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This study explored whether symptom relief differs by sex in patients with cancer receiving medical cannabis (MC) therapy.This is an analysis of data collected from patients with cancer enrolled in the Quebec Cannabis Registry. MC was initiated for the therapeutic management of cancer symptoms. Patients completed the revised Edmonton Symptom Assessment System (ESAS-r) questionnaire at baseline and 3-month follow-up. We examined the interaction between sex and time on each ESAS-r symptom and the interaction between time and tetrahydrocannabinol:cannabidiol (THC:CBD) ratios for each sex on total symptom burden.The analysis included 358 patients (M: 171). There were no sex differences in baseline ESAS-r scores. Three months of MC therapy led to significant improvements in pain (M: - 1.4 ± 0.3, p 0.001; F: - 1.1 ± 0.3, p 0.01), tiredness (M: - 1.7 ± 0.4, p 0.001; F: - 1.2 ± 0.4, p 0.05), anxiety (M: - 1.1 ± 0.4, p 0.05; F: - 1.2 ± 0.4, p 0.001), and well-being (M: - 1.2 ± 0.4, p 0.05; F: - 1.4 ± 0.4, p 0.01) in both sexes. Only F perceived improved drowsiness (- 1.1 ± 0.4, p 0.05), nausea (- 0.9 ± 0.3, p 0.05), lack of appetite (- 1.7 ± 0.4, p 0.001), and shortness of breath (- 0.9 ± 0.3, p 0.05). From baseline to 3-month follow-up, THC-dominant MC significantly reduced pain (- 1.52 ± 0.52, p 0.05) in M, whereas in F it diminished nausea (- 2.52 ± 0.70, p 0.01) and improved well-being (- 2.41 ± 0.79, p 0.05). THC:CBD-balanced products significantly reduced pain (- 1.48 ± 0.49, p 0.05), tiredness (- 1.82 ± 0.62, p 0.05), anxiety (- 1.83 ± 0.54, p 0.05), and improved well-being (- 2.01 ± 0.56, p 0.01) in M. CBD-dominant products did not offer significant symptom relief in either sex.The perceived relief of cancer symptoms from MC differs between sexes. More randomized controlled trials are needed to confirm our findings.

In this paper, we present an exploratory study on the potential impact of holographic heart models and mixed reality technology on medical training, and in particular in teaching complex Congenital Heart Diseases (CHD) to medical students. Fifty-nine medical students were randomly allocated into three groups. Each participant in each group received a 30-minute lecture on a CHD condition interpretation and transcatheter treatment with different instructional tools. The participants of the first group attended a lecture in which traditional slides were projected onto a flat screen (group “regular slideware”, RS). The second group was shown slides incorporating videos of holographic anatomical models (group “holographic videos”, HV). Finally, those in the third group wore immersive, head-mounted devices (HMD) to interact directly with holographic anatomical models (group “augmented reality”, AR). At the end of the lecture, the members of each group were asked to fill in a multiple-choice questionnaire aimed at evaluating their topic proficiency, as a proxy to evaluate the effectiveness of the training session (in terms of acquired notions); participants from group AR were also asked to fill in a questionnaire regarding the recommendability and usability of the MS Hololens HMDs, as a proxy of satisfaction regarding its use experience (UX). The findings show promising results for usability and user acceptance.

The detrimental effects of endometriosis on IVF success are well known, but the underlying mechanisms are still uncertain. The objective of this study was to investigate the possible detrimental effects of the disease on ovarian response and embryo development.IVF cycles performed in the authors' unit between 2014 and 2020 were retrospectively reviewed. Women with a good ovarian reserve who underwent their first IVF cycle were included. A total of 248 women with endometriosis were identified and matched to 248 women without the disease, according to age, type of stimulation, anti-Müllerian hormone concentration and study period. The primary outcome was the number of women without good-quality embryos. Secondary outcomes included the rate of unexpected poor response (retrieval of ≤3 oocytes), the cumulative clinical pregnancy rate and the cumulative live birth rate.The number of women without good-quality embryos did not differ between women with endometriosis (exposed group) and those without it (unexposed group). The adjusted odds ratio was 0.85 (95% CI 0.51-1.44, P = 0.56). The clinical pregnancy rate and the live birth rate were also similar. Conversely, the rate of unexpected poor response was higher among women with endometriosis (23% versus 13%, P = 0.005).Overall, endometriosis does not markedly affect folliculogenesis and embryo development in the context of IVF. Only an increased risk of unexpected poor response emerged.

Trata-se de um artigo teórico-crítico, que discorre bibliograficamente acerca das questões de gênero e sexualidade por meio de um levantamento realizado em sites das Instituições de Ensino Superior (IES) no Brasil. Considera-se importante para a temática indicar como as Instituições de Ensino Superior organizam-se para combater a desigualdade, demonstrando como constroem e articulam ações referentes às questões de gênero e sexualidade relacionadas às pessoas transgêneras. Apresentam-se três quadros com os núcleos de pesquisas em gênero e sexualidade de algumas instituições de educação superior brasileiras, analisam-se os quadros por meio de categorias, buscando articular essas questões com a área de educação. Em relação à temporalidade, o levantamento identifica os primeiros núcleos de pesquisa constituídos e formalizados na década de 1980. Para compor a discussão, apoia-se nas perspectivas teóricas de Lanz (2015), Louro (1997, 2000) e Scott (1995). Organiza-se o artigo tendo em vista a problematização sobre as desigualdades em relação às pessoas transgêneras, retratando as ações que as Instituições de Ensino Superior (IES) realizam para reduzi-las. Conclui-se que as instituições buscam agir nessas questões, e que há, com o passar dos anos, um crescimento e fortalecimento do debate nesses espaços.

Purpose of review In the current review, we will explore the molecular bases that have determined the design of clinical trials exploring the efficacy of antivascular agents in combination with chemotherapy, immune check point inhibitors and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with advanced nonsmall cell lung cancer. Recent findings Recent clinical trials have demonstrated the synergistic effect of antivascular agents with immune checkpoint inhibitors and EGFR-TKIs, despite no molecular marker has been identified yet to select patients. Summary Lung cancer remains one of the first causes of cancer-related death. However, thanks to the development of stratified molecular medicine and the introduction of immune checkpoint inhibitors, patients' survival has significantly improved. Due to the critical role of pro-angiogenic factors in cancer progression, antivascular agents targeting the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been developed. Their efficacy has been explored in combination with chemotherapy, and immune checkpoint inhibitors, with promising but not definitive conclusions about their impact on prolonging patients' survival.

Th1.17 characteristics of CD73+ CD4+ Teff based on the expression of CXCR3, CCR6, CRTH2, the migration in response to CXCL10 or CCL20 gradient and the MDR-1-specific Rhodamine 123 exclusion assay

The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4+ T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39+ Tregs selectively targeted CD73+ Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73+ Teffs to secrete IL17A. CD73+ Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73+ Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity.Significance: Polyfunctional CD73+ T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. Cancer Res; 78(13); 3604–18. ©2018 AACR.

Cumulative data of percentages of memory T CD4+ cells, Treg and CD73+CD4+ Teff and cytokine production profile of CD73neg and CD73+ Teff in HD-Blood, and blood and tumors from breast or ovarian patients.

Impact of CD39 or CD73 inhibitor (ARL67156, APCP) on ATP-mediated inhibition of CD73+ or CD73neg CD4+ Teff in the presence of Treg based on the proliferation markers profiles (Cell trace Violet or CFSE)

Sensitivity of CD73+ and CD73neg CD4+ Teff proliferation to AMP and impact of CD73 inhibitor (APCP) assessed by microscopy and flow cytometry analysis.

Impact of rh-ADA on Ado-mediated inhibition of CD73+ or CD73neg CD4+ Teff based on the proliferation marker profiles (Cell Trace Violet or CFSE)

Worldwide increase in life expectancy has boosted research on aging. Overcoming the concept of chronological age, higher attention has been addressed to biological age, which reflects a person’s real health state, and which may be the resulting combination of both intrinsic and environmental factors. As epigenetics may exert a pivotal role in the biological aging, epigenetic clocks were developed. They are based on mathematical models aimed at identifying DNA methylation patterns that can define the biological age and that can be adopted for different clinical scopes (i.e., estimation of the risks of developing age-related disorders or predicting lifespan). Recently, epigenetic clocks have gained a peculiar attention in the fertility research field, in particular in the female counterpart. The insight into the possible relations between epigenetic aging and women’s infertility might glean additional information about certain conditions that are still not completely understood. Moreover, they could disclose significant implications for health promotion programs in infertile women. Of relevance here is that the impact of biological age and epigenetics may not be limited to fertility status but could translate into pregnancy issues. Indeed, epigenetic alterations of the mother may transfer into the offspring, and pregnancy itself as well as related complications could contribute to epigenetic modifications in both the mother and newborn. However, even if the growing interest has culminated in the conspicuous production of studies on these topics, a global overview and the availability of validated instruments for diagnosis is still missing. The present narrative review aims to explore the possible bonds between epigenetic aging and fertility timeline. In the “infertility” section, we will discuss the advances on epigenetic clocks focusing on the different tissues examined (endometrium, peripheral blood, ovaries). In the “pregnancy” section, we will discuss the results obtained from placenta, umbilical cord and peripheral blood. The possible role of epigenetic aging on infertility mechanisms and pregnancy outcomes represents a question that may configure epigenetic clock as a bond between two apparently opposite worlds: infertility and pregnancy.

Research questionHow accurate is minimally invasive assessment of endometrial receptivity from uterine fluid extracellular vesicles (UF-EVs) using only 68 RNA biomarkers.Study designAssessment of endometrial receptivity by applying the beREADY computational model on transcriptomic data derived from UF-EVs during the pre-receptive (LH+2) and receptive phases (LH+7) of a natural cycle.ResultsbeREADY housekeeping gene transcript levels in UF-EV are not significantly different between LH+2 and LH+7 UF-EVs. Endometrial receptivity can be assessed from UF-EV transcriptomic data using beREADY computational model with specificity of 100% and sensitivity of 75%.ConclusionbeREADY computational model can be used on UF-EVs instead of endometrial tissue biopsy to assess endometrial receptivity. However, further development is needed to fine-tune the model to show that this model can also be used on UF-EV samples from women undergoing hormone-replacement therapy.

The purpose of this study was to determine the effect of obesity on patient outcome, procedure failure rate and osteoarthritis (OA) progression in the tibiofemoral compartments in a series of isolated patellofemoral arthroplasty (PFA) performed with a third-generation implant.The study population was patients who had undergone third-generation PFA at a specialized orthopedic center between 2007 and 2017. Patients were categorized by body-mass index (BMI) as obese (O, BMI 30 kg/mA total of 120 PFAs with a mean follow-up of 6.9 ± 2.5 years were included: 25 in the O group and 95 in the NO group. Significant improvement was noted in in knee range of motion (P 0.001), clinical and functional KSS (P 0.001), UCLA Activity Score (P 0.001), Tegner score (P 0.001) and VAS pain (P 0.001) without inter-groups differences. Worsening of the medial Kellgren-Lawrence (KL) grade (but not the lateral KL grade) was more frequent in the O than the NO group during the follow-up period (P = 0.014). Failure occurred in 4.2% of NO and in 20% of O group patients; the difference was solely due to failure because of OA progression in the tibiofemoral compartment (16% in the O group). There were no between group differences in the failure rate for any cause other than OA progression (4.2% in the NO group, 4.0% in the O group).An equal improvement in function after PFA was noted in both obese and nonobese patients; however, the high failure rate due to OA progression in the medial tibiofemoral compartment warrants caution when considering PFA in obese patients.

Although telemedicine use has been under discussion for decades, this topic has gained unprecedented importance during the COVID-19 pandemic. The Rheumatoid Arthritis Disease Activity Index (RADAI) is a user-friendly tool, fully self-administered, to assess rheumatoid arthritis (RA) disease activity. The aim of this study was to compare the performance of RADAI with other disease activity indices, functional status, and inflammatory markers in a large cohort of RA patients.We assessed the concurrent validity of RADAI against Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 Joints-C-reactive protein, Disease Activity Score in 28 Joints-erythrocyte sedimentation rate, Simplified Disease Activity Index, and physician assessment of disease activity and the correlation of RADAI with Health Assessment Questionnaire-Disability Index and inflammatory markers at the REAL Study baseline. We also evaluated the correlation of the change in RADAI and the change in CDAI over a 6-month follow-up.From the 1115 patients included in the REAL Study, 1113 had RADAI scores in the first assessment. At baseline, correlations between RADAI and other disease activity indices were strong, ranging from 0.64 (comparison with physician assessment) to 0.79 (comparison with CDAI). Correlation between the change in RADAI score over the 6 months of follow-up and the change in CDAI score over the same period was moderate/strong for the overall group and within the stratified analyses.The strong correlation of RADAI with other well-established tools for disease activity measurement reassures its use with RA patients' follow-up, especially in this new era of telemedicine.

The safety of minimally invasive procedures during COVID pandemic remains hotly debated, especially in a country, like Italy, where minimally invasive techniques have progressively and pervasively entered clinical practice, in both the hepatobiliary and pancreatic community. A nationwide snapshot of the management of HPB minimally invasive surgery activity during COVID-19 pandemic is provided: a survey was developed and conducted within AICEP (Italian Association of HepatoBilioPancreatic Surgeons) with the final aim of conveying the experience, knowledge, and opinions into a unitary report enabling more efficient crisis management. Results from the survey (81 respondents) show that, in Italian hospitals, minimally invasive surgery maintains its role despite the COVID-19 pandemic, with the registered reduction of cases being proportional to the overall reduction of the HPB surgical activity. Respondents agree that the switch from minimally invasive to open technique can be considered as a valid option for cases with a high technical complexity. Several issues merit specific attention: screening for virus positivity should be universally performed; only expert surgical teams should operate on positive patients and specific technical measures to lower the biological risk of contamination during surgery must be followed. Future studies specifically designed to establish the true risks in minimally invasive surgery are suggested. Furthermore, a standard and univocal process of prioritization of patients from Regional Healthcare Systems is advisable. Electronic supplementary material The online version of this article (10.1007/s13304-020-00815-5) contains supplementary material, which is available to authorized users.

The breeding blanket (BB) segments are by far the largest in-vessel components of DEMO. For their remote replacement through the upper vertical ports of the vacuum vessel (VV) recently a new concept has been developed. The concept minimizes the spread of contamination as all in-vessel operations are carried out from within a cask that is sealed to the VV and located within a sealed room providing a second confinement barrier inside the nuclear building. The removal of the BB segments from the VV is carried out by a BB transporter that is operated on the elevator system of the >20m higher cask. The limited available space makes the compact design solutions that have been developed critical to the overall concept. The BB transporter is designed according to nuclear design codes and for high payloads since the BB segments may weigh up to 180 tons. Due to the eccentric engagement points on the backside of the BB segments and due to seismic accelerations, that need to be considered, too, the BB transporter resists also to bending moments. It can carry out translational as well as tilting movements as required to disengage the BB segments from their supports and to remove them through the upper VV port. The main requirements regarding integration, BB manipulation and structural integrity have been verified. Next development steps need to include further design improvements, integration of in-vessel position survey, definition and control of motion actuations, supply cable routing, the development of rescue and recovery scenarios as well as the validation in relevant test facilities. This article describes the design of the BB lifting tools including several modifications following a set of analyses that were recently performed., peer-reviewed

BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Many patients with fibromyalgia (FM) report using cannabis as a strategy to improve pain. Given that pain often co-occurs with symptoms of anxiety and depression (i.e., negative affect) and sleep problems among patients with FM, improvements in these symptoms might indirectly contribute to reductions in pain intensity following cannabis use.The main objective of the study was to examine whether changes in pain intensity following initiation of medical cannabis among FM patients could be attributed to concurrent changes (i.e., reductions) in negative affect and sleep problems.This was a 12-month prospective cohort study among FM patients (n = 323) initiating medical cannabis under the care of physicians. Patients were assessed at baseline and follow-up assessment visits occurred every three months after initiation of medical cannabis. Patients' levels of pain intensity, negative affect, and sleep problems were assessed across all visits.Multilevel mediation analyses indicated that reductions in patients' levels of pain intensity were partly explained by concurrent reductions in sleep problems and negative affect (both p's.001). This remained significant even when accounting for patients' baseline characteristics or changes in medical cannabis directives over time (all p's.05).Our findings provide preliminary insights into the potential mechanisms of action underlying pain reductions among FM patients who are using medical cannabis. Given the high attrition rate (i.e., 75 %) observed in the present study at 12 months, our findings cannot be generalized to all FM patients who are using medical cannabis.

Mammalian conception involves a multitude of reciprocal interactions via a molecular dialogue between mother and conceptus. Extracellular vesicles (EVs) are secreted membrane-encapsulated particles that mediate cell-to-cell communication in various contexts. EVs, which are present in seminal, follicular, oviductal, and endometrial fluids, as well as in embryo secretions, carry molecular constituents that impact gamete maturation, fertilization, early embryo development, and embryo–maternal communication. The distribution, concentration, and molecular cargo of EVs are regulated by steroid hormones and the health status of the tissue of origin, and thus are influenced by menstrual phase, stage of conception, and the presence of infertility-associated diseases. EVs have been recognized as a novel source of biomarkers and potential reproductive medicine therapeutics, particularly for assisted reproductive technology (ART). There are still many technological and scientific hindrances to be overcome before EVs can be used in clinical diagnostic and therapeutic ART applications. Issues to be resolved include the lack of standardized measurement protocols and an absence of absolute EV quantification technologies. Additionally, clinically suitable and robust EV isolation methods have yet to be developed. In this review, we provide an overview of EV-mediated interactions during the early stages of reproduction from gamete maturation to embryo implantation and then outline the technological progress that must be made for EV applications to be translated to clinical settings.

ObjectivesTo evaluate the safety and effectiveness of medical cannabis (MC) in reducing pain and concurrent medications in patients with cancer.MethodsThis study analysed data collected from patients with cancer who were part of the Quebec Cannabis Registry. Brief Pain Inventory (BPI), revised Edmonton Symptom Assessment System (ESAS-r) questionnaires, total medication burden (TMB) and morphine equivalent daily dose (MEDD) recorded at 3-month, 6-month, 9-month and 12-month follow-ups were compared with baseline values. Adverse events were also documented at each follow-up visit.ResultsThis study included 358 patients with cancer. Thirteen out of 15 adverse events reported in 11 patients were not serious; 2 serious events (pneumonia and cardiovascular event) were considered unlikely related to MC. Statistically significant decreases were observed at 3-month, 6-month and 9-month follow-up for BPI worst pain (5.5±0.7 baseline, 3.6±0.7, 3.6±0.7, 3.6±0.8; pConclusionsReal-world data from this large, prospective, multicentre registry indicate that MC is a safe and effective complementary treatment for pain relief in patients with cancer. Our findings should be confirmed through randomised placebo-controlled trials.

Background: Intravascular lithotripsy (IVL) showed to be effective in dilating heavily calcified de novo coronary lesions but little is known about its performance in under-expanded stents management. Aim of this study was to assess the feasibility, effectiveness and safety of IVL for the treatment of stent underexpansion refractory to balloon dilatation. Methods: A multicentre, retrospective cohort analysis was performed in patients undergoing IVL to treat under-expanded stents following non-compliant balloon expansion failure. Primary endpoint was successful IVL dilatation defined as IVL balloon delivery and application at the target site followed by an increase of at least 1 mm2 in minimal stent cross-sectional area (MSA) on intracoronary imaging or an increase of at least 20% in minimal stent diameter (MSD) by quantitative coronary analysis (QCA). Results: Thirty-nine under-expanded stents (34 patients) were included. Two cases (5.1%) of multiple stent layers and one (2.5%) acutely under-expanded stent were treated. The median IVL balloon diameter was 3.1 mm (IQR: 2.5–3.5 mm) while the number of pulses emitted was 56.7 (IQR: 30–80). IVL was successful in 34 cases (87.1%), with significant improvement in MSD (post: 3.23 mm [IQR: 3–3.5 mm] vs. pre: 0.81 mm [IQR: 0.35–1.2], p < 0.00001) and MSA (post: 7.61mm2 [IQR: 6.43–7.79mm2] vs. pre: 3.35 [IQR: 2.8–4 mm2], p < 0.00001). Non-fatal peri-procedural ST-elevation myocardial infarction occurred in one case (2.5%) due to IVL balloon rupture. No cardiac death, target lesion revascularization and stent thrombosis occurred in-hospital and at 30-day follow-up. Conclusions: Bailout IVL was feasible, efficacious and safe to improve refractory stent under-expansion.

O presente artigo objetiva situar uma análise sobre um conjunto de artefatos político-pedagógicos, de orientações e de legislações produzidos no contexto de lutas dos movimentos sociais, dos espaços educativos e de suas efetivações nas esferas governamentais que contribuem para o combate à desigualdade de gênero e de sexualidade, bem como para o respeito à diversidade. Incialmente, apresenta-se a discussão com a problematização das desigualdades em relação às pessoas lésbicas, gays, bissexuais e transgêneros – LGBTs, na sequência, o debate sobre direitos humanos e o reconhecimento por parte da sociedade brasileira sobre as questões da diversidade de gênero e de sexualidade em diferentes documentos legais e de orientações sociais e educativas, finalizando a reflexão sobre alguns materiais teóricos voltados às questões dessa diversidade de gênero e de sexualidade com o objetivo de fomentar a formação docente e as práticas educativas. Conclui-se que tais artefatos constituem importantes apoios no reconhecimento às questões da diversidade de gênero e de sexualidade, de construção de práticas democráticas e de respeito no âmbito dos processos educativos.

Background: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed. Methods: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0–2 scores). Results: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate. Conclusions: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.

The frozen embryo transfer (FET) technique has been progressively used more worldwide due to improved culture conditions, as well as enhanced survival rates after vitrification. However, little is known about the effect of the post-thaw blastocyst culture duration prior to transfer on live birth rate in FET cycles. In this retrospective observational study, we evaluated the influence of two distinct post-thaw blastocyst culture spans (2–4 h versus 20–22 h) on clinical pregnancy and live birth rate. A total of n = 1927 frozen–warmed cycles were included in the analysis. Among those, n = 885 warmed blastocysts were cultured for 2–4 h, and n = 1029 were kept in culture for 20–22 h prior to transfer; the remaining blastocysts did not survive the warming protocol. We observed no significant differences in live birth and clinical pregnancy rates between the two groups. The blastocyst morphological evaluation at transfer improved following the longer culture time. No differences between the two groups were found also for gestational and neonatal outcomes. This work shows that different post-thaw embryo culture timings do not negatively impact pregnancy outcomes. Overall, these results are important in the context of the embryological laboratory in order to better organize the workflow and avoid unnecessary timing-related workload.

Reversible protein phosphorylation by kinases controls a plethora of processes essential for the proper development and homeostasis of multicellular organisms. One main obstacle in studying the role of a defined kinase–substrate interaction is that kinases form complex signaling networks and most often phosphorylate multiple substrates involved in various cellular processes. In recent years, several new approaches have been developed to control the activity of a given kinase. However, most of them fail to regulate a single protein target, likely hiding the effect of a unique kinase–substrate interaction by pleiotropic effects. To overcome this limitation, we have created protein binder-based engineered kinases that permit a direct, robust, and tissue-specific phosphorylation of fluorescent fusion proteins in vivo. We show the detailed characterization of two engineered kinases based on Rho-associated protein kinase (ROCK) and Src. Expression of synthetic kinases in the developing fly embryo resulted in phosphorylation of their respective GFP-fusion targets, providing for the first time a means to direct the phosphorylation to a chosen and tagged target in vivo. We presume that after careful optimization, the novel approach we describe here can be adapted to other kinases and targets in various eukaryotic genetic systems to regulate specific downstream effectors.

Background Canadians seeking medical cannabis (MC) may encounter difficulties in finding a healthcare provider (HCP) who authorizes their access to it. Barriers that HCPs face in authorizing MC are unclear. The objectives of this study were to evaluate HCP opinions, knowledge, comfort, and practice in MC prescribing and counseling on recreational cannabis use, and whether the COVID-19 pandemic affected MC prescribing practices. Methods Eligible participants included HCPs (e.g., attending physicians, nurses, pharmacists) in Canada. A questionnaire evaluating their knowledge, comfort, and practice in medical and recreational cannabis was designed based on instruments developed in previous studies. Between April 13th-December 13th 2021, ninety-one healthcare associations were asked to distribute the survey to their members, and an advertisement was placed in the online Canadian Medical Association Journal. Descriptive statistics were used to analyze the results. Results Twenty-four organizations agreed to disseminate the survey and 70 individuals completed it. Of respondents, 71% were attending physicians or medical residents, while the remainder were nurses, pharmacists or other HCPs. Almost none (6%) received training in MC in professional school but 60% did receive other training (e.g., workshops, conferences). Over half (57%) received more questions regarding MC since recreational cannabis was legalized, and 82% reported having patients who use MC. However, 56% felt uncomfortable or ambivalent regarding their knowledge of MC, and 27% were unfamiliar with the requirements for obtaining MC in Canada. The most common symptoms for recommending MC were pain and nausea, whereas the most common conditions for recommending it were cancer and intractable pain. The strongest barrier to authorizing MC was uncertainty in safe and effective dosage and routes of administration. The strongest barrier to recommending or authorizing MC was the lack of research evidence demonstrating its safety and efficacy. During the pandemic, many respondents reported that a greater number of their patients used cannabis to relieve anxiety and depression. Conclusions Our results suggest that HCPs across Canada who responded to our survey are unfamiliar with topics related to MC. The strongest barriers appear to be lack of clinical research, and uncertainty in safe and effective MC administration. Increasing research, training, and knowledge may help HCPs feel more equipped to make informed treatment/prescribing decisions, which may help to improve access to MC.

Taste and smell disturbances in patients affected by cancer are very common, but often under-recognized symptoms. If not addressed properly, they may impact nutritional status, food enjoyment, and quality of life. Treatment tools available for clinicians to manage chemosensory alterations are limited and are often based on personal clinical experiences. The aim of this study was to assess current oncological and palliative care literature through a scoping review, in order to identify available treatments for taste and smell alterations in cancer patients. Medline, Embase, CINAHL, ProQuest Dissertations and Theses, and Google Scholar were searched from inception until January 2020, with subject headings relevant to the domains of chemosensory alterations, palliative, and cancer care. A total of 10,718 English and French language publications were reviewed, yielding 43 articles on the researched topic. The heterogeneity of selected articles led to difficulties in interpretation and analysis of the available evidence. Included publications differed in study design, population sample, anticancer treatments, and measures of assessment for taste and smell disturbances. A broad variety of treatment options were described including zinc and polaprezinc, radio-protectors, vitamins and supplements, anti-xerostomia agents, active swallowing exercises, nutritional interventions, delta-9-tetrahydrocannabinol, and photobiomodulation. This scoping review identifies the current state of knowledge regarding chemosensory alterations within supportive cancer care. Despite not reaching firm conclusions, this article offers therapeutic venues to further explore in larger and more methodologically sound studies.

OBJECTIVE: To analyze the impact of COVID-19 emergency on elective oncological surgical activity in Italy. SUMMARY OF BACKGROUND DATA: COVID-19 emergency shocked national health systems, subtracting resources from treatment of other diseases. Its impact on surgical oncology is still to elucidate. METHODS: A 56-question survey regarding the oncological surgical activity in Italy during the COVID-19 emergency was sent to referral centers for hepato-bilio-pancreatic, colorectal, esophago-gastric, and sarcoma/soft-tissue tumors. The survey portrays the situation 5 weeks after the first case of secondary transmission in Italy. RESULTS: In total, 54 surgical Units in 36 Hospitals completed the survey (95%). After COVID-19 emergency, 70% of Units had reduction of hospital beds (median -50%) and 76% of surgical activity (median -50%). The number of surgical procedures decreased: 3.8 (interquartile range 2.7-5.4) per week before the emergency versus 2.6 (22-4.4) after (P = 0.036). In Lombardy, the most involved district, the number decreased from 3.9 to 2 procedures per week. The time interval between multidisciplinary discussion and surgery more than doubled: 7 (6-10) versus 3 (3-4) weeks (P < 0.001). Two-third (n = 34) of departments had repeated multidisciplinary discussion of patients. The commonest criteria to prioritize surgery were tumor biology (80%), time interval from neoadjuvant therapy (61%), risk of becoming unresectable (57%), and tumor-related symptoms (52%). Oncological hub-and-spoke program was planned in 29 departments, but was active only in 10 (19%). CONCLUSIONS: This survey showed how surgical oncology suffered remarkable reduction of the activity resulting in doubled waiting-list. The oncological hub-and-spoke program did not work adequately. The reassessment of healthcare systems to better protect the oncological path seems a priority.

The Large Scale Polarization Explorer (LSPE) is a cosmology program for the measurement of large scale curl-like features (B-modes) in the polarization of the Cosmic Microwave Background. Its goal is to constrain the background of inflationary gravity waves traveling through the universe at the time of matter-radiation decoupling. The two instruments of LSPE are meant to synergically operate by covering a large portion of the northern microwave sky. LSPE/STRIP is a coherent array of receivers planned to be operated from the Teide Observatory in Tenerife, for the control and characterization of the low-frequency polarized signals of galactic origin; LSPE/SWIPE is a balloon-borne bolometric polarimeter based on 330 large throughput multi-moded detectors, designed to measure the CMB polarization at 150 GHz and to monitor the polarized emission by galactic dust above 200 GHz. The combined performance and the expected level of systematics mitigation will allow LSPE to constrain primordial B-modes down to a tensor/scalar ratio of $10^{-2}$. We here report the status of the STRIP pre-commissioning phase and the progress in the characterization of the key subsystems of the SWIPE payload (namely the cryogenic polarization modulation unit and the multi-moded TES pixels) prior to receiver integration., 8 pages, 5 figures, Accepted for publication in Journal of Low Temperature Physics

Background: Fibromyalgia (FM) is a chronic condition related to dysfunctional central pain processing mechanisms, which affects 3-6% of the world population, leading to widespread pain, stiffness, and tenderness of the muscles, tendons, and joints, as well as restless sleep, fatigue, depression, and anxiety. Exercise is the most effective way of reducing pain and improving global well-being in people with FM, but such patients present an important limitation to exercise adherence. Objective: We aim to evaluate whether a home-based gamification strategy will improve the Fibromyalgia Impact Questionnaire Revised (FIQR) scores in female patients aged 18-60 years old as an alternative to traditional exercise. Methods: The proposed trial is a multicenter, phase II, open-label, parallel, randomized, superiority trial. Female patients ranging from 18 to 60 years old with a diagnosis of FM will be randomized to the intervention group, designed to play the Nintendo Switch Ring Fit Adventure game on three home-based weekly sessions, or to the control group, which will receive general educational guidance through videos and pamphlets provided by the study staff for a total of 12 weeks. The primary outcome will be the mean change in FIQR score results. Discussion: The development of new strategies to increase exercise adherence can enhance the control of symptoms such as pain, depression, low quality of sleep, and physical limitation in FM patients, thereby improving their quality of life. We believe that gamification strategies such as the one used here can make physical activity more playful, accessible, and dynamic, motivating patients and increasing their physical function compared to those seeking center-based or conventional exercises.

The advent of immunotherapy and targeted therapy has outstandingly improved the prognosis in subjects with melanoma. Their use is now advocated also in earlier stages as an adjuvant therapy, and some neoadjuvant clinical trials are ongoing. Consequently, survivors free of disease are increasing, as well as those exposed to these new agents. Parenthood in survivors is, therefore, receiving growing interest. Evidence on the effects of immunotherapy and targeted therapy on future fertility is limited, but not entirely reassuring, in particular for immunotherapy. The necessity of delaying pregnancy seeking up to the end of treatments and follow-up (iatrogenic aging) is an additional albeit neglected source of concern, in particular for women in their late 30s. Subjects with melanoma should be informed on the multifaceted issue of future fertility at the time of cancer diagnosis. Available options of fertility preservations, including sperm and oocytes storage, should also be discussed, especially considering that at the age 0-39, melanoma represents the second most frequent neoplasia. In the decision-making process, most attention should be given to sex, age, and exposure to immunotherapy.

Finding effective ways to perform cancer sub-typing is currently a trending research topic for therapy opti-mization and personalized medicine. Stemming from genomic field, several algorithms have been proposed. In the context of texture analysis, limited efforts have been attempted, yet imaging information is known to entail useful knowledge for clinical practice. We propose a distant supervision model for imaging-based cancer sub-typing in Intrahepatic Cholangiocar-cinoma patients. A clinically informed stratification of patients is built and homogeneous groups of patients are characterized in terms of survival probabilities, qualitative cancer variables and radiomic feature description. Moreover, the contributions of the information derived from the ICC area and from the peri tumoral area are evaluated. The findings suggest the reliability of the proposed model in the context of cancer research and testify the importance of accounting for data coming from both the tumour and the tumour-tissue interface. Clinical relevance - In order to accurately predict cancer prognosis for patients affected by ICC, radiomic variables of both core cancer and surrounding area should be exploited and employed in a model able to manage complex information.

Endometriosis is a benign gynaecological disease. As the lifetime risk of developing an adenocarcinoma of the endometrium is about 2% in the general female population, there seems to be no reason to believe that the same type of mucosa should not undergo malignant derailments at a similar rate when displaced at ectopic sites. The endometrioid ovarian carcinomas and the clear cell ovarian carcinomas are the most frequent histotypes associated with endometriosis. However, determining whether the mere presence of endometrium at ectopic sites should be considered per se a premalignant condition seems crucial and constitutes the conceptual base of any strategy aimed at preventing and treating endometriosis-associated ovarian cancer. Lesions are defined “precancerous” based on definite epidemiologic, morphologic, molecular, and biologic criteria that imply the acquisition of genetic, karyotypic, structural, or functional changes in a cluster of cells that differentiate them from the surrounding normal tissue. In other words, premalignant lesions should reflect an intermediate stage along the pathway leading to cancer. The transformation of a normal cell into a cancer cell is due to the progressive acquisition of driver mutations. With the improvement of sequencing technology, several studies focusing on genomic features or molecular targets have been performed in endometriosis. In particular, studies have evaluated somatic cancer-associated mutations in endometriotic lesions without concurrent cancer to assess whether endometriosis might be considered as a precursor of cancer. It has been reported recently that several ovarian and deep endometriosis lesions harbour cancer-associated mutations. Cancer-driver mutations involve genes coding for AT-rich interactive domain-containing protein 1A (ARID1A), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA), Kirsten rat sarcoma (KRAS), or protein phosphatase 2 scaffold subunit Aα (PPP2R1A). These mutations are quite frequent also in deep endometriosis and this result is surprising considering that deep infiltrating endometriotic lesions very rarely undergo malignant transformation. This poses some doubts on the real oncogenic potential of these mutations. On the other hand, a specific role seems to be played by the ovarian microenvironment in increasing the risk of malignant derailment. The chronic inflammatory environment of women with endometriosis may theoretically facilitate the transformation of abnormal endometrial cell into a malignant cell. The micro-environmental factors such as oxidative stress, immune cell dysfunction, steroid hormones, and stem cells required for malignant transformation have been found in endometriosis. Driver gene mutations have been identified at the genetic level also in the normal endometrium, which is the origin of endometriosis. The next issue is to clarify a trigger of carcinogenesis based on genomic lineage from normal endometrium to ovarian cancers via endometriosis. To address these issues, multiomics analysis combining genomics, transcriptomics, and proteomics will be necessary.

Study question What are the prevalence estimates of post-hematopoietic cell transplantation (HCT) natural conceptions or after ART using stored semen? Summary answer Natural live birth rate following HCT can be estimated at 9% (95%CI:4-22%) but can be increased to 58% (95%CI:43-72%) with the use of frozen semen. What is known already With the improvements and expanding indications of HCT, the number of adult male cancer survivors who received HCT is increasing. These men face the risk of treatment-induced infertility and are generally recommended to store their semen prior to embark in HCT. However, information on long term usage and on effectiveness of frozen sperm samples in this specific population is not well defined. Study design, size, duration All male cancer recipients of autologous or allogeneic transplantation who cryopreserved semen between 1987 and 2016 in the biobank of the Assisted Reproductive Technology Unit of the Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico in Milan were considered. Information was obtained from patients’ charts or through active investigation. The main studied topics included results from semen analyses, attempt to parenthood, use of stored spermatozoa and both natural and Assisted Reproductive Technique (ART) mediated conceptions. Participants/materials, setting, methods The study is restricted to men who met the following eligibility criteria: i) semen cryopreserved for fertility preservation between 1987 and 2016; ii) post-banking follow-up documenting HCT iii) survival of at least 5 years from HCT. Main results and the role of chance One-hundred and two HCT survivors were selected. The median [IQR] age at sperm banking was 29 [23-34]. About half of subjects had autologous HCT (n = 50), the remaining 52 received allogenic HCT. Lymphomas were the most frequent indications. The median spermatozoa concentration at the time storage was 39 [7-85] millions/ml. Fifty-four (53%) men performed a post-treatment sperm analysis and azoospermia was documented in 45 of them (83%, 95%CI: 71-91%). The remaining nine showed viable spermatozoa, of whom six had severe oligospermia (concentration 5 Millions/ml, compatible with a natural conception. Overall, based on semen analyses, one could infer the necessity to use ART in 51 out of 54 subjects, corresponding to 94% (95%CI: 85-98%). Forty-three of the 102 included men (42%) sought childbearing. Four had a natural live birth (9%, 95%CI: 4-22%). Thirty-three used their cryopreserved sperm samples, corresponding to 32% (95%CI: 24-42%) of the whole cohort. Twenty-one of these 33 men had at least one live birth (64%, 95%CI: 47-78%). Finally, six men seeking pregnancy and who did not conceive have not used their frozen semen. Overall, 25 out of 43 men interested in fatherhood had a live birth (58%, 95%CI: 43-72%). Limitations, reasons for caution Limitation of our study is missing detailed information on status of illness and comorbidities (in particular the frequency of Graft-versus host disease) and lack precise information on the myeloablative regimen used. Furthermore, our sample size is not very large and therefore the 95%CI of the reported proportions are wide. Wider implications of the findings Autologous or allogeneic HCT induces infertility in a very high percentage of patients. These findings support the need to prioritize sperm preservation before HCT also in cancer patients who are not candidate for HCT at first instance but who may need this treatment for failure of first line treatments. Trial registration number not applicable