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The European Centre for Medium-Range Weather Forecasts (ECMWF) mission is to deliver high-quality global medium-range numerical weather predictions and monitoring of the Earth system to its member states. The modelling and forecasting of natural hazards are an important part of this mission. Challenges in this area include the integration of innovative observations into the Earth system; realistic representations of water, energy and carbon cycles; coupling and initialisation of all Earth system components; adequate representation of uncertainties; supporting the development of user-specific products to enable optimal decision-making under uncertainties; and advances in software engineering. The new ECMWF strategy identified three pillars to sustain its future development (ECMWF, 2021a): science and technology (world-leading weather and Earth system science, cutting-edge technology and computational science), impact (high-quality products fit for purpose, efficient and easy access to products), and people (inspiring and hiring the best experts). Progress in all these areas will need enhanced collaboration with member states and partners across Europe and beyond.

Purpose: Non-tuberculous mycobacteria (NTM) account for high clinical burden, and treatment can be challenging. Moreover, accessibility of NTM medications varies across centers. These challenges may lead to unplanned therapeutic changes, discontinuations, potentially affecting patient outcomes. Aim of this survey was to evaluate the accessibility of NTM-targeting drugs in Italy (with a particular focus on clofazimine) in centers associated with the IRENE Registry, a collaborative network of healthcare professionals., Methods: A cross-sectional, internet-based, questionnaire-survey on the use and availability of clofazimineand other NTM-targeting drugs was sent to 88 principal investigators of the IRENE network in Italyin 2020. The questionnaires were designed with closed-ended and open-ended questions and distributed using the SurveyMonkey® platform., Results: The surveys underscore the more frequent involvement of pulmonologists (42%) and infectious disease specialists (34%) in NTM treating strategies. Respondents were distributed across 18 out of20 Italian regions, with a significant concentration in the north, encompassing university hospitalsand outpatient clinics. Molecular testing is available in 40% of the involved centers, while phenotypic in 30% of the centers. Centers have a multidisciplinary team and an appointed pharmacy service for NTM drugs distribution in 10 and 75% of the cases, respectively. Substantial variability was observed in drug availability and accessibility, drug regimen composition, and drug dosage, particularly for medications like clofazimine., Conclusions: This study shows the high heterogeneity of anti-NTM drug availability in Italy and prompts toward a harmonization in antibiotic prescription and access; it also emphasizes the challenges in determining the optimal therapeutic strategies for treating NTM-infections., (© 2024. The Author(s).)

Aim: Higher number of monocytes and neutrophils may correlate with active tuberculosis (TB) in children. However, the few paediatric studies available are limited by the small numbers of children with TB disease or infection included., Methods: We calculated the monocyte-to-lymphocyte-ratio (MLR), neutrophil-to-lymphocyte-ratio (NLR) and neutrophil-to-monocyte-plus-lymphocyte-ratio (NMLR) in children with active TB, latent TB infection (LTBI), other infectious and non-infectious conditions and healthy children evaluated in two referral centres in Rome., Results: Overall, 649 children were included (41.8% females, mean age of 5.74 years). MLR, NLR and NMLR values were always significantly higher in patients with TB compared with the other groups (p < 0.001). Considering the entire population with the outcome of TB diagnosis, NMLR, with a cut-off of 1.2, had a sensitivity of 63% and a specificity of 76% (AUC: 0.71 [0.64-0.78]); NLR, with a cut-off of 1.5, had a sensitivity of 61% and a specificity of 79% (AUC: 0.72 [0.65-0.79]); MLR, considering a cut-off of 0.2, was less sensitive (56%) but more specific (82%) with a similar AUC (0.72 [0.65-0.79])., Conclusion: Our study provides further evidence that MLR, NLR and NMLR can serve as first level diagnostics to support the clinical suspicion of TB in children., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Prolonged SARS-CoV-2 infections are widely described in immunosuppressed patients, but safe and effective treatment strategies are lacking. We aimed to outline our approach to treating persistent COVID-19 in patients with immunosuppression from different causes. In this case series, we retrospectively enrolled all immunosuppressed patients with persistent SARS-CoV-2 infections treated at our centers between March 2022 and February 2023. Patients received different sequential or combination regimens, including antivirals (remdesivir, nirmatrelvir/ritonavir, or molnupiravir) and/or monoclonal antibodies (mAbs) (tixagevimab/cilgavimab or sotrovimab). The main outcome was a complete virological response (negative SARS-CoV-2 RT-PCR on nasopharyngeal swabs) at the end of treatment. Fifteen patients were included as follows: eleven (11/15; 73%) with hematological disease and four (4/15; 27%) with recently diagnosed HIV/AIDS infection. Six patients (6/15; 40%) received a single antiviral course, four patients (4/15; 27%) received an antiviral and mAbs sequentially, and two patients (13%) received three lines of treatment (a sequence of three antivirals or two antivirals and mAbs). A combination of two antivirals or one antiviral plus mAbs was administered in three cases (3/15, 20%). One patient died while still positive for SARS-CoV-2, while fourteen (14/15; 93%) tested negative within 16 days after the end of treatment. The median time to negativization since the last treatment was 2.5 days. Both sequential and combination regimens used in this study demonstrated high efficacy and safety in the high-risk group of immunosuppressed patients.

(1) Background: Ceftolozane/tazobactam (C/T) is a novel β-lactam/β-lactamase inhibitor with excellent activity against the multidrug-resistant (MDR) P. aeruginosa . Continuous infusion (CI) dosing allows the optimization of pharmacokinetic and pharmacodynamic (PK/PD) properties of β-lactam antibiotics and may support patients' treatment as outpatients. (2) Methods: Adult patients receiving their entire course of C/T as a CI in the outpatient setting were retrospectively included in the study. The primary outcome evaluated was clinical resolution. The secondary outcomes evaluated were PK/PD target attainment (ƒT > 4 × MIC) and microbiologic clearance at the end of treatment. Therapeutic drug monitoring to assess C/T concentration was performed. (3) Results: Three patients were enrolled in the study and received 9 g of C/T in CI every 24 h. One patient received an additional course of antimicrobial therapy due to disease exacerbation six months after initial treatment, accounting for four evaluated treatments. The primary outcome was achieved in 3/4 treatments and the secondary outcome was achieved in 4/4 and 3/3, respectively. In all patients, free ceftolozane concentrations were >10 times higher than the EUCAST breakpoint (4 mg/L). (4) Conclusions: Elastomeric infusion of C/T delivered in CI can be an effective and convenient way to treat acute diseases caused by MDR- P. aeruginosa , avoid hospital admission, and contribute to infection control strategies. Despite the small number of enrolled patients, clinical and microbiological results support this strategy.

Infections due to carbapenem-resistant Enterobacterales (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes, especially in critically ill patients. Novel beta lactam antibiotics, including ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol, have been released in recent years to face the emerging challenge of multidrug-resistant (MDR) Gram-negative bacteria. Nonetheless, several novel agents lack pediatric indications approved by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA), leading to uncertain pediatric-specific treatment strategies and uncertain dosing regimens in the pediatric population. In this narrative review we have summarized the available clinical and pharmacological data, current limitations and future prospects of novel beta lactam antibiotics in the pediatric population.

Consolidated data from pharmacokinetic and pharmacodynamic studies support the administration of β-lactam antibiotics in prolonged infusion (i.e., extended or continuous) to optimize therapeutic efficacy by increasing the probability of attaining maximal bactericidal activity. This is the longest possible time during which the free drug concentrations are approximately four-fold the minimum inhibitory concentration between dosing intervals. In the context of antimicrobial stewardship strategies, achieving aggressive pharmacokinetic and pharmacodynamic targets is an important tool in the management of multi-drug resistant (MDR) bacterial infections and in the attainment of mutant preventing concentrations. However, prolonged infusion remains an unexploited resource. Novel β-lactam/β-lactamase inhibitor (βL/βLI) combinations (ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam) have been released in recent years to face the emerging challenge of MDR Gram-negative bacteria. Pre-clinical and real-life evidence has confirmed the promising role of prolonged infusion of these molecules in specific settings and clinical populations. In this narrative review we have summarized available pharmacological and clinical data, future perspectives, and current limitations of prolonged infusion of the novel protected β-lactams, their application in hospital settings and in the context of outpatient parenteral antimicrobial therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The current curative approaches for ischemia/reperfusion injury on liver transplantation are still under debate for their safety and efficacy in patients with end-stage liver disease. We present the SIMVA statin donor treatment before Liver Transplants study., Methods: SIMVA statin donor treatment before Liver Transplants is a monocentric, double-blind, randomized, prospective tial aiming to compare the safety and efficacy of preoperative brain-dead donors' treatment with the intragastric administration of 80 mg of simvastatin on liver transplant recipient outcomes in a real-life setting. Primary aim was incidence of patient and graft survival at 90 and 180 d posttransplant; secondary end-points were severe complications., Results: The trial enrolled 58 adult patients (18-65 y old). The minimum follow-up was 6 mo. No patient or graft was lost at 90 or 180 d in the experimental group (n = 28), whereas patient/graft survival were 93.1% ( P = 0.016) and 89.66% ( P = 0.080) at 90 d and 86.21% ( P = 0.041) and 86.2% ( P = 0.041) at 180 d in the control group (n = 29). The percentage of patients with severe complications (Clavien-Dindo ≥IIIb) was higher in the control group, 55.2% versus 25.0% in the experimental group ( P = 0.0307). The only significant difference in liver tests was a significantly higher gamma-glutamyl transferase and alkaline phosphatase at 15 d ( P = 0.017), ( P = 0.015) in the simvastatin group., Conclusions: Donor simvastatin treatment is safe, and may significantly improve early graft and patient survival after liver transplantation, although further research is mandatory., Competing Interests: D.P. and E.O. reported receiving grants from Italian government research funding. The other authors declare no conflicts of interest. The authors hereby certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, Trypanosoma brucei . Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against Trypanosoma brucei spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity.

Background: Identifying determinants of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) transmission in settings of contagion is fundamental to inform containment strategies. We assessed SARS-CoV-2 cycle threshold value (Ct) from the first diagnostic nasal-pharyngeal swab of symptomatic index cases and which demographic or clinical characteristics among cases and contacts are associated with transmission risk within households., Methods: This is a retrospective prevalence study on secondary SARS-CoV-2 cases (SC) among the household contacts of symptomatic adult index cases randomly sampled from all the SARS-CoV-2-positive diagnostic nasopharyngeal swabs analyzed at our regional referral hospital (Amedeo di Savoia Hospital, Turin, Italy) in March, 2020. Index cases underwent a telephone survey to collect their demographic and clinical data and all their household contacts. The Ct value of RdRp gene from the first diagnostic swab of index cases was recorded and index cases were grouped according to Ct tertiles (A < first tertile, first ≤ B ≤ second tertile, C ≥ second tertile). Post hoc analysis was performed in SC as well as contacts that did not undergo SARS-CoV-2 testing but developed compatible signs and symptoms. Non-parametric tests and generalized linear models were run., Results: Index ( n = 72) and contact ( n = 164) median age was 54 (48-63) and 32 (20-56) years, respectively. A total of 60, 50, and 54 subjects were contacts of group A, B, and C index cases, respectively; 35.9% of contacts were SC. Twenty-four further subjects (14.6%) met the criteria for symptom-based likely positive SC. The secondary attack rate was 36.0% (28.6-43.4), assuming a mean incubation period of 5 days and a maximum infectious period of 20 days. SC prevalence differed between Ct groups (53.3% A, 32.0% B, 20.4% C; p < 0.001). No difference in SC was found according to sex, presence of signs/symptoms, and COVID-19 severity of index cases, or according to contacts' sex and number per household. The age of both index cases [aOR 4.52 (1.2-17.0) for 60 vs. ≤45 years old] and contacts [aOR 3.66 (1.3-10.6) for 60 vs. ≤45years old] and the Ct of the index [aOR 0.17 (0.07-0.4) for Ct ≥ 31.8 vs. Ct < 24.4] independently associated with SC risk. Sensitivity analysis including symptoms-based likely positive SC supported all the previous results., Conclusion: In confined transmission settings such as households, PCR Ct values may inform on the contagiousness of infected subjects and age may modulate transmission/contagion risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Trunfio, Richiardi, Alladio, Staffilano, Longo, Venuti, Ghisetti, Burdino, Bonora, Vineis, Di Perri and Calcagno.)

Background: Emerging evidence supports the "variolation hypothesis" in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), but the derivative idea that the viral load of index cases may predict disease severity in secondary cases could be unsubstantiated. We assessed whether the prevalence of symptomatic infections, hospitalization, and deaths in household contacts of 2019 novel coronavirus disease (COVID-19) cases differed according to the SARS-CoV-2 PCR cycle threshold (Ct) from nasal-pharyngeal swab at diagnosis of linked index cases. Methods: Cross-sectional study on household contacts of COVID-19 cases randomly sampled from all the infections diagnosed in March at our Microbiology Laboratory (Amedeo di Savoia, Turin). Data were retrospectively collected by phone interviews and from the Piedmont regional platform for COVID-19 emergency. Index cases were classified as high (HVl) and low viral load (LVl) according to two exploratory cut-offs of RdRp gene Ct value. Secondary cases were defined as swab confirmed or symptom based likely when not tested but presenting compatible clinical picture. Results: One hundred thirty-two index cases of whom 87.9% symptomatic and 289 household contacts were included. The latter were male and Caucasian in 44.3 and 95.8% of cases, with a median age of 34 years (19-57). Seventy-four were swab confirmed and other 28 were symptom based likely secondary cases. Considering both, the contacts of HVl and LVl did not differ in the prevalence of symptomatic infections nor COVID-19-related hospitalization and death. No difference in median Ct of index cases between symptomatic and asymptomatic, hospitalized and not hospitalized, or deceased and survived secondary cases was found. Negative findings were confirmed after adjusting for differences in time between COVID-19 onset and swab collection of index cases (median 5 days) and after removing pediatric secondary cases. Conclusions: The amount of SARS-CoV-2 of the source at diagnosis does not predict clinical outcomes of linked secondary cases. Considering the impelling release of assays for SARS-CoV-2 RNA exact quantification, these negative findings should inform clinical and public health strategies on how to interpret and use the data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Trunfio, Longo, Alladio, Venuti, Cerutti, Ghisetti, Bonora, Di Perri and Calcagno.)

Pharmacists in the community and the essential requirement to safeguard their own health have become fundamental since the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aims of this paper were (I) to analyze the directives provided to pharmacists in 2020 regarding preventative safety measures to be adopted; (II) to determine the number of pharmacists who came into contact with SARS-CoV-2 in North-West Italy and relate this to the adopted preventative measures. The first aim was pursued by conducting a bibliographic research, consulting the principal regulatory sources. The second one was achieved with an observational study by administering a questionnaire and performing a serological test. The various protection measures imposed by national and regional legislation were analyzed. Two hundred and eighty-six pharmacists (about 8% of the invited ones) responded to the survey. Ten pharmacists reported a positive result to the serological test. Of the subjects who presented a positive result, three declared that they had not used a hand sanitizer, while two stated that they had not scheduled the cleaning and decontamination of surfaces. Two interviewees had not set up a system of quota restrictions on admissions. In four cases, a certified cleaning company had decontaminated the premises. The results of our study show that during the coronavirus disease 2019 (COVID-19) pandemic, the most pressing challenge for community pharmacists has been the protection of staff and clients inside the pharmacy; the challenge to be faced in the near future will probably be the management of new responsibilities.

To date, there is no severe acute respiratory syndrome coronavirus 2-(SARS-CoV-2)-specific prognostic biomarker available. We assessed whether SARS-CoV-2 cycle threshold (Ct) value at diagnosis could predict novel CoronaVirus Disease 2019 (COVID-19) severity, clinical manifestations, and six-month sequelae. Hospitalized and outpatient cases were randomly sampled from the diagnoses of March 2020 and data collected at 6 months by interview and from the regional database for COVID-19 emergency. Patients were stratified according to their RNA-dependent-RNA-polymerase Ct in the nasopharyngeal swab at diagnosis as follows: Group A ≤ 20.0, 20.0 < group B ≤ 28.0, and Group C > 28.0. Disease severity was classified according to a composite scale evaluating hospital admission, worst oxygen support required, and survival. Two hundred patients were included, 27.5% in Groups A and B both, 45.0% in Group C; 90% of patients were symptomatic and 63.7% were hospitalized. The median time from COVID-19 onset to swab collection was five days. Lethality, disease severity, type, and number of signs and symptoms, as well as six-month sequelae distributed inversely among the groups with respect to SARS-CoV-2 Ct. After controlling for confounding, SARS-CoV-2 Ct at diagnosis was still associated with COVID-19-related death ( p = 0.023), disease severity ( p = 0.023), number of signs and symptoms ( p < 0.01), and presence of six-month sequelae ( p < 0.01). Early quantification of SARS-CoV-2 may be a useful predictive marker to inform differential strategies of clinical management and resource allocation.

This paper aims to provide a review and critical analysis of the state of the art concerning crowd-structure interaction phenomena on footbridges. The problem of lateral vibrations induced by synchronised pedestrians, namely the Synchronous Lateral Excitation, is specifically addressed. Due to the multi-physic and multi-scale nature of the complex phenomenon, several research fields can contribute to its study, from structural engineering to biomechanics, from transportation engineering to physics and applied mathematics. The different components of the overall coupled dynamical system - the structure, the crowd and their interactions - are separately analysed from both a phenomenological and modelling point of view. A special attention is devoted to those models, which explicitly account for the interaction between mechanical and living systems.

Purpose: The purpose of the study was to evaluate the incidence of incontinence pad use among patients admitted to medical wards, the reasons why nurses decide to use an incontinence pad, the extent to which the use of pads is avoidable, and the outcome of inappropriate pad use after discharge from the hospital., Methods: A prospective cohort study was conducted; patients admitted to medical wards were observed during hospitalization and a 7-day follow-up period after discharge., Subjects and Setting: The study was conducted in 2 acute-care units in Northern Italy. All new patients admitted to the units were recruited., Results: At the time of admission to the hospital, in addition to the 120 patients who already used incontinence pads, there was a 34% incidence of new cases (98/286). The most frequent reason why nurses decided to use this aid was incontinence caused by space-time disorientation, followed by limited mobility, incontinence, patient request, nursing shortage, and involuntary urine leakage not perceived by patient. Seventy patients out of 208 used incontinence pads unnecessarily for a total of 544 days., Conclusions: Decisions about the use of the incontinence pads are not always consistent with research-based or literature-based suggestions. Nurses should develop clinical guidelines or protocols for the appropriate use of incontinence pads.

Aim: Aim of this study is to report our preliminary experience with a minimally invasive surgical procedure using transobturator approach., Methods: We enrolled in our study 19 patients with stress urinary incontinence and urethral hypermobility without genital prolapse. All patients underwent suburethral transobturator tape (TOT) procedure. Four patients underwent previous surgical procedure for incontinence (3 Kelly and 1 Burch). No patients reported previous major gynaecological surgery. Mean age was 58.68 years (range 36-75). The sling was placed according to the technique described by Delorme., Results: Mean operating time was 21 min (range 14-48). No bladder lesions or intraoperative complications occurred. Fifteen patients were dismissed the same day of surgery. Mean hospital staying was 1.4 days (range 1-5). No infections, erosions or sieromas have been observed., Conclusions: Our experience shows as TOT technique is extremely rapid, reproducible and with a very short learning curve. The transobturator approach avoids the risk of bladder, bowel or vascular injuries. Compliance and patient satisfaction have been very encouraging, restoring a real functional well-being. However, the small number of patients in our study and the short follow up do not actually allow us to draw definitive results and further studies are needed to confirm the technique success.

Acetone extract of Peucedanum nebrodense (Guss.) Strohl., a rare endemic species from the Madonie mountains (Sicily), was tested in vitro for its antimicrobial activity against bacterial reference strains and antiproliferative activity against K562 (human chronic myelogenous leukemia), HL-60 (human leukemia) and L1210 (murine leukemia) cell lines. The acetone extract showed antiproliferative IC50 values in the range of 14-0.27 microg/ml.