficult when its onset is gradual and there is litde or no history to suggest its existence or the existence of its underlying cause. Many causes of pulmonary hypertension are known and are often apparent on physical examination or by history. Severe chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and sleep apnea are examples of such conditions. Others may be less apparent or less common, but still suggested by the history or laboratory data. Such conditions as HIV-associated pulmonary hypertension, mixed connective tissue vasculitis, and lupus vasculitis fall into this category. Other causes, which can pose significant diagnostic problems, may have little or no history to suggest the diagnosis and may, therefore, be much more difficult to suspect. Primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension may fall into this latter category. This article will focus on chronic thromboembolic pulmonary hypertension, one of the few truly treatable causes of chronic pulmonary hypertension, and will delineate an approach to diagnosis and treatment with some emphasis on its contrasts with primary pulmonary hypertension.
Diabetic MRSA foot infection — role of linezolid therapy

Diabetic foot ulceration is common and disabling, often leading to amputation of the leg. Foot ulcers commonly become infected and MRSA infection is becoming more prevalent. MRSA is becoming a major public health problem because of its associated high morbidity and mortality, due to difficulty in its eradication with conventional antibiotics. Although vancomycin is the present mainstay of treatment of MRSA infection, a recently introduced antibiotic, linezolid may have benefits. Linezolid can be given orally, obviating the need for i.v. monitoring and offering potential savings in hospital costs with earlier discharge because of its suitability for out-patient eradication of MRSA.
Gallium Disrupts Iron Uptake by Intracellular and Extracellular Francisella Strains and Exhibits Therapeutic Efficacy in a Murine Pulmonary Infection Model

ABSTRACT Francisella tularensis requires iron (Fe) for growth, but the biologic sources of Fe for this organism are largely unknown. We found that Francisella sp. growing in broth culture or within human macrophages can acquire Fe from the two major host Fe-binding proteins, lactoferrin (Lf) and transferrin (Tf). Fe acquisition is a potential target for novel therapies. Gallium (Ga) is a transition metal that interferes with cellular Fe metabolism by competing with Fe for uptake/utilization. Growth of either F. tularensis live vaccine strain (LVS) or Francisella novicida was inhibited by ≥2 μM Ga chelated to Tf or Lf, with GaLf being somewhat more potent. Francisella spp. express two Fe-containing antioxidant enzymes, catalase (KatG) and Fe cofactored superoxide dismutase (FeSOD). Growth of LVS with 10 μM GaTf or GaLf led to a dramatic decrease in bacterial catalase activity and in FeSOD activity that was associated with an increased susceptibility to H2O2. Ga also protected mice from intranasal challenge with F. novicida. Whereas 100% of the F. novicida-infected mice died by day 9, 75% of the mice receiving Ga continued to survive to at least day 15. Thus, a single intranasal dose of Ga followed by daily intraperitoneal Ga at a dose tolerated by the animals resulted in prolonged survival. These data support the potential utility of Ga as a therapy for F. tularensis infection of the lung.
Vancomycin MIC Does Not Predict 90-Day Mortality, Readmission, or Recurrence in a Prospective Cohort of Adults with Staphylococcus aureus Bacteremia

ABSTRACT Staphylococcus aureus bacteremia (SAB) is a tremendous health burden. Previous studies examining the association of vancomycin MIC and outcomes in patients with SAB have been inconclusive. This study evaluated the association between vancomycin MICs and 30- or 90-day mortality in individuals with SAB. This was a prospective cohort study of adults presenting from 2008 to 2013 with a first episode of SAB. Subjects were identified by an infection surveillance system. The main predictor was vancomycin MIC by MicroScan. The primary outcomes were death at 30 and 90 days, and secondary outcomes included recurrence, readmission, or a composite of death, recurrence, and readmission at 30 and 90 days. Covariates included methicillin susceptibility, demographics, illness severity, comorbidities, infectious source, and antibiotic use. Cox proportional-hazards models with propensity score adjustment were used to estimate 30- and 90-day outcomes. Of 429 unique first episodes of SAB, 11 were excluded, leaving 418 individuals for analysis. Eighty-three (19.9%) participants had a vancomycin MIC of 2 μg/ml. In the propensity-adjusted Cox model, a vancomycin MIC of 2 μg/ml compared to <2 μg/ml was not associated with a greater hazard of mortality or composite outcome of mortality, readmission, and recurrence at either 30 days (hazard ratios [HRs] of 0.86 [95% confidence interval {CI}, 0.41, 1.80] [P = 0.70] and 0.94 [95% CI, 0.55, 1.58] [P = 0.80], respectively) or 90 days (HRs of 0.91 [95% CI, 0.49, 1.69] [P = 0.77] and 0.69 [95% CI, 0.46, 1.04] [P = 0.08], respectively) after SAB diagnosis. In a prospective cohort of patients with SAB, vancomycin MIC was not associated with 30- or 90-day mortality or a composite of mortality, disease recurrence, or hospital readmission.
Reliability of Mecholyl Jest

Introduction Funkenstein and his collaborators, in a series of papers, described an autonomic nervous system test of prognostic significance in relation to electroshock. This test originally consisted of intravenous injection of epinephrine (adrenergic stimulation) and intramuscular injection of methacholine U. S. P. (Mecholyl) (cholinergic stimulation). Subsequently, it was found that the Mecholyl test alone predicted the results of the electroshock treatment at a better than P=0.01 level. * Mecholyl is a cholinergic drug, which when injected produces a fall of blood pressure, due to a peripheral action on the blood vessels. This may be followed by a rise in the blood pressure due to a homeostatic reaction of the higher hypothalamic sympathetic center (Gellhorn5). Subjects, irrespective of their diagnosis, who react to injection of Mecholyl by a pronounced fall of the blood pressure respond to the electroshock therapy much better than subjects who respond by a rise of the blood
Exploring the Mode of Action of Antimicrobial Peptide MUC7 12-Mer by Fitness Profiling of Saccharomyces cerevisiae Genomewide Mutant Collection

ABSTRACT The MUC7 12-mer (RKSYKCLHKRCR) is a cationic antimicrobial peptide derived from the human salivary mucin MUC7. To study its effect/mechanism of action on fungi, we performed a fitness screen of a tagged, diploid, homozygous gene deletion mutant pool of the yeast Saccharomyces cerevisiae grown in the presence of the MUC7 peptide. Forty-five strains exhibiting reduced fitness and 13 strains exhibiting increased fitness (sensitivity or resistance, respectively) were identified by hybridization intensities to tag arrays. The strongest fitness defects were observed with deletions in genes encoding elements of the RIM101 signaling pathway (regulating response to alkaline and neutral pH and other environmental conditions) and of the endosomal sorting complex required for transport (ESCRT; functioning mainly in protein sorting for degradation, but also required for activation of the RIM101 pathway). Other deletions identified as conferring fitness defect or gain are in genes associated with a variety of functions, including transcription regulation, protein trafficking, transport, metabolism, and others. The results of the pool fitness screen were validated by a set of mutant strains tested individually in the presence of the MUC7 12-mer. All tested RIM101-related deletion strains showing fitness defects confirmed their sensitivities. Taken together, the results led us to conclude that deletions of genes associated with the RIM101 pathway confer sensitivity to the peptide by preventing activation of this pathway and that this stress response plays a major role in the protection of S. cerevisiae against damage inflicted by the MUC7 12-mer peptide.
Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination

Epstein–Barr virus (EBV) infection is associated with increased multiple sclerosis (MS) risk. Recently, cytomegalovirus (CMV) infection has been proposed as a protective factor against MS development. We determined EBV, herpes simplex virus, varicella-zoster virus and CMV seroprevalence in 247 prospectively followed children with acquired demyelinating syndromes (ADS). Remote EBV infection was more common in children with MS than those with monophasic ADS while CMV infection was more common in children with monophasic ADS. Children displaying evidence of remote EBV without CMV infection were at highest risk of subsequent MS diagnosis. Viral infection repertoire detected at ADS provides important prognostic information.
Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later

Background: The utility of blood–brain barrier (BBB) biomarkers for clinical and magnetic resonance imaging progression in multiple sclerosis (MS) has not been extensively investigated. Objectives: To determine whether cerebrospinal fluid (CSF) measures of BBB at clinical onset predict radiological and clinical deterioration over 48 months. Methods: This longitudinal study included 182 patients after first clinical event suggestive of MS treated with weekly intramuscular interferon beta-1a. CSF and serum samples were analyzed for leukocytes, total protein, albumin, immunoglobulins, and oligoclonal bands. Optimal thresholds for the albumin quotient (QAlb) were determined. Mixed-effect model analyses, adjusted for age, gender, and treatment escalation, were used to analyze relationship between CSF measures and disease activity outcomes over 48 months of follow-up. Results: Increased QAlb at clinical onset was associated with enlargement of lateral ventricles (p = .001) and greater whole brain (p = .003), white matter (p < .001), corpus callosum (p < .001), and thalamus (p = .003) volume loss over 48 months. Higher QAlb was associated with higher Expanded Disability Status Scale score over 48 months (p = .002). Conclusions: Increased QAlb at clinical onset is associated with increased brain atrophy and greater disability in patients after first clinical event suggestive of MS.
No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing–remitting multiple sclerosis (the ARIANNA study)

Background: A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. Objectives: The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing–remitting multiple sclerosis. Methods: This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. Results: A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (−0.38% and −0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. Conclusions: Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing–remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing–remitting multiple sclerosis.
First Report of KPC-Producing Pseudomonas aeruginosa in Brazil

The first report of KPC-producing Pseudomonas aeruginosa isolates was from Colombia (KPC-2) in 2007, followed by reports from Puerto Rico (KPC), Trinidad and Tobago (KPC-2), the United States (KPC-2), and China (KPC-2) ([1][1], [6][2][–][3][10][4]). This report describes the first detection of KPC
Multicenter Retrospective Study of Cefmetazole and Flomoxef for Treatment of Extended-Spectrum-β-Lactamase-Producing Escherichia coli Bacteremia

ABSTRACT The efficacy of cefmetazole and flomoxef (CF) for the treatment of patients with extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) bacteremia (ESBL-CF group) was compared with that of carbapenem treatment for ESBL-EC patients (ESBL-carbapenem group) and with that of CF treatment in patients with non-ESBL-EC bacteremia (non-ESBL-CF group). Adult patients treated for E. coli bacteremia in four hospitals were retrospectively evaluated. The 30-day mortality rates in patients belonging to the ESBL-CF, ESBL-carbapenem, and non-ESBL-CF groups were compared as 2 (empirical and definitive therapy) cohorts. The adjusted hazard ratios (aHRs) for mortality were calculated using Cox regression models with weighting according to the inverse probability of propensity scores for receiving CF or carbapenem treatment. The empirical-therapy cohort included 104 patients (ESBL-CF, 26; ESBL-carbapenem, 45; non-ESBL-CF, 33), and the definitive-therapy cohort included 133 patients (ESBL-CF, 59; ESBL-carbapenem, 54; non-ESBL-CF, 20). The crude 30-day mortality rates for patients in the ESBL-CF, ESBL-carbapenem, and non-ESBL-CF groups were, respectively, 7.7%, 8.9%, and 3.0% in the empirical-therapy cohort and 5.1%, 9.3%, and 5.0% in the definitve-therapy cohort. In patients without hematological malignancy and neutropenia, CF treatment for ESBL-EC patients was not associated with mortality compared with carbapenem treatment (empirical-therapy cohort: aHR, 0.87; 95% confidence interval [CI], 0.11 to 6.52; definitive therapy cohort: aHR, 1.04; CI, 0.24 to 4.49). CF therapy may represent an effective alternative to carbapenem treatment for patients with ESBL-EC bacteremia for empirical and definitive therapy in adult patients who do not have hematological malignancy and neutropenia.