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Urinary incontinence (UI) is a widespread condition affecting about 200 million people worldwide, with women affected more often than men and prevalence increasing with age. UI is a significant health problem that negatively impacts affected women’s well-being, sociality, and productivity. Therefore, seeking medical advice is highly recommended since valid treatment options exist. However, a definitive solution to the problem is not always possible. In these cases, absorbent containment products can help women deal with the persistent symptoms of incontinence, minimising the effects on the quality of life. High-quality products are paramount to avoid or reduce the onset of irritating skin phenomena, which can sometimes lead to more serious consequences, such as skin infections. Cotton is a natural fibre characterised by softness and hypoallergenic properties that has already shown its ability to improve skin health when used as a component of pads and other absorbent containment products. The aim of this work was to assess the safety and efficacy of a new organic cotton pull-on absorbent product in reducing skin erythema and oedema in women suffering from moderate to heavy urinary incontinence. In-vitro and clinical studies were performed. Results showed that the tested product effectively reduces skin erythema and oedema caused by the conventional use of synthetic pull-on absorbent products. Moreover, good compliance with the use was demonstrated compared to a non-cotton competitor device available on the market. In conclusion, the organic cotton absorbent device tested has improved the quality of life of women suffering from moderate to heavy urinary incontinence.

Objectives To assess whether high doses of Low Molecular Weight Heparin (LMWH) (i.e. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (i.e., Enoxaparin 4000 IU once day), in hospitalized patients with COVID19 not requiring Invasive Mechanical Ventilation [IMV], are: more effective in preventing clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: DeathAcute Myocardial Infarction [AMI]Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]Need of either: Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orIMV in patients who at randomisation were receiving standard oxygen therapyIMV in patients who at randomisation were receiving non-invasive mechanical ventilationSimilar in terms of major bleeding risk Trial design Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study. Participants Inpatients will be recruited from 7 Italian Academic and non-Academic Internal Medicine Units, 2 Infectious Disease Units and 1 Respiratory Disease Unit. Inclusion Criteria (all required) Age > 18 and < 80 years Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) Severe pneumonia defined by the presence of at least one of the following criteria: Respiratory Rate ≥25 breaths /minArterial oxygen saturation≤93% at rest on ambient airPaO2/FiO2 ≤300 mmHg Coagulopathy, defined by the presence of at least one of the following criteria: D-dimer >4 times the upper level of normal reference rangeSepsis-Induced Coagulopathy (SIC) score >4 No need of IMV Exclusion Criteria Age 80 years IMV Thrombocytopenia (platelet count < 80.000 mm3) Coagulopathy: INR >1.5, aPTT ratio > 1.4 Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation < 30 ml/min) Known hypersensitivity to enoxaparin History of heparin induced thrombocytopenia Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant cancer at high risk of haemorrhage, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations) Concomitant anticoagulant treatment for other indications (e.g. atrial fibrillation, venous thromboembolism, prosthetic heart valves) Concomitant double antiplatelet therapy Administration of therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for more than 72 hours before randomization; prophylactic doses are allowed Pregnancy or breastfeeding or positive pregnancy test Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) Lack or withdrawal of informed consent Intervention and comparator Control Group (Low-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at standard prophylactic dose (i.e., 4000 UI subcutaneously once day). Intervention Group (High-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at dose of 70 IU/kg every 12 hours, as reported in the following table. This dose is commonly used in Italy when a bridging strategy is required for the management of surgery or invasive procedures in patients taking anti-vitamin K oral anticoagulants Body Weight (kg)Enoxaparin dose every 12 hours (IU)200050-69400070-89600090-1108000>11010000 The treatment with Enoxaparin will be initiated soon after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered every 12 hours in the intervention group and every 24 hours in the control group. Treatments will be administered in the two arms until hospital discharge or the primary outcomes detailed below occur. Main outcomes Primary Efficacy Endpoint: Clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: DeathAcute Myocardial Infarction [AMI]Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]Need of either: Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orIMV in patients who at randomisation were in standard oxygen therapy by delivery interfacesNeed for IMV, in patients who at randomisation were in Cpap or NIV Time to the occurrence of each of these events will be recorded. Clinical worsening will be analysed as a binary outcome as well as a time-to-event one. Secondary Efficacy Endpoints: Any of the following events occurring within the hospital stay DeathAcute Myocardial Infarction [AMI]Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]Need of either: Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orIMV in patients who at randomisation were in standard oxygen therapy by delivery interfacesNeed for IMV in patients who at randomisation were in Cpap or NIVImprovement of laboratory parameters of disease severity, including: o D-dimer levelo Plasma fibrinogen levelso Mean Platelet Volumeo Lymphocyte/Neutrophil ratioo IL-6 plasma levels Mortality at 30 days Information about patients’ status will be sought in those who are discharged before 30 days on Day 30 from randomisation. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Primary safety endpoint: Major bleeding, defined as an acute clinically overt bleeding associated with one or more of the following: Decrease in haemoglobin of 2 g/dl or more;Transfusion of 2 or more units of packed red blood cells;Bleeding that occurs in at least one of the following critical sites [intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal];Bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death);Bleeding that necessitates surgical intervention Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Secondary safety endpoint: Clinically Relevant non-major bleeding, defined as an acute clinically overt bleeding that does not meet the criteria for major and consists of: Any bleeding compromising hemodynamicSpontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic causeIntramuscular hematoma documented by ultrasonographyEpistaxis or gingival bleeding requiring tamponade or other medical interventionBleeding from venipuncture for >5 minutesHaematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive proceduresHaemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical interventionAny other bleeding requiring temporary cessation of a study drug. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Randomisation Randomisation (with a 1:1 randomisation ratio) will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (2) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment. Blinding (masking) The study is conceived as open-label: patients and all health-care personnel involved in the study will be aware of the assigned group. Numbers to be randomised (sample size) The target sample size is based on the hypothesis that LMWH administered at high doses versus low doses will significantly reduce the risk of clinical worsening. The overall sample size in this study is expected to be 300 with 150 in the Low-Dose LMWH control group and 150 in the High-Dose LMWH intervention group, recruited over 10-11 months. Assuming an alpha of 5% (two tailed) and a percentage of patients who experience clinical worsening in the control group being between 25% and 30%, the study will have 80% power to detect at least 50% relative reduction in the risk of death between low and high doses of heparin. Trial Status Protocol version 1.2 of 11/05/2020. Recruitment start (expected): 08/06/2020 Recruitment finish (expected): 30/04/2021 Trial registration EudraCT 2020-001972-13, registered on April 17th, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

The NA62 experiment at the CERN SPS reports the first search for K+ -> pi(+) nu(nu) over bar using the decay-in-flight technique, based on a sample of 1.21 x10(11) K+ decays collected in 2016. The single event sensitivity is 3.15 x10(-10), corresponding to 0.267 Standard Model events. One signal candidate is observed while the expected background is 0.152 events. This leads to an upper limit of 14 x10(-10) on the K+ -> pi(+) nu(nu) over bar branching ratio at 95% CL., The cost of the experiment and of its auxiliary systems were supported by the funding agencies of the Collaboration Institutes. We are particularly indebted to: F.R.S.-FNRS (Fonds de la Recherche Scientifique - FNRS), Belgium; BMES (Ministry of Education, Youth and Science), Bulgaria; NSERC (Natural Sciences and Engineering Research Council), Canada; NRC (National Research Council) contribution to TRIUMF, Canada; MEYS (Ministry of Education, Youth and Sports), Czech Republic; BMBF (Bundesministerium für Bildung und Forschung) contracts 05H12UM5 and 05H15UMCNA, Germany; INFN (Istituto Nazionale di Fisica Nucleare), Italy; MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca), Italy; CONACyT (Consejo Nacional de Ciencia y Tecnología), Mexico; IFA (Institute of Atomic Physics), Romania; INR-RAS (Institute for Nuclear Research of the Russian Academy of Sciences), Moscow, Russia; JINR (Joint Institute for Nuclear Research), Dubna, Russia; NRC (National Research Center) “Kurchatov Institute” and MESRF (Ministry of Education and Science of the Russian Federation), Russia; MESRS (Ministry of Education, Science, Research and Sport), Slovakia; CERN (European Organization for Nuclear Research), Switzerland; STFC (Science and Technology Facilities Council), United Kingdom; NSF (National Science Foundation) Award Number 1506088, U.S.A.; ERC (European Research Council) “UniversaLepto” advanced grant 268062, “KaonLepton” starting grant 336581, Europe. Individuals have received support from: Charles University (project GA UK number 404716), Czech Republic; Ministry of Education, Universities and Research (MIUR “Futuro in ricerca 2012” grant RBFR12JF2Z, Project GAP), Italy; Russian Foundation for Basic Research (RFBR grants 18-32-00072, 18-32-00245), Russia; the Royal Society (grants UF100308, UF0758946), United Kingdom; STFC (Rutherford fellowships ST/J00412X/1, ST/M005798/1), United Kingdom; ERC (grants 268062, 336581).

OBJECTIVE: To assess the efficacy of progestogens for maintenance tocolysis in women undelivered after their first preterm labor episode. METHODS: Women with singleton pregnancies between 22 0/7 and 31 6/7 weeks of gestation with arrested preterm labor and a cervical length 25 mm or less at hospital discharge were eligible. Patients with a previous preterm birth were excluded. In a randomized controlled trial conducted in five university hospitals, women were randomized to receive vaginal progesterone (200 mg per day) or intramuscular 17α-hydroxyprogesterone caproate (341 mg per week) or to an observation groups (control group). The primary outcome was the proportion of women with preterm birth at less than 37 weeks of gestation. A sample size of 160 per group (n=480) was planned to compare vaginal progesterone and 17ahydroxyprogesterone caproate groups with those in the control group. The sample size estimation was based on the hypothesis that the risk of experiencing preterm birth in the control group would be 30% and that 17α-hydroxyprogesterone caproate or progesterone would decrease this risk to 15%. A P value of ≤.025 was defined as statistically significant. At planned interim analysis (n=254), the trial was stopped for futility. RESULTS: Between July 2010 and June 2015, 257 women were eligible and 254 were subsequently randomly assigned to vaginal progesterone (n=86), 17α-hydroxyprogesterone caproate (n=87), or observation (n=81). Nineteen (8%) were excluded from the analysis because they either dropped out or information was missing, leaving 235 women available for analysis. Demographic characteristics were similar across groups. The preterm birth rate did not differ significantly between groups: 23% in the 17a-hydroxyprogesterone caproate group, 39% in the vaginal progesterone group, and 22% in the women in the control group (P=.949 for 17a-hydroxyprogesterone caproate compared with the women in the control group and P=.027 for vaginal progesterone compared with women in the control group). CONCLUSION: The use of progestogens for maintenance tocolysis in women with a short cervix did not reduce the rate of preterm birth.

Introduction Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients.Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. Methods RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Discussion Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. Ethics and dissemination The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.

Background Interstitial lung disease (ILD) is a severe systemic manifestation of rheumatoid arthritis (RA). High-resolution computed tomography (HRCT) represents the gold standard for the diagnosis of ILD, but its routine use for screening programs is not advisable because of both high cost and X-ray exposure. Velcro crackles at lung auscultation occur very early in the course of interstitial pneumonia, and their detection is an indication for HRCT. Recently, we developed an algorithm (VECTOR) to detect the presence of Velcro crackles in pulmonary sounds and showed good results in a small sample of RA patients. The aim of the present investigation was to validate the diagnostic accuracy of VECTOR in a larger population of RA patients, compared with that of the reference standard of HRCT, from a multicentre study. Methods To avoid X-ray exposure, we enrolled 137 consecutive RA patients who had recently undergone HRCT. Lung sounds of all patients were recorded in 4 pulmonary fields bilaterally with a commercial electronic stethoscope (ES); subsequently, all HRCT images were blindly evaluated by a radiologist, and audio data were analysed by means of VECTOR. Results Fifty-nine of 137 patients showed ILD (43.1%). VECTOR correctly classified 115/137 patients, showing a diagnostic accuracy of 83.9% and a sensitivity and specificity of 93.2 and 76.9%, respectively. Conclusions VECTOR may represent the first validated tool for the screening of RA patients who are suspected for ILD and who should be directed to HRCT for the diagnosis. Moreover, early identification of RA-ILD could contribute to the design of prospective studies aimed at elucidating unclear aspects of the disease.

Background The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. Methods The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. Results A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P P P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). Conclusions The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment. Trial registration EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

The duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD. METHODS AND FINDINGS: We investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], -7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days. CONCLUSIONS: Although the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098). TRIAL REGISTRATION: ClinicalTrials.gov NCT01125098. journal.pone.0118241 Background The duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD. Methods and Findings We investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], -7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days. Conclusions Although the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098).