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ObjectiveThere is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics.MethodsA multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared.ResultsThe overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs.ConclusionOur study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53–1203) vs 825 (451–1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

The impact of reperfusion delay in ST-elevation myocardial infarction (STEMI) is well known. We aimed to describe the specific reasons for delay to primary percutaneous coronary intervention (pPCI), and their impact on mortality after adjusting for confounders, using the first-medical-contact-to-device (FMCTD) time to measure the delay.Between January 2006 and December 2019, 2149 STEMI patients underwent pPCI at our centre. Delayed pPCI was defined as FMCTD 90 min or 120 min in the case of inter-hospital transfer. The causes of delay were classified as system-related (related to the network organization) or patient-related (related to the clinical condition of the patient). Primary outcome was 1-year all-cause mortality.The pPCI was timely in 69.9% of patients, delayed for system-related causes in 16.4% or for patient-related causes in 13.7%. Different patient-related causes induced variable median FMCTD time (from 114 min for technically difficult pPCI to 159 min for ECG and/or symptom resolution). By multivariable Cox-regression models, the main independent risk factors for mortality were delay due to comorbidities [hazard ratio (HR) 2.19 (1.22-3.91)], or hemodynamic instability [HR 2.05 (1.25-3.38)], after adjusting for Global Registry of Acute Coronary Events risk score tertiles and angiographic success. The difference in risk of mortality is maintained over the entire spectrum of time from symptom onset.Different causes of delay had different impacts on mortality, generally more important than the length of the delay. Causes of delay such as hemodynamic instability and comorbidities should prompt specific programs of performance improvement. Timely pPCI maintains prognostic advantages after several hours from symptom onset, mandating prompt reperfusion also in late-presenter patients.

Background Since summer 2014, the National MCH Workforce Development Center has placed students from MCH public health graduate (Centers of Excellence and Catalyst) and undergraduate (MCH Pipeline) programs, all funded by the Maternal and Child Health Bureau, in summer internships with state and territorial Title V agencies. In 2020, due to the COVID-19 pandemic the Title V MCH Internship Program was offered virtually. Participants and Methods This manuscript includes quantitative and qualitative data from 2017 to 2020 generated by both Title V MCH Internship student interns (n = 76) and their preceptors (n = 40) with a focus on a comparison between the 2020 virtual year and the 2017–2019 years. Results Evaluation data from the 2017 to 2020 Title V MCH Internship Program from both students and preceptors revealed the implementation of a robust and successful internship program in which students increased their confidence in a variety of team, mentorship, and leadership skills while gaining direct exposure to the daily work of state Title V agencies. However, students and preceptors identified more challenges during 2020 compared to previous years. Conclusions The COVID-19 Pandemic was both a disruption and a catalyst for change in education. While there were clearly some challenges with the pivot to a virtual Title V MCH Internship Program in summer 2020, students were able to participate in meaningful internship experiences. This success can be attributed to the ability of the internship sponsor to engage in best practices, including extensive planning and provision of ongoing support to the students. Going forward, it is recognized that virtual internships may facilitate access to agencies in distant locales, eliminating issues related to housing and transportation. When both virtual and in-person relationships are available, those responsible for internship programs, including the Title V MCH Internship, will need to weigh these type of benefits against the potential missed opportunities students may have when not able to participate in on-site experiences.

Sjögren’s syndrome (SS) is an autoimmune disease that involves the nervous system in about 20% of cases. In 25-92% of patients affected by Sjögren’s syndrome, neurological symptoms may precede the sicca syndrome. A 65-year-old male presented with a seven-month history of episodes of near-syncope, constipation, anhidrosis, disabling fatigue and asthenia. Physical examination was unremarkable, whilst the ECG revealed sinus bradycardia. Laboratory tests showed lymphopenia and normal inflammatory markers. In order to assess a potential autonomic neuropathy, “Deep Breathing Test” (E/I 1.02), “Lying to Standing Test” (R/R’ 0.95), and “Orthostatic Hypotension Tests” (T 120s Systolic reduction >20 mmHg and Diastolic reduction >10 mmHg) were performed, all of which were abnormal. ECG Holter monitoring revealed sinus bradycardia, and right bundle branch block with 24-h blood pressure monitoring revealing a diurnal hypotensive profile. The patient reported a three-month history of worsening dry mouth. On physical examination, the patient had anisocoria in response to light stimulation. Auto-antibody testing was performed to evaluate the presence of any autoimmune disease. The results of these studies included an abnormal elevation of ANA (1:320 speckled pattern), Ro/SS-a (>240U/l), and La/SS-b (162 U/ml) antibodies. The patient was discharged with a diagnosis of “Autonomic Neuropathy Most Likely Due to Primary Sjögren’s Syndrome (SS)” and started the immunotherapy. After one month, he reported a significant improvement in his symptoms with a concomitant normalization of his “Orthostatic Hypotension Tests.” This case underlines the potential for dys-autonomic symptoms to precede the onset of sicca syndrome in patients with Sjogren’s Syndrome.

Purpose No accepted benchmarks for open pancreaticoduodenectomy (PD) exist. The study assessed the time to functional recovery after open PD and how this could be affected by the magnitude of midline incision (MI). Materials and methods Prospective snapshot study during 1 year. Time to functional recovery (TtFR) was assessed for the entire cohort. Further analyses were conducted after excluding patients developing a Clavien-Dindo ≥ 2 morbidity and after stratifying for the relative length of MI. Results The overall median TtFR was 7 days (n = 249), 6 days for uncomplicated patients (n = 124). A short MI (SMI, n = 62) was compared to a long MI (LMI, n = 62) in uncomplicated patients. The choice of a SMI was not affected by technical issues and provided a significantly shorter TtFR (5 vs 6 days, p = 0.002) especially for pain control (4 vs. 5 days, p = 0.048) and oral food intake (5 vs. 6 days, p = 0.001). Conclusion Functional recovery after open PD with MI is achieved within 1 week from surgery in half of the patients. This should be the appropriate benchmark for comparison with minimally invasive PD. Moreover, PD with a SMI is feasible, safe, and associated with a faster recovery.

Background This study was designed to demonstrate the non-inferiority (NI) in overall survival (OS) of suspension of androgen deprivation therapy (ADT) versus maintenance and intermittent versus continuous docetaxel administration in metastatic castration-resistant prostate cancer (mCRPC) patients. Patients and methods mCRPC patients were randomised to first-line docetaxel with maintenance or suspension of ADT. Patients attaining a prostate-specific antigen (PSA) response after four chemotherapy cycles underwent second randomisation to receive continuous or intermittent docetaxel therapy. Six hundred patients were to be randomised to achieve 80% statistical power to demonstrate an NI hazard ratio (HR) of 1.25 of interruption versus maintenance of ADT. Results The trial was prematurely closed when 198 participants were randomised. OS was similar in patients who continued (N = 96) versus those who interrupted (n = 102) ADT during docetaxel therapy (HR 0.98, 95% confidence interval [CI] 0.72–1.33] and those on a continuous (N = 35) versus an intermittent (N = 42) docetaxel schedule (HR 0.86, 95% CI 0.55–1.43). No difference in radiological progression-free survival, PSA response, or toxicity was observed between the study arms. The actual NI hazard margins of OS in Arms A and B patients were 1.33 and 1.43, respectively. Conclusions This trial enrolled one-third of the planned patients; this main weakness dramatically limits the interpretation of the results. ADT discontinuation and switching to an intermittent schedule did not seem to affect docetaxel efficacy. The absence of testosterone recovery in the majority of patients could have been a contributory factor. In men with mCRPC, ADT discontinuation should only be done with regular biochemical and clinical monitoring, with the option of quickly restarting ADT at disease progression.

Early identification of preeclampia in the first trimester of pregnancy represents one of the major challenges of modern fetal medicine. The primary aim of our study was to evaluate the effectiveness of implementation of preeclampsia screening in Tuscany, Italy. The secondary aim was to evaluate pregnancy/neonatal outcome in the positive screening group compared with the negative screening group.Retrospective study including singleton pregnancies undergoing screening for preeclampsia. The screening test was a multiparametric algorithm based on maternal history, biochemical and biophysical parameters (Fetal Medicine Foundation algorithm).The overall performance of the test was calculated, in terms of sensitivity, specificity, positive and negative predictive value and in relation to gestational age at onset (primary aim). Pregnancy and neonatal outcomes were then compared between the positive and negative population at preeclampsia screening test (secondary aim).Of the 5719 patients enrolled, 4797 were included in the analysis. The sensitivity for early onset of preeclampsia (≤34 weeks) was 0.75 (CI:0.41-0.93) and specificity 0.93 (CI:0.92-0.94) for a false positive rate of 7%. The population that tested positive for preeclampsia screening showed a higher incidence of deliveries at lower gestational ages (p 0.001), preeclampsia onset despite prophylaxis with aspirin (p 0.001), emergency caesarean section (p 0.001), low fetal birth weight (p 0.001) and neonatal admission in intensive care unit (p 0.001).Our data confirm the validity of first trimester screening test in identifying a category of patients at greatest risk for preeclampsia even in the presence of a post-test pharmacological prophylaxis.

BackgroundDignity is a basic principle of palliative care and is intrinsic in the daily practice of professionals assisting individuals with incurable diseases. Dignity Therapy (DT) is a short-term intervention aimed at improving the sense of purpose, meaning and self-worth and at reducing the existential distress of patients facing advanced illness. Few studies have examined how DT works in countries of non-Anglo Saxon culture and in different real-life settings. Moreover, most studies do not provide detailed information on how DT is conducted, limiting a reliable assessment of DT protocol application and of its evaluation procedure.The aim of this study was to assess the feasibility and acceptability of a nurse-led DT intervention in advanced cancer patients receiving palliative care.MethodThis is a mixed-method study using before and after evaluation and semistructured interviews. Cancer patients referred to a hospital palliative care unit were recruited and provided with DT. The duration of sessions, and timeframes concerning each step of the study, were recorded, and descriptive statistical analyses were performed.The patients' dignity-related distress and feedback toward the intervention were assessed through the Patient Dignity Inventory and the Dignity Therapy Patient Feedback Questionnaire, respectively. Three nurses were interviewed on their experience in delivering the intervention, and the data were analyzed qualitatively.ResultsA total of 37/50 patients were enrolled (74.0%), of whom 28 (75.7%) completed the assessment. In 76.7% of cases, patients completed the intervention in the time limit scheduled in the study. No statistically significant reduction in the Patient Dignity Inventory scores was observed at the end of the intervention; most patients found DT to be helpful and satisfactory. Building opportunities for personal growth and providing holistic care emerged among the facilitators to DT implementation. Nurses also highlighted too great of a time commitment and a difficult collaboration with ward colleagues among the barriers.ConclusionsOur findings strongly support the acceptability, but only partially support the feasibility, of nurse-led DT in advanced cancer patients in a hospital setting. Further research is needed on how to transfer the potential benefits of DT into clinical practice.Trial registrationRetrospectively registered on ClinicalTrial.govNCT04738305.

Background Several advantages and pitfalls have been related to externalized trans-anastomotic stents (ETS) after pancreaticoduodenectomy. The purpose of this study was to investigate the effect of an ETS effect in a risk-stratified setting. Methods Data from patients at either intermediate- or high-risk for postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy were prospectively analyzed from January 2016 to December 2019. Outcomes included POPF rate, mean complication burden (ACB), and complications related to ETS malfunction. Results A total of 540 patients met the inclusion criteria. Following an intention-to-treat analysis, there was no difference in terms of POPF and the ACB in the intermediate (22 vs.29%, p = 0.148; 0.38 vs.0.24, p = 0.082) and high-risk categories (58 vs.37%, p = 0.103; 0.33 vs.0.33, p = 0.478) comparing PJ to PJ-ETS. Excluding patients experiencing ETS malfunction (n = 45, 22%), ETS was associated with a significantly reduced ACB in the intermediate-risk (0.38 vs.0.26, p = 0.009) and POPF rate in the high-risk category (58 vs.32%, p = 0.033). In patients with ETS malfunction an increased rate of severe morbidity (Clavien-Dindo ≥ III, 33 vs.19%, p = 0.044) was observed as compared to patients with functioning ETS. Conclusion ETS provides crucial advantages for prevention and mitigation of POPF depending on risk setting and its correct functioning. ETS malfunction is not uncommon and increases morbidity. Improving ETS design and fixing technique might lead to better outcomes.

Aims: \ud Iron deficiency (ID) and anaemia are common in heart failure; less is known about changes over time.\ud \ud Methods and results: \ud We investigated prevalence, incidence and resolution of ID and anaemia in 906 patients with chronic heart failure (median age 73 (65–79) years, 70% men, 51% with heart failure with reduced ejection fraction) 1 year apart. ID was defined as serum iron ≤13 µmol/L and anaemia as haemoglobin 13 µmol/L), mortality was higher in those with persistent or incident ID at 1 year [hazard ratio (HR) 1.81 (1.23–2.67), and HR 1.40 (0.91–2.14), respectively] in multivariable models (P = 0.02). Compared to persistent ID, resolution of ID was associated with a lower mortality [HR 0.61 (0.44–0.86); P = 0.004]. Changes in ID defined by FAIR-HF criteria were not similarly associated with mortality. Anaemia was associated with a poor outcome even if it resolved.\ud \ud Conclusions: \ud The prevalence and incidence of ID and anaemia are high in chronic heart failure but so is the rate of resolution. Persistent or incident ID, defined by a serum iron ≤13 µmol/L, is associated with higher mortality and resolution of ID with lower mortality.

BACKGROUND: TB is the leading cause of mortality among people living with HIV (PLHIV), for whom isoniazid preventive therapy (IPT) has a proven mortality benefit. Despite WHO recommendations, countries have been slow in scaling up IPT. This study describes processes, challenges, solutions, outcomes and lessons learned during IPT scale‐up in Kenya.METHODS: We conducted a desk review and analyzed aggregated Ministry of Health (MOH) IPT enrollment data from 2014 to 2018 to determine trends and impact of program activities. We further analyzed IPT completion reports for patients initiated from 2015 to 2017 in 745 MOH sites in Nairobi, Central, Eastern and Western Kenya.RESULTS: IPT was scaled up 75‐fold from 2014 to 2018: the number of PLHIV covered increased from 9,981 to 749,890. The highest percentage increases in the cumulative number of PLHIV on IPT were seen in the quarters following IPT pilot projects in 2014 (49%), national launch in 2015 (54%), and HIV treatment acceleration in 2016 (158%). Among 250,069 patients initiating IPT from 2015 to 2017, 97.5% completed treatment, 0.2% died, 0.8% were lost to follow‐up, 1.0% were not evaluated, and 0.6% discontinued treatment.CONCLUSIONS: IPT can be scaled up rapidly and effectively among PLHIV. Deliberate MOH efforts, strong leadership, service delivery integration, continuous mentorship, stakeholder involvement, and accountability are critical to program success.

Background: Regular physical activity (PA) practice during pregnancy offers health and fitness benefits for both mother and baby. Therefore, healthy pregnant women with no contraindications to exercise should be encouraged to perform PA. Nevertheless, their levels of PA are generally low. The aim of the WELL-DONE! Study is to co-design an adapted physical activity intervention (APAI) for pregnant women to include in childbirth preparation classes (CPCs) evaluating its feasibility and efficacy on quality of life (QoL), PA levels and other outcomes. Methods: A quasi-experimental study was divided in two progressive stages. First, APAI was developed in collaboration with pregnant women and midwives using focus groups; second, APAI’s efficacy was evaluated comparing two groups: the experimental group engaged in the CPCs integrated with 1 h/week of the APAI administered by midwives and the control group participating in the standard CPCs. Pre-post evaluation was carried out in three stages through questionnaires and tests. Data analysis involved the combination of qualitative and quantitative methodologies. Discussion: Findings from the WELL-DONE! Study will help to assess the feasibility, sustainability, and efficacy of incorporating APAI inside CPCs as a new public health strategy oriented to QoL, well-being, and PA level improvements.

Context Iodide transport defect (ITD) (Online Mendelian Inheritance in Man No. 274400) is an uncommon cause of dyshormonogenic congenital hypothyroidism due to loss-of-function variants in the SLC5A5 gene, which encodes the sodium/iodide symporter (NIS), causing deficient iodide accumulation in thyroid follicular cells. Objective This work aims to determine the molecular basis of a patient’s ITD clinical phenotype. Methods The propositus was diagnosed with dyshormonogenic congenital hypothyroidism with minimal 99mTc-pertechnetate accumulation in a eutopic thyroid gland. The propositus SLC5A5 gene was sequenced. Functional in vitro characterization of the novel NIS variant was performed. Results Sanger sequencing revealed a novel homozygous missense p.G561E NIS variant. Mechanistically, the G561E substitution reduces iodide uptake, because targeting of G561E NIS to the plasma membrane is reduced. Biochemical analyses revealed that G561E impairs the recognition of an adjacent tryptophan-acidic motif by the kinesin-1 subunit kinesin light chain 2 (KLC2), interfering with NIS maturation beyond the endoplasmic reticulum, and reducing iodide accumulation. Structural bioinformatic analysis suggests that G561E shifts the equilibrium of the unstructured tryptophan-acidic motif toward a more structured conformation unrecognizable to KLC2. Consistently, knockdown of Klc2 causes defective NIS maturation and consequently decreases iodide accumulation in rat thyroid cells. Morpholino knockdown of klc2 reduces thyroid hormone synthesis in zebrafish larvae leading to a hypothyroid state as revealed by expression profiling of key genes related to the hypothalamic-pituitary-thyroid axis. Conclusion We report a novel NIS pathogenic variant associated with dyshormonogenic congenital hypothyroidism. Detailed molecular characterization of G561E NIS uncovered the significance of KLC2 in thyroid physiology.

Lessons Learned Background The objectives of this study were to compare the safety profiles of sodium levofolinate (Na-Lev) and calcium levofolinate (Ca-Lev) in combination with 5-fluorouracil (5-FU) in the FOLFIRI regimen and to measure the organizational impact of the introduction of Na-Lev on drug production and administration. Methods The study opened in November 2015 and closed in August 2019. Patients with gastrointestinal cancers who were candidates for treatment with the FOLFIRI regimen were included in this nonrandomized study. Age ≥18 years, life expectancy Results Sixty patients were enrolled, 30 in each arm. Patient characteristics were balanced. Grade (G)1–2 adverse events occurred in 18 (60.0%) and 19 (63.4%) patients of Na-Lev and Ca-Lev cohorts, respectively, whereas G3–4 adverse events occurred in 12 (40.0%) and 11 (36.6%) patients, respectively. The use of Na-Lev enabled us to save approximately 13 minutes for drug preparation and 2 hours for treatment administration, per patient per cycle. Conclusion Na-Lev showed a reassuring toxicity profile and a favorable impact on drug preparation and administration.

The Italian Society of Diabetology and the Italian Association of Clinical Diabetologists are developing new guidelines for drug treatment of type 2 diabetes. The effects of anti-hyperglycaemic drugs on all-cause mortality and major adverse cardiovascular events (MACEs) were included among the critical clinical outcomes. We have therefore carried out an updated meta-analysis on the effects of metformin on these outcomes.A MEDLINE and EMBASE search was performed to identify all randomized controlled trials (RCTs) with duration ≥52 weeks (published up to August 2020), in which metformin was compared with either placebo/no therapy or active comparators. MACEs (restricted for RCT reporting MACEs within their study endpoints) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified endpoints) were considered as the primary endpoints. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence interval was calculated for all endpoints considered. Metformin was associated with a nonsignificant reduction of all-cause mortality (n = 13 RCTs; MH-OR 0.80 [95% CI 0.60, 1.07]). However, this association became statistically significant after excluding RCTs comparing metformin with sulfonylureas, SGLT-2 inhibitors or GLP-1 analogues (MH-OR 0.71 [0.51, 0.99]). Metformin was associated with a lower risk of MACEs compared with comparator treatments (n = 2 RCTs; MH-OR 0.52 [0.37, 0.73]), p 0.001. Similar results were obtained in a post-hoc analysis including all RCTs fulfilling criteria for inclusion in the analysis (MH-OR: 0.57 [0.42, 0.76]).This updated meta-analysis suggests that metfomin is significantly associated with lower risk of MACEs and tendentially lower all-cause mortality compared to placebo or other anti-hyperglycaemic drugs.

Objective: The aim of this study was to report the rate of additional anomalies detected exclusively at prenatal magnetic resonance imaging (MRI) in fetuses with isolated severe ventriculomegaly undergoing neurosonography. Method: Multicenter, retrospective, cohort study involving 20 referral fetal medicine centers in Italy, United Kingdom, Spain and Denmark. Inclusion criteria were fetuses affected by isolated severe ventriculomegaly (≥15 mm), defined as ventriculomegaly with normal karyotype and no other additional central nervous system (CNS) and extra-CNS anomalies on ultrasound. In all cases, a multiplanar assessment of fetal brain as suggested by ISUOG guidelines on fetal neurosonography had been performed. The primary outcome was the rate of additional CNS anomalies detected exclusively at fetal MRI within two weeks from neurosonography. Subgroup analyses according to gestational age at MRI (

Background In 2019, a multidisciplinary panel of experts from eight Italian scientific paediatric societies developed a consensus document for the use of inhaled corticosteroids in the management and prevention of the most common paediatric airways disorders. The aim is to provide healthcare providers with a multidisciplinary document including indications useful in the clinical practice. The consensus document was intended to be addressed to paediatricians who work in the Paediatric Divisions, the Primary Care Services and the Emergency Departments, as well as to Residents or PhD students, paediatric nurses and specialists or consultants in paediatric pulmonology, allergy, infectious diseases, and ear, nose, and throat medicine. Methods Clinical questions identifying Population, Intervention(s), Comparison and Outcome(s) were addressed by methodologists and a general agreement on the topics and the strength of the recommendations (according to the GRADE system) was obtained following the Delphi method. The literature selection included secondary sources such as evidence-based guidelines and systematic reviews and was integrated with primary studies subsequently published. Results The expert panel provided a number of recommendations on the use of inhaled corticosteroids in preschool wheezing, bronchial asthma, allergic and non-allergic rhinitis, acute and chronic rhinosinusitis, adenoid hypertrophy, laryngitis and laryngospasm. Conclusions We provided a multidisciplinary update on the current recommendations for the management and prevention of the most common paediatric airways disorders requiring inhaled corticosteroids, in order to share useful indications, identify gaps in knowledge and drive future research.

Objective To assess the performance of fetal magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses diagnosed with isolated corpus callosal (CC) anomaly on multiplanar ultrasound evaluation of the fetal brain (neurosonography). Methods This was a multicenter, retrospective cohort study involving 14 fetal medicine centers in Italy, UK, Portugal, Canada, Austria and Spain. Inclusion criteria were fetuses with an apparently isolated CC anomaly, defined as an anomaly of the CC and no other additional central nervous system (CNS) or extra-CNS abnormality detected on expert ultrasound, including multiplanar neurosonography; normal karyotype; maternal age >= 18 years; and gestational age at diagnosis >= 18 weeks. The primary outcome was the rate of additional CNS abnormalities detected exclusively on fetal MRI within 2 weeks following neurosonography. The secondary outcomes were the rate of additional abnormalities according to the type of CC abnormality (complete (cACC) or partial (pACC) agenesis of the CC) and the rate of additional anomalies detected only on postnatal imaging or at postmortem examination. Results A total of 269 fetuses with a sonographic prenatal diagnosis of apparently isolated CC anomalies (207 with cACC and 62 with pACC) were included in the analysis. Additional structural anomalies of the CNS were detected exclusively on prenatal MRI in 11.2% (30/269) of cases, with malformations of cortical development representing the most common type of anomaly. When stratifying the analysis according to the type of CC anomaly, the rate of associated anomalies detected exclusively on MRI was 11.6% (24/207) in cACC cases and 9.7% (6/62) in pACC cases. On multivariate logistic regression analysis, only maternal body mass index was associated independently with the likelihood of detecting associated anomalies on MRI (odds ratio, 1.07 (95% CI, 1.01-1.14); P = 0.03). Associated anomalies were detected exclusively after delivery and were missed on both types of prenatal imaging in 3.9% (8/205) of fetuses with prenatal diagnosis of isolated anomaly of the CC. Conclusion In fetuses with isolated anomaly of the CC diagnosed on antenatal neurosonography, MRI can identify a small proportion of additional anomalies, mainly malformations of cortical development, which are not detected on ultrasound. (c) 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Background: The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations. Objective: This study aims to investigate the prevalence of symptomatic Covid-19 and its correlations with both organ involvement and ongoing treatments in a large series of Italian ASD patients during the first wave of pandemic. Methods: Our multicenter telephone 6-week survey included 3,029 unselected ASD patients enrolled at 36 tertiary referral centers of northern, central, and southern Italian macro-areas with different diffusion of the pandemic. Symptomatic SARS-CoV-2 infection was classified as definite Covid-19 (presence of symptoms plus positive oral/nasopharyngeal swabs) or highly suspected Covid-19 (highly suggestive symptoms, in the absence of a swab testing). Results: A significantly higher prevalence of definite plus highly suspected Covid-19 compared to the Italian general population was detected in the whole ASD series (p=.000), as well as in patients from the three macro-areas (p=.000 in all). Statistically higher prevalence of Covid-19 was also found in connective tissue diseases compared to chronic arthritis subgroup (p=.000) and in ASD patients with pre-existing interstitial lung involvement (p=.000). Patients treated with either conventional disease-modifying anti-rheumatic drugs (DMARDs) and/or biological DMARDs showed a significantly lower prevalence of Covid-19 (p=.000 in both). Finally, scleroderma patients undergoing low-dose aspirin showed a significantly lower rate of Covid-19 compared to those without (p=0.003). Conclusion: The higher prevalence of Covid-19 in ASD patients, along with the significant correlations with important clinical features and therapeutic regimens, suggests the need to develop targeted prevention/management strategies during the current pandemic wave.

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We investigate the relationship between maternal cardiovascular (CV) function and fetal Doppler changes in healthy pregnancies and those with pre-eclampsia (PE), small for gestational age (SGA) or fetal growth restriction (FGR). This was a three-centre prospective study, where CV assessment was performed using inert gas rebreathing, continuous Doppler or impedance cardiography. Maternal cardiac output (CO) and peripheral vascular resistance (PVR) were analysed in relation to the uterine artery, umbilical artery (UA) and middle cerebral artery (MCA) pulsatility indices (PI, expressed as z-scores by gestational week) using polynomial regression analyses, and in relation to the presence of absent/reversed end diastolic (ARED) flow in the UA. We included 81 healthy controls, 47 women with PE, 65 with SGA/FGR and 40 with PE + SGA/FGR. Maternal CO was inversely related to fetal UA PI and positively related to MCA PI, the opposite was observed for PVR, which was also positively associated with increased uterine artery impedance. CO was lower (z-score 97, p = 0.02) and PVR higher (z-score 2.88, p = 0.02) with UA ARED flow. We report that maternal CV dysfunction is associated with fetal vascular changes, namely raised impedance in the fetal-placental circulation and low impedance in the fetal cerebral vessels. These findings are most evident with critical UA Doppler changes and represent a potential mechanism for therapeutic intervention.

Background: Considering the growing genitourinary (GU) cancer population undergoing systemic treatment with immune checkpoint inhibitors (ICIs) in the context of the COVID-19 pandemic, we planned a clinical audit in 24 Italian institutions treating GU malignancies. Objective: The primary objective was investigating the clinical impact of COVID-19 in GU cancer patients undergoing ICI-based therapy during the first outbreak of SARS-CoV-2 contagion in Italy. Design, setting, and participants: The included centers were 24 Oncology Departments. Two online forms were completed by the responsible Oncology Consultants, respectively, for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) patients receiving at least one administration of ICIs between 31 January 2020 and 30 June 2020. Results and limitation: In total, 287 mRCC patients and 130 mUC patients were included. The COVID-19 incidence was, respectively, 3.5%, with mortality 1%, in mRCC patients and 7.7%, with mortality 3.1%, in mUC patients. In both groups, 40% of patients developing COVID-19 permanently discontinued anticancer treatment. The pre-test SARS-CoV-2 probability in the subgroup of patients who underwent nasal/pharyngeal swab ranged from 14% in mRCC to 26% in mUC. The main limitation of the work was its nature of audit: data were not recorded at the single-patient level. Conclusion: GU cancer patients undergoing active treatment with ICIs have meaningful risk factors for developing severe events from COVID-19 and permanent discontinuation of therapy after the infection. Treatment delays due to organizational issues during the pandemic were unlikely to affect the treatment outcome in this population.

The process of bone loss occurs silently and progressively with age, often appearing as osteopenia or osteoporosis or related fractures. Given the rapid raise in disease burden and socio-economic costs of these conditions worldwide, drug therapy combined with physical activity can be a useful strategy and bone biomarkers, can represent a useful evaluation tool to assess their effects. The objective of this systematic review, conducted according to PRISMA statement, was to investigate the effects of physical activity interventions combined with drug treatments on bone biomarkers in people with osteopenia and osteoporosis. Through PubMed, Cochrane, Cinahl, Embase, Trip, a comprehensive literature search was performed. Each study’s quality was assessed according to the Cochrane risk-of-bias tool. Out of 582 identified articles, 50 full texts were screened. Only one matched the eligibility criteria. The study, scored as high quality, showed, in both experimental and control groups, an increase of CTX and P1NP bone biomarkers, without statistically significant differences. Based on available evidence, no exhaustive conclusion can be drawn. However, this systematic review critically analyses the literature, highlighting the knowledge gap on combined treatments efficacy assessed by bone biomarkers. Moreover, an outlook is provided for the planning of future studies.

The purpose of the study was to investigate the magnitude of bilateral deficit (BLD) in trained males and examine its relationship with functional performance and recent resistance training history. Ten physically active males (age: 23.02±1.27 years) self-reported the number of unilateral and bilateral exercises within their structured resistance training schedule. During two visits to the laboratory, participants performed unilateral and bilateral squat jumps (SJ) and isometric leg extensions (ILE) for the quantification of BLD. Participants also performed bilateral countermovement jumps (CMJ) and a change of direction (COD) test to quantify functional performance. The performance outcomes and information regarding training history were then correlated with the bilateral index (BLI) metric. The key findings were that: (a) a lower BLD in SJ peak power related to a greater CMJ peak force (r=.728; p=.02) and peak power (r=.750; p=.01), (b) the BLI in the ILE was unrelated to performance outcomes, and (c) BLI was unrelated to the mean number of bilateral and unilateral exercises in the structured resistance training programme of participants. In conclusion, lower levels of BLD may be advantageous for bilateral tests of functional performance (i.e. jumps) however there is a need to consider the mechanical similarity between the performance and BLD measure. Finally, the balance of unilateral and bilateral exercises in an individual’s recent resistance training history is not sensitive to the BLI measured during dynamic or isometric assessments.

BackgroundThe prevalence of diseases other than TB detected during chest X-ray (CXR) screening is unknown in sub-Saharan Africa. This represents a missed opportunity for identification and treatment of potentially significant disease. Our aim was to describe and quantify non-TB abnormalities identified by TB-focused CXR screening during the 2016 Kenya National TB Prevalence Survey.MethodsWe reviewed a random sample of 1140 adult (≥15 years) CXRs classified as ‘abnormal, suggestive of TB’ or ‘abnormal other’ during field interpretation from the TB prevalence survey. Each image was read (blinded to field classification and study radiologist read) by two expert radiologists, with images classified into one of four major anatomical categories and primary radiological findings. A third reader resolved discrepancies. Prevalence and 95% CIs of abnormalities diagnosis were estimated.FindingsCardiomegaly was the most common non-TB abnormality at 259 out of 1123 (23.1%, 95% CI 20.6% to 25.6%), while cardiomegaly with features of cardiac failure occurred in 17 out of 1123 (1.5%, 95% CI 0.9% to 2.4%). We also identified chronic pulmonary pathology including suspected COPD in 3.2% (95% CI 2.3% to 4.4%) and non-specific patterns in 4.6% (95% CI 3.5% to 6.0%). Prevalence of active-TB and severe post-TB lung changes was 3.6% (95% CI 2.6% to 4.8%) and 1.4% (95% CI 0.8% to 2.3%), respectively.InterpretationBased on radiological findings, we identified a wide variety of non-TB abnormalities during population-based TB screening. TB prevalence surveys and active case finding activities using mass CXR offer an opportunity to integrate disease screening efforts.FundingNational Institute for Health Research (IMPALA-grant reference 16/136/35).

Background Immunotherapy has brought clinical benefits to patients with metastatic renal cell cancer (mRCC). Most patients tolerate immunotherapy but serious immune-related adverse events (irAEs) have been reported. Some studies indicate a correlation between irAEs and clinical response in other cancer types (eg, lung cancer and melanoma). For patients with mRCC, the impact of irAE on clinical outcome is unknown. Patients and Methods A retrospective review of 167 patients with mRCC treated with nivolumab as standard of care between March 2017 and January 2018 in 16 Italian centers was performed. irAEs were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results Any grade and grade 3/4 irAEs occurred in 46% and 8.9% of patients, respectively. The median time to appearance of irAEs was 10 weeks; 38.8% of patients required steroid treatment. The most common irAEs were cutaneous (33.7%) and gastrointestinal (23.3%). The median overall survival and progression-free survival were 20.13 and 7.86 months, respectively. Patients with irAEs showed a greater overall survival (hazard ratio, 0.38; 95% confidence interval [CI], 0.23-0.63) and progression-free survival (hazard ratio, 0.44; 95% CI, 0.29-0.66) benefit as well as better overall response rate (27.3% vs. 13.7%; odds ratio, 2.36; 95% CI, 1.03-5.44) and disease control rate (68.8% vs. 48%; odds ratio, 2.4; 95% CI, 1.23-4.67) if compared with those without irAEs. No correlation was found between steroid use and clinical outcomes. Conclusions Our analysis revealed that the appearance of irAEs was associated with better outcomes in patients treated with nivolumab. This data may be limited by sample size and the retrospective nature of the study.

Neoadjuvant chemotherapy has become a powerful tool to convert borderline resectable (BRPC) and locally advanced pancreatic cancers (LAPC) into a resectable scenario. However, data analyzing the optimal type of therapy are scarce. In the present multicenter retrospective study, we evaluated the influence of FOLFIRINOX (FFX) and gemcitabine (GEM)-based neoadjuvant therapy on patient prognosis.Data on 239 patients from 7 centers across Europe was gathered using an online database. Patients having received their first cycle of chemotherapy for BRPC/LAPC before 06/2017, with a minimum follow-up of 12 months, were included in the intention-to-treat analysis.Patients treated with neoadjuvant FFX (n = 135) or gemcitabine + nab-paclitaxel (GNP) (n = 38) had significantly improved radiological response according to RECIST criteria as compared to single-agent GEM (n = 16), with a partial/complete response of 59.3%, 55.3% and 6.25% respectively (p = 0.001). Treatment with FFX (n = 135) and GNP (n = 38) resulted in higher resection rates compared to GEM (73.3%, 81.6% and 43.8%; p = 0.01 and p = 0.005). Regardless of regimen, patients who were resected had significantly prolonged overall survival compared to non-resected patients (p 0.01). Complete pathological responses (ypT0 ypN0) were predominantly observed with FFX (p = 0.01). Adjuvant GNP in addition to successful neoadjuvant therapy and surgery resulted in a trend towards improved median survival as compared to postoperative observation (47.0 vs. 30.1 months, p = 0.06).Representing one of the largest studies published so far, our results reveal that patients with BRPC/LAPC should be offered either FFX or GNP to improve chances of resection and with this also survival.

46, XY disorders (or differences) of sex development (DSD) are a group of clinical conditions with variable genetic background; correct diagnosis is often difficult, but it permits to optimize the management. The aim of this study is to identify clinical and genetics features of a group of women with 46, XY DSD to define some issues characterizing people with 46, XY DSD in Italy. Retrospective analysis of girls and women with 46, XY DSD and female phenotype evaluated between year 2000 and 2016, performed by anonymised database, focusing on the clinical features and management, including presentation, first diagnostic suspect, gonadal surgery and molecular diagnostic delay. A total of 84 records were collected (mean age at clinical presentation: 9.1 ± 7.9 years; mean age at definitive diagnosis: 20.1 ± 15.0 years). Complete androgen insensitivity syndrome was the most common diagnosis (60%). Only 12 patients (14.3%) did not receive a molecular diagnosis. Early misdiagnoses frequently occurred; diagnostic delay was 10.2 ± 11.2 years, being reduced in patients presenting from 2007 to 2016. The discordance between genotypic and phenotypic sex during pregnancy or at birth determined early reason for referral in a considerable percentage (4.9%). Misdiagnosis and long diagnostic delays are present in females with 46, XY DSD in Italy, but the new genetic techniques permit faster right diagnoses in the last years. The centralization in dedicated third level units permits to reduce the number of patients without a molecular diagnosis, allowing better clinical management and appropriate genetic counselling.

Objectives: Cardiac autonomic neuropathy is among the known cardiovascular complications of systemic sclerosis and may affect the whole prognosis of the disease. The aim of our study was to assess cardiac autonomic neuropathy prevalence in our cohort of systemic sclerosis patients and compare its main features with clinical and epidemiological data, particularly with the severity of microvascular damage, as detected by nailfold videocapillaroscopy. Methods: Twenty-six patients with definite systemic sclerosis were consecutively enrolled at our outpatient rheumatology clinic. All patients underwent physical examination, nailfold videocapillaroscopy, and autonomic neuropathy diagnostic tests (orthostatic hypotension test, deep breathing test, lying-to-standing, and Valsalva maneuvers). Results: Cardiac autonomic neuropathy prevalence was 50% (13 cases). On univariate analysis, cardiac autonomic neuropathy was shown to be significantly associated with an active pattern on nailfold videocapillaroscopy (odds ratio 5.86, 95% confidence interval 1.59–9.24; p = 0.032), whereas anti-Scl-70 positivity (odds ratio, 0.24; 95% confidence interval, 0.03–2.12; p = 0.049) and C-reactive protein (odds ratio, 19.32; 95% confidence interval, 1.79–56.71; p = 0.036) reached only a borderline statistical association. The time-dependent Cox multivariate regression model showed cardiac autonomic neuropathy development to be independently associated with an active pattern on nailfold videocapillaroscopy (odds ratio, 7.19; 95% confidence interval, 1.87–8.96; p = 0.042) and anti-Scl-70 positivity (odds ratio, 5.92; 95% confidence interval, 1.06–18.43; p = 0.048). Conclusions: Severe microvascular damage, as detected by nailfold videocapillaroscopy, may suggest the coexistence of autonomic dysfunction and should be considered as a red flag for the identification of patients particularly at risk of cardiac morbidity and mortality.

Aim Patient education is an essential component of the treatment of type 2 diabetes mellitus (T2DM). The present meta-analysis was aimed at verifying the efficacy of group-based versus individual education for self-management in patients with T2DM. Methods A Medline and Embase search up to January 1st, 2021, was performed, including Randomized Controlled Trials (RCT) with duration>6 months, enrolling patients with T2DM and comparing individual-based with group-based educational programs. The primary outcome was endpoint HbA1c; secondary endpoints were lipid profile, body weight, blood pressure, patients’ adherence/knowledge, and quality of life. The weighed difference in means (WMD) and Mantel-Haenzel Odds Ratio (MH-OR), with 95% Confidence Interval (CI), were calculated. Results We retrieved 14 RCT. No significant between-group difference in HbA1c (WMD -0.39[-0.89;0.09] mmol/mol, p=0.11) was observed. At metaregression analyses, longer trial duration, higher baseline mean age and duration of diabetes, and lower baseline HbA1c were correlated with greater efficacy of group-based programs in reducing HbA1c. When analyzed separately, trials excluding insulin-treated patients showed a significant reduction of HbA1c in favor of group education. Conclusions In patients with T2DM, group education has similar efficacy as individual education on glucose control. Group programs are associated with an improved quality of life and patients’ knowledge. PROSPERO and OSF registration ID243149.

Objectives: To assess the role of fetal magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses presenting with mild or moderate isolated ventriculomegaly (VM) undergoing multiplanar ultrasound evaluation of the fetal brain. Methods: This was a multicenter, retrospective, cohort study involving 15 referral fetal medicine centers in Italy, the UK and Spain. Inclusion criteria were fetuses affected by isolated mild (ventricular atrial diameter, 10.0–11.9 mm) or moderate (ventricular atrial diameter, 12.0–14.9 mm) VM on ultrasound, defined as VM with normal karyotype and no other additional central nervous system (CNS) or extra-CNS anomalies on ultrasound, undergoing detailed assessment of the fetal brain using a multiplanar approach as suggested by the International Society of Ultrasound in Obstetrics and Gynecology guidelines for the fetal neurosonogram, followed by fetal MRI. The primary outcome of the study was to report the incidence of additional CNS anomalies detected exclusively on prenatal MRI and missed on ultrasound, while the secondary aim was to estimate the incidence of additional anomalies detected exclusively after birth and missed on prenatal imaging (ultrasound and MRI). Subgroup analysis according to gestational age at MRI (< 24 vs ≥ 24 weeks), laterality of VM (unilateral vs bilateral) and severity of dilatation (mild vs moderate VM) were also performed. Results: Five hundred and fifty-six fetuses with a prenatal diagnosis of isolated mild or moderate VM on ultrasound were included in the analysis. Additional structural anomalies were detected on prenatal MRI and missed on ultrasound in 5.4% (95% CI, 3.8–7.6%) of cases. When considering the type of anomaly, supratentorial intracranial hemorrhage was detected on MRI in 26.7% of fetuses, while polymicrogyria and lissencephaly were detected in 20.0% and 13.3% of cases, respectively. Hypoplasia of the corpus callosum was detected on MRI in 6.7% of cases, while dysgenesis was detected in 3.3%. Fetuses with an associated anomaly detected only on MRI were more likely to have moderate than mild VM (60.0% vs 17.7%; P < 0.001), while there was no significant difference in the proportion of cases with bilateral VM between the two groups (P = 0.2). Logistic regression analysis showed that lower maternal body mass index (adjusted odds ratio (aOR), 0.85 (95% CI, 0.7–0.99); P = 0.030), the presence of moderate VM (aOR, 5.8 (95% CI, 2.6–13.4); P < 0.001) and gestational age at MRI ≥ 24 weeks (aOR, 4.1 (95% CI, 1.1–15.3); P = 0.038) were associated independently with the probability of detecting an associated anomaly on MRI. Associated anomalies were detected exclusively at birth and missed on prenatal imaging in 3.8% of cases. Conclusions: The incidence of an associated fetal anomaly missed on ultrasound and detected only on fetal MRI in fetuses with isolated mild or moderate VM undergoing neurosonography is lower than that reported previously. The large majority of these anomalies are difficult to detect on ultrasound. The findings from this study support the practice of MRI assessment in every fetus with a prenatal diagnosis of VM, although parents can be reassured of the low risk of an associated anomaly when VM is isolated on neurosonography. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Contains fulltext : 231528.pdf (Publisher’s version ) (Closed access) BACKGROUND: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking. OBJECTIVE: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses. METHODS: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria. RESULTS: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P 85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies. CONCLUSION: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.

Background: The retrospective studies that have so far described the outcomes of the sequential use of life-prolonging agents (LPAs) did not include metastatic castration-resistant prostate cancer (mCRPC) patients who received radium-223 (223Ra) as part of their treatment. Consequently, it is not known whether including 223Ra in the therapeutic sequence has an impact on cumulative survival. The aim of this study was to evaluate this impact by comparing the cumulative overall survival (OS) in two series of mCRPC patients sequentially treated with two or three LPAs after first-line docetaxel (DOC), including 223Ra and not. Materials and Methods: The authors retrospectively reviewed the records of mCRPC patients with bone involvement alone who received two or three LPAs (including 223Ra) after first-line DOC. The control group was a contemporary series of mCRPC patients with bone involvement alone treated with sequences of two or three LPAs other than 223Ra after first-line DOC. Results: Median cumulative OS was 40.6 months in the 223Ra group of 78 patients and 36.2 months in the non-223Ra group of 186 patients (p = 0.08). OS outcomes were significantly influenced by the number of treatment lines, and baseline Eastern Cooperative Oncology Group performance status (PS) and prostate-specific antigen levels. Conclusions: To the best of the authors' knowledge, this is the first study designed to evaluate the impact of introducing 223Ra in the treatment sequences for mCRPC patients, and the results show that its use does not negatively affect cumulative OS.

Background: Bone imbalance between anabolic and catabolic processes at the level of remodeling unit due to the prevalence of resorbing activity, represents a health problem of aging. The consequence is the negative balance of bone turnover that can lead to osteoporosis. Physical activity (PA) can play a central role in the comprehensive management of osteoporosis, since it induces the anabolism of bone tissue. Bone turnover biomarkers, reflecting the cellular activity linked to bone metabolism, can represent an evaluation tool to assess the efficacy of PA in the osteoporotic population. The aimof this systematic review, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, was to investigate the effects of PA interventions on bone biomarkers in people with osteoporosis. Methods: A comprehensive literature search of electronic databases was conducted through PubMed, Cochrane, Cinahl, Embase, Trip, to find randomized controlled trials (RCTs) investigating the topic of PA and bone turnover biomarkers in the osteoporosis population. In accordance with the Cochrane risk-of-bias tool, the quality of each study was assessed. Results: Out of 992 identified articles, 136 full texts were screened. Only three RTCs matched the eligibility criteria. In one study, sub-maximal aerobic exercise improved Bone-specific alkaline phosphatase (bone formation biomarker) and Amino-terminal Crosslinked Telopeptide of type 1 collagen (bone resorption biomarker) in osteoporotic women. The other two studies showed a positive effect on total alkaline phosphatase (a non-specific bone formation biomarker) in women with osteoporosis. Conclusion: The systematic review revealed possible exercise benefits in terms of improving bone formation and decreasing bone resorption biomarkers in the osteoporotic population. However, these results should be interpreted with caution, especially due to the limited number and poor quality of the studies included. Further research is needed to estimate the influence of PA on bone biomarkers in the osteoporosis management.

Background: Children and adolescents should perform, according to the World Health Organization guidelines, at least 60 min of moderate-to-vigorous physical activity per-day in order to avoid the risk of metabolic and cardiovascular diseases. The school represents a fundamental setting to conduct interventions to promote physical activity (PA) and contrast sedentary behaviors. Active breaks (ABs), bouts of 10 min of PA conducted inside the classroom, seem to be a good strategy to promote PA and improve classroom behavior. The aim of this study protocol is to describe the design and the assessment of the Imola Active Breaks I-MOVE study. Methods: The I-MOVE study is a school-based intervention trial, with a quasi-experimental design, performed in a primary school. It involves one experimental-group performing the intervention, focused on ABs, and one control-group. Nine main outcomes are evaluated: PA and sedentary behaviors; health related fitness; motor control development; dietary patterns; anthropometric evaluation; sociodemographic determinants; cognitive function; time-on-task behavior and quality of life. Conclusions: Results from the I-MOVE study will help to clarify the effects of incorporating ABs in the Italian school curriculum as a new public health strategy and an innovative school model oriented to the well-being of children and teachers for the best quality of school life.

Background: The school gives access to children, regardless of age, ethnicity, gender and socio-economic class and can be identified as the key environment in which to promote children&rsquo, s physical activity (PA). The guidelines of the European Union recommend accumulating at least 10-min bouts of PA to reach the daily 60 min. Active breaks (ABs) led by teachers inside the classroom represent a good strategy to promote PA. The aim of this pilot and feasibility study was to evaluate the feasibility and effectiveness in terms of PA level of an AB programme in children aged 8&minus, 9 years attending primary school. Methods: A pre-post quasi-experimental pilot and feasibility study was performed in two primary school classes, one of which was assigned to a 14-week AB intervention (AB group) and the other to the control group (CG). At baseline and at follow-up, children were monitored for sedentary and motor activity during an entire week using ActiGraph Accelerometer (ActiLife6 wGT3X-BT). The satisfaction of children and teachers was assessed by self-administered questionnaires. Results: In the pre-post comparison, AB group (n = 16) showed a reduction in the minutes spent in weekly sedentary activity (-168.7 min, p &gt, 0.05), an increase in the number of step counts (+ 14,026.9, p &lt, 0.05) and in time spent in moderate to vigorous PA (MVPA): weekly MVPA: + 64.4 min, daily MVPA: + 8.05 min, percentage of MVPA: + 0.70%. On the contrary, CG showed a worsening in all variables. ANCOVA analysis, after adjusting for baseline values, showed significant differences between the AB group and CG for time spent in MVPA, percentage of MVPA and step counts. The satisfaction of children and teachers was good. Teachers were able to adapt the AB protocol to the needs of the school curriculum, thus confirming the feasibility of the AB programme. Conclusions: This pilot and feasibility study showed the feasibility and effectiveness of the AB protocol and represented the basis for a future controlled trial.

BackgroundCommunity-based screening for tuberculosis (TB) could improve detection but is resource intensive. We set out to evaluate the accuracy of computer-aided TB screening using digital chest X-ray (CXR) to determine if this approach met target product profiles (TPP) for community-based screening.MethodsCXR images from participants in the 2016 Kenya National TB Prevalence Survey were evaluated using CAD4TBv6 (Delft Imaging), giving a probabilistic score for pulmonary TB ranging from 0 (low probability) to 99 (high probability). We constructed a Bayesian latent class model to estimate the accuracy of CAD4TBv6 screening compared to bacteriologically-confirmed TB across CAD4TBv6 threshold cut-offs, incorporating data on Clinical Officer CXR interpretation, participant demographics (age, sex, TB symptoms, previous TB history), and sputum results. We compared model-estimated sensitivity and specificity of CAD4TBv6 to optimum and minimum TPPs.ResultsOf 63,050 prevalence survey participants, 61,848 (98%) had analysable CXR images, and 8,966 (14.5%) underwent sputum bacteriological testing; 298 had bacteriologically-confirmed pulmonary TB. Median CAD4TBv6 scores for participants with bacteriologically-confirmed TB were significantly higher (72, IQR: 58-82.75) compared to participants with bacteriologically-negative sputum results (49, IQR: 44-57, pConclusionsCAD4TBv6 met the optimal TPP for TB community screening. To optimise screening accuracy and efficiency of confirmatory sputum testing, we recommend that an adaptive approach to threshold setting is adopted based on participant characteristics.Take home messageCAD4TBv6 met the optimal WHO target product profile for a community TB screening tool. Specificity was lower in adults with previous TB and those aged 41 years or older; an adaptive approach to setting CAD thresholds will likely be required to optimize use.

Background SARS-CoV-2 outbreak pushed the Italian government to start a strict lockdown, replacing school attendance with long-distance learning. This caused reduced exposure to sunlight but increased exposure to screens. Vernal keratoconjunctivitis (VKC) is a chronic inflammatory ocular condition in which exposure to light plays a cardinal role. We conducted an online survey to evaluate the impact of screen exposure in children with VKC during the lockdown. Methods We performed a survey-based observational study, asking patients followed at the Allergology of Meyer Children’s University Hospital in Florence and of Policlinico Umberto I in Rome to provide grading on 6 subjective ocular clinical manifestations presented during the lockdown and to give an estimate of the hours/day of screen exposure. Results Mean scores of signs and symptoms increased homogeneously when studying patients exposed to longer screen time. When comparing scores collected in 2019 versus 2020, there was not a significant reduction in clinical manifestations, although the situation differed between the two centres due to geographical differences in sunlight exposure. Conclusion During the lockdown, there was a reduction of sunlight exposure but conversely an increase in the time spent in front of screens that correlated with the worsening of VKC signs symptoms in direct proportion to the hours/day of screen exposure. Our results also showed a statistically significant difference in the relative impact of long-distance learning on VKC clinical manifestations in the different Italian regions.

Haematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant and nonmalignant diseases both in adults and children, but this procedure can be burdened by the so-called “late-onset non-infectious pulmonary complications” (LONIPCs), which are characterised by significant morbidity and mortality [1]. LONIPCs include different forms of inflammatory lung involvement, occurring after 100 days and within 2–3 years following HSCT [2]., Ruxolitinib could be considered as an option in the treatment of LONIPCs in children when other treatments are ineffective. Spirometry is a valuable tool for both diagnosis and follow-up of LONIPCs in children. https://bit.ly/3BmOYfb

Normal tissue radiosensitivity is thought to be influenced by an individual’s genetic background. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2–3 subcutaneous fibrosis and/or grade 2–3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance (p &lt, 0.05). In the replication study, which consisted of an additional 45 cases and 192 controls, none of the SNVs identified by targeted NGS achieved nominal replication. Nevertheless, TP53 rs1042522 (G &gt, C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82–2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51–14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06–3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients, however, large replication studies are warranted for conclusive evidence.

Glaucoma is a multifactorial neuropathy characterized by increased intraocular pressure (IOP), and it is the second leading cause of blindness worldwide after cataracts. Glaucoma combines a group of optic neuropathies characterized by the progressive degeneration of retinal ganglionic cells (RGCs). Increased IOP and short-term IOP fluctuation are two of the most critical risk factors in glaucoma progression. Histamine is a well-characterized neuromodulator that follows a circadian rhythm, regulates IOP and modulates retinal circuits and vision. This review summarizes findings from animal models on the role of histamine and its receptors in the eye, focusing on the effects of histamine H3 receptor antagonists for the future treatment of glaucomatous patients.

It is widely reported in the literature that CD4, CD8 and total T cell count are significantly reduced in critically ill patients with COVID‐19. Few weeks ago, we suggested natural killer (NK) cell count as a marker of severity in 34 hospitalized COVID‐19 patients. On this topic, our research group firstly described a novel potential COVID19 severity marker, Krebs von den Lungen‐6. This study aimed to investigate how a combination of COVID19 severity markers could be helpful in the clinical management of these patients. The combination of these validated, reproducible and non‐expensive bioindicators showed a good accuracy in discriminating between severe and non‐severe patients, suggesting a promising value of this approach in the early prediction of a more aggressive disease phenotype. Despite its monocentric design, our study confirms the reliable dysregulation of innate immune responses, particularly involving NK cells, and suggests that surveillance of a peripheral biomarkers’ panel, including lymphocyte cell counts and KL‐6, may be useful in the clinical management of severe COVID‐19 patients. This article is protected by copyright. All rights reserved.

Background To evaluate the appropriateness of chemotherapy use at the Oncology Department of the Bugando Medical Centre of Mwanza, Tanzania. Methods The study was an observational prevalence‐based study designed to evaluate a single‐chemotherapy cycle during a defined time period for a cross‐section of patients at varying stages of their clinical history. The sample included 103 consecutive subjects who were treated during January‐March 2017 and had at least one previous cycle. Chemotherapy treatment omissions, cycle delays, and dose reductions and their causes were recorded using a standard form that included demographic, anthropometric, and clinical items. The data were analyzed descriptively. Results There were 59 males (57.3%) and 44 females (42.7%). Ninety‐four patients were aged ≥18 years. Considering cancer type/site, there were 23 distinct groups of patients. The recorded number of drugs in the chemotherapy regimens varied between one and five. The median cycle number was three (range: 2‐11). Sixty‐eight (66.0%) patients were treated in a standard fashion. For the remaining, cycle delay and dose reduction were the most common cause for nonstandard treatment. Hematologic toxicity was responsible for the greater part of cycle delays, whereas dose reductions were accounted for by a larger spectrum of causes. Overall, toxicity explained 21/35 (60.0%) patients receiving nonstandard treatment. The distribution of toxic events was skewed toward grade 1 and grade 2. Conclusions The observed level of appropriateness of chemotherapy was encouraging. The proportion of patients experiencing severe toxic effects was lower than expected., The study aims to evaluate the appropriateness of chemotherapy use at the Oncology Department of the Bugando Medical Centre of Mwanza, Tanzania. The study was an observational prevalence‐based study designed to evaluate a single‐chemotherapy cycle during a defined time period for a cross‐section of patients at varying stages of their clinical history. The observed level of appropriateness of chemotherapy was encouraging. The proportion of patients experiencing severe toxic effects was lower than expected.

PURPOSE We aimed to investigate whether transabdominal uterine artery (UtA) pulsatility index (PI) differs between monochorionic (MC) diamniotic and dichorionic (DC) twins and is useful to predict pregnancy complications. METHODS A total of 406 uncomplicated twin pregnancies (94 MC, 312 DC) were examined at 22+0 -24+6 weeks and compared for demographic characteristics, mean UtA PI, presence of notch, development of preeclampsia, fetal growth restriction (FGR), placental abruption, intrauterine fetal death and preterm delivery. Mann-Whitney and Fisher's exact tests were performed for continuous and categorical variables, respectively. Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio were calculated for mean PI >95th percentile, presence of notch, and presence of either elevated PI or notch. RESULTS Median mean UtA PI was 0.68 in DC and 0.75 in MC pregnancies (P = .005). Bilateral notches were observed in one MC pregnancy; unilateral notch was seen in 8 DC (2.6%) and 5 MC diamniotic (5.3%) pregnancies. FGR occurred more frequently in DC twin pregnancies, while intrauterine fetal death in MC. Overall, the sensitivity of the parameters tested was low. Pregnancies with both PI above 95th percentile and presence of notch were all associated with complications, particularly FGR. CONCLUSION MC pregnancies have higher mean UtA PI. UtA screening in twins shows lower performances than in singletons for the detection of complications.

Objectives To report on the prenatal ultrasonographic diagnosis of spina bifida (SB) and its natural history, treatment and long-term outcome in a large tertiary referral center. Methods All cases of SB diagnosed between February 1980 and December 2015 in the Obstetric Prenatal Diagnosis Day Unit of the Obstetrics and Gynecology Department at the Catholic University of the Sacred Heart, Rome, were reviewed. All infants with an open defect were delivered by elective Cesarean section and underwent early repair of the spinal defect. A ventriculoperitoneal (VP) shunt and/or third ventriculostomy was performed when needed. Complete postnatal follow-up was carried out by our multidisciplinary team in the majority of cases. The cohort was analyzed in two groups: Group 1 included patients referred between February 1980 and December 1999; Group 2 included patients referred between January 2000 and December 2015. Results There was a total of 222 cases of SB with a prenatal diagnosis rate of 94.6% (n = 210), with the majority of defects being meningomyeloceles (n = 142 (64.0%)), affecting the lumbosacral level (n = 110 (49.5%)) and being ≥ 2 cm in size (n = 163/195 (83.6%)). There were 174 (78.4%) live births, with more terminations in Group 2 (26.1%) than in Group 1 (10.8%; P = 0.003). Postnatal surgical repair was conducted in 157 cases (99.4% of eligible cases), with death of an infant who was operated on occurring more often in Group 1 (14.1%) than in Group 2 (4.2%; P = 0.03). VP shunt placement was required in 60.3% of infants operated on after January 2000. Long-term follow-up was available for 136 children (111 with open defects and 25 with closed defects). Infants born since 2000 with an open defect had normal ambulation or a mild defect in 50% of cases and normal or mild deficit of sphincter function in 37.8% of cases. An intelligence quotient of ≥ 70 was observed in the majority of children (81.4%; 35/43 cases). Worse motor function was associated with progressive prenatal ventriculomegaly, level of lesion and VP shunt placement. Conclusions We describe the prenatal diagnosis, natural history and long-term outcome of a large contemporary cohort of SB fetuses and infants. In an era of pioneering fetal surgical techniques for in-utero SB repair, it is important to acknowledge that advances in conventional neonatology and pediatric neurosurgery have allowed increased life expectancy and improved quality of life in patients with SB. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.