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Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.

Immunotherapy is now widely established as a potent and effective treatment option across several types of cancer. However, there is increasing recognition that not all patients respond to immunotherapy, focusing attention on the immune contexture of the tumor microenvironment (TME), drivers of the immune response and mechanisms of tumor resistance to immunity. The development of novel immunotherapeutics and their use in combination with checkpoint inhibitors and other standard of care and novel treatment modalities is an area of particular attention across several tumor types, including melanoma, lung, ovarian, breast, pancreatic, renal, head and neck, brain and non-melanoma skin cancers. The 4th Immunotherapy Bridge meeting (28-29 November, 2018, Naples, Italy) focused on a wide range of evolving topics and trends in the field of cancer immunotherapy and key presentations from this meeting are summarised in this report.

Sarah Hudson Scholle,1 Tam T Nguyen-Louie,1 Lauren Bifulco,2 Jacquelyn W Blaz,1 Mary L Blankson,2 Veena Channamsetty,2 Daren R Anderson2 1National Committee for Quality Assurance, Washington, DC, USA; 2Weitzman Institute, Community Health Center, Inc., Middletown, CT, USACorrespondence: Sarah Hudson Scholle, National Committee for Quality Assurance (NCQA), 1100 13th St. NW, Third Floor, Washington, DC, 20005, USA, Tel +1-202-955-1726, Fax +1-202-955-3500, Email scholle@ncqa.orgPurpose: To determine if pain screening and functional assessment results are associated with new diagnoses and treatment for pain in primary care.Patients and Methods: Observational study at 13 primary care sites of a statewide federally qualified health center that implemented routine screening and functional assessment for all adults in primary care. The study group included 10,091 adults aged 18+ who had an in-person visit between July 2, 2018, and June 1, 2019, where they screened positive for chronic pain and completed a 3-question functional assessment with the PEG (Pain, Enjoyment of Life, General Activity). Multivariate logistic regressions quantified associations between pain frequency, diagnosis and treatment, sociodemographics, comorbidities, and self-reported severe pain impairment with pain diagnoses and treatment documented after screening.Results: Patients were mostly women (60.3%), Latinx (41.1%), English-speaking (80.1%), and Medicaid-insured (62.0%); they averaged 49.1 years old (SD = 13.7 years). Patients with severe pain impairment or who were Latinx were more likely to get a newly documented pain diagnosis (absolute risk difference [ARD]: 13.2% and 8.6%, ps < 0.0001), while patients with mental health/substance use or medical comorbidities were less likely (ARDs: − 20.0% to − 6.2%, ps < 0.001). Factors most consistently associated with treatment were prior treatment of the same modality (4 of 7 treatments, ARDs = 27.3% to 44.1%, ps < 0.0001), new pain diagnosis (5 of 7, ARDs = 3.2% to 27.4%, ps < 0.001), and severe impairment (4 of 7, ARDs = 2.6% to 6.5%, ps < 0.0001). A new diagnosis had the strongest association with non-opioid pain analgesics and physical medicine (ARD = 27.0% and 27.4%, p < 0.0001). Latinx patients were less likely to receive opioid analgesics and mental health/substance use medications and counseling (ARDs = − 3.3% to 7.5%, ps < 0.0001).Conclusion: Screening and assessment with patient-reported tools may influence pain care. Care for Latinx patients differed from non-Latinx white patients.Keywords: PEG, chronic pain, primary care, patient-reported outcome measures, federally qualified health center, equity

Adhesion formation following gynecological surgery remains a challenge. The adoption of minimally invasive surgical approaches, such as conventional or robotic-assisted laparoscopy combined with meticulous microsurgical principles and the application of adhesion–reducing substances, is able to reduce the risk of de novo adhesion formation but do not eliminate it entirely. Myomectomy is the most adhesiogenic surgical procedure and postoperative adhesions can have a significant impact on the ability to conceive. Therefore, when surgery is performed as infertility treatment, attention should be paid to whether the benefits outweigh the risks. Among several factors, the size and the location of fibroids are the most accountable factors in terms of adhesion development and post surgical infertility; therefore, the search for effective strategies against adhesion formation in this setting is of paramount importance. The purpose of this review is to evaluate the incidence and factors of adhesion formation and the best preventive measures current available.

Aim: Educational practitioners are increasingly aware of trauma experiences in students as a factor in child disturbance and schooling problems. This discussion paper aims to clarify definitions of trauma and differentiate them from other adverse childhood experiences (ACE), describe trauma impact in terms of clinical outcomes (PTSD, emotional and behavioural disorder) and how attachment factors mediate risk and discuss the challenges and ethics of identifying and enquiring about trauma experience in a school setting. Rationale: Schools are increasingly required to be 'trauma sensitive' and to intervene where possible, with government requirements of improving mental health in schools. However, this poses a real challenge for educationalists given the barriers due to ethics, stigma/secrecy, referral implications and measurement availability for whole school approaches. Universal screening may provide a framework that helps schools recognise, measure and treat trauma. Findings: A conceptual model clarifying trauma exposure, trauma impact and mediating factors is identified to aid understanding for teachers. Use of technological screening methods for whole school monitoring of trauma impacts, including mediating risks, are outlined. Limitations: A full literature review of trauma or school-based interventions is not provided. Nor are biological impacts of trauma at different developmental stages described. Conclusion: Teachers would benefit from having a psychological understanding of trauma models and their component parts in order to identify what lies within the remit of schools for identification and intervention.

Background: Childhood familial trauma is a major contributor to psychological disorder. One of its key impacts is insecure attachment style, which impedes the development of close relationships. Trauma-related vulnerability is important to assess in primary school but there is a gap in age-appropriate measurement tools. This paper outlines the development of the Child Attachment Style Interview (Child-ASI) suitable for 6 to 11-year olds. This can be utilised on-site to identify damaging effects of trauma experience at an early stage. Method: The Child-ASI was developed from an existing adolescent/adult measure and tested on a sample of children in primary school (N=42) together with a subsample of those in care (N=20). A checklist of life events and the Mood and Feeling Questionnaire (MFQ) for depression was also administered. Results: Acceptable inter-rater reliability was found ([kappa]=0.84 for overall attachment style). A factor analysis of subscales produced the expected five factors for classification. Rates of insecure styles (38 per cent in school and 90 per cent in care) were consistent with other studies and related to separation from parent and depression. Logistic regression showed insecure attachment style and negative life events provided the best model for depression. Conclusion: Preliminary findings indicate the Child-ASI provides an effective way of assessing attachment style in children. Its use is for more intensive investigation of trauma-related interpersonal problems, administered by trained teachers. It is less intrusive than direct trauma assessments and fits with the policy need to identify vulnerability for mental health issues in schools.

Abstract The aim of this study is to characterise the transient mechanical response and the neuromuscular activation of lower limb muscles in subjects undergoing Whole Body Vibration (WBV) at different frequencies while holding two static postures, with focus on muscles involved in shaping postural responses. Twenty-five participants underwent WBV at 15, 20, 25 and 30 Hz while in hack squat or on fore feet. Surface electromyography and soft tissue accelerations were collected from Gastrocnemius Lateralis (GL), Soleus (SOL) and Tibialis Anterior (TA) muscles. Estimated displacement at muscle bellies revealed a pattern never highlighted before that differed across frequencies and postures (p

Abstract Targeting necroptosis is considered a promising therapeutic strategy in cancer, including Glioblastoma Multiforme (GBM), one of the most lethal brain tumors. Necroptosis is a mechanism of programmed cell death overcoming the apoptosis resistance mechanism underlying GBM tumorigenesis and malignant progression. N6-isopentenyladenosine (iPA), adenosine modified with isoprenoid derivative, displays antitumor activity in different cancer models. In previous studies, we demonstrated that iPA interferes with EGFR signaling reducing glioma cell viability. Here, we show that iPA induces necroptosis in glioblastoma cell lines and in primary cells established from tumor explants, without affecting the viability of non-cancerous brain cell lines, (Normal Human Astrocyte). The activation of RIP1, RIP3, and MLKL and the upregulation of necrosome formation were increased upon iPA treatment while caspase-3, caspase-8, and PARP were not activated in GBM cells. Co-treatment with specific necroptosis inhibitor necrostatin-1 (Nec-1) or Necrosulfonamide (NSA) prevented cell death caused by iPA treatment while the general caspase inhibitor Z-VAD-fluoromethylketone (z-VAD-fmk) did not elicit any effect, suggesting that this molecule induces caspase-independent necroptosis. These results suggest that iPA treatment can be able to bypass the apoptosis resistance mechanism in glioblastoma thereby offering higher therapeutic efficacy.

Objective: To evaluate the impact of COVID-19 pandemic on termination of pregnancy. Methods: This was a retrospective study aimed to assess the impact of COVID-19 pandemic on termination of pregnancy in a single center in Italy. Consecutive data on pregnant women who requested induced termination of pregnancy (I-TOP) from February 2018 to December 2021 were included in a dedicated database. The data were divided into two groups according to the COVID-19 outbreak. Women who requested I-TOP from February 2018 to January 2020 were included into the group ‘before COVID-19 pandemic’. Women who requested I-TOP from February 2020 to January 2022 were included into the group ‘during COVID-19 pandemic’. Indications for I-TOP included elective abortion and therapeutic for fetal or maternal indication. Results: A total of 2578 women were included in the study. Of them, 1637 had I-TOP before COVID-19, and 941 had I-TOP during COVID-19. During the pandemic, the request for elective abortion decreased from 76.2% to 67.7% (p

Background and Objectives: Minimally invasive cardiac surgery is an established approach for the treatment of heart valve pathologies and is associated with excellent technical and early postoperative outcomes. Data from medium- and long-term longitudinal evaluation of patients who underwent mitral valve repair (MVr) through transaxillary approach (TAxA) are still lacking. The aim of this study is to investigate mid-term results in patients who underwent TAxA MVr. Materials and Methods: Prospectively collected data of patients who underwent first-time MVr for MV regurgitation between 2017 and 2022, were reviewed. A total of 308 patients received TAxA, while in 220 cases, traditional full sternotomy (FS) was performed. Concomitant aortic and coronary artery bypass grafting (CABG) procedures, infective endocarditis or urgent operations were excluded. A propensity match (PS) analysis was used to overcome preoperative differences between the populations. Follow-up data were retrieved from outpatients’ clinic, telephone calls and municipal administration records. Results: After PS-matching, two well-balanced cohorts of 171 patients were analysed. The overall 30-day mortality rate was 0.6% in both cohorts. No statistical difference in postoperative complications was reported. TAxA cohort experienced earlier postoperative extubation (p < 0.001) with a higher rate of extubation performed in the operating theatre (p < 0.001), shorter intensive care unit (ICU) stay (p < 0.001), and reduced hospitalization with 51% of patients discharged home (p < 0.001). Estimated survival at 5 years was 98.8% in TAxA vs. 93.6% in FS cohort (Log rank p = 0.15). The cumulative incidence of reoperation was 2.6% and 4.4% at 5 years, respectively, in TAxA and FS cohorts (Gray test p = 0.49). Conclusions: TAxA approach for MVr was associated with low rates of in-hospital mortality and major postoperative complications being furthermore associated with shorter mechanical ventilation time, shorter ICU stay and reduced hospitalization with a higher rate of patients able to be discharged home. At mid-term, TAxA was associated with excellent survival and low rate of MV reoperation.

Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation promotes the expression of antioxidant enzymes in response to rising oxidative stress, resulting in reactive oxygen species (ROS) detoxification and playing a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Moreover, the biological effects of Nrf2 pathway activation contribute to reducing apoptosis and enhancing cell survival. The activity of Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). Prompted by the recent results reporting the impact of xanthone metabolites on oxidative stress, cancer, and inflammation, the antioxidant properties of xanthones isolated from Garcinia mangostana (γ-mangostin, α-mangostin, 8-deoxygartanin, demethylcalabaxanthone, garcinone D) were assessed. In particular, the capability of these natural products to disrupt the interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2), triggering the activation of the Nrf2-mediated pathway, was evaluated using molecular docking experiments and in vitro tests. The modulation of some key Nrf2-related mediators like glutathione (GSH) and lactate dehydrogenase (LDH) to highlight a possible direct antioxidant effect was investigated. Among the tested compounds, demethylcalabaxanthone showed an indirect antioxidant effect, as corroborated by a Western blot assay, displaying a significant increase in the translocated protein upon its administration.

We estimate the effects of accountability-driven school closure in New York City on students who attended middle schools that were closed at the time of closure and students who would have likely attended a closed middle school had it remained open. We find that students who would have entered the closed school had it not closed attended schools that perform better on standardized exams and have higher value-added measures than did the closed schools. While we find that closure did not have any measurable effect on the average student in this group, we do find that high-performing students in this group attended higher-performing schools and experienced economically-meaningful and statistically-significant improvements in their 6th-, 7th-, and 8th-grade math test scores. We find that these benefits persisted for several cohorts after closure. We also find that closure adversely affected students, low-performing students in particular, who were attending schools that closed. For policymakers, our results highlight a key trade-off of closing a low-performing school: future cohorts of relatively high-performing students may benefit from closure while low-performing students in schools designated for closure are adversely affected.

In this paper we point out the topic and the rational of the symposium aiming on the one hand to connect preparedness to the uncertainty that characterizes society-environment relation, on the other hand to emphasise the need for sociology not only to denounce the governmental implications of preparedness but also to engage constructively with this category. We begin by recalling the framework changes that have characterized the social sciences’ understanding of disasters by showing how progressively the idea of disaster as a one-time event that disrupts a society from the outside has been complemented by an idea of disaster as a critical moment embedded in historically determined social structures. We will then discuss how the emergence of the preparedness paradigm fits within these developments and how sociological research can help to better understand what is at stake in the governing of (and by) preparedness. In this perspective we advance a reading of preparedness from the vantage point of knowledge. As a conclusion, we discuss how the understanding of preparedness as dependent on socio-ecological transformation raises specific challenges for territorial governance.

This is an introduction to the Symposium on “Preparedness in an Uncertain and Risky World”.

Introduction: Endometriosis is a very common disease that affects up to 10% of the female population. Although medical therapy represents the first-line treatment for endometriosis, it does not always manage to control symptoms. Laparoscopy represents the standard surgical treatment in endometriosis. Robotic-assisted laparoscopy is an innovative mini-invasive surgical technique. Its application in gynecological surgery and in endometriosis has increased in the last decade. Our purpose is to offer an overview of the role of robotic-assisted laparoscopy in the surgical treatment of endometriosis. Methods: We evaluated studies dealing with the new technique in surgery for endometriosis with a focus on robotic surgery. We performed a compressive literature research on PubMed and the Cochrane Library in December 2022. Expert opinion: Robotic-assisted surgery is a feasible and safe approach to endometriosis surgery and is superimposable to laparoscopy in terms of complication rate, blood loss, hospitalization, and long-term improvement of symptoms. The effect of robotic-assisted surgery on operative time is still contradictory and needs to be further investigated. Robotic-assisted laparoscopic surgery can provide particular benefit in the management of women with severe endometriosis secondary to its advantage in surgical precision and ergonomics. Indocyanine green fluorescence angiography could be useful to assist in the vascularization of ureters and bowel anastomosis, to prevent postoperative complication and leakage.

People of Hispanic or Latino ethnicity (Latinx people) experience pain diagnosis, treatment, and care disparities relative to non-Latinx Whites. Those whose preferred language is Spanish may experience additional disparities when receiving care in a language-discordant environment. In order to better understand medically underserved Spanish-speaking Latinx patients' pain care experience in primary care, we conducted semi-structured qualitative interviews with federally qualified health center staff members (n = 9) and Spanish-speaking adult Latinx patients with chronic pain (n = 12) to capture data on their perspectives. Interview data were mapped to the individual (microsystem), interpersonal (mesosystem), organizational (exosystem), and environmental (macrosystem) levels of Bronfenbrenner's Ecological Systems Theory and analyzed using thematic content analysis informed by the Framework Method. Findings suggest that Spanish-speaking patients and English-speaking care team members may interpret information about pain state and severity differently, may have misaligned expectations about care, treatment methodologies, and treatment goals, and may experience difficulty forming a mutual understanding during health care encounters due to cross-linguistic and cross-cultural miscommunication. Patients preferred to describe their pain in words rather than with numbers or standardized scales, and both patients and frontline care team members expressed frustration with medical interpretation services, which added time and complexity to visits. Patients and health center staff emphasized the diversity of experiences among Spanish-speaking Latinx people, and the need to account for both linguistic and cultural differences during care encounters. Both groups supported hiring more Spanish-speaking, Latinx healthcare personnel who better resemble the patient population, which has the potential to improve linguistic and cultural concordance and competence, with the aim of improving care outcomes and patient satisfaction. Further study is warranted to examine how linguistic and cultural communication barriers impact pain assessment and treatment in primary care, the extent to which patients feel understood by their care teams, and their confidence in their ability to understand and interpret treatment recommendations.

IntroductionSkin-reducing mastectomy has been applied to several surgical techniques in which subcutaneous mastectomy is associated with various types of skin reduction, with preservation of a lower dermal flap to reinforce the inferior lateral seat of an implant. The aim of the study is to present a case series of patients with pendulous/ptotic and/or large-sized breasts treated for breast cancer at the Breast Surgery Unit of Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy, with the superomedial pedicle skin-reducing mastectomy technique, two-stage reconstruction, and transaxillary video-assisted technique, when a postoperative radiotherapy was indicated. We verified its effectiveness by discussing its results, especially in patients who are candidates for postmastectomy radiotherapy.Materials and methodsA single-center retrospective study was performed between January 2020 and March 2021 on a prospectively filled database of conservative mastectomies. Of the 64 patients who underwent nipple/skin-sparing mastectomies in the mentioned period, 17 (mean age 46 years, range 30–62 years) were treated with superomedial pedicle skin-reducing mastectomy, with two-stage breast reconstruction through transaxillary video-assisted replacement expander with definitive prosthesis and contralateral symmetrization, selected for postmastectomy radiotherapy.ResultsWe had only three minor complications. No flap necrosis, no infections, no breast seromas, and no reconstructive failures were observed. During follow-up of the patients treated with video-assisted reconstruction, there were no cases of infection, hematoma, implant rupture, or suture dehiscence in the reconstructed breast.DiscussionSkin-reducing mastectomy with superomedial pedicle is a safe and reliable procedure to treat breast cancer in selected patients, i.e., those with pendulous/ptotic and or large-sized breasts. Particularly, in patients who undergo postmastectomy radiotherapy, the two-stage reconstruction with video-assisted transaxillary endoscopic approach can find its main indication, using incisions positioned far from the mammary region, offering numerous advantages.

Abstract Background Men who have sex with men (MSM) are at increased risk for extra-genital sexually transmitted infections (STIs). Without extra-genital screening, many chlamydia and gonorrhea infections would be missed among MSM. Yet, many barriers exist to extra-genital testing, and, in particular, to rectal collection. Self-collection increases screening and detection of asymptomatic chlamydia and gonorrhea among at-risk MSM and transgender women. This feasibility study assessed use of rectal self-collection and its acceptance among patients and primary care providers (PCPs) at a large, general practice community health center. The primary objective of this project was to assess the feasibility of including rectal self-collection as part of an implementation study looking to embed an STI care program in a safety-net primary care setting that would shift routine screening tasks to non-provider clinical team members such as medical assistants and nurses. Methods Three PCPs identified and offered rectal self-collection to their MSM and transgender female patients who were due for routine or risk-based STI screening. For those patients who elected to participate in the study, the PCP’s medical assistant (MA) reviewed the self-collection instructions with them as part of their routine preventive care duties, and patients collected their own sample. Patients and PCPs completed brief cross-sectional surveys assessing the self-collection process. Results Of 1191 patients with sexual orientation and gender identity (SOGI) data on file who were seen for a medical visit by one of the three PCPs, 87 (7.3%) identified as MSM or transgender female. Seventy-five were due for rectal screening, of whom 33 (44%) were offered and completed rectal self-collection. Survey results indicated that self-collection was acceptable to and preferred over clinician-collection by both PCPs and patients. Conclusions This study demonstrated that rectal self-collection is feasible as part of STI screening in a high-volume primary care setting, and can be administered as part of the clinical tasks that MAs routinely conduct. The overall acceptance by both PCPs and patients will allow the inclusion of rectal self-collection in an implementation study looking to increase STI screening at a large community health center by facilitating MA-led collection during medical provider visits and by establishing standalone nurse-led STI visits.

This article focuses on financial education with the aim to explore the relationship between finance, welfare policies and the governance of uncertainties and risks also in the light of the Covid-19 pandemic. The article discusses the normative substratum that lies at the intersection of daily life and changes in the institutional and regulatory structures of welfare policies. In doing so, it shows how financial education turns protection from critical events, including pandemics, into a financial skills issue that vulnerable individuals and families must address through individual and financialised coping strategies, without broader social factors and contexts of vulnerability being taken into account and addressed. Finally, it points out that the pandemic situation does not seem to be a factor of discontinuity in this respect. Rather, the pandemic emergency appears to be used to support the further development of long-term trends, particularly processes of depoliticization and individualisation.

Tumor mutational burden (TMB), a surrogate for tumor neoepitope burden, is used as a pan-tumor biomarker to identify patients who may benefit from anti-program cell death 1 (PD1) immunotherapy, but it is an imperfect biomarker. Multiple additional genomic characteristics are associated with anti-PD1 responses, but the combined predictive value of these features and the added informativeness of each respective feature remains unknown. We evaluated whether machine learning (ML) approaches using proposed determinants of anti-PD1 response derived from whole exome sequencing (WES) could improve prediction of anti-PD1 responders over TMB alone. Random forest classifiers were trained on publicly available anti-PD1 data (n = 104), and subsequently tested on an independent anti-PD1 cohort (n = 69). Both the training and test datasets included a range of cancer types such as non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, and smaller numbers of patients from other tumor types. Features used include summaries such as TMB and number of frameshift mutations, as well as more gene-level features such as counts of mutations associated with immune checkpoint response and resistance. Both ML algorithms demonstrated area under the receiver-operator curves (AUC) that exceeded TMB alone (AUC 0.63 “human-guided,” 0.64 “cluster,” and 0.58 TMB alone). Mutations within oncogenes disproportionately modulate anti-PD1 responses relative to their overall contribution to tumor neoepitope burden. The use of a ML algorithm evaluating multiple proposed genomic determinants of anti-PD1 responses modestly improves performance over TMB alone, highlighting the need to integrate other biomarkers to further improve model performance.

BackgroundObesity is a risk factor for atrial fibrillation (AF) and strongly influences the response to treatment. Atrial fibrosis shows similar associations. Epicardial adipose tissue (EAT) may be a link between these associations. We sought to assess whether EAT is associated with body mass index (BMI), left atrial (LA) fibrosis and volume.MethodsLA fibrosis and EAT were assessed using late gadolinium enhancement, and Dixon MRI sequences, respectively. We derived 3D models incorporating fibrosis and EAT, then measured the distance of fibrotic and non-fibrotic areas to the nearest EAT to assess spatial colocalization.ResultsOne hundred and three AF patients (64% paroxysmal, 27% female) were analyzed. LA volume index was 54.9 (41.2, 69.7) mL/m2, LA EAT index was 17.4 (12.7, 22.9) mL/m2, and LA fibrosis was 17.1 (12.4, 23.1)%. LA EAT was significantly correlated with BMI (R = 0.557, p < 0.001); as well as with LA volume and LA fibrosis after BSA adjustment (R = 0.579 and R = 0.432, respectively, p < 0.001 for both). Multivariable analysis showed LA EAT to be independently associated with LA volume and fibrosis. 3D registration of fat and fibrosis around the LA showed no clear spatial overlap between EAT and fibrotic LA regions.ConclusionLA EAT is associated with obesity (BMI) as well as LA volume and fibrosis. Regions of LA EAT did not colocalize with fibrotic areas, suggesting a systemic or paracrine mechanism rather than EAT infiltration of fibrotic areas.

Objective: In this article, we report a severe case of placenta percreta in order to present our surgical approach for bladder dissection in a pregnancy with placenta accreta spectrum (PAS). Case(s): Bladder dissection was performed using bipolar forceps and bipolar scissors and with a meticulous lateral-to-medial dissection on each side. Conclusion: We recommend electrodissection of the bladder using bipolar forceps. Bipolar device may indeed help in the hemostasis of the placenta vessels while performing the bladder dissection.

Cardio-mechanical monitoring techniques, such as Seismocardiography (SCG) and Gyrocardiography (GCG), have received an ever-growing interest in recent years as potential alternatives to Electrocardiography (ECG) for heart rate monitoring. Wearable SCG and GCG devices based on lightweight accelerometers and gyroscopes are particularly appealing for continuous, long-term monitoring of heart rate and its variability (HRV). Heartbeat detection in cardio-mechanical signals is usually performed with the support of a concurrent ECG lead, which, however, limits their applicability in standalone cardio-mechanical monitoring applications. The complex and variable morphology of SCG and GCG signals makes the ECG-free heartbeat detection task quite challenging; therefore, only a few methods have been proposed. Very recently, a template matching method based on normalized cross-correlation (NCC) has been demonstrated to provide very accurate detection of heartbeats and estimation of inter-beat intervals in SCG and GCG signals of pathological subjects. In this study, the accuracy of HRV indices obtained with this template matching method is evaluated by comparison with ECG. Tests were performed on two public datasets of SCG and GCG signals from healthy and pathological subjects. Linear regression, correlation, and Bland-Altman analyses were carried out to evaluate the agreement of 24 HRV indices obtained from SCG and GCG signals with those obtained from ECG signals, simultaneously acquired from the same subjects. The results of this study show that the NCC-based template matching method allowed estimating HRV indices from SCG and GCG signals of healthy subjects with acceptable accuracy. On healthy subjects, the relative errors on time-domain indices ranged from 0.25% to 15%, on frequency-domain indices ranged from 10% to 20%, and on non-linear indices were within 8%. The estimates obtained on signals from pathological subjects were affected by larger errors. Overall, GCG provided slightly better performances as compared to SCG, both on healthy and pathological subjects. These findings provide, for the first time, clear evidence that monitoring HRV via SCG and GCG sensors without concurrent ECG is feasible with the NCC-based template matching method for heartbeat detection.

We examine the identity of British Poles born in the UK, whose parents arrived as allied servicemen and their families, seeking asylum following WW2. The two authors are from this community, and here examine their British-Polish identity along with other second-generation Poles in the UK. These individuals grew up in distinct communities exposed to the Polish language and culture but with restricted contact with communist Poland. The themes of response to parents’ trauma experience, Polish identity in childhood and in midlife, Polish language, and visiting family in Poland were explored. Many described parents as secretive about the horrors of war but keen to retain and propagate their Polish identity. Some felt they were not fully Polish, but their identity increased with access to modern Poland as adults. The Polish language was important to identity but linked to feeling inadequacy when not fluent. Visiting family in Poland enhanced identity, was valued, and provided information on family history. European identity was adopted by some to cover both their British and Polish identity. Genealogy and family history are popular and linked to community, and British Poles have a distinct contribution and a voice in showing how identity can emerge out of family trauma.

Canine mammary tumours (CMTs) are the most common cancer in intact female dogs. In addition to surgery, additional targeted and non-targeted therapies may offer survival benefits to these patients. Therefore, exploring new treatments for CMT is a promising area in veterinary oncology. CMT cells have an altered lipid metabolism and use the oxidation of fatty acids for their energy needs. Here we investigated the tumoricidal effects of teglicar, a reversible inhibitor of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme for fatty acid import into mitochondria, on two CMT cells, P114 and CMT-U229. Viability and apoptosis were examined in CMT cells using the crystal violet assay, trypan blue assay, and flow cytometry analysis. The expression of mediators of apoptosis signalling (e.g., caspase-9, caspase-8, and caspase-3) was assessed by quantitative real-time polymerase chain reaction and western blot analyses. Teglicar was able to decrease cell viability and induce apoptosis in P114 and CMT-U229 cells. At the molecular level, the effect of teglicar was associated with an upregulation of the mRNA expression levels of caspase-9, caspase-8, and caspase-3 and an increase in their protein levels. In summary, our results show that teglicar has a potential effect against CMTs through the induction of apoptotic cell death, making it a promising therapeutic agent against CMTs.

A heartbeat generates tiny mechanical vibrations, mainly due to the opening and closing of heart valves. These vibrations can be recorded by accelerometers and gyroscopes applied on a subject’s chest. In particular, the local 3D linear accelerations and 3D angular velocities of the chest wall are referred to as seismocardiograms (SCG) and gyrocardiograms (GCG), respectively. These signals usually exhibit a low signal-to-noise ratio, as well as non-negligible amplitude and morphological changes due to changes in posture and the sensors’ location, respiratory activity, as well as other sources of intra-subject and inter-subject variability. These factors make heartbeat detection a complex task; therefore, a reference electrocardiogram (ECG) lead is usually acquired in SCG and GCG studies to ensure correct localization of heartbeats. Recently, a template matching technique based on cross correlation has proven to be particularly effective in recognizing individual heartbeats in SCG signals. This study aims to verify the performance of this technique when applied on GCG signals. Tests were conducted on a public database consisting of SCG, GCG, and ECG signals recorded synchronously on 100 patients with valvular heart diseases. The results show that the template matching technique identified heartbeats in GCG signals with a sensitivity and positive predictive value (PPV) of 87% and 92%, respectively. Regression, correlation, and Bland–Altman analyses carried out on inter-beat intervals obtained from GCG and ECG (assumed as reference) reported a slope of 0.995, an intercept of 4.06 ms (R2 > 0.99), a Pearson’s correlation coefficient of 0.9993, and limits of agreement of about ±13 ms with a negligible bias. A comparison with the results of a previous study obtained on SCG signals from the same database revealed that GCG enabled effective cardiac monitoring in significantly more patients than SCG (95 vs. 77). This result suggests that GCG could ensure more robust and reliable cardiac monitoring in patients with heart diseases with respect to SCG.

Introduction To evaluate the feasibility and safety of robotic hysterectomy in the “transgender male/non-conforming” population and the short and long-term surgical outcomes of robotic surgery in these patients. Materials and methods A retrospective analysis was carried out from February 2016 to January 2018. Twenty female transgender patients with a previous psychiatric diagnosis of gender dysphoria who did not present genital pathologies were included in the study. The robotic hysterectomies were performed from June 2016 to March 2018 using a Da Vinci Xi Robot (Intuitive Surgical, Sunnyvale, CA, USA). Results No intraoperative or postoperative complications were recorded. The median duration of the intervention was of 90 minutes, including docking which lasted 16 minutes, while the median stay in the operating room was of 140 minutes. The median time of duration of intervention was of 90 minutes. The median blood loss was about 90 ml with a percentage decrease in hemoglobin between pre- and post-operative of about 8%. Postoperative pain was assessed using the VAS scale in the immediate postoperative period, on the first and second day, resulting of 3 and 2, respectively. The pathological examination of surgical specimens confirmed the absence of malignancy. Conclusions The robotic approach represents a feasible, safe, and effective surgical option for hysterectomy for “transgender male” affected by gender dysphoria.

Borderline ovarian tumors (BOTs) account for approximately 15% of all epithelial ovarian cancers. In 80% of cases the diagnosis of BOTs is done at stage I and more than a third of BOTs occurs in women younger than 40 years of age wishing to preserve their childbearing potential; the issue of conservative surgical management (fertility-sparing treatment) is thus becoming of paramount importance. At early stages, the modalities of conservative treatment could range from mono-lateral cystectomy to bilateral salpingo-oophorectomy. Although cystectomy is the preferred method to promote fertility it can lead to an elevated risk of recurrence; therefore, an appropriate counseling about the risk of relapse is mandatory before opting for this treatment. Nevertheless, relapses are often benign and can be treated by repeated conservative surgery. Besides the stage of the disease, histological subtype is another essential factor when considering the proper procedure: as most mucinous BOTs (mBOTs) are more commonly unilateral, the risk of an invasive recurrence seems to be higher, compared to serous histotype, therefore unilateral salpingo-oophorectomy is recommended. In the appraisal of current literature, this review aims to gain better insight on the current recommendations to identify the right balance between an accurate staging and an optimal fertility outcome.

Here we report the application of a multi-disciplinary protocol for investigating thiazolidin-4-one-based compounds as new promising anti-inflammatory agents interfering with the eicosanoid biosynthesis pathways. The workflow foresaw the generation of a focused virtual library of ∼4.2 ​× ​104 molecules featuring the thiazolidin-4-one core based on the related one-pot synthetical combinatorial route. The built library was initially screened in silico against the microsomal prostaglandin E2 synthase-1 (mPGES-1) enzyme and, afterwards, 23 selected chemical items were synthesized for the subsequent biological screening, applying the one-pot multicomponent synthetic strategy. Preliminary results highlighted the moderate ability of several tested thiazolidin-4-one-based compounds in inhibiting mPGES-1. On the other hand, further computational repurposing investigations were performed on a set of synthesized compounds, highlighting the promising binding of a several items against the soluble epoxide hydrolase (sEH) enzyme, whose inhibition leads to an increase of epoxyeicosatrienoic acids (EETs) that are anti-inflammatory mediators. Three molecules (3, 9 and 21) were able to inhibit sEH featuring IC50 values in the low micromolar range. In order to further profile their anti-inflammatory properties, additional investigations of the three identified hits highlighted their ability to inhibit 5-lipoxygenase (5-LO) and thus to interfere with leukotriene biosynthesis in neutrophils, devoid of activity against cyclooxygenases (COXs) and cytotoxic effects on human monocytes. Our results, obtained by applying a multidisciplinary approach, highlight the thiazolidin-4-one-core as a valuable template for developing novel anti-inflammatory compounds able to synergistically inhibit different targets involved in the arachidonic acid cascade.

IntroductionLynch Syndrome (LS) represents the hereditary condition that is most frequently associated with endometrial cancer (EC). The aim of this study is to assess the presence of Lynch Syndrome (LS) in young women with mismatch repair (MMR)-deficient atypical endometrial hyperplasia (AEH) and non-myoinvasive FIGO G1 endometrioid EC and its possible impact on the outcome of conservative treatment.MethodsSix MMR-deficient cases identified from a previous cohort of 69 conservatively treated patients were selected to be screened for germline mutations in MMR genes. In each patient, the outcomes of conservative treatment for AEH and EEC, including response, relapse, progression, and pregnancy, were assessed.ResultsFive out of 6 patients underwent genetic test for LS. Three out of these 5 patients showed a positive genetic test. Patient 1 showed the c.942 + 2 T>A heterozygous variant of MSH2 mutation; after 12 months of complete response, she had relapse and progression of disease. Patient 4 showed the c.2459-1G>C variant of MSH2 mutation; after complete response, she failed to achieve pregnancy; she had relapse after 24 months and underwent hysterectomy. Patient 6 showed the c.803 + 1 heterozygous variant of PMS2 mutation; she had relapse of disease after 18 months from the first complete response and then underwent hysterectomy.ConclusionsIn this series, 3 out of 6 women with MMR-deficiency had LS. None of the patients achieved pregnancy, and those who responded to treatment had subsequent relapse of disease. Patients undergoing fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer should perform MMR immunohistochemical analysis in order to screen LS.

Abstract Improved understanding of tumor immunology has enabled the development of therapies that harness the immune system and prevent immune escape. Numerous clinical trials and real-world experience has provided evidence of the potential for long-term survival with immunotherapy in various types of malignancy. Recurring observations with immuno-oncology agents include their potential for clinical application across a broad patient population with different tumor types, conventional and unconventional response patterns, durable responses, and immune-related adverse events. Despite the substantial achievements to date, a significant proportion of patients still fail to benefit from current immunotherapy options, and ongoing research is focused on transforming non-responders to responders through the development of novel treatments, new strategies to combination therapy, adjuvant and neoadjuvant approaches, and the identification of biomarkers of response. These topics were the focus of the virtual Immunotherapy Bridge (December 2nd–3rd, 2020), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer and are summarised in this report.

Trauma experience is understood through its expression in language, with implications for psycholinguistic and clinical research and analysis. Clinical research approaches often approach childhood trauma through investigative, semi-structured, retrospective interviews (e.g. Childhood Experience of Care and Abuse, CECA). This facilitates the narration of abuse history for systematic analysis in relation to clinical disorder. Interview techniques assist such history-telling, for example by ‘scaffolding’ the account, aiding memory through chronological questioning, using a factual focus and using probing questions to collect detail and resolve inconsistencies. However, some personal narratives are fragmented, incomplete, contradictory or highly emotional/dissociated from emotion. This can be explained by trauma impacts such as being emotionally frozen (forgetting and avoidance) or overwhelmed (emotional over-remembering) and is termed ‘unresolved trauma’ with links to attachment vulnerability. These narratives can make investigative interview research more challenging but can offer opportunities for secondary psycholinguistic analysis. Illustrative interview quotes from CECA childhood physical and sexual abuse narratives of three women are provided with comment on style of reporting. The women had recurrent trauma experience and later life depression and anxiety. The interview responses are examined in terms of seven characteristics taken from available literature (e.g. incoherent, contradictory, lack recall, time lapses, emotionality, blame and vividness). The concept of unresolved loss is discussed and whether the linguistic characteristics are specific to a trauma or to an individual. Factual investigative interviews and psycholinguistic analysis of narrative may find ways of combining for greater depth of understanding of unresolved trauma, to extend available methods and aid therapy.

Low steady‐state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor‐positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z‐endoxifen and Z‐4‐hydroxy‐tamoxifen (Z‐4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n = 191) we confirmed an inferior BC ‐specific survival in patients with the previously described serum concentration threshold of Z‐4OHtam ≤ 3.26 nm (HR = 2.37, 95% CI = 1.02–5.48, P = 0.039). The ‘dose–response’ survival trend in patients categorized to ordinal concentration cut‐points of Z‐4OHtamoxifen (≤ 3.26, 3.27–8.13, > 8.13 nm) was also replicated (P‐trend log‐rank = 0.048). Z‐endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5‐year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.

Abstract Background Low-dose X-ray images have become increasingly popular in the last decades, due to the need to guarantee the lowest reasonable patient’s exposure. Dose reduction causes a substantial increase of quantum noise, which needs to be suitably suppressed. In particular, real-time denoising is required to support common interventional fluoroscopy procedures. The knowledge of noise statistics provides precious information that helps to improve denoising performances, thus making noise estimation a crucial task for effective denoising strategies. Noise statistics depend on different factors, but are mainly influenced by the X-ray tube settings, which may vary even within the same procedure. This complicates real-time denoising, because noise estimation should be repeated after any changes in tube settings, which would be hardly feasible in practice. This work investigates the feasibility of an a priori characterization of noise for a single fluoroscopic device, which would obviate the need for inferring noise statics prior to each new images acquisition. The noise estimation algorithm used in this study was tested in silico to assess its accuracy and reliability. Then, real sequences were acquired by imaging two different X-ray phantoms via a commercial fluoroscopic device at various X-ray tube settings. Finally, noise estimation was performed to assess the matching of noise statistics inferred from two different sequences, acquired independently in the same operating conditions. Results The noise estimation algorithm proved capable of retrieving noise statistics, regardless of the particular imaged scene, also achieving good results even by using only 10 frames (mean percentage error lower than 2%). The tests performed on the real fluoroscopic sequences confirmed that the estimated noise statistics are independent of the particular informational content of the scene from which they have been inferred, as they turned out to be consistent in sequences of the two different phantoms acquired independently with the same X-ray tube settings. Conclusions The encouraging results suggest that an a priori characterization of noise for a single fluoroscopic device is feasible and could improve the actual implementation of real-time denoising strategies that take advantage of noise statistics to improve the trade-off between noise reduction and details preservation.

A growing number of cities and states have been providing large tuition subsidies for residents through initiatives often called "place-based" or "Promise" scholarship programs. We examine the effects of a prominent last-dollar, place-based scholarship program, Say Yes to Education in Buffalo, NY, on college matriculation and persistence. Employing a difference-in-differences strategy comparing changes across cohorts of students eligible and ineligible for large college scholarships, we find that scholarship eligibility is associated with an increase of 20 percent in the likelihood of matriculating into college within one year of graduation, and an increase in the likelihood of persistence into a second year of college of nearly 16 percent. Increases in matriculation are largely at four-year institutions, where most of the additional funding from Say Yes is concentrated, exclusively at in-state institutions, both public and private, and are largest at colleges with more selective admission rates. Finally, we see the largest increases in matriculation and persistence among students who attend high schools in the middle third of the poverty distribution. These results suggest that the additional aid provided by Say Yes plays an important role in increasing college matriculation and encouraging students to attend more selective schools.