Search

Health economists have written extensively on the design and implementation of coverage with evidence development (CED) schemes and have proposed theoretical frameworks based on cost-effectiveness modeling and value of information analysis. CED may aid decision-makers when there is uncertainty about the (cost-)effectiveness of a new health technology at the time of reimbursement. Medical devices are potential candidates for CED schemes, as regulatory regimes do not usually require the same level of efficacy and safety data normally needed for pharmaceuticals. The purpose of this research is to assess whether the actual practice of CED for medical devices in Europe meets the theoretical principles proposed by health economists and whether theory and practice can be more closely aligned. Based on decision-makers' perceptions of the challenges associated with CED schemes, plus examples from the schemes themselves, we discuss a series of proposals for assessing the desirability of schemes, their design, implementation, and evaluation. These proposals, while reflecting the practical challenges with developing CED programs, embody many of the principles suggested by economists and should support decision-makers in dealing with uncertainty about the real-world performance of devices.

Introduction Bone metastases are frequent in patients with cancer. Electrochemotherapy (ECT) is a minimally invasive treatment. Preclinical and clinical studies supported the use of ECT in patients with metastatic bone disease (MBD). The purposes of this multicentre study are to confirm the safety and efficacy of ECT, and to identify appropriate operating procedures in different MBD conditions. Materials and methods 102 patients were treated in 11 Centres and recorded in the REINBONE registry (a shared database protected by security passwords): clinical and radiological information, ECT session, adverse events, response, quality of life indicators and duration of follow-up were registered. Results 105 ECT sessions were performed (one ECT session in 99 patients, two ECT sessions in 3 patients). 24 patients (23.5%) received a programmed intramedullary nail after ECT, during the same surgical procedure. Mean follow-up was 5.9 ± 5.1 months (range 1.5–52). The response to treatment by RECIST criteria was 40.4% objective responses, 50.6% stable disease and 9% progressive disease. According to PERCIST criteria the response was: 31.4% OR; 51.7% SD, 16.9% PD with no significant differences between the 2 criteria. Diagnosis of breast cancer and ECOG values 0–1 were significantly associated to objective response. A significant decrease in pain intensity and significant better quality of life was observed after ECT session at follow-up. Conclusion The results are encouraging on pain and tumour local control. ECT proved to be an effective and safe treatment for MBD and it should be considered as an alternative treatment as well as in combination with radiation therapy.

Objective: The assessment of benefits and harms from experimental treatments often ignores the association between outcomes. In a randomized trial, generalized pairwise comparisons (GPC) can be used to assess a Net Benefit that takes this association into account. Study design and settings: We use GPC to analyze a fictitious trial of treatment versus control, with a binary efficacy outcome (response) and a binary toxicity outcome, as well as data from two actual randomized trials in oncology. In all cases, we compute the Net Benefit for scenarios with different orders of priority between response and toxicity, and a range of odds ratios (ORs) for the association between these outcomes. Results: The GPC Net Benefit was quite different from the benefit/harm computed using marginal treatment effects on response and toxicity. In the fictitious trial using response as first priority, treatment had an unfavorable Net Benefit if OR < 1, but favorable if OR > 1. With OR = 1, the Net Benefit was 0. Results changed drastically using toxicity as first priority. Conclusion: Even in a simple situation, marginal treatment effects can be misleading. In contrast, GPC assesses the Net Benefit as a function of the treatment effects on each outcome, the association between outcomes, and individual patient priorities. (C) 2021 The Authors. Published by Elsevier Inc. Brussels-Capital (Innoviris); EORTC Cancer Research Fund; regions of Wallonia (BioWin Consortium) [7979]

Growing bodies of evidence have demonstrated that the identification of prostate cancer (PCa) biomarkers in the patients' blood and urine may remarkably improve PCa diagnosis and progression monitoring. Among diverse cancer-derived circulating materials, extracellular RNA molecules (exRNAs) represent a compelling component to investigate cancer-related alterations. Once outside the intracellular environment, exRNAs circulate in biofluids either in association with protein complexes or encapsulated inside extracellular vesicles (EVs). Notably, EV-associated RNAs (EV-RNAs) were used for the development of several assays (such as the FDA-approved Progensa Prostate Cancer Antigen 3 (PCA3 test) aiming at improving early PCa detection. EV-RNAs encompass a mixture of species, including small non-coding RNAs (e.g. miRNA and circRNA), lncRNAs and mRNAs. Several methods have been proposed to isolate EVs and relevant RNAs, and to perform RNA-Seq studies to identify potential cancer biomarkers. However, EVs in the circulation of a cancer patient include a multitude of diverse populations that are released by both cancer and normal cells from different tissues, thereby leading to a heterogeneous EV-RNA-associated transcriptional signal. Decrypting the complexity of such a composite signal is nowadays the major challenge faced in the identification of specific tumor-associated RNAs. Multiple deconvolution algorithms have been proposed so far to infer the enrichment of cancer-specific signals from gene expression data. However, novel strategies for EVs sorting and sequencing of RNA associated to single EVs populations will remarkably facilitate the identification of cancer-related molecules. Altogether, the studies summarized here demonstrate the high potential of using EV-RNA biomarkers in PCa and highlight the urgent need of improving technologies and computational approaches to characterize specific EVs populations and their relevant RNA cargo.

Objectives The management of non-metastatic castration-resistant prostate cancer (nmCRPC) is rapidly evolving; however, little is known about the direct healthcare costs of nmCRPC. We aimed to estimate the cost-of-illness (COI) of nmCRPC from the Italian National Health Service perspective. Methods Structured, individual qualitative interviews were carried out with clinical experts to identify what healthcare resources are consumed in clinical practice. To collect quantitative estimates of healthcare resource consumption, a structured expert elicitation was performed with clinical experts using a modified version of a previously validated interactive Excel-based tool, EXPLICIT (EXPert eLICItation Tool). For each parameter, experts were asked to provide the lowest, highest, and most likely value. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to test the robustness of the results. Results Ten clinical experts were interviewed, and six of them participated in the expert elicitation exercise. According to the most likely estimate, the yearly cost per nmCRPC patient is €4,710 (range, €2,243 to €8,243). Diagnostic imaging (i.e., number/type of PET scans performed) had the highest impact on cost. The PSA showed a 50 percent chance for the yearly cost per nmCRPC patient to be within €5,048 using a triangular distribution for parameters, and similar results were found using a beta-PERT distribution. Conclusions This study estimated the direct healthcare costs of nmCRPC in Italy based on a mixed-methods approach. Delaying metastases may be a reasonable goal also from an economic standpoint. These findings can inform decision-making about treatments at the juncture between non-metastatic and metastatic prostate cancer disease.

IntroductionUsing a surrogate endpoint as a substitute for a primary patient-relevant outcome enables randomised controlled trials (RCTs) to be conducted more efficiently, that is, with shorter time, smaller sample size and lower cost. However, there is currently no consensus-driven guideline for the reporting of RCTs using a surrogate endpoint as a primary outcome; therefore, we seek to develop SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) extensions to improve the design and reporting of these trials. As an initial step, scoping and targeted reviews will identify potential items for inclusion in the extensions and participants to contribute to a Delphi consensus process.Methods and analysisThe scoping review will search and include literature reporting on the current understanding, limitations and guidance on using surrogate endpoints in trials. Relevant literature will be identified through: (1) bibliographic databases; (2) grey literature; (3) handsearching of reference lists and (4) solicitation from experts. Data from eligible records will be thematically analysed into potential items for inclusion in extensions. The targeted review will search for RCT reports and protocols published from 2017 to 2021 in six high impact general medical journals. Trial corresponding author contacts will be listed as potential participants for the Delphi exercise.Ethics and disseminationEthical approval is not required. The reviews will support the development of SPIRIT and CONSORT extensions for reporting surrogate primary endpoints (surrogate endpoint as the primary outcome). The findings will be published in open-access publications.This review has been prospectively registered in the OSF Registration DOI: 10.17605/OSF.IO/WP3QH.

This study aims at comparing the severity score assessed using high-resolution computed tomography (HRCT) in vaccinated and unvaccinated COVID-19 patients.From the first of December 2021 to first of February 2022, we conducted a single-center retrospective analysis on COVID-19 patients who accessed ED services. The hospital in question is a level II facility with a catchment area of around 200,000 people. According to the Italian recommendations, patients were divided into four groups based on the CT score of Micheal Chung. The sum of acute inflammatory lung lesions involving each lobe was scored as 1 (0-25%), 2 (26-50%), 3 (51-75%) or 4 (76-100%) on a visual quantitative assessment of CT. The total severity score (TSS) was determined by summing the five lobe scores.The study included 134 patients divided into two groups: 67 vaccinated and 67 unvaccinated people. 53 people had incomplete (single dose/double dose) immunization, while 14 people completed the vaccination cycle. It was discovered that the mean CT severity score was lower in fully vaccinated patients compared to partially vaccinated or unvaccinated patients. The mean CT score was significantly lower in fully vaccinated patients aged 60 compared to older patients. The mean CT score was higher in unvaccinated patients compared to fully vaccinated patients.Individuals who received three doses of COVID-19 vaccination had lower CT severity scores than patients who received only one dose of vaccine or no vaccines at all.

No abstract available.

Objectives Medical devices are potentially good candidates for coverage with evidence development (CED) schemes, as clinical data at market entry are often sparse and (cost-)effectiveness depends on real-world use. The objective of this research was to explore the diffusion of CED schemes for devices in Europe, and the factors that favour or hamper their utilization. Methods We conducted structured interviews with 25 decision-makers from 22 European countries to explore the characteristics of existing CED programmes for devices, and how decision makers perceived 13 pre-identified challenges associated with initiating and operating CED schemes for devices. We also collected data on individual schemes that were either initiated or still ongoing in the last 5 years. Results We identified seven countries with CED programmes for devices and 78 ongoing schemes. The characteristics of CED programmes varied across countries, including eligibility criteria, roles and responsibilities of stakeholders, funding arrangements, and type of decisions being contemplated at the outset of each scheme. We observed a high variability in how decision makers perceived CED-related challenges possibly reflecting country-specific arrangements and different experiences with CED. One general finding across all countries was that relatively little attention was paid to the evaluation of schemes, both during and at their completion. Conclusions CED programmes for devices with different characteristics exist in Europe. Decision-makers’ perceptions differ on the challenges associated with these schemes. More exchange of knowledge and experience will help decision makers anticipate the likely challenges in CED schemes for devices, and to learn from good practices existing elsewhere.

Introduction Quality in medical care must be measured in order to be improved. Trauma management is part of health care, and by definition, it must be checked constantly. The only way to measure quality and outcomes is to systematically accrue data and analyze them. Material and methods A systematic revision of the literature about quality indicators in trauma associated to an international consensus conference Results An internationally approved base core set of 82 trauma quality indicators was obtained: Indicators were divided into 6 fields: prevention, structure, process, outcome, post-traumatic management, and society integrational effects. Conclusion Present trauma quality indicator core set represents the result of an international effort aiming to provide a useful tool in quality evaluation and improvement. Further improvement may only be possible through international trauma registry development. This will allow for huge international data accrual permitting to evaluate results and compare outcomes.

Differing contexts have greatly influenced HTA development in various countries, with considerable effort recently made by international HTA networks (e.g., EUnetHTA) and the European Union (EU) to make HTA a more coherent, equal, and efficient process. Medical devices (MDs) present particular challenges for HTA because of frequent, rapid innovation, outcomes influenced by end-user competence, dynamic pricing and often low-quality scientific evidence. Our objective is to describe the development, structure and governance of a National HTA Program for MDs (PNHTADM) in Italy, a highly participatory, stakeholder-engaged, evidence-based process to reform a fragmented system of appraisal and approval. Based largely on EUnetHTA methods, the resulting process delineates a standardized system for proposing MDs by any stakeholders, accrediting HTA producers, setting criteria for prioritization and appraisals, and innovatively linking recommendations with coverage, reimbursement and procurement of MDs. Expected benefits include reduced disparities in pricing and reimbursement policies and improved access to new technologies across 21 regional healthcare systems in Italy's decentralized, universal system, complete with provisions to require additional evidence collection and centrally monitor diffusion. Though devised for Italy, the design, resources and underlying analysis provide a framework for other nations seeking to consolidate HTA initiatives, particularly in light of new EU regulation.

ObjectivePedophilia is a disorder of public concern because of its association with child sexual offense and recidivism. Previous neuroimaging studies identified inconsistent brain abnormalities underlying pedophilic behavior both in idiopathic and acquired (i.e., emerging following brain damage) pedophilia. This study sought to explore the neural underpinnings of pedophilic behavior and to determine the extent to which brain alterations may be related to distinct psychopathological features in pedophilia.MethodsA coordinate based meta-analysis on previously published papers reporting whole brain analysis and a lesion network analysis using brain lesions as seeds in a resting state connectivity analysis were run to investigate the presence of consistent neural basis of idiopathic and acquired pedophilic behavior, respectively. The behavioral profiling approach was applied to link identified regions with corresponding psychological processes.ResultsWhile no consistent neuroanatomical alterations have been identified in idiopathic pedophilia, the current results support that all the lesions causing acquired pedophilia localized to a shared resting state network including posterior midlines structures, right inferior temporal gyrus and bilateral orbitofrontal cortex. These regions are associated with action inhibition and social cognition, abilities that are consistently described as severely impaired in acquired pedophiles.ConclusionsThis study suggests that idiopathic and acquired pedophilia may be two distinct disorders, in line with their distinctive clinical features, including age of onset, reversibility and modus operandi. Understanding the neurobiological underpinnings of pedophilic behavior may contribute to a more comprehensive characterization of these individuals on a clinical ground and to develop more efficient therapeutic rehabilitation strategies.

In the drive toward faster patient access to treatments, health technology assessment (HTA) agencies and payers are increasingly faced with reliance on evidence based on surrogate endpoints, increasing decision uncertainty. Despite the development of a small number of evaluation frameworks, there remains no consensus on the detailed methodology for handling surrogate endpoints in HTA practice. This research overviews the methods and findings of four empirical studies undertaken as part of COMED (Pushing the Boundaries of Cost and Outcome Analysis of Medical Technologies) program work package 2 with the aim of analyzing international HTA practice of the handling and considerations around the use of surrogate endpoint evidence. We have synthesized the findings of these empirical studies, in context of wider contemporary body of methodological and policy-related literature on surrogate endpoints, to develop a web-based decision tool to support HTA agencies and payers when faced with surrogate endpoint evidence. Our decision tool is intended for use by HTA agencies and their decision-making committees together with the wider community of HTA stakeholders (including clinicians, patient groups, and healthcare manufacturers). Having developed this tool, we will monitor its use and we welcome feedback on its utility.

Using a surrogate endpoint as a substitute for a patient-relevant final outcome enables randomised controlled trials (RCTs) to be conducted more efficiently. However, the use of surrogates remains controversial and there is currently no guideline for the reporting of RCTs using surrogate endpoints; therefore, we seek to develop SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) extensions to improve the reporting of these trials. We would like to invite interested individuals (trial methodologists, journal editors, healthcare industry, regulators and payers, and patient/public representative groups), particularly those with experience in the use of surrogate endpoints in trials.

Purpose this study was designed to measure the concentration of Vitamin D in the aqueous and to investigate if its topical application can increase quantities in aqueous humor. Methods 29 patients scheduled for cataract surgery were divided into two groups. Group 1 was used as a control group, in group 2 patients were instructed to instill one drop of vitamin D eye drops three times daily 10 days before surgery .Aqueous humor was collected with a 30-gauge needle immediately before surgery. Vitamin D concentrations were analyzed by liquid chromatography tandem mass spectrometry. Results Aqueous humor (AH) samples in both groups had small but detectable vitamin D levels. In the AH concentrations of vitamin D were, respectively, 2.1ng/mL 土0.4 in group 1 and 2.1ng/mL土0.3 in group 2(P = 0.9). Conclusion Our study confirmed the presence of vitamin D in AH. No significant difference of vitamin D concentration in AH was observed between the treatment and control group.

Introduction: Studies focusing on enchondroma and atypical cartilaginous tumour (ACT) of the pelvis are lacking. The purpose of this study was to verify possible clinical and radiological findings with regard to distinguishing enchondromas from ACT of the pelvis. In addition, this study analysed functional and oncological outcomes in patients with enchondromas or ACT of the pelvis treated with curettage or resection. Materials and methods: We retrospectively reviewed the medical records of 21 patients with confirmed enchondroma or ACT of the pelvis treated by curettage or resection from 1985 to 2018. The minimum follow-up was 18months. The relationship between clinical and radiological factors and tumour type or local recurrence was assessed using Fisher exact test and Mann–Whitney U test. Results: Endosteal scalloping (p = 0.039), tumour size (0.005) and age (0.006) were shown to statistically favour ACT over enchondroma; by contrast, enchondroma and ACT patients had no difference in pain frequency (p = 0.5528). All patients with enchondroma had no local recurrence; in contrast, local recurrence occurred in one patient with ACT, initially treated with resection. The patient with local recurrence had a disease progression with a higher histological grade than the original tumour. Patients treated with curettage had better functional outcomes than patients treated with resection (p = 0.001). Discussion: Endosteal scalloping, tumour size and age could be helpful in the differential diagnosis between enchondroma and ACT of the pelvis. In addition, our study showed that ACT of the pelvis can be safely treated with curettage due to a low risk of local recurrence and better functional results compared with resection. In case of recurrence, we suggest to treat these patients with resection for the risk of disease progression.

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients die significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment., The immunopathological features of SARS-CoV-2 infection in the lungs remain unclear. Here, the authors provide a comprehensive characterization of post mortem lung tissues of COVID-19 patients and find two distinct patterns characterized by differential expression of interferon stimulated genes (ISGs), which correlate to viral loads, cytokines, lung damage and time of hospitalization, suggesting ISG profiles to mark disease progression

In the drive towards faster patient access to treatments, health technology assessment (HTA) agencies are increasingly faced with reliance on evidence from surrogate endpoints, leading to increased decision uncertainty. This study undertook an updated survey of methodological guidance for using surrogate endpoints across international HTA agencies. We reviewed HTA and economic evaluation methods guidance from European, Australian and Canadian HTA agencies. We considered how guidelines addressed the methods for handling surrogate endpoints, including (1) level of evidence, (2) methods of validation, and (3) thresholds of acceptability. Across the 73 HTA agencies surveyed, 29 (40%) had methodological guidelines that made specific reference to consideration of surrogate outcomes. Of the 45 methods documents analysed, the majority [27 (60%)] were non-technology specific, 15 (33%) focused on pharmaceuticals and three (7%) on medical devices. The principles of the European network for Health Technology Assessment (EUnetHTA) guidelines published in 2015 on the handling of surrogate endpoints appear to have been adopted by many European HTA agencies, i.e. preference for final patient-relevant outcomes and reliance on surrogate endpoints with biological plausibility and epidemiological evidence of the association between the surrogate and final endpoint. Only a small number of HTA agencies (UK National Institute for Care and Excellence; the German Institute for Medical Documentation and Information and Institute for Quality and Efficiency in Health Care; the Australian Pharmaceutical Benefits Advisory Committee; and the Canadian Agency for Drugs and Technologies in Health) have developed more detailed prescriptive criteria for the acceptance of surrogate endpoints, e.g. meta-analyses of randomised controlled trials showing strong association between the treatment effect on the surrogate and final outcomes. As the decision uncertainty associated with reliance on surrogate endpoints carries a risk to patients and society, there is a need for HTA agencies to develop more detailed methodological guidance for consistent selection and evaluation of health technologies that lack definitive final patient-relevant outcome evidence at the time of the assessment.

Motivation The use of liquid biopsies for cancer patients enables the non-invasive tracking of treatment response and tumor dynamics through single or serial blood drawn tests. Next-generation sequencing assays allow for the simultaneous interrogation of extended sets of somatic single-nucleotide variants (SNVs) in circulating cell-free DNA (cfDNA), a mixture of DNA molecules originating both from normal and tumor tissue cells. However, low circulating tumor DNA (ctDNA) fractions together with sequencing background noise and potential tumor heterogeneity challenge the ability to confidently call SNVs. Results We present a computational methodology, called Adaptive Base Error Model in Ultra-deep Sequencing data (ABEMUS), which combines platform-specific genetic knowledge and empirical signal to readily detect and quantify somatic SNVs in cfDNA. We tested the capability of our method to analyze data generated using different platforms with distinct sequencing error properties and we compared ABEMUS performances with other popular SNV callers on both synthetic and real cancer patients sequencing data. Results show that ABEMUS performs better in most of the tested conditions proving its reliability in calling low variant allele frequencies somatic SNVs in low ctDNA levels plasma samples. Availability and implementation ABEMUS is cross-platform and can be installed as R package. The source code is maintained on Github at http://github.com/cibiobcg/abemus, and it is also available at CRAN official R repository. Supplementary information Supplementary data are available at Bioinformatics online.

Digital health and mobile medical apps (MMAs) have shown great promise in transforming health care, but their adoption in clinical care has been unsatisfactory, and regulatory guidance and coverage decisions have been lacking or incomplete. A multidimensional assessment framework for regulatory, policymaking, health technology assessment, and coverage purposes based on the MMA lifecycle is needed. A targeted review of relevant policy documents from international sources was conducted to map current MMA assessment frameworks, to formulate 10 recommendations, subsequently shared amongst an expert panel of key stakeholders. Recommendations go beyond economic dimensions such as cost and economic evaluation and also include MMA development and update, classification and evidentiary requirements, performance and maintenance monitoring, usability testing, clinical evidence requirements, safety and security, equity considerations, organizational assessment, and additional outcome domains (patient empowerment and environmental impact). The COVID-19 pandemic greatly expanded the use of MMAs, but temporary policies governing their use and oversight need consolidation through well-developed frameworks to support decision-makers, producers and introduction into clinical care processes, especially in light of the strong international, cross-border character of MMAs, the new EU medical device and health technology assessment regulations, and the Next Generation EU funding earmarked for health digitalization.

On 31st January 2020, the Italian cabinet declared a 6-month national emergency after the detection of the first two COVID-19 positive cases in Rome, two Chinese tourists travelling from Wuhan. Between then and the total lockdown introduced on 22nd March 2020 Italy was hit by an unprecedented crisis. In addition to being the first European country to be heavily swept by the COVID-19 pandemic, Italy was the first to introduce stringent lockdown measures. The SARS-CoV-2 outbreak and related COVID-19 pandemic have been the worst public health challenge endured in recent history by Italy. Two months since the beginning of the first wave, the estimated excess deaths in Lombardy, the hardest hit region in the country, reached a peak of more than 23,000 deaths. The extraordinary pressures exerted on the Italian Servizio Sanitario Nazionale (SSN) inevitably leads to questions about its preparedness and the appropriateness and effectiveness of responses implemented at both national and regional levels. The aim of the paper is to critically review the Italian response to the COVID-19 crisis spanning from the first early acute phases of the emergency (March–May 2020) to the relative stability of the epidemiological situation just before the second outbreak in October 2020.

IntroductionRandomised controlled trials (RCTs) may use surrogate endpoints as substitutes and predictors of patient-relevant/participant-relevant final outcomes (eg, survival, health-related quality of life). Translation of effects measured on a surrogate endpoint into health benefits for patients/participants is dependent on the validity of the surrogate; hence, more accurate and transparent reporting on surrogate endpoints is needed to limit misleading interpretation of trial findings. However, there is currently no explicit guidance for the reporting of such trials. Therefore, we aim to develop extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines to improve the design and completeness of reporting of RCTs and their protocols using a surrogate endpoint as a primary outcome.Methods and analysisThe project will have four phases: phase 1 (literature reviews) to identify candidate reporting items to be rated in a Delphi study; phase 2 (Delphi study) to rate the importance of items identified in phase 1 and receive suggestions for additional items; phase 3 (consensus meeting) to agree on final set of items for inclusion in the extensions and phase 4 (knowledge translation) to engage stakeholders and disseminate the project outputs through various strategies including peer-reviewed publications. Patient and public involvement will be embedded into all project phases.Ethics and disseminationThe study has received ethical approval from the University of Glasgow College of Medical, Veterinary and Life Sciences Ethics Committee (project no: 200210051). The findings will be published in open-access peer-reviewed publications and presented in conferences, meetings and relevant forums.

Objectives To test the feasibility of using videoconferencing (VC) administered interviews and to derive an EQ-5D-5L value set for Italy. Methods Preferences were collected using the EuroQol standardized valuation protocol (EQ-VT) administered via VC. Two valuation methods were employed, composite time trade-off (cTTO) and discrete choice experiment (DCE). Technical, organizational and protocol feasibility were tested in a pilot of 198 interviews. Upon positive assessment, data collection continued with a target sample of 1000–1200 participants including the pilot. Quality control (QC) procedures were employed to monitor interviewers’ performance during the pilot and the data collection. Data were modelled using GLS, Tobit, Logit and Hybrid models with different error specifications. Monotonicity of coefficients, statistical significance, and theoretical considerations informed the model choice. Results Dropouts and technical problems occurred in less than 5% of the 198 pilot interviews. Protocol compliance was demonstrated with significant improvements in QC parameters and limited interviewers’ effects, for all interviewers. Overall, interviewers were satisfied with this mode of administration, highlighting it allows flexibility and efficient scheduling. Based on these results, VC was deemed as a feasible mode of administration. The study collected preferences for 1182 responders, including the pilot interviews. The demographic characteristics of the sample were representative of the Italian general population for age, gender and geographical macro-areas. The hybrid Tobit heteroscedastic model without constant estimated on the full sample (including pilot) was selected for the derivation of the value set. Values ranged from −0.571 for the worst health state (55555) to 1 for the best health state (11111). Pain/discomfort registered the largest decrement, followed by mobility, anxiety/depression, self-care, and usual activities. 523 health states were worse than dead. Conclusions VC is viable for the conduct of valuation interviews. The Italian value set for the EQ-5D-5L can be used for value determinations of health technologies.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for CDKL5 deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that CDKL5 may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD. Previous findings showed that a single-target therapy aimed at normalizing impaired GSK-3β or histone deacetylase (HDAC) activity improved neurodevelopmental and cognitive alterations in a mouse model of CDD. Here we tested the ability of a first-in-class GSK-3β/HDAC dual inhibitor, Compound 11 (C11), to rescue CDD-related phenotypes. We found that C11, through inhibition of GSK-3β and HDAC6 activity, not only restored maturation, but also significantly improved survival of both human CDKL5-deficient cells and hippocampal neurons from Cdkl5 KO mice. Importantly, in vivo treatment with C11 restored synapse development, neuronal survival, and microglia over-activation, and improved motor and cognitive abilities of Cdkl5 KO mice, suggesting that dual GSK-3β/HDAC6 inhibitor therapy may have a wider therapeutic benefit in CDD patients.

COVID-19 lockdown brought to a drastic reduction of anthropic impacts on the environment worldwide, including the marine-coastal system. Earth-Observation (EO) data have the potential to monitor and diagnose the effects of the lockdown in terms of water quality. Here we connect the dots among some coastal environmental changes that occurred during the Italian COVID-19 lockdown by using EO data, also seeking to assess connectivity between inland and marine systems. We present a holistic analysis of spatial and temporal variability of environmental parameters in the North Adriatic Sea, Mediterranean basin, exploiting the synergy of different satellite sensors, as well as hydrologic data from in situ observations. Our analysis indicates a favourable interplay of environmental variability that resulted in negative anomalies of Chlorophyll-a concentration, with respect to the climatologic values. Peculiar meteo-oceanographic and hydrological conditions made hard to disentangle potential anthropogenic effects. However, a multi-year hierarchical cluster analysis of riverine remote sensing reflectances groups together the optical properties of inland waters during the lockdown. This emergent cluster highlights the possibility of a second-order, anthropogenic effect that, superimposed to the (first-order) environmental natural causes, may have enhanced water quality during the lockdown., Graphical abstract Unlabelled Image

Objectives Preoperative radiation therapy (RT) followed by wide-local excision with or without chemotherapy is widely accepted as management for soft tissue sarcomas (STS). Although studies have demonstrated excellent local control with this technique, there can be significant morbidity with the development of wound complications. It has been shown that sarcoma resections performed at a high-volume center lead to improved survival and functional outcomes. It is unclear, however, if radiation performed in a high-volume center leads to improved outcomes especially related to morbidity. The goal of this study was to determine whether preoperative RT performed at an academic cancer center have lower rates of wound complication compared with RT performed in community cancer centers. Materials and methods A total of 204 patients with STS were treated with preoperative RT±chemotherapy followed by limb-sparing resection. Of these, 150 patients had preoperative RT performed at an academic sarcoma center. wound complication were defined as those requiring secondary operations or prolonged wound care for 4 months following surgery. Predictors for wound complication were evaluated using a Fisher exact test for univariate analysis and logistic regression for multivariate analysis. Results The overall incidence of wound complication was 28.3%. Significant predictors for wound complication include tumor location and radiation delivered at a community hospital. The postoperative incidence of wound complication was 21% when the preoperative RT was performed at an academic cancer center versus 39% when performed at a community cancer center (P=0.009). On multivariate analysis, both tumor location (P=0.0012, 95% confidence interval: 0.03-0.45, odds ratio: 0.13) and RT performed at a community cancer center (P=0.02, 95% confidence interval: 1.13-4.48, odds ratio: 2.25) remained significant in correlation with postoperative wound complication. Conclusions Preoperative RT performed at an academic cancer center led to lower rates of postoperative wound complication. This may support the recommendation that preoperative RT and resection of STS be performed at an experienced sarcoma center.

Chemoresistance poses a great barrier to breast cancer treatment and is thought to correlate with increased matrix stiffness. We developed two-dimensional (2D) polyacrylamide (PAA) and three-dimensional (3D) alginate in vitro models of tissue stiffness that mimic the stiffness of normal breast and breast cancer. We then used these to compare cell viability in response to chemotherapeutic treatment. In both 2D and 3D we observed that breast cancer cell growth and size was increased at a higher stiffness corresponding to tumours compared to normal tissue. When chemotherapeutic response was measured, a specific differential response in cell viability was observed for gemcitabine in 2 of the 7 breast cancer cell lines investigated. MCF7 and T-47D cell lines showed gemcitabine resistance at 4 kPa compared to 500 Pa. These cell lines share a common phenotype of progesterone receptor (PGR) expression and, indeed, pre-treatment with the selective progesterone receptor modulator (SPRM) mifepristone abolished resistance to gemcitabine at high stiffness. Our data reveals that combined treatment with SPRMs may therefore help in reducing resistance to gemcitabine in stiffer breast tumours which are PGR positive.

Sell, KM, Ghigiarelli, JJ, Prendergast, JM, Ciani, GJ, Martin, J, and Gonzalez, AM. Comparison of V̇o2peak and V̇o2max at different sampling intervals in collegiate wrestlers. J Strength Cond Res 35(10): 2915-2917, 2021-The purpose of this study was to determine the difference in the highest oxygen uptake (V̇o2peak) achieved during a maximal effort graded exercise test (GXT) in 20 NCAA Division I male wrestlers using breath-by-breath (BbB) values to the maximal uptake averaged across different time- and breath-based oxygen consumption sampling intervals (V̇o2max). Given the need for aerobic fitness and anaerobic power in wrestling, the accurate determination of V̇o2max is imperative if it is to be used to identify current aerobic fitness and consequently guide sport-specific training programs to address weaknesses in this area. Each subject completed a cycle ergometer GXT during which BbB data were collected via indirect calorimetry and V̇o2peak determined as the highest value. V̇o2max was considered as the average value of 3-s, 5-s, 10-s, 20-s, and 30-s sampling, and 3-b, 7-b, and 11-b sampling during the GXT. Results show that the BbB V̇o2peak was significantly higher than the 5-s, 10-s, 20-s, 30-s, and 11-b (p0.05). The 3-b V̇o2max was significantly higher than the 20-s and 30-s V̇o2max values (p0.05). The underestimation of V̇o2peak for each time-based interval sampling approach compared with BbB V̇o2peak is consistent with previous research, but the comparison of BbB data to breath-based interval sampling has not been widely addressed in prior research. The use of a 7-b sampling interval for the determination of V̇o2max may be a promising approach to minimize the systematic errors associated with BbB or less frequent sampling intervals, but future research is needed to further support its application with elite athletic populations such as those in the current study.

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p

Purpose: Surgical options for long bone metastases include intramedullary nail fixation or prosthetic reconstruction. Patients with a short life expectancy may benefit from less invasive surgery such as intramedullary nail fixation, while patients with a long life expectancy could be treated with more invasive surgery such as prosthetic reconstruction. The purpose of our study was to analyze the survival of patients treated surgically for long bone metastases, determining the prognostic factors affecting survival and analyzing the surgical complications and reoperation rates. Based on our results, we developed a prognostic score that helps to choose the best treatment for these patients. In addition, we compared the performance of our prognostic score with other previous prognostic models. Method: We investigated prospectively potential clinical and laboratory prognostic factors in 159 patients with metastatic bone disease who underwent surgery with intramedullary nail fixation or prosthetic reconstruction. Clinical data were collected, recording the following data: age and sex of patients, primary tumour and time of diagnosis, number (single or multiple) and presentation (synchronous or metachronous) of bone metastases, presence of visceral metastases. The following laboratory data were analyzed: hemoglobin, leukocyte counts, lymphocyte counts, platelets count, alkaline phosphatase, and C-reactive protein. Results: Our study showed that pathological C-reactive protein and primary tumour diagnosis were significant negative independent prognostic factors at 12-month survival. Based on our results, we created a score using C-reactive protein and primary tumour diagnosis, creating three different prognostic groups: (A) good prognosis primary tumour and physiological CRP with probability of survival at 12 months of 88.9 [80.1–98.5]; (B) bad prognosis primary tumour and physiological CRP or good prognosis primary tumour and pathological CRP with a probability of survival at 12 months of 56.7 [45.4–70.7]; (C) bad prognosis primary tumour and pathological CRP with a probability of survival at 12 months of 12.5 [5.0–28.3]. Using ROC multiple analysis, our score (AUC = 0.816) was the most accurate in predicting a 12-month survival compared to previous prognostic models. Discussion: Patients treated surgically for long bone metastases with a life expectancy over 12 months should be treated with more durable reconstruction, while patients with a life expectancy less than 12 months should be treated with less invasive surgery. The diagnosis of primary cancer and C-reactive protein are two very simple data which every orthopaedic surgeon in any community hospital can easily rely on for any decision-making in the surgical treatment of a complex patient as with a patient with skeletal metastases. Conclusion: Our prognostic score based on only two simple variables (C-reactive protein and primary tumour diagnosis) was able to predict the 12-month survival of patients treated surgically for long bone metastases and could be helpful in choosing the best treatment for these patients.

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism., Nature Communications, 12 (1), ISSN:2041-1723

There are conflicting reports regarding the outcome and effect of denosumab for distal radius giant cell tumor of bone (GCTB). The authors performed this study to evaluate the behavior of distal radius GCTB in relation to the type of treatment and the administration of denosumab. The files of 72 patients with distal radius GCTB treated from 1984 to 2018 were reviewed. Fourteen patients were administered denosumab. Surgical treatment consisted of curettage (25 patients) or resection (47 patients) and allograft or vascularized fibular head graft reconstruction. Median follow-up was 63.1 months (interquartile range [IQR], 35.5–107.1 months). The authors evaluated local recurrences, metastasis, function, and complications. The local recurrence rate was 30.6% at a median of 14.0 months (IQR, 10–19 months), with no difference between curettage and resection. The local recurrence rate was significantly higher in the patients who received denosumab. The metastasis rate was 9.7% at a median of 41.0 months (IQR, 15–114 months), with no difference regarding denosumab administration. Function was significantly better in patients after curettage. The complication rate was 25%; vascularized fibular graft reconstruction was associated with fewer complications. This study found that denosumab increases the risk of local recurrence after curettage, function is better after curettage, and vascularized fibular graft is the optimal reconstruction after resection of distal radius GCTB. [ Orthopedics . 2020;43(5):284–291.]

Objectives Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations. Methods SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses. Results The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]. Conclusion Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a severe neurodevelopmental disorder, CDKL5 deficiency disorder (CDD). CDKL5 is fundamental for correct brain development and function, but the molecular mechanisms underlying aberrant neurologic dysfunction in CDD are incompletely understood. Here we show a dysregulation of hippocampal and cortical serotonergic (5-HT) receptor expression in heterozygous Cdkl5 knockout (KO) female mice, suggesting that impaired 5-HT neurotransmission contributes to CDD. We demonstrate that targeting impaired 5-HT signaling via the selective serotonin reuptake inhibitor (SSRI) sertraline rescues CDD-related neurodevelopmental and behavioral defects in heterozygous Cdkl5 KO female mice. In particular, chronic treatment with sertraline normalized locomotion, stereotypic and autistic-like features, and spatial memory in Cdkl5 KO mice. These positive behavioral effects were accompanied by restored neuronal survival, dendritic development and synaptic connectivity. At a molecular level, sertraline increased brain-derived neurotrophic factor (BDNF) expression and restored abnormal phosphorylation levels of tyrosine kinase B (TrkB) and its downstream target the extracellular signal-regulated kinase (ERK1/2). Since sertraline is an FDA-approved drug with an extensive safety and tolerability data package, even for children, our findings suggest that sertraline may improve neurodevelopment in children with CDD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Mutations in the CDKL5 gene, which encodes a serine/threonine kinase, causes a rare encephalopathy, characterized by early-onset epilepsy and severe intellectual disability, named CDKL5 deficiency disorder (CDD). In vitro and in vivo studies in mouse models of Cdkl5 deficiency have highlighted the role of CDKL5 in brain development and, in particular, in the morphogenesis and synaptic connectivity of hippocampal and cortical neurons. Interestingly, Cdkl5 deficiency in mice increases vulnerability to excitotoxic stress in hippocampal neurons. However, the mechanism by which CDKL5 controls neuronal survival is far from being understood. To investigate further the function of CDKL5 and dissect the molecular mechanisms underlying neuronal survival, we generated a human neuronal model of CDKL5 deficiency, using CRISPR/Cas9-mediated genome editing. We demonstrated that CDKL5 deletion in human neuroblastoma SH-SY5Y cells not only impairs neuronal maturation but also reduces cell proliferation and survival, with alterations in the AKT and ERK signaling pathways and an increase in the proapoptotic BAX protein and in DNA damage-associated biomarkers (i.e., γH2AX, RAD50, and PARP1). Furthermore, CDKL5-deficient cells were hypersensitive to DNA damage-associated stress, accumulated more DNA damage foci (γH2AX positive) and were more prone to cell death than the controls. Importantly, increased kainic acid-induced cell death of hippocampal neurons of Cdkl5 KO mice correlated with an increased γH2AX immunostaining. The results suggest a previously unknown role for CDKL5 in DNA damage response that could underlie the pro-survival function of CDKL5.

Objective There is no comprehensive assessment of which patient-reported outcomes (PROs) are recommended in core outcome sets (COS), and how they should be measured. The aims of this study are to review COS that include patient-reported outcomes measures (PROMs), identify their target health domains, main characteristics, and their overlap within and across different disease areas. Study design and setting We selected COS studies collected in a publicly available database that included at least one recommended PROM. We gathered information on study setting, disease area, and targeted outcome domains. Full-text of recommended instruments were obtained, and an analysis of their characteristics and content performed. We classified targeted domains according to a predefined 38-item taxonomy. Results Overall, we identified 94 COS studies that recommended 323 unique instruments, of which: 87% were included in only one COS; 77% were disease-specific; 1.5% preference-based; and 61% corresponded to a full questionnaire. Most of the instruments covered broad health-related constructs, such as global quality of life (25%), physical functioning (22%), emotional functioning and wellbeing (7%). Conclusion The wealth of recommended instruments observed even within disease areas does not fit with a vision of systematic, harmonized collection of PROM data in COS within and across disease areas.

Wine can be defined as a complex microbial ecosystem, where different microorganisms interact in the function of different biotic and abiotic factors. During natural fermentation, the effect of unpredictable interactions between microorganisms and environmental factors leads to the establishment of a complex and stable microbiota that will define the kinetics of the process and the final product. Controlled multistarter fermentation represents a microbial approach to achieve the dual purpose of having a less risky process and a distinctive final product. Indeed, the interactions evolved between microbial consortium members strongly modulate the final sensorial properties of the wine. Therefore, in well-managed mixed fermentations, the knowledge of molecular mechanisms on the basis of yeast interactions, in a well-defined ecological niche, becomes fundamental to control the winemaking process, representing a tool to achieve such objectives. In the present work, the recent development on the molecular and metabolic interactions between non-Saccharomyces and Saccharomyces yeasts in wine fermentation was reviewed. A particular focus will be reserved on molecular studies regarding the role of nutrients, the production of the main byproducts and volatile compounds, ethanol reduction, and antagonistic actions for biological control in mixed fermentations.

This retrospective review evaluated 25 patients with 29 shoulders treated with arthroplasty for humeral head avascular necrosis (HHAVN) between 2004 and 2015. We hypothesized that regardless of implant, radiographic stage, or etiology, patients would appreciate significant improvement in pain, range of motion, and shoulder functionality after surgical intervention.Data were obtained by record review on all patients meeting inclusion criteria. Outcomes were evaluated using Simple Shoulder Test, Modified Constant Score, University of California Los Angeles Shoulder Rating Scale, and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form. The data were assessed by all patients and subcategories (treatment, avascular necrosis stage, and underlying cause).At a mean follow-up of 3.9 years (range, 1-8.5 years), all patients who underwent operative intervention for HHAVN showed statistically significant improvement in functionality measurements (P .01). Patients who underwent total shoulder arthroplasty (TSA) noted higher median outcome scores and greater improvement in all scoring methods compared with their hemiarthroplasty counterparts. The high-stage disease shoulders showed similar trends over low-stage counterparts. The shoulders in the trauma causal group had the highest scores in 3 of 4 outcome measures and favorable change in all scoring methods. These differences were not statistically significant (P .05). No revision arthroplasties were required. Minor complications (suture abscess and intraoperative calcar fracture requiring cabling) occurred in 2 TSA patients.Our outcomes demonstrate that in the short- to midterm follow-up, TSA or hemiarthroplasty is a safe and equally effective treatment for patients diagnosed with HHAVN regardless of etiology and radiographic staging.

In this paper, we propose an unobtrusive method and architecture for monitoring a person’s presence and collecting his/her health-related parameters simultaneously in a home environment. The system is based on using a single ultra-wideband (UWB) impulse-radar as a sensing device. Using UWB radars, we aim to recognize a person and some preselected movements without camera-type monitoring. Via the experimental work, we have also demonstrated that, by using a UWB signal, it is possible to detect small chest movements remotely to recognize coughing, for example. In addition, based on statistical data analysis, a person’s posture in a room can be recognized in a steady situation. In addition, we implemented a machine learning technique (k-nearest neighbour) to automatically classify a static posture using UWB radar data. Skewness, kurtosis and received power are used in posture classification during the postprocessing. The classification accuracy achieved is more than 99%. In this paper, we also present reliability and fault tolerance analyses for three kinds of UWB radar network architectures to point out the weakest item in the installation. This information is highly important in the system’s implementation.

Therapeutic education for Type 1 Diabetes involves the process of transmitting knowledge and developing the skills and behavior required to treat the disease. guidelines agree on stressing the importance of therapeutic educational intervention in teaching self-management skills to children and adolescents with Type 1 Diabetes (T1D). This study presents the results of the "Pediatric Education for Type 1 Diabetes (T1D)" (PED) project, specifically designed for children and adolescents aged 6 to 16, and structured on guidelines indications, as part of a broader clinical-educational intervention for Type 1 diabetes.Twenty-four patients with Type 1 diabetes (mean age: 12,13 y; SD=1.48 y; range 9-14) were studied in a 12-month PED structured project followed by an educational summer camp. All the activities were designed and organized by a multidisciplinary team (dietitian, pediatric diabetologist, nurse, psychologist and adult diabetologist). Glycated hemoglobin (HbA1C), knowledge about Type 1 Diabetes (T1D) (self-monitoring and nutrition), self-management (self-monitoring, nutrition and flexibility of medical treatment), and wellbeing were used as outcome measures.Data suggest that the PED had a positive impact on all the targeted levels indicated for recommended care.The results of this study seem to confirm the effectiveness in altering the three levels of "knowing," "know-how" and "wellbeing" required to optimize the quality of life of young patients with Type 1 diabetes. In addition, the proposed model, where a pediatric diabetologist always cooperates with an adult diabetologist, seems to be a permanent solution to the transitional gap widely discussed in the literature.

We have summarized the abstract section as follows: "We report a son and his father affected by Attention Deficit Hyperactivity Disorder (ADHD). They belonged to a larger cohort (116 ADHD children, 20 related parents, 77 controls) wholly genotyped for

The paper discusses the responses to the COVID-19 crisis in the acute phase of the first wave of the pandemic (February-May 2020) by different Italian regions in Italy, which has a decentralised healthcare system. We consider five regions (Lombardy, Veneto, Emilia-Romagna, Umbria, Apulia) which are located in the north, centre and south of Italy. These five regions differ both in their healthcare systems and in the extent to which they were hit by the first wave of COVID-19 pandemic. We investigate their different responses to COVID-19 reflecting on seven management factors: (1) monitoring, (2) learning, (3) decision-making, (4) coordinating, (5) communicating, (6) leading, and (7) recovering capacity. In light of these factors, we discuss the analogies and differences among the regions and their different institutional choices.

Introduction: The unparalleled surge in digital health adoption during the COVID-19 pandemic has emphasized the potential of mHealth apps. However, the quality of available evidence is generally low, and regulatory frameworks have focused on apps with medical purposes only, overlooking apps with significant interactions with patients that may require stronger oversight. Areas covered: To support this expanded evidence generation process, we identified the reasons that distinguish mHealth apps compared to medical devices at large and that should differentially feature their assessment. mHealth apps are characterized by the iterative nature of the corresponding interventions, frequent user interactions with a non-linear relationship between technology usage, engagement and outcomes, significant organizational implications, as well as challenges associated with genericization, their broad diagnostic potential, and price setting. Expert Opinion: The renewed reliance experienced during the pandemic and the unprecedented injection of resources through recovery instruments can further boost the development of apps. Only robust evidence of the benefits of mHealth apps will persuade health-care professionals and beneficiaries to systematically deploy them. Regulatory bodies will need to question their current approaches by adopting comprehensive evaluation processes that adequately consider the specific features of mHealth apps.