A urokinase-associated outbreak of Ralstonia mannitolilytica bloodstream infections in haemodialysis patients in north-eastern Italy, January to April 2023.

An outbreak of Ralstonia mannitolilytica bloodstream infections occurred in four hospitals in north-eastern Italy, involving 20 haemodialysis patients with tunnelled central vascular catheter access. We identified as the outbreak source a batch of urokinase vials imported from India contaminated with R. mannitolilytica. Whole genome sequences of the clinical and urokinase strains were highly related, and only urokinase-treated patients were reported with R. mannitolilytica infections (attack rate = 34%; 95% confidence interval: 22.1-47.4). Discontinuation of the contaminated urokinase terminated the outbreak.

Advances in Catchment Science, Hydrochemistry, and Aquatic Ecology Enabled by High-Frequency Water Quality Measurements.

High-frequency water quality measurements in streams and rivers have expanded in scope and sophistication during the last two decades. Existing technology allows in situ automated measurements of water quality constituents, including both solutes and particulates, at unprecedented frequencies from seconds to subdaily sampling intervals. This detailed chemical information can be combined with measurements of hydrological and biogeochemical processes, bringing new insights into the sources, transport pathways, and transformation processes of solutes and particulates in complex catchments and along the aquatic continuum. Here, we summarize established and emerging high-frequency water quality technologies, outline key high-frequency hydrochemical data sets, and review scientific advances in key focus areas enabled by the rapid development of high-frequency water quality measurements in streams and rivers. Finally, we discuss future directions and challenges for using high-frequency water quality measurements to bridge scientific and management gaps by promoting a holistic understanding of freshwater systems and catchment status, health, and function.

Identifying Predictors of Anal HPV Status in HPV-Vaccinated MSM: A Machine Learning Approach.

Anal human papillomavirus (HPV) infection has a high prevalence in men who have sex with men (MSM), resulting in an increased risk for anal cancer. The present work aimed to identify factors associated with HPV in a prospective cohort of HPV-vaccinated MSM using a random forest (RF) approach. This observational study enrolled MSM patients admitted to an Italian (sexually transmitted infection) STI-AIDS Unit. For each patient, rectal swabs for 28 different HPV genotype detection were collected. Two RF algorithms were applied to evaluate predictors that were most associated with HPV. The cohort included 135 MSM, 49% of whom were HIV-positive with a median age of 39 years. In model 1 (baseline information), age, age sexual debut, HIV, number of lifetime sex partners, STIs, were most associated with the HPV. In model 2 (follow-up information), age, age sexual debut, HIV, STI class, and follow-up. The RF algorithm exhibited good performances with 61% and 83% accuracy for models 1 and 2, respectively. Traditional risk factors for anal HPV infection, such as drug use, receptive anal intercourse, and multiple sexual partner, were found to have low importance in predicting HPV status. The present results suggest the need to focus on HPV prevention campaigns.

Prenatal Stress Impairs Spinal Cord Oligodendrocyte Maturation via BDNF Signaling in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

One of the most substantial and established environmental risk factors for neurological and psychiatric disorders is stress exposure, whose detrimental consequences hinge on several variables including time. In this regard the gestational period is known to present an intrinsic vulnerability to environmental insults and thus stressful events during pregnancy can lead to severe consequences on the offspring's brain development with long-term repercussions throughout adulthood. On this basis, we investigated the long-lasting impact of prenatal stress exposure on the susceptibility to the experimental autoimmune encephalomyelitis (EAE), a well-established murine model of multiple sclerosis. Although stress is considered a triggering factor for this chronic, progressive, autoimmune disease, little is known about the underlying mechanisms. To this end, EAE was induced by immunization with MOG35-55/CFA and pertussis toxin administration in adult female C57BL/6 mice born from control or stressed dams exposed to restraint stress during the last days of gestation. Our results demonstrate that gestational stress induces a marked increase in the severity of EAE symptoms in adulthood. Further, we highlight an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE mice, as indicated by the higher levels of GPR17, a marker of immature oligodendrocyte precursor cells. These behavioral and molecular alterations are paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination. Since several already marketed drugs are able to modulate BDNF levels, these results pave the way to the possibility of repositioning these drugs in multiple sclerosis.

In vivo silencing of miR-125a-3p promotes myelin repair in models of white matter demyelination.

In the last decade, microRNAs have been increasingly recognized as key modulators of glial development. Recently, we identified miR-125a-3p as a new player in oligodendrocyte physiology, regulating in vitro differentiation of oligodendrocyte precursor cells (OPCs). Here, we show that miR-125a-3p is upregulated in active lesions of multiple sclerosis (MS) patients and in OPCs isolated from the spinal cord of chronic experimental autoimmune encephalomyelitis (EAE) mice, but not in those isolated from the spontaneously remyelinating corpus callosum of lysolecithin-treated mice. To test whether a sustained expression of miR-125a-3p in OPCs contribute to defective remyelination, we modulated miR-125a-3p expression in vivo and ex vivo after lysolecithin-induced demyelination. We found that lentiviral over-expression of miR-125a-3p impaired OPC maturation, whereas its downregulation accelerated remyelination. Transcriptome analysis and luciferase reporter assay revealed that these effects are partly mediated by the direct interaction of miR-125a-3p with Slc8a3, a sodium-calcium membrane transporter, and identified novel candidate targets, such as Gas7, that we demonstrated necessary to correctly address oligodendrocytes to terminal maturation. These findings show that miR-125a-3p upregulation negatively affects OPC maturation in vivo, suggest its role in the pathogenesis of demyelinating diseases and unveil new targets for future promyelinating protective interventions.

Enhancing hyper-thermophilic hydrolysis pre-treatment of chicken manure for biogas production by in-situ gas phase ammonia stripping.

Hydrolysis is normally the rate limiting step for anaerobic digestion (AD). In this study, hyper-thermophilic (70 °C) pre-treatment of chicken manure under HRTs of 10, 5, 3, 2 and 1 d(s) was investigated to enhance the hydrolysis efficiency for biogas production. In-situ phase gas stripping was integrated into the pre-treatment reactor to remove ammonia-N and to enhance the hydrolysis performance. The results showed that in-situ gas stripping removed 18%-31% of ammonia-N and improved hydrolysis by 2.6%-31.1%. The methane yield of pre-hydrolyzed chicken manure reached 518 mL g-VS-1 under optimal HRT 3 days, which was 54.6% higher than that obtained from the control reactor. However, shortening HRTs below 3 days resulted in a significant reduction in hydrolysis efficiency. The percent of hydrolysis and acidogenesis bacteria reduced to 40.6% at HRT 1 d. 16sRNA results indicated existence of methanogens in pre-hydrolysis reactor. Further optimizing of ammonia stripping was thus needed for hydrolysis pre-treatment.

Did Frédéric Chopin Die From Heart Failure?

On October 17, 1849, Poland's greatest composer, Frédéric Chopin (1810-1849) died aged 39. His cause of death remains unknown. An investigation of the documental sources was performed to reconstruct the medical history of the artist. Since his earliest years, his life had been dominated by poor health. Recurrent episodes of cough, fever, headaches, lymphadenopathy- a series of symptoms that may be attributed to viral respiratory infections- manifested in his teens. Later in life, he had chest pain, hemoptysis, hematemesis, neuralgia, and arthralgia. Exhaustion and breathlessness characterized all his adult life. Coughing, choking, and edema of the legs and ankles manifested four months before his death. Several hypotheses ranging from cystic fibrosis to alpha-1 anti-trypsin deficiency and pulmonary tuberculosis have been proposed to explain Chopin's lifelong illness. We suggest that Chopin had dilated cardiomyopathy with consequent heart failure and cirrhosis that caused his death.

Differential local tissue permissiveness influences the final fate of GPR17-expressing oligodendrocyte precursors in two distinct models of demyelination.

Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreERT2 xCAG-eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+ cells at damaged areas. However, only in the cuprizone model reacting GFP+ cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+ cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery.

Prospectively validated dosing nomograms for maximizing the pharmacodynamics of vancomycin administered by continuous infusion in critically ill patients.

The efficacy of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA)-related infections has been called into question by recent findings of higher rates of failure of vancomycin treatment of infections caused by strains with high MICs. Continuous infusion may be the best way to maximize the time-dependent activity of vancomycin. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL(Cr)) estimates for use in daily clinical practice to target the steady-state concentrations (C(ss)s) of vancomycin during continuous infusion at 15 to 20 mg/liter (after the administration of an initial loading dose of 15 mg/kg of body weight over 2 h). The correlation between vancomycin clearance (CL(v)) and CL(Cr) was retrospectively assessed in a cohort of critically ill patients (group 1, n = 70) to create a formula for dosage calculation to target C(ss) at 15 mg/liter. The performance of this formula was prospectively validated in a similar cohort (group 2, n = 63) by comparison of the observed and the predicted C(ss)s. A significant relationship between CL(v) and CL(Cr) was observed in group 1 (P < 0.001). The application of the calculated formula to vancomycin dosing in group 2 {infusion rate (g/24 h) = [0.029 x CL(Cr) (ml/min) + 0.94] x target C(ss) x (24/1,000)} led to a significant correlation between the observed and the predicted C(ss)s (r = 0.80, P < 0.001). Two dosing nomograms based on CL(Cr) were created to target the vancomycin C(ss) at 15 and 20 mg/liter in critically ill patients. These nomograms could be helpful in improving the vancomycin treatment of MRSA infections, especially in the presence of borderline-susceptible pathogens and/or of pathophysiological conditions which may enhance the clearance of vancomycin, while potentially avoiding the increased risk of nephrotoxicity observed with the use of high intermittent doses of vancomycin.

Treatment of pyogenic (non-tuberculous) spondylodiscitis with tailored high-dose levofloxacin plus rifampicin.

The purpose of this study was to assess the clinical efficacy of high-dose levofloxacin plus rifampicin in the empirical treatment of non-tuberculous spondylodiscitis in an epidemiological context of low incidence of staphylococcal fluoroquinolone resistance. All consecutive adult patients with spondylodiscitis (January 2003 to December 2006) were empirically treated with high-dose levofloxacin (500 mg every 12 h normalised to renal function and optimised by means of therapeutic drug monitoring whenever feasible) plus rifampicin 600 mg every 24 h. Trough and peak plasma concentrations were targeted at 1-3 mg/L and 6-9 mg/L, respectively, to maximise the concentration-dependent activity of levofloxacin in bone. Follow-up was performed until 9 months after the end of therapy. Forty-eight patients were included. Eleven patients underwent a surgical approach for spine stabilisation. Among the 29 bacterial isolates, Staphylococcus aureus was the most frequent (65.5%) (all meticillin-susceptible strains). Tailored levofloxacin plasma exposure over time was ensured in most cases. Median treatment duration was 15.1 weeks. Overall response rates were: 77.1% at the intent-to-treat analysis; 84.1% among patients who completed therapy (N=44); and 96.3% among those receiving targeted therapy against documented levofloxacin-susceptible isolates (N=27). No patient had evidence of disease relapse at follow-up. Our findings suggest that high-dose levofloxacin regimens may be highly effective in the treatment of non-tuberculous spondylodiscitis and support its putative role in combination with rifampicin against S. aureus.

Human granulocytic anaplasmosis in northeastern Italy.

Sporadic cases of human granulocytic anaplasmosis (HGA) have been reported in areas with a high prevalence of tick-borne diseases (TBDs) in Europe. We aimed at estimating the sero-prevalence of A. phagocytophilum and other TBDs in northeastern Italy in outpatients with a history of recent tick bite or suspected TBD. In the 1-year study, 79 patients were enrolled and 30 (38%) received a diagnosis of TBD: 24 (30%) with Lyme disease and 5 (6%) with HGE. Our findings indicate the presence of HGA in northeastern Italy; so, since co-infection with Lyme disease appeared to be frequent, physicians assessing patients after a tick bite should consider HGA in the diagnosis.