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Domestic violence creates multiple harms for women's health and is a ‘wicked problem’ for health professionals and public health systems. Brazil recently approved public policies to manage and care for women victims of domestic violence. Facing these policies, this study aimed to explore how domestic violence against women is usually managed in Brazilian primary health care, by investigating a basic health unit and its family health strategy. We adopted qualitative ethnographic research methods with thematic analysis of emergent categories, interrogating data with gender theory and emergent Brazilian collective health theory. Field research was conducted in a local basic health unit and the territory for which it is responsible, in Southern Brazil. The study revealed: 1) a yawning gap between public health policies for domestic violence against women at the federal level and its practical application at local/decentralized levels, which can leave both professionals and women unsafe; 2) the key role of local community health workers, paraprofessional health promotion agents, who aim to promote dialogue between women experiencing violence, health care professionals and the health care system. Resumo A violência doméstica (VD) cria múltiplos agravos à saúde das mulheres e é um desafio para profissionais e para os sistemas de saúde. O Brasil aprovou recentemente políticas públicas (PP) para manejo e cuidado de mulheres em situação de VD. Considerando essas PP, este estudo objetivou explorar como a VD contra mulheres é usualmente manejada na atenção primária à saúde brasileira, por meio da investigação de uma unidade básica de saúde e de sua estratégia de saúde da família. Foi adotada metodologia de pesquisa qualitativa de cunho etnográfico, com análise temática de categorias emergentes, interrogando os dados com teoria de gênero e com a produção teórica do campo da saúde coletiva brasileira. A pesquisa de campo foi conduzida em uma unidade básica de saúde e em seu território adscrito, localizado na região sul do Brasil. O estudo revelou: 1) um hiato entre PP direcionadas à VD contra mulheres implantadas a nível federal e sua aplicação prática a nível local/descentralizado, que pode deixar tanto profissionais quanto mulheres em risco; 2) o papel chave de agentes comunitários de saúde, profissionais de promoção da saúde, que objetivam promover o diálogo entre as mulheres experienciando violência, profissionais de saúde e o sistema de saúde.

Background Improved outcome in tobacco smoking patients with non‐small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. Methods We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first‐line pembrolizumab and platinum‐based chemotherapy. Results A total of 962 NSCLC patients with PD‐L1 expression ≥50% who received first‐line pembrolizumab and 462 NSCLC patients who received first‐line platinum‐based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15–1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02–1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52–1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45–1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression‐free survival (PFS) (HR = 1.68 [95% CI: 1.17–2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84–2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49–0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45–0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts. Conclusions Among metastatic NSCLC patients with PD‐L1 expression ≥50% receiving first‐line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first‐line chemotherapy., Improved outcome in tobacco smoking NSCLC patients following treatment with immune checkpoint inhibitors (ICIs) has previously been reported. Little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. Clinical outcomes according to the smoking status of two large multicenter cohorts were compared in this study. Smokers with high PD‐L1 expression ≥ 50% experienced improved progression‐free survival (PFS) and overall survival (OS) with first‐line pembrolizumab. The opposite trend was found in NSCLC patients treated with first‐line platinum‐based chemotherapy.

Background Moderate to vigorous physical activity (MVPA) can help to prevent depression, but identification of the most important psycho-biological pathways involved is unclear. The improvement of cardio-respiratory fitness (CRF) in response to MVPA can vary markedly, we therefore examined the association between CRF and the incidence of depressive symptoms. Methods We used data from The Maastricht Study, a large population-based prospective-cohort study. CRF was estimated at baseline from a graded submaximal exercise protocol and MVPA was measured with accelerometry. Depressive symptoms were assessed using the validated Dutch version of the 9-item Patient Health Questionnaire, both at baseline and during annual follow-up over five years. Cox proportional hazards models were used. Results A total of 1,730 individuals without depressive symptoms at baseline were included in the analysis. During the 5-year follow-up, n = 166 (9.6%) of individuals developed depressive symptoms. Compared to individuals with a low CRF, those with a moderate-to-high CRF had a significantly lower risk of developing depressive symptoms, independent of MVPA (medium CRF: HR = 0.49 (95%CI = 0.33–0.72); high CRF: HR = 0.48 (95% CI = 0.30–0.75). These associations were adjusted for age, sex, level of education, diabetes status, smoking status, alcohol use, energy intake, waist circumferences and antidepressant medications. Limitations PHQ-9 is a validated screening instrument, but it is not a diagnostic tool of depression. Conclusions Higher CRF was strongly associated with a lower risk of incident depressive symptoms over 5-year follow-up, independent of the level of MVPA at baseline, suggesting that interventions aimed at improving CRF could reduce the risk of depression.

The extremely rapid spread of the SARS-CoV-2 has already resulted in more than 1 million reported deaths of coronavirus disease 2019 (COVID-19). The ability of infectious particles to persist on environmental surfaces is potentially considered a factor for viral spreading. Therefore, limiting viral diffusion in public environments should be achieved with correct disinfection of objects, tissues, and clothes. This study proves how two widespread disinfection systems, short-wavelength ultraviolet light (UV-C) and ozone (O3), are active in vitro on different commonly used materials. The development of devices equipped with UV-C, or ozone generators, may prevent the virus from spreading in public places.

Background: Smoking is one of the leading causes of death worldwide, and it is strongly associated with several human cancers. However, the differential effects of cigarette smoke on the development and progression of different types of cancer remain unclear, and related data are limited. Methods: In this longitudinal cohort study conducted among 75,324 women aged 41-76 years, we aimed to evaluate the effect of exposure to tobacco smoke on cancer development. The participants completed a questionnaire assessing socio-demographic characteristics, anthropometric measures, health status, and lifestyle habits, including smoking and dietary habits; Cox proportional hazards regression modelling was used to evaluate the association between smoking and 21 different types of cancer. Results: After a 15-year follow-up, we identified 9,487 cases of cancer through record linkage with the Cancer Registry of Milan. Smoking was found to be positively associated with all neoplasms, with a Hazard Ratio (HR) of 1.10 (95% Confidence Interval (CI), 1.04-1.16). Regarding the specific types, we found the following associations: cancer of the oral cavity HR = 2.63 ( 95% CI 1.72-4.01]), oesophagus HR = 3.09 (95% CI 1.37-6.96), stomach HR = 1.52 (95% CI 1.10-2.11), pancreas HR = 1.69 (95% CI 1.29-2.21), larynx HR= 34.81 (95% CI 8.07-150.14), lung HR = 8.48 (95% CI 7.09-10.14), cervix uteri HR = 2.51 (95% CI 1.38-4.57), and bladder and urinary tract HR = 5.67 ( 95% CI 3.96-8.14); lymphoma HR = 1.37 (95% CI 1.03-1.83); and colorectal cancer HR = 1.30 (95% CI 1.11-1.51). Conclusions: Our results thus demonstrate how smoke exposure increases the risk of several types of cancer. Considering the increasing prevalence of smoking among women, our results highlight the need to prioritize the development of anti-smoking campaigns targeted at women in order to contrast the evident gender inequality with respect to healthcare.

Understanding mechanisms of coexistence is a central topic in ecology. Mathematical analysis of models of competition between two identical species moving at different rates of symmetric diffusion in heterogeneous environments show that the slower mover excludes the faster one. The models have not been tested empirically and lack inclusions of a component of directed movement toward favourable areas. To address these gaps, we extended previous theory by explicitly including exploitable resource dynamics and directed movement. We tested the mathematical results experimentally using laboratory populations of the nematode worm, Caenorhabditis elegans. Our results not only support the previous theory that the species diffusing at a slower rate prevails in heterogeneous environments but also reveal that moderate levels of a directed movement component on top of the diffusive movement allow species to coexist. Our results broaden the theory of species coexistence in heterogeneous space and provide empirical confirmation of the mathematical predictions.

Background Although Personal Electronic Health Records (PEHR) have been identified as innovative tools enabling the provision of patient-centered care and prevention, evidence on the impact of their use is scant. With PEHRs being more and more marketed as easily implementable and cost-effective instruments to provide people with direct control on their health, the question on whether their use might be associated with the priority to improve vaccine coverage arises. Methods We conducted a systematic review following the PRISMA guidelines to retrieve, quantitatively pool and critically appraise the effectiveness of PEHR access on vaccine uptake. Analysis on PEHR effectiveness were carried out for the following comparison strata: i) PEHR access vs no intervention (standard care, no access to PEHR), ii) PEHR access only vs access to PEHR with additional features (e.g. health education materials, active reminders). Results Of 3114 identified citations, 8 studies were included, the majority published in the US and before 2015; 62% were randomized trials, the rest having an observational study design. Evidence suggests a moderate positive impact of PEHR access in increasing vaccine uptake, with data available for influenza and pneumococcal vaccines, diabetic patients and childhood immunization. Pooled data report the addition of digital communication features, i.e. the delivery of educational messages, reminders and availability of scheduling features might increase vaccine uptake, as compared to PEHR access alone. However, evidence is not conclusive. Conclusion While immunization programs are struggling to achieve optimal coverage targets, it seems the potential of PEHRSs supporting informed adherence to vaccines recommendations is neither fully exploited nor explored. Which factors mediate the association between PEHRs access and vaccine uptake? Which PEHRs’ design and functional components can maximize their impact? On which target populations? Which PEHR models works better for high-risk populations? Our findings can only partially answer those questions and further experimental research is needed.

Autophagy is a conserved catabolic process that plays an essential role under nutrient starvation conditions and influences different developmental processes. We observed that seedlings of autophagy mutants (atg2, atg5, atg7, and atg9) germinated in the dark showed delayed chloroplast development following illumination. The delayed chloroplast development was characterized by a decrease in photosynthetic and chlorophyll biosynthetic proteins, lower chlorophyll content, reduced chloroplast size, and increased levels of proteins involved in lipid biosynthesis. Confirming the biological impact of these differences, photosynthetic performance was impaired in autophagy mutants 12 h post-illumination. We observed that while gene expression for photosynthetic machinery during de-etiolation was largely unaffected in atg mutants, several genes involved in photosystem assembly were transcriptionally downregulated. We also investigated if the delayed chloroplast development could be explained by lower lipid import to the chloroplast or lower triglyceride (TAG) turnover. We observed that the limitations in the chloroplast lipid import imposed by trigalactosyldiacylglycerol1 are unlikely to explain the delay in chloroplast development. However, we found that lower TAG mobility in the triacylglycerol lipase mutant sugardependent1 significantly affected de-etiolation. Moreover, we showed that lower levels of carbon resources exacerbated the slow greening phenotype whereas higher levels of carbon resources had an opposite effect. This work suggests a lack of autophagy machinery limits chloroplast development during de-etiolation, and this is exacerbated by limited lipid turnover (lipophagy) that physically or energetically restrains chloroplast development.

Background Systemic lupus erythematosus (SLE) and Primary Antiphospholipid Syndrome (PAPS) overlap clinical and immunological features. Therefore, misclassification of PAPS patients as SLE is a concern. The ACR/EULAR 2019 SLE classification has never been studied in PAPS. Objective To verify if the ACR/EULAR 2019 SLE classification can correctly classify a PAPS patient as not having SLE and compare its performance with the SLICC 2012 SLE classification. Methods: One-hundred thrombotic PAPS patients who fulfilled the Sidney criteria were consecutively screened and those who attended the inclusion criteria were submitted to ACR/EULAR 2019 and SLICC 2012 classifications. Results Sixty-seven PAPS patients were included in this study. The majority was female (89.6%) with median age at study inclusion of 45 years (35–53) and median PAPS disease duration of 13 years (8–19). PAPS correct classification was observed more often with ACR/EULAR 2019 than SLICC 2021 criteria (94.0% vs. 64.2%; p Conclusion ACR/EULAR 2019 had high accuracy for distinguishing PAPS from SLE, whereas the SLICC 2012 incorrectly classified more than one third of the PAPS patients as having SLE.

The study of states of arousal is key to understand the principles of consciousness. Yet, how different brain states emerge from the collective activity of brain regions remains unknown. Here, we studied the fMRI brain activity of monkeys during wakefulness and anesthesia-induced loss of consciousness. We showed that the coupling between each brain region and the rest of the cortex provides an efficient statistic to classify the two brain states. Based on this and other statistics, we estimated maximum entropy models to derive collective, macroscopic properties that quantify the system’s capabilities to produce work, to contain information, and to transmit it, which were all maximized in the awake state. The differences in these properties were consistent with a phase transition from critical dynamics in the awake state to supercritical dynamics in the anesthetized state. Moreover, information-theoretic measures identified those parameters that impacted the most the network dynamics. We found that changes in the state of consciousness primarily depended on changes in network couplings of insular, cingulate, and parietal cortices. Our findings suggest that the brain state transition underlying the loss of consciousness is predominantly driven by the uncoupling of specific brain regions from the rest of the network. A.P.A., B.J., and G.D. received funding from the FLAG-ERA JTC (PCI2018-092891). G.D. acknowledges funding from the European Union’s Horizon 2020 FET Flagship Human Brain Project under Grant Agreement 785907 HBP SGA1, SGA2, and SGA3, the Spanish Ministry Research Project PSI2016-75688-P (AEI/FEDER), the Catalan Research Group Support 2017 SGR 1545, and AWAKENING (PID2019-105772GB-I00, AEI FEDER EU) funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI) and European Regional Development Funds (FEDER). M.L.K. is supported by the ERC Consolidator Grant: CAREGIVING (n. 615539), Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117), and Centre for Eudaimonia and Human Flourishing funded by the Pettit and Carlsberg Foundations. BJ received funding from Fondation Bettencourt-Schueller, Université Paris-Saclay (UVSQ), Fondation de France, Collège de France and from INSERM. CMS was supported by Comisión Nacional de Investigación Ciencia y Tecnología (CONICYT, currently ANID) through Programa Formacion de Capital Avanzado (PFCHA), Doctoral scholarship Becas Chile: CONICYT PFCHA/DOCTORADO BECAS CHILE/2016—72170507.

Background To evaluate the performance of a decision support system (DSS) based on radiomics and machine learning in predicting the risk of malignancy of ovarian masses (OMs) from transvaginal ultrasonography (TUS) and serum CA-125. Methods A total of 274 consecutive patients who underwent TUS (by different examiners and with different ultrasound machines) and surgery, with suspicious OMs and known CA-125 serum level were used to train and test a DSS. The DSS was used to predict the risk of malignancy of these masses (very low versus medium-high risk), based on the US appearance (solid, liquid, or mixed) and radiomic features (morphometry and regional texture features) within the masses, on the shadow presence (yes/no), and on the level of serum CA-125. Reproducibility of results among the examiners, and performance accuracy, sensitivity, specificity, and area under the curve were tested in a real-world clinical setting. Results The DSS showed a mean 88% accuracy, 99% sensitivity, and 77% specificity for the 239 patients used for training, cross-validation, and testing, and a mean 91% accuracy, 100% sensitivity, and 80% specificity for the 35 patients used for independent testing. Conclusions This DSS is a promising tool in women diagnosed with OMs at TUS, allowing to predict the individual risk of malignancy, supporting clinical decision making.

OBJECTIVE Sentinel node mapping (SLN) has replaced lymphadenectomy for staging surgery in apparent early-stage low and intermediate risk endometrial cancer (EC). Only limited data about the adoption of SNM in high risk EC is still available. Here, we evaluate the outcomes of high-risk EC undergoing SNM (with or without back-up lymphadenectomy). METHODS This is a multi-institutional international retrospective study, evaluating data of high-risk (FIGO grade 3 endometrioid EC with myometrial invasion >50% and non-endometrioid histology) EC patients undergoing SNM followed by back-up lymphadenectomy and SNM alone. RESULTS Chart of consecutive 196 patients were evaluated. The study population included 83 and 113 patients with endometrioid and non-endometrioid EC, respectively. SNM alone and SNM followed by back-up lymphadenectomy were performed in 50 and 146 patients, respectively. Among patients having SNM alone, 14 (28%) were diagnosed with nodal disease. In the group of patients undergoing SNM plus back-up lymphadenectomy 34 (23.2%) were diagnosed with nodal disease via SNM. Back-up lymphadenectomy identified 2 (1%) additional patients with nodal disease (in the para-aortic area). Back-up lymphadenectomy allowed to remove adjunctive positive nodes in 16 (11%) patients. After the adoption of propensity-matched algorithm, we observed that patients undergoing SNM plus back-up lymphadenectomy experienced similar disease-free survival (p��=��0.416, log-rank test) and overall survival (p��=��0.940, log-rank test) than patients undergoing SLN alone. CONCLUSIONS Although the small sample size, and the retrospective study design this study highlighted that type of nodal assessment did not impact survival outcomes in high-risk EC. Theoretically, back-up lymphadenectomy would be useful in improving the removal of positive nodes, but its therapeutic value remains controversial. Further prospective evidence is needed.

Background Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00809-w.

Introduction A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality. Aim We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients. Methods In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores. Results Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49–0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation. Conclusion In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations.

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction ( p < 0.001 ). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.

The Erice 56 Charter titled "Impact of the environment on the health: from theory to practice" was unanimously approved at the end of the 56th course of the "International School of Epidemiology and Preventive Medicine G. D'Alessandro" held from 3th to 7th November 2019 in Erice - Sicily (Italy) and promoted by the Study Group of "Environment and Health" of the Italian Society of Hygiene, Preventive Medicine and Public Health. The course, that included lectures, open discussions and guided working groups, was aimed to provide a general training on epidemiological and toxicological aspects of the environmental health impact, to be used by public health professionals for risk assessment, without forgetting the risk communications. At the end of the course 12 key points were agreed among teachers and students: they underlined the need of specific training and research, in the perspective of "One Health" and "Global Health", also facing emerging scientific and methodological issues and focusing on communication towards stakeholders. This Discussion highlight the need to improve knowledge of Health and Environment topic in all sectors of health and environmental prevention and management.

Objective: To evaluate the outcomes of high-risk (HR) HPV-positive and -negative women affected by high-grade cervical dysplasia. Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with high-grade cervical dysplasia undergoing conization between 2010 and 2014 were retrieved. All patients included had at least 5 years of follow-up. A propensity-score matching was adopted in order to reduce the presence of confounding factors between groups. Kaplan-Meir and Cox hazard models were used to estimate 5-year outcomes. Results: Overall, data of 2966 women, affected by high-grade cervical dysplasia were reviewed. The study population included 1478 (85%) and 260 (15%) women affected by HR-HPV-positive and HR-HPV-negative high-grade cervical dysplasia. The prevalence of CIN2 and CIN3 among the HR-HPV-positive and -negative cohort was similar (p = 0.315). Patients with HR-HPV-positive high-grade cervical dysplasia were at higher risk of 5-year recurrence (after primary conization) that HR-HPV-negative patients (p < 0.001, log-rank test). Via multivariate analysis, HR-HPV-negative women were at low risk of recurrence (HR: 1.69 (95%CI: 1.05, 4.80); p = 0.018, Cox Hazard model). A propensity-score matched comparison was carried out in order to reduce biases that are related to the retrospective study design. In comparison to HR-HPV-negative patients, thosewith HR-HPV-positive CIN3 was associate with a 8-fold increase in the risk of recurrence (p < 0.001, log-rank test). Conclusions: HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data.

STUDY QUESTION Are uterine fluid-derived extracellular vesicles (UF-EVs) a ‘liquid biopsy’ reservoir of biomarkers for real-time monitoring of endometrial status? SUMMARY ANSWER The transcriptomic cargo of UF-EVs reflects the RNA profile of the endometrial tissue as well as changes between the non-receptive and the receptive phase, possibly supporting its use for a novel endometrial receptivity test. WHAT IS KNOWN ALREADY EVs have been previously isolated from uterine fluid, where they likely contribute to the embryo-endometrium crosstalk during implantation. Based on a meta-analysis of studies on endometrial tissue implantation-associated genes and the human exosomes database, 28 of the 57 transcripts considered as receptivity markers refer to proteins present in human exosomes. However, the specific transcriptomic content of receptive phase UF-EVs has yet to be defined. STUDY DESIGN, SIZE, DURATION Two experimental series were set up. First, we simultaneously sequenced RNA species derived from paired UF-EVs and endometrial tissue samples collected from physiologically cycling women. Second, we analyzed RNA species of UF-EVs collected during the non-receptive (LH + 2) and receptive (LH + 7) phase of proven fertile women and from the receptive (LH + 7) phase of a population of women undergoing ART and transfer of euploid blastocysts. PARTICIPANTS/MATERIALS, SETTING, METHODS For paired UF—endometrial tissue sampling, endometrial tissue biopsies were obtained with the use of a Pipelle immediately after UF collection performed by lavage of the endometrial cavity. Overall, n = 87 UF samples were collected and fresh-processed for EV isolation and total RNA extraction, while western blotting was used to confirm the expression of EV protein markers of the isolated vesicles. Physical characterization of UF-EVs was performed by Nanoparticle Tracking Analysis. To define the transcriptomic cargo of UF-EV samples, RNA-seq libraries were successfully prepared from n = 83 UF-EVs samples and analyzed by RNA-seq analysis. Differential gene expression (DGE) analysis was used to compare RNA-seq results between different groups of samples. Functional enrichment analysis was performed by gene set enrichment analysis with g:Profiler. Pre-ranked gene set enrichment analysis (GSEA) with WebGestalt was used to compare RNA-seq results with the gene-set evaluated in a commercially available endometrial receptivity array. MAIN RESULTS AND THE ROLE OF CHANCE A highly significant correlation was found between transcriptional profiles of endometrial biopsies and pairwise UF-EV samples (Pearson’s r = 0.70 P LARGE SCALE DATA Transcriptomic data were deposited in NCBI Gene Expression Omnibus (GEO) and can be retrieved using GEO series accession number: GSE158958. LIMITATIONS, REASONS FOR CAUTION Separation of RNA species associated with EV membranes might have been incomplete, and membrane-bound RNA species—rather than the internal RNA content of EVs—might have contributed to our RNA-seq results. Also, we cannot definitely distinguish the relative contribution of exosomes, microvesicles and apoptotic bodies to our findings. When considering patients undergoing ART, we did not collect UFs in the same cycle of the euploid embryo transfer but in the one immediately preceding. We considered this approach as the most appropriate in relation to the novel, explorative nature of our study. Based on our results, a validation of UF-EV RNA-seq analyses in the same cycle in which embryo transfer is performed could be hypothesized. WIDER IMPLICATIONS OF THE FINDINGS On the largest sample size of human EVs ever analyzed with RNA-seq, this study establishes a gene signature to use for less-invasive endometrial receptivity tests. This report is indeed the first to show that the transcriptome of UF-EVs correlates with the endometrial tissue transcriptome, that RNA signatures in UF-EVs change with endometrial status, and that UF-EVs could serve as a reservoir for potential less-invasive collection of receptivity markers. This article thus represents a step forward in the design of less-invasive approaches for real-time monitoring of endometrial status, necessary for advancing the field of reproductive medicine. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by a competitive grant from European Society of Human Reproduction and Embryology (ESHRE Research Grant 2016-1). The authors have no financial or non-financial competing interests to disclose. TRIAL REGISTRATION NUMBER NA.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease in which anti-mitochondrial antibodies (AMA) are the diagnostic hallmark. Whether AMA-negative PBC patients represent a different phenotype of disease is highly debated. The purpose of our study was to compare AMA-positive and AMA-negative PBC patients in a large non-white admixed Brazilian cohort. The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian PBC patients, stratifying data according to AMA status. A total of 464 subjects (95.4% females, mean age 56 ± 5 years) with PBC were included. Three hundred and eighty-four (83%) subjects were AMA-positive, whereas 80 (17%) had AMA-negative PBC. Subjects with AMA-negative PBC were significantly younger (52.2 ± 14 vs. 59.6 ± 11 years, p = 0.001) and had their first symptom at an earlier age (43.2 ± 13 vs. 49.5 ± 12 years, p = 0.005). Frequency of type 2 diabetes was significantly increased in subjects with AMA-negative PBC (22.5% vs. 12.2%, p = 0.03). Lower IgM (272.2 ± 183 vs. 383.2 ± 378 mg/dL, p = 0.01) and triglycerides (107.6 ± 59.8 vs.129.3 ± 75.7 mg/dL, p = 0.025) and higher bilirubin (3.8 ± 13.5 vs. 1.8 ± 3.4 mg/dL, p = 0.02) levels were also observed in this subgroup. Response to ursodeoxycholic acid varied from 40.5 to 63.3% in AMA-positive and 34 to 62.3% in AMA-negative individuals, according to different response criteria. Outcomes such as development of liver-related complications, death and requirement for liver transplantation were similar in both groups. AMA-negative PBC patients are similar to their AMA-positive counterparts with subtle differences observed in clinical and laboratory features.

To assess the tracheal volume and the effect of respiration through segmentation on CT-scans in children.Chest-CT of 100 patients divided into males and females, aged 3-16 years, were retrospectively assessed. Subjects underwent inspiratory and expiratory CT-scans. Tracheal volume was segmented through ITK-SNAP software. Volume, length, anteroposterior, laterolateral diameters, and T1-T10 distance were measured. The percentage ratio between expiratory and inspiratory phases was calculated: significant differences according to sex for inspiratory and expiratory measurements were assessed through a one-way ANCOVA test using T1-T10 distance as covariate (p 0.05). Differences in percentage changes according to sex and age were assessed through Mann-Whitney test and calculation of Pearson's correlation coefficient, respectively (p 0.05).No statistically significant difference according to sex was found for any measurement (p 0.05). For the percentage ratio between inspiratory and expiratory phase, no difference was found according to sex for any measurement (p 0.05). The percentage ratio of tracheal volume and length between expiratory and inspiratory phases showed a negative correlation with age (p 0.05).This study provides a novel contribution to the assessment of tracheal size in healthy children: future studies will verify the same measurements in patients affected by tracheomalacia to improve diagnosis.

Background: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This ‘drug score’ was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1–2 and poor risk with score 3–4. Methods: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non–small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy). Results: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts. Conclusion: Our ‘drug score’ showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients.

Introduction An anatomical study was conducted to test a modified C-shaped flap designed for patients undergoing a keyhole approach and/or minicraniotomy for retrosigmoid approach (KRSA). Materials and Methods Ten heads specimens were used. The surgical technique investigated was based on a 4-cm C-shaped skin incision with medial convexity (placed 8 cm laterally to the external occipital protuberance, with the lower edge terminating 1.5 to 2 cm above the mastoid tip), which followed by careful subperiosteal dissection and completed by reflecting and securing the skin flap layer anteriorly and the muscle flaps superiorly and inferiorly by stitches. Anatomical findings, including depth of surgical corridor till to the cerebellopontine cistern (CPC) as well as the sparing of neurovascular structures, were evaluated in every specimen. Results Twenty surgical approaches to CPC were conducted, resulting in a short working distance to the target (32 mm) without any need for a self-retaining retractor. In every specimen, the integrity of occipital muscles and cutaneous nerves was maintained, and a solid multilayer closure was always achieved. These data suggest that landmarks-based design of this C-shaped incision could be helpful in avoiding damages to the soft tissues encountered during KRSA. Conclusion This modified approach provides a wide surgical corridor to access the CPC while ensuring the minimal invasiveness of the standard S-shaped incision. Compared with the latter, it preserves better the integrity of the surrounding soft tissues and appears less likely to cause any iatrogenic injury to occipital muscles and cutaneous nerves.

Unresectable malignant pleural mesothelioma (MPM) is an aggressive disease with a 5-year survival rate of approximately 10%. Recent data suggest that MPM is an immunologically active tumor, in which checkpoint inhibition through the blockade of the anti-cytotoxic T lymphocyte antigen-4 (-CTLA-4) or anti-programmed cell death 1 (PD-1) could play a major therapeutic role. Initially, clinical trials evaluated immune checkpoint inhibitors (ICIs) in the salvage setting after platinum-based chemotherapy with mixed results in terms of efficacy. More recently, the combination of the anti-CTLA-4 agent ipilimumab plus the anti-PD-1 agent nivolumab was tested in the front-line setting, and reported a superior survival as compared to platinum/pemetrexed. While other clinical trials ore ongoing in order to investigate ICIs for MPM, it seems now evident that we have entered a new “era” for the treatment of MPM. In the future, a few issues need to be solved with regard to the use of ICIs for MPM. Among them, there is the identification of biomarkers of sensitivity to immunotherapy that may help enrich the patient population who could benefit the most from treatment, while avoiding for some other patients the potential occurrence of immune-related side effects from therapies that are anticipated to be ineffective.

In the popular imaginary, cocoa-derived products, like chocolate, represent a panacea for mood and affectivity. However, whether this is a myth or a fact has yet to be clarified. A systematic review and meta-analysis were conducted according to the PRISMA guidelines to investigate the effect of cocoa-derived food on depressive and anxiety symptoms, positive and negative affect. We searched Web of Knowledge

BackgroundBovine mastitis, an inflammatory disease of the mammary gland, is classified as subclinical or clinical. Circulating neutrophils are recruited to the udder to combat infection. We compared the transcriptomic profiles in circulating leukocytes between healthy cows and those with naturally occurring subclinical or clinical mastitis.Methods and ResultsHolstein Friesian dairy cows from six farms in EU countries were recruited. Based on milk somatic cell count and clinical records, cows were classified as healthy (n = 144), subclinically (n = 48) or clinically mastitic (n = 22). Circulating leukocyte RNA was sequenced with Illumina NextSeq single end reads (30 M). Differentially expressed genes (DEGs) between the groups were identified using a DESeq2 package, followed by GO enrichment analysis. Both subclinical and clinical mastitis caused significant changes in the leukocyte transcriptome, with more intensive changes attributed to clinical mastitis. We detected 491 DEGs between clinical and healthy groups, 350 DEGs between subclinical and healthy groups and 170 DEGs between clinical and subclinical groups. Most DEGs were associated with cell killing and immune processes. Many upregulated DEGs in clinical mastitis encoded antimicrobial peptides (AZU1, CAMP, CATHL1, CATHL2, CATHL4, CATHL5, CATHL6, DEFB1, DEFB10, DEFB4A, DEFB7, LCN2, PGLYRP1, S100A9, TF and LTF) which were not upregulated in subclinical mastitis. This suggests that the leukocytes may have greater killing capacity in cows with clinical mastitis.ConclusionWe have, for the first time, described circulating leukocyte transcriptomic profiles in naturally occurring subclinical mastitis and assessed their differences from healthy cows and those with clinical mastitis.

This is the first case report of a patient with ALK-rearranged metastatic lung adenocarcinoma who became pregnant during treatment with alectinib. A multidisciplinary team of gynecologists, neonatologists, oncologists, psychologists, and pharmacologists was set up to handle the case. According to patient's preference, the study drug was continued throughout pregnancy and the woman delivered a healthy baby girl at 35 weeks and 5 days of gestation. Fetal parameters remained normal during pregnancy. At birth, alectinib levels were 14 times higher in maternal plasma than in the fetus (259 versus 18 ng/mL). The average concentration of alectinib in the placenta was 562 ng/g. The baby was followed during her first 20 months, and no developmental anomalies were observed. After 32 months from diagnosis, the mother is well and in partial remission.

Approccio multidisciplinare alla giunzione cranio vertebrale. Cenni storici, attuali orientamenti e prospettive future nell’alleanza tra neurochirurgia ed otorinolaringoiatria.Storicamente considerata “terra di nessuno”, la regione della giunzione cranio-vertebrale, così come la chirurgia di questa sede, hanno guadagnato altissima considerazione negli anni recenti per la complessità anatomica, funzionale e tecnica. La gestione multidisciplinare e l’alleanza tra neurochirurghi e otorinolaringoiatri anche in questo ambito è diventata sempre più forte negli anni. La giunzione cranio-vertebrale ha una architettura anatomica ossea, neurovascolare e muscolare unica e complessa in quanto non solo separa e congiunge il cranio con il rachide cervicale, ma presenta pattern speciali di flessione, estensione e rotazione assiale. La stabilità è garantita da una complessa combinazione di supporti ossei e ligamentosi, che consentono ampi gradi di motilità. La conoscenza dell’anatomia e della fisiologia della giunzione cranio-vertebrale consente di comprendere meglio le procedure chirurgiche e le patologie specifiche che interessano questa regione anatomica. Sebbene siano passati anni dell’inizio della chirurgia pioneristica di questa regione, le lesioni situate nella porzione anteriore della giunzione cranio-vertebrale rimangono ancora una stimolante sfida per il neurochirurgo. Molti studi sono presenti in letteratura con l’intento di esaminare l’anatomia microchirurgica delle porzioni anteriori, posteriori, extra e intradurali della giunzione cranio-vertebrale, così come le differenze e tutte le possibili vie di approccio a 360° per esporre al meglio e trattare patologie di questa regione. In questa revisione verrà effettuata una disamina sullo stato dell’arte in tale chirurgia, partendo dall’esperienza personale, dalle pubblicazioni e dalla letteratura più recente, al fine di sottolineare quando la collaborazione multidisciplinare sia fondamentale, altamente consigliata o non strettamente necessaria nella gestione delle patologie della regione cranio-vertebrale.Historically considered as a nobody’s land, craniovertebral junction (CVJ) surgery or specialty recently gained high consideration as symbol of challenging surgery as well as selective top level qualifying surgery. The alliance between Neurosurgeons and Otorhinolaringologists has become stronger in the time. CVJ has unique anatomical bone and neurovascular structures architecture. It not only separates from the subaxial cervical spine but it also provides a special cranial flexion, extension, and axial rotation pattern. Stability is provided by a complex combination of osseous and ligamentous supports which allows a large degree of motion. The perfect knowledge of CVJ anatomy and physiology allows to better understand surgical procedures of the occiput, atlas and axis and the specific diseases that affect the region. Although many years passed since the beginning of this pioneering surgery, managing lesions situated in the anterior aspect of the CVJ still remains a challenging neurosurgical problem. Many studies are available in the literature so far aiming to examine the microsurgical anatomy of both the anterior and posterior extradural and intradural aspects of the CVJ as well as the differences in all the possible surgical exposures obtained by 360° approach philosophy. Herein we provide a short but quite complete at glance tour across the personal experience and publications and the more recent literature available in order to highlight where this alliance between Neurosurgeon and Otorhinolaringologist is mandatory, strongly advisable or unnecessary.

Background Molecular brain therapies require the development of molecular switches to control gene expression in a limited and regulated manner in time and space. Light-switchable gene systems allow precise control of gene expression with an enhanced spatio-temporal resolution compared to chemical inducers. In this work, we adapted the existing light-switchable Light-On system into a lentiviral platform, which consists of two modules: (i) one for the expression of the blue light-switchable trans-activator GAVPO and (ii) a second module containing an inducible-UAS promoter (UAS) modulated by a light-activated GAVPO. Results In the HEK293-T cell line transfected with this lentiviral plasmids system, the expression of the reporter mCherry increased between 4 to 5 fold after light induction. A time expression analysis after light induction during 24 h revealed that mRNA levels continuously increased up to 9 h, while protein levels increased throughout the experiment. Finally, transduction of cultured rat hippocampal neurons with this dual Light-On lentiviral system showed that CDNF, a potential therapeutic trophic factor, was induced only in cells exposed to blue light. Conclusions In conclusion, the optimized lentiviral platform of the Light-On system provides an efficient way to control gene expression in neurons, suggesting that this platform could potentially be used in biomedical and neuroscience research, and eventually in brain therapies for neurodegenerative diseases. How to cite: Zarate RV, Arancibia D, Fernandez A, et al. Optimization of the Light-On system in a lentiviral platform to a light-controlled expression of genes in neurons. Electron J Biotechnol 2021;51. https://doi.org/10.1016/j.ejbt.2021.03.006

Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/Pubmed and MeSH Database using the terms “Li-Fraumeni” AND “pediatric high-grade glioma (HGG)”, identifying six cases of HGGs in pediatric patients with LFS. We added a further case with peculiar features such as no familiar history of LFS, association of embryonal rhabdomyosarcoma and bithalamic HGG, whose immunohistochemical profile was accurately defined by Next Generation Sequencing. Knowledge synthesis and case analysis grounded the discussion about challenges in the management of this pathology in pediatric age.

Background: Reproductive complications for cancer survivors are identified as one of the top unmet needs in the survivorship period. However, current models of cancer care do not routinely incorpor...

Despite the increasing incidence rate of vestibular schwannomas (VS), controversies in their management are still present.A 35-item multiple-choice survey investigating the current practice patterns of VS care was sent to the members of the Italian Society of Otolaryngology, Head and Neck Surgery (SIO) and of the Italian Society of Neurosurgery (SINCH).Among 66 respondents, 37 (56.0%) claimed to be actively involved in VS management. Most interviewees (35.1%) declared20 years of experience and 59.5% claimed to work in an academic practice. The number of cases evaluated in each centre per year varied widely, with 54.0% evaluating25 cases/year and only 13.6%100 cases/year. Multidisciplinary care for VS evaluation was confirmed by 50.0% of respondents, and multidisciplinary surgical care by 62.2%. Observation and surgery were the most common management options proposed. Further details regarding VS care are presented.The present study provides the first overview on the current practice patterns of VS care in Italy. Although integrated in most centres, a multidisciplinary model of care needs to be encouraged. Wide heterogeneity in experience and practices is mostly influenced by the surgeon's different specialties and by the lack of shared guidelines.L’attuale gestione dello schwannoma vestibolare in Italia: risultati di una survey nazionale.Nonostante il costante incremento di incidenza dello schwannoma vestibolare (VS), non vi è ancora uniformità nella gestione di tale patologia.Un questionario di 35 domande sulle strategie di trattamento del VS è stato sottoposto ai membri della SIO e della SINCH.Tra i 66 intervistati che hanno risposto al questionario, il 56,0% ha confermato di prendere parte attivamente nel trattamento dello VS. La maggioranza dei partecipanti (35,1%) dichiarava20 anni di esperienza nel settore, e il 59,5% di lavorare in un contesto accademico. Il 54,0% degli intervistati ha affermato di valutare25 casi/anno, mentre solo il 13,6%100 casi/anno. Il 50,0% ha dichiarato di valutare lo VS nell’ambito di un gruppo multidisciplinare, mentre il 62,2% di operare in un contesto multidisciplinare. L’approccio conservativo e la chirurgia si confermavano le strategie terapeutiche più frequentemente proposte.Lo studio presenta una prima panoramica sulle strategie di trattamento dello VS in Italia. Nonostante un modello multidisciplinare di gestione dello VS sia già diffuso in molti centri, è necessario incrementarne ulteriormente lo sviluppo. Le diverse specializzazioni del chirurgo e la mancanza di linee guida condivise contribuiscono a determinare la vasta eterogeneità osservata nella gestione del VS nel nostro Paese.

Brain metastases from hepatocellular carcinoma (HCCBM) are encountered very rarely in clinical practice, especially in western countries. Only a minority of patients undergoes resective surgery, as clinical picture is usually complex and presentation is often catastrophic with intra-cerebral hemorrhage (ICH). Neurosurgical intervention can be not only life-saving but may also alleviate significantly the burden of symptoms. We present the case of a patient with six metachronous hemorrhagic HCCBM in which emergent surgery extended survival by 9 months, of which seven spent in near-normal life quality, stressing the role of neurosurgery in the evaluation of HCCBM patients.

Background Irisin, a myokine, is a polypeptide derived from the cleavage of the extracellular domain of fibronectin domain-containing protein 5, a receptor that is present on different tissues (skeletal muscle, pericardium, myocardium, and brain), whose functions are not yet fully defined. Purpose The main aim of our study was to evaluate the effect of competitive physical activity on serum irisin levels and bone turnover markers. Methods Fifteen male footballers and an equal number of subjects of the same age and gender, but with a predominantly sedentary lifestyle, had their serum levels of irisin and bone turnover markers measured. Bone mineral status was evaluated in both groups by quantitative bone ultrasound of the calcaneus. In addition, only in footballers, biochemical analyses were repeated after 3 months. Results We did not observe significant differences in the serum levels of calcium, phosphorus, and parathyroid hormone between the two groups. The footballers had significantly higher quantitative bone ultrasound, 25-OH vitamin D, and creatinine values than the controls. There were also no significant differences in the bone alkaline phosphatase, carboxy-terminal telopeptide of type I collagen, osteoprotegerin, sclerostin or Dkk-1 values, while the irisin levels (+ 89%, p Conclusion Our study shows that footballers have significantly higher serum irisin values than the general population. Irisin could be the "trait d’union" between bone health and physical activity.

Background In preparation for the 2021 revision of the European Union Tobacco Products Directive, the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) has posted its Preliminary Opinion on Electronic Cigarettes. They concluded that e-cigarettes only achieve a sub-optimal level of protection of human health. In this paper, we provide evidence that the Opinion’s conclusions are not adequately backed up by scientific evidence and did not discuss the potential health benefits of using alternative combustion-free nicotine-containing products as substitute for tobacco cigarettes. Methods Searches for articles were conducted in PubMed and by citation chasing in Google Scholar. Articles were also retrieved with a review of references in major publications. Primary data from World Health Organization surveys, the conclusions of reviews, and peer-reviewed non-industry studies were cited to address errors and omissions identified in the Opinion. Results The Opinion omitted reporting on the individual and population health benefits of the substitution of e-cigarettes (ENDS) for cigarette smoking. Alternative hypotheses to the gateway theory were not evaluated. Its assessment of cardiovascular risk is contradicted by numerous reviews. It cites ever-use data that do not represent current patterns of use. It did not report non-nicotine use. It presented erroneous statements on trends in ENDS prevalence. It over-emphasized the role of flavours in youth ENDS initiation. It did not discuss cessation in sufficient length. Conclusions For the delivery of a robust and comprehensive final report, the members of the Working Group of the Scientific Committee on Health, Environmental and Emerging Risks will need to consider (1) the potential health benefits of ENDS substitution for cigarette smoking, (2) alternative hypotheses and contradictory studies on the gateway effect, (3) its assessment of cardiovascular risk, (4) the measurements of frequency of use, (5) non-nicotine use, (6) the role of flavours, and (7) a fulsome discussion of cessation.

In a previous work, we found that an Intracranial Elastance Index (IEI) ≥0.3 at ventricular infusion test had a high accuracy in predicting shunt response at 6 and 12 months in idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to verify the accuracy of IEI to predict response to shunt at both short- and long-term follow-up. Retrospective evaluation of 64 patients undergoing ventriculo-peritoneal shunting for iNPH between 2006 and 2015 based on a positive ventricular infusion test (IEI≥0.3). Patients were classified according to Krauss scale and mRS preoperatively, at 1-year and at last follow-up. An improvement of at least one point at Krauss score or at mRS was considered as a good outcome; unchanged or worsened patients were grouped as poor outcome. Mean follow-up was 6.6 years. Improvement at Krauss scale was seen in 62.5% and 64.3% of patients at 1-year and last follow-up, respectively. Patients in good functional status (mRS≤2) increased from 25 in the preoperative period to 57% at both 1-year and last follow-up. IEI was significantly associated with Krauss (p=0.041) and mRS (p=0.036) outcome at last follow-up. Patients with worse preoperative Krauss and mRS had higher chance to improve but higher overall scores after treatment. At ROC curves, IEI showed a good long-term prediction of change in mRS from first year to last follow-up. IEI≥0.3 predicts outcomes at both short- and long-term, with more than 50% of patients being able to look after themselves after 6 years from treatment.

Background Previous studies have shown that acidic bleaching gels could lead to worse collateral effects during an in-office bleaching procedure, while neutral or basic products leads towards a better experience. Considering this fact, the main purpose of this study was to evaluate the pH behavior of 6 in-office bleaching gels, compared to the information provided by their manufacturers. Material and methods Thirty enamel discs of bovine teeth were prepared, the initial colors of which were measured by a spectrophotometer and then divided into 6 groups. A pH meter was used to measure the pH every 30 seconds until the end of each procedure, when a new color evaluation was then made. The Tukey test was used for statistical analysis of the results. Results There was no difference in the color variation (ΔE) between the groups (p> 0.05). In two groups, the pH variation (ΔpH) showed neutral stability, with initial and final pH averages of 7.04 and 7.11 (p = 0.08) and 7.21 and 7.19 (p = 0.55), respectively; in another, there was alkaline stability, with an initial and final pH average of 8.54 and 8.37 (p = 0.14). In the other three brands, however, the results showed acidification, with initial and final pH averages of 6.14 and 5.22 (p = 0.001), 6.05 and 5.16 (p = 0.001) and 7.14 and 5.83 (p = 0.001), respectively. Conclusions In 3 of the evaluated gels, a discrepancy existed between the manufacturer's information and the data obtained, which could lead, considering previous studies discussed throughout this article, to unexpected collateral effects on the patients, especially dental sensitivity. Thus, clinicians and researchers should be aware about pH stability studies of in-office bleaching gels for better predictability and safety on their clinical usage. Key words:Tooth bleaching, Bleaching agents, Hydrogen-ion concentration, Dentin sensitivity, Hydrogen peroxide.

Background A comparison of clinical and radiological outcomes after two different variants of open door laminoplasty for cervical spondylotic myelopathy (CSM) is described. Methods Fifty-five patients underwent cervical laminoplasty for CSM. Between 2005 to 2009, 32 patients underwent open-door laminoplasty (Group A) performed with a monolateral exposure with contralateral "green stick" laminar fracture. A technical variant consisting in bilateral exposure, spinous process removal and symmetrical muscular closure was applied in the other 23 (Group B), from 2009 to 2016. A retrospective analysis of surgical results between the two groups was performed. Results In group B, the mean operative time was longer and the mean volume of intraoperative blood loss was much higher than in group A. Both differences were not significant (p=0.1601 and p=0.0884, respectively). The average hospitalization was nonsignificantly longer in group B (7.3±1.8 vs. 6.5±1.6 d; p= 0.0947). Postoperatively, axial neck pain was more severe in group A at last follow-up than preoperatively (P>0.05). mJOA scores and Nurick grades improved significantly in both groups at last follow-up; in group A, the mean recovery rates were 41.5 % by mJOA scores and 29.4 % by Nurick grades, whereas in group B they were 52.7 % and 36.8 %, respectively. Conclusions Applying some few variations to a standard monolateral approach, although slightly more time and blood consuming, could reduce the incidence of long term axial symptoms and, in our experience, are not burdened by worsening of outcomes. A prospective, multicentric study with a longer follow-up should be conducted in order to confirm our findings.

Background: Primary prevention through vaccination is a prophylactic approach aiming to reduce the risk of developing human papillomavirus (HPV)-related lesions. No mature and long-term data supported the adoption of vaccination in women undergoing conization. Methods: This is a retrospective multi-institutional study. Charts of consecutive patients undergoing conization between 2010 and 2014 were collected. All patients included had at least 5 years of follow-up. We compared outcomes of patients undergoing conization plus vaccination and conization alone. A propensity-score matching algorithm was applied in order to reduce allocation biases. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. Results: Overall, charts of 1914 women were analyzed. The study group included 116 (6.1%) and 1798 (93.9%) women undergoing conization plus vaccination and conization alone, respectively. Five-year recurrence rate was 1.7% (n = 2) and 5.7% (n = 102) after conization plus vaccination and conization alone, respectively (p = 0.068). After the application of a propensity-score matching, we selected 100 patients undergoing conization plus vaccination and 200 patients undergoing conization alone. The crude number of recurrences was 2 (2%) and 11 (5.5%) for patients undergoing conization plus vaccination and conization alone, respectively (p = 0.231). Vaccination had no impact on persistent lesions (no negative examination between conization and new cervical dysplasia, p = 0.603), but reduced the risk of recurrent disease (patients who had at least one negative examination between conization and the diagnosis of recurrent cervical dysplasia, p = 0.031). Conclusions: Patients having vaccination experience a slightly lower risk of recurrence than women who had not, although not statistically significantly different. Further evidence is needed to assess the cost effectiveness of adopting vaccination in this setting.

Background and aims There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. Methods and results Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6–14.7 for age ≥85 vs 18–44 y); HR = 4.7; 2.9–7.7 for estimated glomerular filtration rate levels, Highlights • Impaired renal function, elevated C-reactive protein and advanced age were major indicators of death in COVID-19 patients. • These associations were substantially homogenous across all sub-groups analysed. • No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. • Death rates were higher in the Northern as opposed to Central-Southern Italian regions.

Background Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19. Objective We set-up a multicenter Italian collaboration to investigate the relationship between HCQ therapy and COVID-19 in-hospital mortality. Methods In a retrospective observational study, 3,451 unselected patients hospitalized in 33 clinical centers in Italy, from February 19, 2020 to May 23, 2020, with laboratory-confirmed SARS-CoV-2 infection, were analyzed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received HCQ with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores, with the addition of subgroup analyses. Results Out of 3,451 COVID-19 patients, 76.3% received HCQ. Death rates (per 1,000 person-days) for patients receiving or not HCQ were 8.9 and 15.7, respectively. After adjustment for propensity scores, we found 30% lower risk of death in patients receiving HCQ (HR=0.70; 95%CI: 0.59 to 0.84; E-value=1.67). Secondary analyses yielded similar results. The inverse association of HCQ with inpatient mortality was particularly evident in patients having elevated C-reactive protein at entry. Conclusions HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients. Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.

The anterolateral ligament (ALL) has been suggested as an important secondary knee restrain on the dynamic laxity in anterior cruciate ligament- (ACL-) deficient knees. Nevertheless, its kinematical contribution to the pivot-shift (PS) phenomenon has not been clearly and objectively defined, and noninvasive sensor technology could give a crucial contribution in this direction. The aim of the present study was to quantify in vitro the PS phenomenon in order to investigate the differences between an ACL-deficient knee and an ACL+ALL-deficient knee. Ten fresh-frozen paired human cadaveric knees ( n = 20 ) were included in this controlled laboratory study. Intact, ACL-deficient, and ACL+ALL-deficient knees were subjected to a manual PS test quantified by a noninvasive triaxial accelerometer (KiRA, OrthoKey). Kinematic data (i.e., posterior acceleration of the tibial lateral compartment) were recorded and compared among the three statuses. Pairwise Student’s t -test was used to compare the single groups ( p < 0.05 ). Intact knees, ACL-deficient knees, and ACL+ALL-deficient knees showed an acceleration of 5.3 ± 2.1 m/s2, 6.3 ± 2.3 m/s2, and 7.8 ± 2.1 m/s2, respectively. Combined sectioning of ACL and ALL resulted in a statistically significant acceleration increase compared to both the intact state ( p < 0.01 ) and the ACL-deficient state ( p < 0.01 ). The acceleration increase determined by isolated ACL resection compared to the intact state was not statistically significant ( p > 0.05 ). The ALL sectioning increased the rotatory laxity during the PS after ACL sectioning as measured through a user-friendly, noninvasive triaxial accelerometer.

Improving real-life functioning is the main goal of the most advanced integrated treatment programs in people with schizophrenia. The Italian Network for Research on Psychoses previously explored, by using network analysis, the interplay among illness-related variables, personal resources, context-related factors and real-life functioning in a large sample of patients with schizophrenia. The same research network has now completed a 4-year follow-up of the original sample. In the present study, we used network analysis to test whether the pattern of relationships among all variables investigated at baseline was similar at follow-up. In addition, we compared the network structure of patients who were classified as recovered at follow-up versus those who did not recover. Six hundred eighteen subjects recruited at baseline could be assessed in the follow-up study. The network structure did not change significantly from baseline to follow-up, and the overall strength of the connections among variables increased slightly, but not significantly. Functional capacity and everyday life skills had a high betweenness and closeness in the network at follow-up, as they had at baseline, while psychopathological variables remained more peripheral. The network structure and connectivity of non-recovered patients were similar to those observed in the whole sample, but very different from those in recovered subjects, in which we found few connections only. These data strongly suggest that tightly coupled symptoms/dysfunctions tend to maintain each other's activation, contributing to poor outcome in schizophrenia. Early and integrated treatment plans, targeting variables with high centrality, might prevent the emergence of self-reinforcing networks of symptoms and dysfunctions in people with schizophrenia.

Objective The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID−19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418 ) to retrospectively investigate the relationship between RAAS inhibitors and COVID−19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies. Methods We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting–enzyme inhibitors (ACE I) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method. Results Out of 4069 COVID−19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID−19 treatments: 0.96, 95% confidence interval 0.77–1.20 and HR = 0.89, 0.67–1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78–1.26 and HR = 0.88, 0.65–1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID−19 adult patients, 9700 with hypertension) confirmed the absence of association. Conclusions In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID−19 patients.

Background Healthcare-associated infections (HAIs) are the most frequent adverse events in healthcare and a global public health concern. Surveillance is the foundation for effective HAIs prevention and control. Manual surveillance is labor intensive, costly and lacks standardization. Artificial Intelligence (AI) and machine learning (ML) might support the development of HAI surveillance algorithms aimed at understanding HAIs risk factors, improve patient risk stratification, identification of transmission pathways, timely or real-time detection. Scant evidence is available on AI and ML implementation in the field of HAIs and no clear patterns emerges on its impact. Methods We conducted a systematic review following the PRISMA guidelines to systematically retrieve, quantitatively pool and critically appraise the available evidence on the development, implementation, performance and impact of ML-based HAIs detection models. Results Of 3445 identified citations, 27 studies were included in the review, the majority published in the US (n = 15, 55.6%) and on surgical site infections (SSI, n = 8, 29.6%). Only 1 randomized controlled trial was included. Within included studies, 17 (63%) ML approaches were classified as predictive and 10 (37%) as retrospective. Most of the studies compared ML algorithms’ performance with non-ML logistic regression statistical algorithms, 18.5% compared different ML models’ performance, 11.1% assessed ML algorithms’ performance in comparison with clinical diagnosis scores, 11.1% with standard or automated surveillance models. Overall, there is moderate evidence that ML-based models perform equal or better as compared to non-ML approaches and that they reach relatively high-performance standards. However, heterogeneity amongst the studies is very high and did not dissipate significantly in subgroup analyses, by type of infection or type of outcome. Discussion Available evidence mainly focuses on the development and testing of HAIs detection and prediction models, while their adoption and impact for research, healthcare quality improvement, or national surveillance purposes is still far from being explored.

This study, based on the 'Servizi Territoriali Associati per la Ricerca' (STAR) Network Depot Study nationwide baseline data, explored whether individual symptoms severity and clusters might influence the prescription of paliperidone palmitate 1-month (PP1M) vs. aripiprazole monohydrate. The Brief Psychiatric Rating Scale (BPRS) was used to assess psychopathology and relevant symptoms clusters. Drug Attitude Inventory, 10 items, was used to test attitude towards medications. Adherence to treatments was rated according to the Kemp seven-point scale. We assessed for eligibility 451 individuals and, among them, we included 195 subjects (n = 117 who started PPM1 and n = 78 aripiprazole monohydrate). Individuals were comparable in terms of age, gender, treatment years, recent hospitalizations, previous long-acting injectable antipsychotic treatments, additional oral treatments, attitude toward drugs, medication adherence, and alcohol/substance-related comorbidities. Subjects starting PP1M presented higher BPRS overall (P = 0.009), positive (P = 0.015), and negative (P = 0.010) symptom scores compared to subjects starting aripiprazole monohydrate. Results were confirmed by appropriate regression models and propensity score matching analysis. No differences were found comparing the other BPRS subscale scores: affect, resistance, and activation. Clinicians may be more prone to prescribe PPM1, rather than aripiprazole monohydrate, to subjects showing higher overall symptom severity, including positive and negative symptoms. No additional clinical factors influenced prescribing attitudes in our sample.

Objective: Conization aims to remove pre-neoplastic lesions of the uterine cervix. Several techniques for conization have been compared, but evidence regarding the most effective therapeutic option is scant. Here, we aimed to compare the recurrence rate following laser conization and loop electrosurgical excision procedure (LEEP) in patients with high-grade cervical dysplasia (HSIL/CIN2+). Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with HSIL/CIN2+ undergoing conization between 2010 and 2014 were retrieved. A propensity-score matching (PSM) was applied in order to reduce allocation bias. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. Results: Overall, 2966 patients had conization over the study period, including 567 (20%) and 2399 (80%) patients having laser conization and LEEP, respectively. Looking at predictors of recurrence, diagnosis of CIN3 (HR:3.80 (95%CI:2.01,7.21); p < 0.001) and HPV persistence (HR:1.81 (95%CI:1.11,2.96); p < 0.001) correlated with an increased risk of recurrence. After applying a PSM we selected 500 patients undergoing laser conization and 1000 undergoing LEEP. Patients undergoing LEEP were at higher risk of having positive surgical margins in comparison to patients undergoing laser conization (11.2% vs. 4.2%). The risk of having persistence of HPV was similar between the two groups (15.0% vs. 11.6%;p = 0.256). Five-year recurrence rate was 8.1% and 4% after LEEP and laser conization, respectively (p = 0.023). HPV persistence was the only factor associated with [5-]year recurrence after both laser conization (p = 0.003) and LEEP (p = 0.001). Conclusions: HPV persistence is the only factor associated with an increased risk of recurrence after either laser conization or LEEP. Owing to the lack of data regarding obstetrical outcomes, we are not able to assess the best therapeutic option for women with cervical dysplasia.

Coronavirus disease 2019 (COVID-19) is a major worldwide threat caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly spreading to a global pandemic. As of May 11, 2020, 4,176,346 cases have been reported worldwide, 219,814 in Italy, and of them, 81,871 occurred in the Lombardy region.1 Although the respiratory manifestations of COVID-19 have been widely described, the impact on the gastrointestinal (GI) system remains less clear. The reported prevalence of digestive symptoms ranges from 3% to 79%, depending on the setting,2–5 but data on GI endoscopic and histologic findings in COVID-19 patients are lacking. Therefore, the aim of this study is to describe the GI endoscopic and histologic findings in COVID-19 patients.

Background Autism spectrum is a psychopathological dimension which encompasses a wide range of clinical presentations: from subthreshold forms and autistic traits (AT), that can be found in the general population, to full-blown autism spectrum disorder (ASD). Many studies reported high rates of comorbidity between both ASD and AT and mood disorders, as well as a high prevalence of suicidal ideation among patients with ASD/AT. The aim of this study was to investigate the presence of mood symptoms and suicidal ideation and behaviors in patients with full-blown ASD and in subjects with AT, as well in a healthy control (HC) group, with a specific focus on which of the autistic features may be predictive of suicidal ideation and behaviors. Methods We recruited 262 adult subjects: 34 with ASD without intellectual impairment or language disability (ASD group), 68 fulfilling only one symptom criterion for ASD according to DSM-5 but who do not meet criteria for a full-blown diagnosis of ASD (AT group), and 160 HC. All subjects were assessed with the Structured Clinical Interview for DSM-5 (SCID-5); in addition, they were asked to fill two questionnaires: The Mood Spectrum, Self-report (MOODS-SR) and the Adult Autism Subthreshold Spectrum (AdAS Spectrum). Results ASD subjects reported significantly higher AdAS Spectrum and MOODS-SR total scores, as well as higher MOODS-SR depressive component total scores, when compared with AT and HC subjects. AT subjects scored significantly higher than the HC group. No significant differences were reported between ASD and AT subjects for the suicidality score according to MOODS-SR, despite both groups scored significantly higher than the HC group. The strongest predictor of suicidality score were MOODS-SR depressive component score and AdAS Spectrum Restricted interests and rumination domain score. Conclusions Our results highlight a correlation between autism and mood spectrum, as well as between suicidality and both ASD and AT. Subthreshold forms of ASD should be accurately investigated due to their relationship with suicidal thoughts and behaviors.

Drought is the main cause of productivity losses in soybean plants, triggering physiological and biochemical responses, stomatal closure being essential to prevent water losses and thus mitigate the negative effects of drought. Abscisic acid (ABA) is the main molecule involved in stomatal closure under drought conditions along with nitric oxide (• NO). However, the role of • NO in this process is not yet fully understood and contrasting findings about its role have been reported. Most of the assays in the literature have been carried out under in vitro conditions using • NO donors or scavengers, but little is known about the effects of endogenously produced • NO under drought conditions. This study is aimed to determine the pattern of endogenous • NO accumulation from the establishment of water stress and how this relates to stomatal closure and other biochemical and physiological responses. The analysis of soybean plant responses to drought revealed no correlation between whole-leaf • NO accumulation and typical water-deficit stress markers. Moreover, • NO accumulation did not explain oxidative damage induced by drought. However, endogenous • NO content correlated with the early stomatal closure. Analysis of stomatal behavior and endogenous • NO content in guard cells through epidermal peel technique showed a stomatal population with high variation in stomatal opening and • NO content under the initial stages of water stress, even when ABA responses are activated. Our data suggest that upon early stress perception, soybean plants respond by accumulating • NO in the guard cells to inhibit stomatal closure, potentially through the inhibition of ABA responses.

The Italian Ophthalmological Society (SOI) has developed clinical practice guidelines for the care of ophthalmic patients during the coronavirus disease 2019 (COVID-19) pandemic. The aim of this document is to define guidelines that would help ophthalmologists in their clinical activities through the adoption of recommended procedures to avoid common organization and management of positive asymptomatic contagious patients and healthy people. They are based on data available in scientific literature and real clinical experience. The document underlines the unique nature of ophthalmology and its impact on people’s health and wellbeing, outlines minimal requirements to be able to perform ophthalmology procedures, discusses the use of disposable devices and materials and outlines the criteria to manage potentially contagious patients and healthy people.