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Background: Ovarian cancer (OC) is a significant cause of cancer-related mortality in women globally, with a five-year survival rate of approximately 49%. Standard therapy involves cytoreductive surgery followed by chemotherapy. Its poor prognosis has driven interest in alternative therapies such as targeted molecular agents like bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi)., Materials and Methods: This review systematically searched PubMed from January 2018 to December 2023 for studies on PARPi in OC. Emphasis was on identifying relevant Phase III trials, extracting data on study design, patient demographics, and outcomes. Special focus was on assessing PARPi efficacy, safety, impact on quality of life, and ongoing trials, including those on Clinicaltrials.gov., Results: The efficacy of PARPi in first-line therapy for OC has been extensively studied. Trials like SOLO-1, PRIMA, and ATHENA-MONO have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS), particularly in patients with BRCA mutations. Additionally, the combination of PARPi with other agents like bevacizumab has shown promising results in extending PFS. However, PARPi treatment is associated with various adverse effects, including hematologic toxicities like anemia, thrombocytopenia, and neutropenia. While most adverse events are manageable, some patients may require dose adjustments or discontinuation of treatment. Importantly, PARPi maintenance therapy has not adversely affected health-related quality of life (HRQoL), with studies reporting similar HRQoL scores between PARPi-treated and placebo-treated patients., Conclusions: PARPi offer effective treatment with manageable side effects, suitable even for medically fragile patients. Individualized dosing can optimize benefits while minimizing adverse events. Exploring diverse treatment approaches, particularly in patients with limited life expectancy or high disease burden, could improve outcomes. Ongoing research is investigating alternative therapies and combinations to broaden treatment options. Combining bevacizumab with PARPi may be justified for first-line and recurrent maintenance therapy. Regardless of mutational status, PARPi should be considered for maintenance therapy in newly diagnosed advanced OC. Platinum sensitivity remains crucial for treatment decisions and predicting survival outcomes.

The efficacy of hyaluronic acid instillations as therapy for patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) has been demonstrated in some clinical studies, with response rates up to 70%. The aim of the study is to investigate the change in symptoms and quality of life in female patients with IC/BPS after intravesical instillations of hyaluronic acid used as first-line treatment. A retrospective single-center cohort study was conducted. Female patients, whose symptoms were compatible with the diagnosis of IC/BPS as defined by the International Continence Society, were treated with a variable number of intravesical instillations of a hyaluronic acid-based drug. Three validated questionnaires were administered by telephone to all patients, before the beginning of the treatment and 6 months after the last administration of the drug. A total of 50 patients with symptoms compatible with the diagnosis of IC/BPS were included in the study. The median number of instillations performed is 4. For all questionnaires, the median value was significantly reduced following treatment with intravesical instillations ( p = 0.000). The present study has shown that intravesical hyaluronic acid treatment results in both statistically and clinically significant symptomatic improvement, thereby improving the quality of life of patients with IC/BPS.

Background: Tremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high., Objectives: To compare the clinical features of Essential Tremor without other features (pure ET), ET plus soft dystonic signs (ET + DS), and tremor combined with dystonia (TwD)., Methods: We compared the clinical features of patients with pure ET, ET + DS, and TwD enrolled in The ITAlian tremor Network (TITAN). Linear regression models were performed to determine factors associated with health status and quality of life., Results: Three-hundred-eighty-three patients were included. Sex distribution was significantly different between the groups with males being more represented in pure ET and females in TwD. The initial site of tremor was different between the groups with about 40% of TwD having head tremor and ET + DS unilateral upper limb tremor at onset. This pattern mirrored the distribution of overt dystonia and soft dystonic signs at examination. Sensory trick, task-specificity, and position-dependence were more common, but not exclusive, to TwD. Pure ET patients showed the lowest degree of alcohol responsiveness and ET + DS the highest. Midline tremor was more commonly encountered and more severe in TwD than in the other groups. Regression analyses demonstrated that tremor severity, sex, age, and to a lesser degree the variable "group", independently predicted health status and quality of life, suggesting the existence of other determinants beyond tremor., Conclusions: Pure ET and TwD manifest with a phenotypic overlap, which calls for the identification of diagnostic biomarkers. ET + DS shared features with both syndromes, suggesting intra-group heterogeneity., (© 2024 International Parkinson and Movement Disorder Society.)

The Cancer Genome Atlas (TCGA) has radically changed the history of endometrial cancer by outlining a new classification, based on its molecular characteristics. In the field of oncology, we are approaching the new era of molecular biology, particularly regarding endometrial cancer, with the increasing importance of targeted therapy. This paper is a review of phase III randomized controlled trials published in English between January 2019 and December 2023, comparing drugs of interest with standard adjuvant treatment and molecular subtypes in endometrial cancer. The use of immunotherapy alone or in combination with chemotherapy as therapy in patients with recurrent or advanced primary or metastatic endometrial cancer significantly improves the prognosis of these patients. The results show greater efficacy of all proposed treatments for mismatch repair deficiency (dMMR/MSI-H) patients compared to mismatch repair proficiency (pMMR) patients. Progression-free survival (PFS) and overall survival (OS) are better in dMMR patients in all studies analysed. Immunotherapy has the potential to revolutionize the gynaecological cancer treatment landscape, offering a new pathway and new hope for endometrial cancer patients, improving their outcomes in the future. Given the exciting results obtained in dMMR/MSI-H patients, MMR status should be investigated in every patient with advanced endometrial cancer at the time of diagnosis.

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D / MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4 , a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib ( P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies., Competing Interests: Competing interests statement:A.D.S. is listed as author in a paper (i.e., N. Engl. J. Med. 2022; 386:437–448, DOI: 10.1056/NEJMoa2108330) where G.E.K. is listed as group author. A.D.S. had no interactions with G.E.K. (or any other of the 309-KEYNOTE-775 multicenter clinical trial Investigators) over the course of the research and writing of this paper.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

The adoption of advanced artificial intelligence (AI) systems in healthcare is transforming the healthcare-delivery landscape. Artificial intelligence may enhance patient safety and improve healthcare outcomes, but it presents notable ethical and legal dilemmas. Moreover, as AI streamlines the analysis of the multitude of factors relevant to malpractice claims, including informed consent, adherence to standards of care, and causation, the evaluation of professional liability might also benefit from its use. Beginning with an analysis of the basic steps in assessing professional liability, this article examines the potential new medical-legal issues that an expert witness may encounter when analyzing malpractice cases and the potential integration of AI in this context. These changes related to the use of integrated AI, will necessitate efforts on the part of judges, experts, and clinicians, and may require new legislative regulations. A new expert witness will be likely necessary in the evaluation of professional liability cases. On the one hand, artificial intelligence will support the expert witness; however, on the other hand, it will introduce specific elements into the activities of healthcare workers. These elements will necessitate an expert witness with a specialized cultural background. Examining the steps of professional liability assessment indicates that the likely path for AI in legal medicine involves its role as a collaborative and integrated tool. The combination of AI with human judgment in these assessments can enhance comprehensiveness and fairness. However, it is imperative to adopt a cautious and balanced approach to prevent complete automation in this field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Terranova, Cestonaro, Fava and Cinquetti.)

Objectives: The aim of the study was to compare, in patients undergoing minor gynecological laparoscopic procedures, the effects of ultrasound (US)-guided transversus abdominis plane (TAP) + rectus sheath (RS) block versus no TAP/RS block in terms of post-surgical pain control using the numeric pain rating scale (NRS) and the degree of patient satisfaction, according to the main goals of Early Recovery After Surgery (ERAS) programs. The primary outcome is to value the postoperative abdominal pain using NRS in both groups. Secondary outcomes are to evaluate blood values, presence of postoperative nausea and vomiting (PONV), postoperative ileus, level of patient expected satisfaction, time of discharge, length of stay (LOS), and the amounts of additional analgesics required., Design: In this prospective randomized controlled trial, patients were randomly assigned to loco-regional anesthesia (LRA) group, who received TAP and RS block under US guidance, or no loco-regional anesthesia (N-LRA) group. Enrolled patients were randomized 1:1 to either receive bilateral TAP/RS block with ropivacaine or sham treatment (patches were applied on the abdominal wall of the patients under general anesthesia)., Participants: All patients aged between 18 and 75 years, with ASA (American Society of Anesthesiologists) physical status 1-2, undergoing laparoscopic minor gynecological surgery, were enrolled., Setting: The study was conducted to the University of Campus Bio-Medico Hospital of Rome., Methods: Half an hour before surgery, all patients received gabapentin 300 mg per os. Once the patient underwent general anesthesia, US-guided bilateral TAP/RS block was performed by the anesthesiology team, while the uterine manipulator was positioned by a gynecology resident (not involved in the study). In the operative room, all patients received the same standardized anesthetic regimen. Postoperative abdominal pain was assessed at rest, after palpation, during movement, and after a cough by evaluating the patient at 6, 12, 18, 24, 36, 48, and 72 h after surgery, using the NRS from 0 to 10 in both groups. The amount of drug used for analgesia in the first 48 h after surgery was recorded. Moreover, hemoglobin, white blood cells, and c-reactive protein levels were recorded at 24, 48, and 72 h. The presence of PONV and the postoperative ileus was recorded throughout convalescence. The expected level of patient satisfaction at discharge and finally the LOS were assessed., Limitations: The major weakness of this study is that 60 mL of 0.5% ropivacaine was administered to each patient, without considering weight differences, yet contemporary literature rarely suggests volume/dose titration in fascial blocks., Results: A total of 104 women, undergoing gynecological minor laparoscopic surgery, were enrolled and assigned to LRA group (53 pts) and N-LRA group (51 pts). Postoperative pain was significantly reduced in patients who received TAP/RS block. A reduction in the intake of non-steroidal anti-inflammatory drugs after surgery was registered in LRA group (p &lt; 0.01). Moreover, a significant reduction of LOS (45.97 ± 9.87 vs. 65.08 ± 17.32 h; p &lt; 0.01) and PONV was observed in the LRA group, as well as a better level of patient satisfaction at discharge (9.43 ± 0.94 vs. 8.26 ± 1.19; p &lt; 0.01), compared to the N-LRA group., Conclusions: US-guided TAP and RS block significantly reduces postoperative pain after minor gynecologic laparoscopic surgery and improves patients' post-operative recovery., (© 2024 S. Karger AG, Basel.)

Objective: The first aim of the study was to identify sex differences in the use of psychoactive substances among subjects with a previous driving under the influence (DUI) episode. The secondary objective was to propose specific strategies for medico-legal improvements., Methods: This was a retrospective observational study that took place between June 1, 2019, and August 31, 2023. It was conducted on DUI subjects examined for reinstatement of their driver's license using an integrated medico-legal and toxicological approach. Ethyl glucuronide (EtG) and illicit psychoactive substances were determined from hair samples. We performed descriptive statistical analyses for the entire sample as well as separately by sex. Additionally, we conducted binary logistic regression analyses separately for males and females to identify protective/risk factors associated with previous road accidents and judgments of unfitness to drive due to excessive alcohol consumption (EtG ≥ 30 pg/mg)., Results: The study included 2,221 subjects, comprising 1,970 men and 251 women. Men exhibited a higher prevalence of tobacco, alcohol, and illicit psychoactive substance use. Women were more frequently co-users of alcohol and psychoactive substances and involved in road accidents at the time of DUI. Among the men, being married or having a partner was found to be a protective factor concerning past traffic accidents. For both sexes, a DUI episode with a blood alcohol concentration (BAC) exceeding 1.5 g/L or the co-ingestion of alcohol and drugs was identified as a risk factor for road accident involvement. For men, smoking more than 20 cigarettes per day and, for women, having a DUI episode with a BAC over 1.5 g/L were the main factors indicating unfitness to drive, as determined through high hair EtG levels (> 30 pg/mg). Women with a previous history of road accidents were less likely to have EtG levels of 30 pg/mg or more., Conclusions: The study confirmed sex differences in subjects with a previous DUI episode. A BAC exceeding 1.5 g/L or the simultaneous use of alcohol and drugs at the time of DUI necessitate careful assessment of both men and women seeking driver's license reinstatement. In women, a BAC exceeding 1.5 g/L is considered a risk factor for a subsequent judgment of unfitness to drive. The medico-legal assessment should also involve a thorough investigation of smoking habits in men, as these habits could be related to an increased risk of excessive alcohol consumption.

Introduction: Cannabis consumption is associated with driving impairment and increased crash risk, endangering road safety. Toxicological analyses play a fundamental role in detecting a recent consumption of psychoactive substances. The aim of this study was to examine the concentration of cannabinoids in blood samples of driving-under-the-influence (DUI) offenders in order to investigate whether delayed sample collection affects the toxicological assessment of the offenders., Materials and Methods: An observational retrospective study was performed using anonymized toxicological data referring to cannabis-related DUI offenders involved in road traffic accidents (RTA) or apprehended by the police from 1 January 2017-31 December 2021 archived at Legal Medicine and Toxicology Department of the University Hospital of Padova, Italy., Results: In a total sample of 318 drivers, 143 blood samples tested positive for tetrahydrocannabinol (THC) and metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), and 173 blood samples were positive for THC-COOH with THC negative. In the first group, the mean concentrations of THC and THC-COOH were 4.05 ng/mL and 28.29 ng/mL, respectively. In THC-negative cases, the mean THC-COOH concentration was 7.3 ng/mL. The time elapsed between the event and sample collection varied from 15 min to 7 h (mean 2 h 29 min). The average estimated time elapsed after consumption of cannabinoids was 3 h 7 min (Model I) and 2 h 36 min (Model II)., Conclusions: The present research discussed the main difficulties in the toxicological evaluation of drivers under the influence of Cannabis. Issues related to the time between RTA and sample collection, the laws and legal limits in force in various Countries were presented., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Endometrial cancer represents an ideal target to evaluate the impact of COVID-19 being the most frequent gynecological malignancy in Italy, generally detected at early stages and correlated with favorable oncological outcomes. The present comparative retrospective study carried out at Campus Bio-medico University Foundation in Rome aims to evaluate the impact of the COVID-19 pandemic on the presentation, diagnosis and treatment of EC. All women with a histological diagnosis of non-endometrioid and endometrioid endometrial cancer between 1 March 2018 and 31 October 2022 were included. The number of cases was higher in period 2 (95 vs. 64 cases). Time to diagnosis did not show statistically significant differences but in period 2, 92.06% of the diagnoses were made following abnormal uterine bleeding, while in period 1, only 67.02% were. The waiting time for the intervention was significantly shorter in period 2. Definitive histology, FIGO staging, surgical technique and adjuvant therapy did not show significant differences between the two periods. The study demonstrates that the impact of the COVID-19 pandemic did not have a direct effect on the diagnostic delay, tumor staging and type of therapy but rather on the presentation pattern of endometrial cancer.

Background: Although acquired dystonia may develop following ischaemic/haemorrhagic stroke, the relationship between cerebrovascular disease and idiopathic dystonia has been poorly investigated. This cross sectional study aimed at evaluating the impact of cerebrovascular risk factors on the clinical expression of idiopathic adult onset dystonia (IAOD), with reference to dystonia localization and dystonia-associated features., Methods: Data were obtained from the Italian Dystonia Registry. Patients with IAOD were stratified into two groups according to the presence of diabetes mellitus and/or arterial hypertension and/or dyslipidemia and/or heart disease. The two groups were compared for demographic features, dystonia phenotype, and dystonia-associated features (sensory trick, tremor, eye symptoms in blepharospasm, and neck pain in cervical dystonia)., Results: A total of 1108 patients participated into the study. Patients who reported one cerebrovascular factor or more (n = 555) had higher age and longer disease duration than patients who did not. On multivariable logistic regression analysis, blepharospasm was the only localization, and sensory trick was the only dystonia-associated feature that was significantly associated with cerebrovascular risk factors. Linear regression analysis showed that the strength of the association between cerebrovascular factors and blepharospasm/sensory trick increased with increasing the number of cerebrovascular factors per patient., Conclusions: Results of the present study showed that cerebrovascular risk factors may be associated with specific features of IAOD that is development of blepharospasm and sensory trick. Further studies are needed to better understand the meaning and the mechanisms underlying this association., Competing Interests: Declaration of competing interest None, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Although more than ten years have passed since the marketing of Ulipristal acetate in Europe, emergency contraception remains a complex issue with many scientific, legal, ethical and social implications. The topic is an example of the differences that can exist between scientific evidence, the certainties on which law is based, and social implications. This paper shows the incompleteness of the scientific reconstruction on the effects of emergency hormonal contraceptives and the dangerousness of the decision to alienate the supply of over-the-counter drugs from the general rules of health care. This report shows the incompleteness of the scientific reconstruction on the effects of emergency hormonal contraceptives and the dangerousness of the decision to alienate the supply of over-the-counter drugs from the general rules of health care. Various ethical and medico-legal issues will be addressed, also focusing attention on underage women whose sexual and reproductive health requires not abandoning them, but actually taking charge of them without medicalizing their choices., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Scendoni, Cingolani, Cembriani, Fedeli, Tambone, Terranova and De Micco.)

Driving under the influence (DUI) of alcohol is a road safety problem. Driving license regranting is based on the evaluation of medicolegal and toxicological variables that may include serum carbohydrate-deficient transferrin (CDT) and hair ethyl glucuronide (hEtG). The aim of the study was to compare the diagnostic performance of CDT and hEtG in a population of DUI offenders. Other factors potentially associated with heavy alcohol use were explored. The population included DUI offenders examined during the period of January 1, 2019, through June 30, 2022. Sociodemographic, medicolegal, and toxicological variables were collected. CDT in serum and EtG in head hair were determined in all subjects. Excessive alcohol intake (hEtG ≥30 pg/mg) was considered cause for unfitness to drive. Cohen's kappa coefficient was calculated. Descriptive analyses were performed using chi-square and Mann-Whitney tests. Variables significantly different between the groups were included in a multivariate binary logistic regression model. The sample encompassed 838 subjects (case group: 179, comparison group: 689). CDT exhibited poor agreement (κ = 0.053) with hEtG as the reference test. Lower education, age at DUI, heavy smoking, and GGT levels associated with heavy alcohol consumption differentiated the two groups. For DUI offenders, the use of CDT to assess heavy alcohol consumption is limited, possibly due to the time-window assessed, the time required for normalization, and the different amount of ethanol needed to reach higher CDT levels, in comparison to hEtG; thus, hEtG assessment is strongly recommended for this population. Heavy smoking, GGT, education, and age could be related to heavy alcohol consumption and higher risk of DUI., (© 2022 John Wiley & Sons Ltd.)

Background: To date, there are no large studies delineating the clinical correlates of "pure" essential tremor (ET) according to its new definition., Methods: From the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of "pure" ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum., Results: Out of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) "pure" ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options., Discussion: The findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of "pure" ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of "pure" ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies., Competing Interests: RE receives royalties from the publication of Case Studies in Movement Disorders—Common and Uncommon Presentations (Cambridge University Press, 2017) and of Paroxysmal Movement Disorders (Springer, 2020). He has received consultancies from Sanofi and honoraria for speaking from the International Parkinson's Disease and Movement Disorders Society. PB received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie, and Acorda. APi received grant support from the Ministry of Education, Research and University (MIUR) and IMI H2020 Initiative (IDEA-FAST project- MI2-2018-15-06), received research support from Zambon SrL Italy and Bial Italy; he received speaker honoraria from AbbVie, BioMarin, Bial, and Zambon Pharmaceuticals. APa received grant support from the Ministry of Health (MINSAL) and the Ministry of Education, Research and University (MIUR), from CARIPLO Foundation; personal compensation as a consultant/scientific advisory board member for Biogen 2019-2020-2021 Roche 2019-2020 Nutricia 2020-2021 General Healthcare (GE) 2019; he received honoraria for lectures at meeting ADPD2020 from Roche, lecture at meeting of the Italian Society of Neurology 2020 from Biogen and from Roche, and lecture at meeting AIP 2020 and 2021 from Biogen and from Nutricia, Educational Consulting 2019-2020-2021 from Biogen. AD reports advisory board fees from Sanofi and speaking honoraria from Sanofi, Zambon, and Bial. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Erro, Lazzeri, Gigante, Pilotto, Magistrelli, Bologna, Terranova, Olivola, Dallocchio, Moschella, Valentino, Di Biasio, Nicoletti, De Micco, Brusa, Sorrentino, Matinella, Bertino, Paparella, Modugno, Contaldi, Padovani, Di Fonzo, Restaino, Barone and TITAN study group.)

Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones 1 . Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRAS G12D and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP) 2 , revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8 + T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Laparoscopic surgery offers many advantages compared to invasive surgery but one of the main problems is postoperative pain, partially resulting from the peritoneal inflammatory process mediated by inflammatory cytokines. The rationale of this study is that intraperitoneal washing could remove inflammatory mediators that are the cause of postoperative pain and could help in the removal of CO2 from the abdominal cavity. This article aims to analyze the effects of peritoneal lavage in the reduction of postoperative shoulder pain., Patients and Methods: 277 patients enrolled to undergo laparoscopic gynecologic surgery were included in the study. Women are randomized into two groups, according to the use or non-use of peritoneal lavage with saline solution at the end of laparoscopic gynecological major procedures., Results: Data show that the peritoneal lavage can significantly reduce postoperative pain in the first 36 hours after surgery, as well as patients' requests for analgesics: during the first 3 postoperative days, requests for paracetamol were lower in the YW (Yes Washing) group than the NW (No Washing) group (77 vs. 101; p<0.05); similar results are obtained considering ketorolac administration (62 vs. 71; p<0.05)., Conclusions: Peritoneal lavage after gynecological laparoscopic procedures may be effective in the reduction of postoperative pain and use of analgesics.

Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias., Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias., Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia., Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor., Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories., (© 2023 International Parkinson and Movement Disorder Society.)

Purpose: Uterine myomas are the most common gynecological disease. In these cases, a myomectomy is performed traditionally laparotomically. However, alternatives have been widely used, including laparoscopic, endoscopic, and robotic surgery. During these techniques, diffuse parenchymatous bleeding remains one of the main intraoperative and postoperative complications and sometimes requires unplanned hysterectomies. Recently, hemostatic agents and sealants have been used to prevent excessive blood loss during surgical repair., Methods: We propose a prospective case-control study on the use of a sealing hemostat patch (HEMOPATCH ® ) on uterine sutures in laparotomic myomectomy. In the period between July 2016 and April 2017, 46 patients with symptomatic uterine fibromatosis underwent surgery. They were divided into two groups of 23 patients, with different treatments in the hemostatic phase of oozing bleeding. HEMOPATCH ® is applied in group A, and spray electrocoagulation is applied in group B., Results: In group A, we achieve faster hemostasis (p < 0.05), than in group B. We report a significantly lower C-reactive protein value on the second and third days after surgery for group A compared to group B., Conclusions: HEMOPATCH ® , during laparotomic myomectomy, is a valid alternative solution for obtaining rapid hemostasis and consequently intraoperative and postoperative bleeding. Furthermore, we suggest that a lower inflammatory peritoneal state is probably correlated with the barrier effect of the patch on the suture., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Usually, in stress urinary incontinence (SUI), nonsurgical therapy such as pelvic floor muscle training (PFMT) and lifestyle changes are proposed before surgical treatment. Laser therapy has recently been recommended for the treatment of SUI, helping to reconstruct the collagen that supports the vagina and the pelvic floor. The aim of the study was to evaluate the efficacy of SUI treatment with a CO 2 intravaginal laser in patients waiting for anti-incontinence surgery (TVT-O)., Methods: This is a prospective, case-control study. Fifty-two patients have been included in our study and we divided them into two groups: atrophy and no atrophy. We also adopted a control group retrospectively identified from our database of patients undergoing PFMT. The subjective estimation of SUI symptoms before and after treatment was evaluated using the Visual Analog Scale before and after 1, 6, and 12 months of treatment. The objective evaluation with the urodynamic study with the stress test and a 3-day voiding diary to count the number of episodes of incontinence, before and after treatment., Results: The intravaginal CO 2 laser improved all the parameters considered for SUI in both groups. Its results were more relevant in the atrophy group, in comparison to the no atrophy group, even if they were both statistically significant. There were no statistically significant differences for all the parameters evaluated for SUI between laser treatment and PFMT in the control group., Conclusion: The CO 2 laser is well-tolerated, minimally invasive, safe, and showing efficacy for SUI. More studies are needed to consider it as first-instance therapy, like PFMT, or at least, as a bridge therapy to surgery., (© 2022 Wiley Periodicals LLC.)

The equilibrium between stem cell self-renewal and differentiation followed by proper lineage specification of progenitor cells is considered imperative for maintaining intestinal homeostasis. In the hierarchical model, intestinal differentiation is defined by the stepwise acquisition of lineage-specific mature cell features, where Notch signaling and lateral inhibition instructively regulate the cell-fate decisions. Recent studies reveal a broadly permissive intestinal chromatin underlies the lineage plasticity and adaptation to diet mediated by Notch transcriptional program. Here, we review the conventional understanding of Notch programming in intestinal differentiation and describe how new data from epigenetic and transcriptional analyses may refine or revise the current view. We provide instructions on sample preparation and data analysis and explain how to use ChIP-seq and scRNA-seq in combination of lineage tracing assay to determine the dynamics of Notch program and intestinal differentiation in the context of dietary and metabolic regulation of cell-fate decisions., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Nocturia was commonly treated with drugs burdened with high costs and numerous side effects; in fact, more than 70% of patients drop out of long-term treatment. Protopine and nuciferine are two alkaloids that have different effects on the neurotransmitter receptors involved in the regulation mechanism of the onset of urinary stimuli. The aim of the study was to evaluate the efficacy in controlling primarily nocturia and secondarily urgency and dysuria after 3 months of treatment with combination therapy of protopine and nuciferine syrup., Design: This is a prospective cohort study in which all patients were diagnosed with overactive bladder syndrome (OAB) and the presence of the following symptoms: nocturia, urgency, and dysuria. Thirty patients were administered 10 mL/die (16.6 mg of nuciferine, 0.09 mg of protopine) of syrup for 3 months. Patients were evaluated at baseline (T0) with the International Consultation on Incontinence Questionnaire (ICIQ), Visual Analogue Scale (VAS) for the evaluation of dysuria, Patient Perception of Intensity of Urgency Scale (PPIUS) and at 3 months (T1) with the Patients' Global Impression of Change (PGI-C) scale, PPIUS, VAS, and ICIQ., Participants: Women with diagnosis of OAB; the presence of nocturia, urgency, and dysuria symptoms agreeing to undergo treatment and compiling informed consent; and the absence of contraindications to the use of active ingredients were included in the study., Setting: Patients were recruited at T0 during the visit to the Uro-Gynecology clinic of the University of "Campus Bio-Medico" and visited again 3 months (T1) after the initiation of therapy., Methods: We explored survey data by descriptive statistics: in particular, continuous values (i.e., ICIQ) have been summarized by mean and standard deviation of discrete ordinal values (i.e., VAS, PPIUS, and bladder diary parameters at T0 and T1) by median, minimum, and maximum reported scores. Where we could assume normality in distribution, assessed by the Shapiro-Wilk test and the evaluation of the QQ plot, we compared the observation of T0 and T1 with the paired Student's t test; otherwise, we tested differences in distribution with the paired Mann-Whitney U test., Results: Thirty patients completed a 3-month therapy. The ICIQ and VAS questionnaires for the assessment of dysuria, both, reported an improvement in dysuria at T1 (p < 0.001). The PPIUS questionnaire reported an improvement in urinary urgency at T1 (p < 0.001). The PGI-C scale in T1 indicated an improvement in symptoms: 93% for nocturia, 70% for urinary urgency, and 63% for dysuria., Limitations: The weaknesses of this study are the small number of patients; as a pilot study, the study design was not randomized with a placebo and without blinding; and the short follow-up., Conclusions: Protopine and nuciferine can be an interesting alternative to primarily treat and reduce nocturia episodes, in addition to improving OAB-related urgency and dysuria., (© 2022 S. Karger AG, Basel.)

Objective: There is a lack of information about the normal trend of C-reactive protein (CRP) blood levels in the postoperative days after gynecological benign surgery. We investigated the impact of different surgical techniques on CRP trend. We performed a comparative analysis between a CRP and white blood cell (WBC) trend in postoperative monitoring., Methods: We studied 207 surgical patients for benign gynecological pathology. We analyzed CRP and WBC levels after surgery in the total number of women and separately by approaches., Results: CRP mean log scores showed a typical behavior. Moreover, results from chi-square test underline that the proportion of women with this result is independent from the type of surgery they underwent. Log score mean values of CPR differed between all groups and between times. No difference in the mean number of white cells between the second and the third day was found, as observed for CRP., Conclusions: Our study shows a trend reference model in postoperative monitoring of patients with benign gynecological surgery. The comparative analysis between the CRP and WBC trend in the postoperative days provided us data demonstrating the superiority of CRP in postsurgical patient outcomes monitoring., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Purpose: In Vitro Fertilization (IVF) techniques make up 1.5-5% of all births in developed countries. These pregnancies are characterized by implantation and functional alterations of the placenta, higher incidence of multiple pregnancies, higher incidence of hypertensive syndromes and pre and post partum hemorrhage (PPH)., Methods: Since January 2017 to May 2018 all single IVF pregnancies coming to San Camillo Hospital were considered prospectively for routine pregnancy checks until delivery and compared with a control group of spontaneous pregnancies. Each patient underwent to an obstetrical ultrasound of the third trimester at our clinic, with particular attention on the study of the placenta. Birth modalities, type and timing of third stage of labor, peri and post-partum complications were recorded., Results: We had a higher incidence of cesarean sections in the IVF group (85% versus 25%) and peri and post-partum complications (38% versus 5%). We recorded a statistically significant difference of reduction in IVF pregnancies of VI ( p  = .0039) and VFI ( p  = .0043), while the FI index was not statistically significant in the two study groups ( p  = .4351)., Conclusion: Despite the small sample size of our study, our data follow the trend of scientific literature, with an effective increase in placental anomalies in IVF pregnancies compared to healthy controls.

Purpose/aim: Diabetic chorea is a rare movement disorder associated with diabetes mellitus. We report the case of a patient that benefited from pimozide and died of pancreatic cancer., Case Report: A 70-year-old woman presented with pollakiuria and involuntary movements of left limbs since three months. Laboratory tests revealed high serum levels of glycemia and glycated haemoglobin. She was admitted to internal medicine department and discharged one week later: insulin was administered with normalization of blood glucose levels and the involuntary movements gradually disappeared. Three weeks later she was admitted to neurological department due to the recurrence of the involuntary movements. Glycemia and other routine laboratory tests were normal. Neurological examination showed choreic movements involving left limbs. MRI showed a hyperintensity on T1- and T2-weighted sequences of right putamen and caudate nucleus head. Haloperidol was administered without improvement, it was successively substituted with tetrabenazine and the patient was discharged with an unvaried clinical picture. Two months later tetrabenazine was discontinued because of inefficacy and pimozide was started. The choreic movements considerably diminished after few days. Four months later, a pancreatic cancer was diagnosed and the patient died in the same month., Conclusion: Clinical and radiological features were suggestive of diabetic chorea. Our patient benefited exclusively from pimozide, it could be reasonable to use pimozide in resistant form and also propose it as first choice treatment. Another important element is the diagnosis of pancreatic cancer some months after chorea onset: a causal link could exist.

Introduction: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking., Methods: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes., Results: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia., Conclusions: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research., (© 2022. The Author(s).)

Background and Aims: Recent years have witnessed the switch from considering essential tremor (ET) a monosymptomatic disorder to consider it as part of a spectrum, including other neurological signs, such as mild cognitive impairment and dementia, thus defining it as "ET plus." There are few data on cognitive impairment in ET patients. The aim of this review is to analyze the clinical characteristics of ET patients developing cognitive impairment, their neuropsychological profile, the underpinning mechanisms, and the possible biomarkers., Methods: The authors performed a narrative review on cognitive decline in essential tremor, including articles written in English since the year 2000., Discussion: The most recent pathogenetic theories of cognitive impairment in ET rely on the cerebellar dysfunction, being part of the Cerebellar Cognitive Affective Syndrome spectrum. Cognitive impairment in ET patients could be assessed through many tests that demonstrate the involvement of different domains, such as attention, executive functions, and language. There are some clinical characteristics of ET that may indicate a greater risk of developing cognitive impairment, namely, cerebellar symptoms, falls, age at onset, and family history. However, there are no established clinical, neurophysiological, neuropathological, and fluid biomarkers of cognitive impairment in ET., Conclusions: Increasing data are showing in ET the presence of cerebellar symptoms and cognitive impairment. Further studies are needed to better understand cognition in ET patients, and to define the boundary between ET and ET plus, since deeper phenotyping might have important clinical and therapeutic implications., (© 2022. Fondazione Società Italiana di Neurologia.)

The intentional homicide of female victims, which is most commonly perpetrated by intimate partners or family members, has been recognized in recent years as a matter of grave public concern that needs to be addressed from the cultural and judicial perspectives. To allow an in-depth criminological and psychopathological evaluation of female homicide in Italy in 2021 to be conducted, the authors performed a newspaper report analysis of the phenomenon. All female homicides that occurred in Italy in 2021 ( n = 119) were included in the study. The analysis confirmed the low rate of female homicides in Italy when compared with other countries and also showed the phenomenon to be more complex than usually described. The highest rate of homicides was observed in elderly females when compared with other age groups, implying different criminological considerations and suggesting that gender-based violence may only explain some of the identified cases. The high incidence of suicide or attempted suicide among offenders, together with the high incidence of reported mental disorders in that population, suggests that a psychopathological perspective on the phenomenon of female homicide could help with the development and implementation of preventive strategies that focus on managing mental health at a territorial level and intervening in difficult domestic situations.

Introduction: After the diagnosis of L-SIL, 77. 3% had a persistent infection and anomalous Pap Test results. Many of these patients had highlighted psychological consequences such as anxiety, hypochondria, fear of cancer, and sexual problems. Several studies suggested that the clearance of HR-HPV infection could be accelerated by cervical excisional procedures, especially in L-SIL. In consideration of the psychological implications for HPV infection and related dysplasia in patients with CIN1 at PAP-smear and HR-HPV positivity at least for 6 months, we decided to plan a prospective study where we tried to anticipate excisional cervical using a minimally invasive treatment: thin loop electrosurgical excision procedure (t-LEEP). This study aims to analyze the clearance of HR-HPV after 6 and 12 months, clinical outcomes related to t-LEEP, and the psycho-relational impact at 12 months after t-LEEP., Materials and Methods: We enrolled patients with the diagnosis of L-SIL at PAP-smear and HR-HPV positivity with a persistent CIN 1 (at least for 6 months), confirmed by cervical biopsy. All enrolled patients underwent t-LEEP. We followed prospectively and performed for all patients the HPV DNA test at 6 (T1) and 12 months (T2) and STAI-Y and FSFI scores at T0 and T2., Results: We prospectively enrolled 158 patients, 22 are excluded for the established criteria. Patients with HR-HPV and CIN 1 lesions treated with t-LEEP had an overall clearance of 83.8% at T2. In subgroups analysis at T2, we had a regression: in smoker 71.8%, in contraceptive users 69.5%, in patients aged <25 years 100%, aged 25-30 years 85%, aged 30-35 years 94.4%, aged 35-40 years 92%, and aged ≥40 years 89.1%, in HPV-16 96.4%, in HPV-53 89.5%, in HPV-18 87.5%, in HPV-31 86.6%, and in coinfected 3.5%. STAI-Y and FSFI after t-LEEP (T2) were statistically significant, reducing anxiety status and improving sexual function., Conclusion: Based on these results, the use of t-LEEP in patients with persistent CIN 1 and HPV-HR at least for 6 months could be useful for accelerating HPV-HR clearance, in particular, for a subpopulation patient with an increased risk of progression and/or patients with psychological and sexual consequences of carrying an HR-HPV infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SL declared a past co-authorship with the authors to the handling editor., (Copyright © 2022 Plotti, Rossini, Ficarola, De Cicco Nardone, Montera, Guzzo, Luvero, Fabris, Angioli and Terranova.)

Objective: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described., Design: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin., Results: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups., Conclusion: Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Illicit drug use is a global problem that also affects pregnant women. Substance use and alcohol abuse during pregnancy may have various harmful consequences for both mothers and foetuses. Intrauterine exposure to illicit substances can be investigated through maternal reports and toxicological tests on mothers' and/or newborns' samples. While the negative effects of alcohol and opioid use on pregnancy, the foetus, and/or newborn are well established, the effects of cocaine use remain controversial. We performed a review of the literature to evaluate the current state of knowledge of the effects of intrauterine cocaine exposure on newborns' and children's long-term development and to highlight possible implications for health professionals dealing with women who use cocaine during pregnancy. Although intrauterine cocaine exposure has been associated with reduced infant measurements, no specific amount of cocaine use exerting such effects has been determined, and no long-term effects have been confirmed. The evidence of cocaine use during pregnancy justifies a clinical and social takeover of the mother and newborn without assuming that there will certainly be long-term damage related to intrauterine cocaine exposure, but also considering other possible associated factors.

In March 2020, WHO declared Covid-19 outbreak pandemic. There has been increasing evidence that frail, old, multi-pathological patients are at greater risk of developing severe Covid-19 infection than younger, healthy ones. Covid-19's impact on Parkinson's Disease (PD) patients could be analysed through both the influence on PD patients' health and their risk of developing severe Covid-19, and the consequences of lockdown and restrictive measures on mental and cognitive health on both patients and caregivers. Moreover, there are critical issues to be considered about patients' care and management through an unprecedented time like this. One important issue to consider is physiotherapy, as most patients cannot keep exercising because of restrictive measures which has profoundly impacted on their health. Lastly, the relationship between PD and Sars-Cov2 may be even more complicated than it seems as some studies have hypothesized a possible Covid-19-induced parkinsonism. Hereby, we review the state of the art about the relationship between Covid-19 and Parkinson's Disease, focusing on each of these five points., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

This study aimed to investigate the predictors of recidivism in first-time driving under the influence (DUI) offenders, analyzing variables derived from medico-legal and toxicological examinations. The research was structured as a comparative study for the period 2012-2019. DUI offenders with a blood alcohol concentration >0.5 were included in the study. The case group consisted of recidivist offenders, while the comparison group consisted of first-time offenders. Personal data, socioeconomics, and parameters linked to the DUI were compared between the two groups. Significance was determined by chi-square and Mann-Whitney tests. To prevent confounding effects, multivariate binary logistic regression analysis was performed. Our sample encompassed 1678 subjects (196 in the case group, 1482 in the comparison group). Gender, driving license category, education, and tobacco use resulted in significant differences between the groups. In a model including age at DUI, education, and smoking habit as independent variables, higher educational levels (high school, bachelor's) and older age protected against recidivism, whereas smoking >20 cigarettes/day was an independent risk factor for recidivism. Recidivist offenders have specific characteristics indicating different therapeutic programs and carefulness in driving license regranting. A higher tobacco consumption in recidivists suggests that the use of this substance could influence the risk of DUI for reasons that will need to be explored.

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that frequently harbor genetic alterations in polycomb repressor complex 2 (PRC2) components-SUZ12 and EED. Here, we show that PRC2 loss confers a dedifferentiated early neural-crest phenotype which is exclusive to PRC2-mutant MPNSTs and not a feature of neurofibromas. Neural crest phenotype in PRC2 mutant MPNSTs was validated via cross-species comparative analysis using spontaneous and transgenic MPNST models. Systematic chromatin state profiling of the MPNST cells showed extensive epigenomic reprogramming or chromatin states associated with PRC2 loss and identified gains of active enhancer states/super-enhancers on early neural crest regulators in PRC2-mutant conditions around genomic loci that harbored repressed/poised states in PRC2-WT MPNST cells. Consistently, inverse correlation between H3K27me3 loss and H3K27Ac gain was noted in MPNSTs. Epigenetic editing experiments established functional roles for enhancer gains on DLX5-a key regulator of neural crest phenotype. Consistently, blockade of enhancer activity by bromodomain inhibitors specifically suppressed this neural crest phenotype and tumor burden in PRC2-mutant PDXs. Together, these findings reveal accumulation of dedifferentiated neural crest like state in PRC2-mutant MPNSTs that can be targeted by enhancer blockade., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Brain tumors can cause different changes in excitation and inhibition at the neuronal network level. These changes can be generated from mechanical and cellular alterations, often manifesting clinically as seizures. Objective/Hypothesis: The effects of brain tumors on cortical excitability (CE) have not yet been well-evaluated. The aim of the current study was to further investigate cortical-cortical and cortical-spinal excitability in patients with brain tumors using a more extensive transcranial magnetic stimulation protocol. Methods: We evaluated CE on 12 consecutive patients with lesions within or close to the precentral gyrus, as well as in the subcortical white matter motor pathways. We assessed resting and active motor threshold, short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition, cortical silent period, and interhemispheric inhibition. Results: CE was reduced in patients with brain tumors than in healthy controls. In addition, SICI, ICF, and SAI were lower in the affected hemisphere compared to the unaffected and healthy controls. Conclusions: CE is abnormal in hemispheres affected by brain tumors. Further studies are needed to determine if CE is related with motor impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rizzo, Terranova, Raffa, Cardali, Angileri, Marzano, Quattropani, Germanò, Girlanda and Quartarone.)

A comparative case study (2017-2020) was conducted to identify demographic, social, medico-legal, and toxicological variables associated with non-fatal accidents in driving under the influence (DUI) subjects. A second aim was to identify the factors predictive of substance use disorders among subjects. Drivers charged with alcohol DUI (blood alcohol concentration (BAC) > 0.5) and/or psychoactive substance DUI were included; cases included those involved in an accident while intoxicated, and the comparison group included DUI offenders negative for road accident involvement. Significance was determined by chi-square and Mann-Whitney tests. To prevent confounding effects, a multivariate binary logistic regression analysis was performed. Our sample encompassed 882 subjects (381 in the case group and 501 in the comparison group). Parameters such as psychoactive substances and BAC at the time of the road crash/DUI and the day of the week, when subjects were involved in the road accident or found DUI, resulted in significant differences ( p  < 0.01) between groups. The model's independent variables of BAC > 1.5 g/L ( p  = 0.013), BAC > 2.5 g/L ( p  < 0.001), and concurrent alcohol and psychoactive substance use ( p  < 0.001) were independent risk factors for an accident. Smoking >20 cigarettes/day was an independent risk factor for unfitness to drive ( p  < 0.01). Unfitness to drive was based primarily on ethyl glucuronide levels >30 pg/mg. Our results suggest a detailed assessment of DUI subjects with variables associated with accidents (BAC > 1.5 g/L and concurrent intake of psychoactive substances). Hair analysis, including ethylglucuronide (EtG) concentration, should be always performed. Based on our results, nicotine use should be investigated in cases of driving license regranting.

Background: Adult-onset focal dystonia can spread to involve one, or less frequently, two additional body regions. Spread of focal dystonia to a third body site is not fully characterized., Materials and Methods: We retrospectively analyzed data from the Italian Dystonia Registry, enrolling patients with segmental/multifocal dystonia involving at least two parts of the body or more. Survival analysis estimated the relationship between dystonia features and spread to a third body part., Results: We identified 340 patients with segmental/multifocal dystonia involving at least two body parts. Spread of dystonia to a third body site occurred in 42/241 patients (17.4%) with focal onset and 10/99 patients (10.1%) with segmental/multifocal dystonia at onset. The former had a greater tendency to spread than patients with segmental/multifocal dystonia at onset. Gender, years of schooling, comorbidity, family history of dystonia/tremor, age at dystonia onset, and disease duration could not predict spread to a third body site. Among patients with focal onset in different body parts (cranial, cervical, and upper limb regions), there was no association between site of focal dystonia onset and risk of spread to a third body site., Discussion and Conclusion: Spread to a third body site occurs in a relative low percentage of patients with idiopathic adult-onset dystonia affecting two body parts. Regardless of the site of dystonia onset and of other demographic/clinical variables, focal onset seems to confer a greater risk of spread to a third body site in comparison to patients with segmental/multifocal dystonia at onset., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Cervical cancer is currently one of the most common cancers afflicting the female population worldwide and in industrialized countries the presence of screening and a specific diagnostic and therapeutic process has favored early diagnosis of cervical cancer. In literature have found that reducing the radicality on the parametria in early cervical cancer (ECC), reduces complications without impacting oncological outcomes, but the data in the literature are not yet clear., Evidence Acquisition: Searching on PubMed, we included 1473 articles from January 1974 to 2020. We identified all the studies that compared different type of radical hysterectomy in the primary surgical treatment of ECC. 16 articles were elected for the review., Evidence Synthesis: Modified radical hysterectomy (Piver II/Querleu-Morrow Type B) in ECC, if compared to CRH (Piver III/Querleu-Morrow Type C2), is not associated with worse cancer outcome and patient survival, but it is associated with a minor operating time, lower blood loss and minor bladder dysfunction. Nerve sparing radical hysterectomy approach (NSRH/Querleu-Morrow Type C1) compared to CRH (Piver III/Type C2) in the ECC, with our data we can confirm a non-inferiority regarding the oncological outcome., Conclusions: Reduced radicality on the parametrium offers positive effects on the quality of life (sexual life and bladder function) of patients without impacting on survival, oncological outcome.

Along with rising levels of the infection around the world, the state of emergency prompted by the COVID-19 pandemic has also been having a heavy legal impact. The situation is posing important criminal challenges, as well as an ocean of social and public health issues around the world. It has not only directly affected constitutionally-guaranteed rights and individual freedoms, but also brought to the fore certain types of criminal offence that had previously been of little practical importance, such as the crime of 'maliciously or unintentionally causing an epidemic'. Different countries and states have introduced policies to manage the emergency at different times and in different ways. The measures adopted have been the object of much criticism, also raising questions of constitutional legitimacy in countries like Italy. The present contribution begins with a brief outline of the different international scenarios. Then we examine some of the medicolegal aspects of criminal offences previously envisaged and newly introduced since the arrival of the pandemic. We suggest the need for a sort of 'code of public health laws for the time of coronavirus', that could also be applied to other public health emergencies, pandemic or otherwise. The idea is to give operators in the sector and the general population the opportunity to identify clear and simple rules to follow in the current complex global situation. We need a new, appropriate interpretation of the 'boundaries' of our individual rights in relation to the need to safeguard the wider community and its more vulnerable members., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: In the past few years, treatment of multiple myeloma has undergone a deep change for the employment of novel treatment comprising proteasome inhibitors. Bortezomib is a first-line drug in therapy of multiple myeloma. The onset of peripheral neuropathy is a dose-limiting collateral effect of the drug. This neuropathy is a distal symmetric neuropathy that affects both large and small fibers. Nerve conduction study (NCS) can be used for the diagnosis of bortezomib neuropathy, but this technique demonstrates alterations of the large nerve fibers. Sudoscan is a novel technique utilized to offer an evaluation of sudomotor function. The main objective of this study was to compare the sensitivity and diagnostic specificity of Sudoscan with respect to the nerve conduction study after bortezomib treatment., Material and Methods: A total of 18 multiple myeloma patients were studied, 10 (55.5%) men and 8 (44.5%) women. Patients were analyzed at baseline and after 6 months of treatment with bortezomib. Subjects were submitted to nerve conduction study and electrochemical skin conductance evaluation with the Sudoscan device. Patients were also submitted to a clinical measure of pain and neuropathy., Results: At baseline NCS showed that only the mean sural SAP amplitude was below the 2SD lower limit of normal in 3 (16.7%) patients, while at same time we found an alteration of Sudoscan profiles in 2 (11.1%) patients. After 6 months of treatment, the NCS profiles were altered in 13 (72.2%) patients, and the Sudoscan profiles were modified in 11 (61.1%) subjects., Conclusions: Our results suggest that Sudoscan can be considered for the diagnosis of bortezomib-induced neuropathy. It is objective, reproducible, and surely easier than the traditional nerve conduction study. Sudoscan may be a useful help to manage the therapeutic interventions in multiple myeloma., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia & Banach.)

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.

Introduction: The concealment of the body following a homicide undermines different moments of the forensic and medico-legal investigations. The aim of the present study is to provide an overview of the literature and the forensic casuistry of the Institute of Legal Medicine of Padova for analyzing and discussing diverse methodological approaches for the forensic pathologist dealing with covered-up homicides., Material and Methods: A literature review, updated until September 2019, was performed, and a literature pool of forensic cases was built. In-house cases were included by conducting a retrospective analysis of the forensic caseworks of Padova of the last 20 years. Data regarding epidemiology, methodology of assessment, methods of concealment, and answers to medico-legal issues were extracted for both data sets., Results and Discussion: Seventy-eight papers were included in the literature review (78.2% being case reports or case series, 17% retrospective studies, and 6% experimental studies or reviews). Literature and in-house data sets consisted of 145 and 13 cases, respectively. Death scene investigation, radiology, toxicology, and additional analyses were performed in 20-54% of literature and 62-77% of in-house cases. Cover-up by multiple methods prevailed. Death was caused by head trauma in about 40% of cases (both data sets), strangulation in 21% of literature, and 7% of in-house cases, and was undetermined in 17% of literature and 7% of in-house cases., Conclusions: The methodology of ascertainment should be case-specific and based on a multidisciplinary and multimodal evaluation of all data, including those gained through novel radiological and/or analytical techniques.

Objective: This study investigates the consequences of the SarS-CoV-2 outbreak and of the resulting control measures on alcohol and illicit substance use in a high-risk population for substance-related disorders, utilizing an integrated medico-legal and toxicological approach., Methods: The research was structured as a retrospective case-control study of subjects found to be driving under the influence (DUI) of alcohol and/or other psychoactive substances who were examined for driver's license regranting. Alcohol and/or drug use was assessed by comparing cases examined in the period from May to August 2020 (immediately after the lockdown in Italy) to control subjects examined in the same period in 2019. DUI subjects were examined by an integrated approach, descriptive analyses were conducted, and significance was determined by chi-square and Mann-Whitney tests. Variables linked to the pandemic outbreak and resulting lockdown were investigated as predictive factors in determining unfitness to drive., Results: Cases (281) were significantly different from controls (261) concerning the judgment of unfitness to drive (p<.001) and had more subjects with chronic excessive alcohol use and/or illicit substance use. The two groups were rather homogeneous concerning the other variables, except for a difference in blood alcohol concentration (BAC) at the time of DUI (p = .027). No statistical association was found between the investigated variables linked to the lockdown and the judgment of unfitness to drive., Conclusions: Chronic excessive alcohol consumption and illicit substance use were more frequently observed in cases, which suggests a possible correlation between the pandemic/lockdown restrictions and an increase in psychoactive substance misuse. While these potentially correlative factors are discussed in this article, they require further study. If confirmed, the results should be considered in forensic and clinical settings.

Introduction: Sentinel lymph node detection is a surgical procedure that allow to avoid systematic lymphadenectomy in those tumors in early stage where lymph node spread is not sure. If the sentinel lymph node is not involved by tumor in 98-99% of case other lymph nodes are clean. The reason why less radical surgery is chosen is linked to the lower postoperative morbidity rate, the risk of lower limb lymphedema decreases. The aim of this review was to summarize what is the state of art of using the sentinel lymph node dissection (SLD) technique and what are the future goals to improve the safety and the reliability., Evidence Acquisition: We have conducted a review of the literature of the past 10 years to understand the attitudes of oncologist gynecologists in the world to the conservative treatment of cervical cancer. We only selected articles from 2010 onwards, which meet the inclusion criteria., Evidence Synthesis: The detection rate varies from 83% to 100%. The bilateral detection rate, on the other hand, varies from 42% to 100%. The false negative rate ranges from 4% to 12%. Sensitivity varies from 20.7% (considering the frozen section) to 100%., Conclusions: Indocyanine green is the most reliable and performing tracer for the search of the sentinel lymph node; that the false intraoperative negative rate is too high to be sure not to subject the patient to an incorrect therapeutic procedure; data concerning the safety and survival of conservative lymphadenectomy (SLND) compared to systematic lymphadenectomy are still lacking in the literature and therefore we are awaiting the results of the two ongoing randomized clinical trials that will allow us to have more significant scientific data.

Background and Aim: Infertility affects ~20% of the couples in the world. Assisted reproductive technologies (ARTs) are currently the most common treatment option for infertility. Nevertheless, ARTs may be associated with complications for mothers and/or offspring. Natural procreative technology (NaProTechnology) is a natural treatment which minimizes these risks by seeking to identify the causes of infertility to enable better treatments. This narrative review summarizes the complications related to ARTs and clarifies how the NaProTechnology approach can help ARTs to achieve better results or be used in alternative to ARTs., Methods: Data in the literature indicate that NaProTechnology is a natural approach for treating infertility., Results: The percentage of live births obtained by NaProTechnology is similar to that of ARTs., Conclusions: An extensive search for the genetic defects causing infertility or subfertility through genetic testing can help both ARTs and NaProTechnology to achieve successful pregnancies. By discovering the underlying causes of infertility, genetic tests enable better family counseling, like the implications of transmitting risk- and disease-alleles to future generations.

Background: Fetal abnormalities cause 20% of perinatal deaths. Advances in prenatal genetic and other types of screening offer great opportunities for identifying high risk pregnancies., Methods: Through a literature search, here we summarise what are the prenatal diagnostic technique that are being used and how those techniques may allow for prenatal interventions., Results: Next generation sequencing and non-invasive prenatal testing are fundamental for clinical diagnostics because of their sensitivity and accuracy in identifying point mutations, aneuploidies, and microdeletions, respectively. Timely identification of genetic disorders and other fetal abnormalities enables early intervention, such as in-utero gene therapy, fetal drug therapy and prenatal surgery., Conclusion: Prenatal intervention is mainly focused on conditions that may cause death or lifelong disabilities, like spina bifida, congenital diaphragm hernia and sacrococcygeal teratoma; and may be an alternative therapeutic option to termination of pregnancy. However, it is not yet widely available, due to lack of specialized centers.