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STUDY QUESTION Is the total number of oocytes retrieved with dual ovarian stimulation in the same cycle (duostim) higher than with two consecutive antagonist cycles in poor responders? SUMMARY ANSWER Based on the number of total and mature oocytes retrieved in women with poor ovarian response (POR), there is no benefit of duostim versus two consecutive antagonist cycles. WHAT IS KNOWN ALREADY Recent studies have shown the ability to obtain oocytes with equivalent quality from the follicular and the luteal phase, and a higher number of oocytes within one cycle when using duostim. If during follicular stimulation smaller follicles are sensitized and recruited, this may increase the number of follicles selected in the consecutive luteal phase stimulation, as shown in non-randomized controlled trials (RCT). This could be particularly relevant for women with POR. STUDY DESIGN, SIZE, DURATION This is a multicentre, open-labelled RCT, performed in four IVF centres from September 2018 to March 2021. The primary outcome was the number of oocytes retrieved over the two cycles. The primary objective was to demonstrate in women with POR that two ovarian stimulations within the same cycle (first in the follicular phase, followed by a second in the luteal phase) led to the retrieval of 1.5 (2) more oocytes than the cumulative number of oocytes from two consecutive conventional stimulations with an antagonist protocol. In a superiority hypothesis, with power 0.8 alpha-risk 0.05 and a 35% cancellation rate, 44 patients were needed in each group. Patients were randomized by computer allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS Eighty-eight women with POR, defined using adjusted Bologna criteria (antral follicle count ≤5 and/or anti-Müllerian hormone ≤1.2 ng/ml) were randomized, 44 in the duostim group and 44 in the conventional (control) group. HMG 300 IU/day with flexible antagonist protocol was used for ovarian stimulation, except in luteal phase stimulation of the duostim group. In the duostim group, oocytes were pooled and inseminated after the second retrieval, with a freeze-all protocol. Fresh transfers were performed in the control group, frozen embryo transfers were performed in both control and duostim groups in natural cycles. Data underwent intention-to-treat and per-protocol analyses. MAIN RESULTS AND THE ROLE OF CHANCE There was no difference between the groups regarding demographics, ovarian reserve markers, and stimulation parameters. The mean (SD) cumulative number of oocytes retrieved from two ovarian stimulations was not statistically different between the control and duostim groups, respectively, 4.6 (3.4) and 5.0 (3.4) [mean difference (MD) [95% CI] +0.4 [−1.1; 1.9], P = 0.56]. The mean cumulative numbersof mature oocytes and total embryos obtained were not significantly different between groups. The total number of embryos transferred by patient was significantly higher in the control group 1.5 (1.1) versus the duostim group 0.9 (1.1) (P = 0.03). After two cumulative cycles, 78% of women in the control group and 53.8% in the duostim group had at least one embryo transfer (P = 0.02). There was no statistical difference in the mean number of total and mature oocytes retrieved per cycle comparing Cycle 1 versus Cycle 2, both in control and duostim groups. The time to the second oocyte retrieval was significantly longer in controls, at 2.8 (1.3) months compared to 0.3 (0.5) months in the duostim group (P LIMITATIONS, REASONS FOR CAUTION The RCT was impacted by the coronavirus disease 2019 pandemic and the halt in IVF activities for 10 weeks. Delays were recalculated to exclude this period; however, one woman in the duostim group could not have the luteal stimulation. We also faced unexpected good ovarian responses and pregnancies after the first oocyte retrieval in both groups, with a higher incidence in the control group. However, our hypothesis was based on 1.5 more oocytes in the luteal than the follicular phase in the duostim group, and the number of patients to treat was reached in this group (N = 28). This study was only powered for cumulative number of oocytes retrieved. WIDER IMPLICATIONS OF THE FINDINGS This is the first RCT comparing the outcome of two consecutive cycles, either in the same menstrual cycle or in two consecutive menstrual cycles. In routine practice, the benefit of duostim in patients with POR regarding fresh embryo transfer is not confirmed in this RCT: first, because this study demonstrates no improvement in the number of oocytes retrieved in the luteal phase after follicular phase stimulation, in contrast to previous non-randomized studies, and second, because the freeze-all strategy avoids a pregnancy with fresh embryo transfer after the first cycle. However, duostim appears to be safe for women. In duostim, the two consecutive processes of freezing/thawing are mandatory and increase the risk of wastage of oocytes/embryos. The only benefit of duostim is to shorten the time to a second retrieval by 2 weeks if accumulation of oocytes/embryos is needed. STUDY FUNDING/COMPETING INTERESTS This is an investigator-initiated study supported by a research Grant from IBSA Pharma. N.M. declares grants paid to their institution from MSD (Organon France); consulting fees from MSD (Organon France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. I.A. declares honoraria from GISKIT and support for travel and meetings from GISKIT. G.P.-B. declares Consulting fees from Ferring and Merck KGaA; honoraria from Theramex, Gedeon Richter, and Ferring; payment for expert testimony from Ferring, Merck KGaA, and Gedeon Richter; and support for travel and meetings from Ferring, Theramex, and Gedeon Richter. N.C. declares grants from IBSA pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. E.D. declares support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Ferring, Gedeon Richter, Theramex, and General Electrics. C.P.-V. declares support for travel and meetings from IBSA Pharma, Merck KGaA, Ferring, Gedeon Richter, and Theramex. M.Pi. declares support for travel and meetings from Ferring, Gedeon Richetr, and Merck KGaA. M.Pa. declares honoraria from Merck KGaA, Theramex, and Gedeon Richter; support for travel and meetings from Merck KGaA, IBSA Pharma, Theramex, Ferring, Gedeon Richter, and MSD (Organon France). H.B.-G. declares honoraria from Merck KGaA, and Gedeon Richter and support for travel and meetings from Ferring, Merck KGaA, IBSA Pharma, MSD (Organon France), Theramex, and Gedeon Richter. S.G. and M.B. have nothing to declare. TRIAL REGISTRATION NUMBER Registration number EudraCT: 2017-003223-30. ClinicalTrials.gov identifier: NCT03803228. TRIAL REGISTRATION DATE EudraCT: 28 July 2017. ClinicalTrials.gov: 14 January 2019. DATE OF FIRST PATIENT’S ENROLMENT 3 September 2018.

In this work, we unveil the fluorescence features of citric acid and urea-based Carbon Dots (CDs) through a photo-physical characterization of nanoparticles synthesized, under solvent-free and open-air conditions, within silica-ordered mesoporous silica, as a potential host for solid-state emitting hybrids. Compared to CDs synthesized without silica matrices and dispersed in water, silica-CD hybrids display a broader emission in the green range whose contribution can be increased by UV and blue laser irradiation. The analysis of hybrids synthesized within different silica (MCM-48 and SBA-15) calls for an active role of the matrix in directing the synthesis toward the formation of CDs with a larger content of graphitic N and imidic groups at the expense of N-pyridinic molecules. As a result, CDs tuned in size and with a larger green emission are obtained in the hybrids and are retained once extracted from the silica matrix and dispersed in water. The kinetics of the photo-physics under UV and blue irradiation of hybrid samples show a photo-assisted formation process leading to a further increase of the relative contribution of the green emission, not observed in the water-dispersed reference samples, suggesting that the porous matrix is involved also in the photo-activated process. Finally, we carried out DFT and TD-DFT calculations on the interaction of silica with selected models of CD emitting centers, like surface functional groups (OH and COOH), dopants (graphitic N), and citric acid-based molecules. The combined experimental and theoretical results clearly indicate the presence of molecular species and surface centers both emitting in the blue and green spectral range, whose relative contribution is tuned by the interaction with the surrounding media.

Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) is a key diagnostic tool in the differential diagnosis between non-ischemic cause of cardiac chest pain. Some patients are not eligible for a gadolinium contrast-enhanced CMR; in this scenario, the diagnosis remains challenging without invasive examination. Our purpose was to derive a machine learning model integrating some non-contrast CMR parameters and demographic factors to identify Takotsubo cardiomyopathy (TTC) in subjects with cardiac chest pain.Three groups of patients were retrospectively studied: TTC, acute myocarditis, and healthy controls. Global and regional left ventricular longitudinal, circumferential, and radial strain (RS) analysis included were assessed. Reservoir, conduit, and booster bi-atrial functions were evaluated by tissue-tracking. Parametric mapping values were also assessed in all the patients. Five different tree-based ensemble learning algorithms were tested concerning their ability in recognizing TTC in a fully cross-validated framework.The CMR-based machine learning (ML) ensemble model, by using the Extremely Randomized Trees algorithm with Elastic Net feature selection, showed a sensitivity of 92% (95% CI 78-100), specificity of 86% (95% CI 80-92) and area under the ROC of 0.94 (95% CI 0.90-0.99) in diagnosing TTC. Among non-contrast CMR parameters, the Shapley additive explanations analysis revealed that left atrial (LA) strain and strain rate were the top imaging markers in identifying TTC patients.Our study demonstrated that using a tree-based ensemble learning algorithm on non-contrast CMR parameters and demographic factors enables the identification of subjects with TTC with good diagnostic accuracy.Our results suggest that non-contrast CMR features can be implemented in a ML model to accurately identify TTC subjects. This model could be a valuable tool for aiding in the diagnosis of subjects with a contraindication to the contrast media. Furthermore, the left atrial conduit strain and strain rate were imaging markers that had a strong impact on TTC identification. Further prospective and longitudinal studies are needed to validate these findings and assess predictive performance in different cohorts, such as those with different ethnicities, and social backgrounds and undergoing different treatments.

Purpose The effect of systemic hemostatic agents initiated during pre-hospital care of severely injured patients with ongoing bleeding or traumatic brain injury (TBI) remains controversial. A systematic review and meta-analysis was therefore conducted to assess the effectiveness and safety of systemic hemostatic agents as an adjunctive therapy in people with major trauma and hemorrhage or TBI in the context of developing the Italian National Institute of Health guidelines on major trauma integrated management. Methods PubMed, Embase, and Cochrane Library databases were searched up to October 2021 for studies that investigated pre-hospital initiated treatment with systemic hemostatic agents. The certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation approach, and the quality of each study was determined with the Cochrane risk-of-bias tool. The primary outcome was overall mortality, and secondary outcomes included cause-specific mortality, health-related quality of life, any adverse effects and blood product use, hemorrhage expansion, and patient-reported outcomes. Results Five trials of tranexamic acid (TXA) met the inclusion criteria for this meta-analysis. With a high certainty of evidence, when compared to placebo TXA reduced mortality at 24 h (relative risk = 0.83, 95% confidence interval = 0.73–0.94) and at 1 month among trauma patients (0.91, 0.85–0.97). These results depend on the subgroup of patients with significant hemorrhage because in the subgroup of TBI there are no difference between TXA and placebo. TXA also reduced bleeding death and multiple organ failure whereas no difference in health-related quality of life. Conclusion Balancing benefits and harms, TXA initiated in the pre-hospital setting can be used for patients experiencing major trauma with significant hemorrhage since it reduces the risk of mortality at 24 h and one month with no difference in terms of adverse effects when compared to placebo. Considering the subgroup of severe TBI, no difference in mortality rate was found at 24 h and one month. These results highlight the need to conduct future studies to investigate the role of other systemic hemostatic agents in the pre-hospital settings.

Background: Several studies have reported an association between perinatal complications and the severity of the hypertensive disease. The increasing number of pregnancies complicated by hypertension and the small assurance about the perinatal effects of hypertensive drug use during pregnancy involves the need of studying the better management of hypertensive mothers. Objective: To evaluate the association between maternal use of antihypertensive drugs and maternal and neonatal outcomes in women with chronic hypertension. Study design: We conducted a population-based study including all deliveries of hypertensive women that occurred between 2007–2017 in the Lombardy region, Italy. We evaluated the risk of several maternal and neonatal outcomes among women who filled antihypertensive prescriptions within the 20th week of gestation. Propensity score stratification was used to account for key potential confounders. Results: Out of 5,553 pregnancies, 2,138 were exposed to antihypertensive treatment. With respect to no-users, users of antihypertensive drugs showed an increased risk of preeclampsia (RR:1.68, 95%CI:1.42–1.99), low birth weight (1.30,1.14–1.48), and preterm birth (1.25,1.11–1.42). These results were consistent in a range of sensitivity and subgroup analyses. Conclusion: Early exposure to antihypertensive drugs in the first 20 weeks of gestation was associated with an increased risk of preeclampsia, low birth weight, and preterm birth.

Left ventricular assist devices take an important place in the armamentarium of end-stage heart failure therapy. Outflow graft obstruction by extrinsic compression is a rare but possibly life-threatening complication of these types of devices. Pathophysiology is not completely elucidated but seems to be related to the common design of these devices, because of a porous Dacron graft surrounded within an impervious Teflon bend relief. In the absence of pump thrombosis, the pump replacement is not necessarily indicated, and only removal of the obstruction may be sufficient. Both surgical and interventional procedures are described. We reported a case successfully treated by angioplasty-stenting. We discussed the diagnosis, the pathophysiology, and the treatment of this specific complication of left ventricular assist devices. Finally, we open the discussion to the prevention of this complication.

Background: First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear. Methods: This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Results: 31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension. Conclusions: The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable. Trial registration number: NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681

The beers’ lag time measured with the PBN (N-t-Butyl-α-phenylnitrone) spin trapping experiments coupled with EPR spectroscopy is related to their antioxidant capacity and shelf life. The effect on the lag time of the alcohol content of the beer (starting values, 9 and 13%) and PBN concentration (50 or 200 mM) was analyzed on three samples, a pilsner, a strong lager, and a blonde Ale heated at 60 °C to trigger the production of the 1-hydroxyethyl radical. The lag time was determined only for the strong lager beer, with the values depending on the experimental conditions, being higher when PBN had a lower concentration. The antioxidant activity of the three beers gave the following values: 0.9089 mL pilsner beer/mg DPPH, 0.8510 mL strong lager beer/mg DPPH, and 0.7184 mL blonde Ale beer/mg DPPH, indicating that the unsuccessful determination of the lag time was not due to stale beers. The EPR intensity of the PBN adduct after 150 min (I150) and the area under the curve (AUC) were also measured and related to the oxidative stability of beers. Further studies are needed to verify the influence of the heating temperature in samples that do not show a lag time at 60 °C.

Purpose Preventing fragility fractures by treating osteoporosis may reduce disability and mortality worldwide. Algorithms combining clinical risk factors with bone mineral density have been developed to better estimate fracture risk and possible treatment thresholds. This systematic review supported panel members of the Italian Fragility Fracture Guidelines in recommending the use of best-performant tool. The clinical performance of the three most used fracture risk assessment tools (DeFRA, FRAX, and FRA-HS) was assessed in at-risk patients. Methods PubMed, Embase, and Cochrane Library were searched till December 2020 for studies investigating risk assessment tools for predicting major osteoporotic or hip fractures in patients with osteoporosis or fragility fractures. Sensitivity (Sn), specificity (Sp), and areas under the curve (AUCs) were evaluated for all tools at different thresholds. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies-2; certainty of evidence (CoE) was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. Results Forty-three articles were considered (40, 1, and 2 for FRAX, FRA-HS, and DeFRA, respectively), with the CoE ranging from very low to high quality. A reduction of Sn and increase of Sp for major osteoporotic fractures were observed among women and the entire population with cut-off augmentation. No significant differences were found on comparing FRAX to DeFRA in women (AUC 59–88% vs. 74%) and diabetics (AUC 73% vs. 89%). FRAX demonstrated non-significantly better discriminatory power than FRA-HS among men. Conclusion The task force formulated appropriate recommendations on the use of any fracture risk assessment tools in patients with or at risk of fragility fractures, since no statistically significant differences emerged across different prediction tools.

À partir d’un échantillon de 1 503 personnes, cette étude s’intéresse aux patients des centres d’assistance médicale à la procréation (AMP) pris en charge en France en 2020 afin d’interroger leur parcours médical comme leurs expériences de l’infertilité dans la vie professionnelle, intime, familiale et conjugale. Le questionnaire en ligne, composé de 178 questions, offre trois grandes familles de résultats : les domaines dans lesquels l’AMP donne satisfaction à une majorité de personnes ; les points de vigilance ; les résultats les plus frappants, notamment l’invisibilité des jeunes et des hommes parmi les patients, le pessimisme quant aux résultats de leur traitement et la difficile relation au corps pour les femmes. L’ensemble des résultats souligne l’importance d’une conception globale des patients infertiles, hommes et femmes, jeunes et moins jeunes, au-delà de la seule dimension médicale, pour une prise en compte aussi bien psychologique, sociale que professionnelle, sous-tendue par une équipe d’accompagnants élargie.

Social media marketing communication is among the current strategies used to provide visibility to cultural heritage, sales promotions being especially relevant. Nevertheless, despite the fact that social media has now built significant momentum, there is still a dearth of research on the relationship between social marketing activities and brand equity. In this context, this study seeks to determine how the use of promotional discounts and free gifts on social media contributes to building heritage brand equity. To pursue this research aim, a quasi-experimental study was designed and carried out among online users, based on two promotional stimuli (discount vs. free gift). The findings suggest that gifts perform better in terms of increasing brand equity, except where the user presents a high level of sales promotion-proneness, in which case promotional discounts are more effective., Campus of International Excellence BioTic Granada 20F12/43, Spanish National Research Programme (R+D+i Research Project) ECO201788458-R

Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the best curative option for the majority of patients with hematologic malignancies (HM); however, many elderly patients are excluded from transplant and outcome data in this population is still limited. The novel two-step graft engineering approach has been the main platform for allo-SCT at Thomas Jefferson University since 2006. Following administration of the preparative regimen, we infuse donor lymphocytes, followed by cyclophosphamide to induce bidirectional tolerance, then infusion of CD34-selected cells. A total of 76 patients ≥ 65 years old with HM underwent haploidentical (haplo) allo-SCT on the two-step transplant platform between 2007 and 2021. The median time to neutrophil engraftment was 11 days and platelet engraftment was 18 days. With a median follow up of 44 months, the 3-year overall survival (OS) and progression-free survival (PFS) were 36.3% and 35.6%, respectively. The cumulative incidences of non-relapse mortality (NRM) and relapse at 3 years were 43.5% and 21.0% at 3 years, respectively. The cumulative incidence of grade III-IV acute graft-versus-host-disease (GVHD) was 11.1% at 6 months, and chronic GVHD requiring treatment was 15.1% at 2 years. The two-step haplo allo-SCT is a novel alternative platform for high-risk older HM patients, achieving fast engraftment, low relapse rates and promising survival.

Background. Cancer patients are among the main consumers of traditional, complementary, integrative, and alternative medicine (TCIM) such as natural products (herbals, integrators, etc.) and mind and body practices (yoga, acupuncture, etc.). Methods. A questionnaire on TCIM was submitted to 415 Italian cancer patients. The questionnaire consisted of three sections: (i) biographical and clinical information; (ii) use of natural substances; and (iii) use of mind-body practices. Results. 406 patients completed the questionnaire. The prevalence of TCIM use was 72.3%. Of them, 75.6% started to use TCIM after a tumor diagnosis. The main reasons for using TCIM were to mitigate side effects (65.0%), to regain physical and mental balance (35.9%), to relieve pain (18.3%), and to improve the efficacy of cancer therapy (16.0%). 44.7% of patients taking natural products used them during conventional therapies (chemotherapy, radiotherapy, etc.), and in 67.5% of cases without consulting a doctor. As a consequence, only about 50% of patients taking natural substances used these compounds appropriately, and the most common errors were related with the purpose of reducing the side effects of the therapy (52.3%) and for boosting immune system (32.1%). Conclusions. There is an impelling need to provide patients with scientifically validated information to raise awareness about the benefits and risks of using TCIM.

Background: Scientific evidence shows that hazardous industrial facilities are disproportionately distributed among socially deprived communities; however, environmental distributive justice resear...

Purpose Various prognostic indexes have been proposed to improve physicians’ ability to predict survival time in advanced cancer patients admitted to palliative care (PC), but no optimal score has still been identified. The study therefore aims to develop and externally validate a new multivariable predictive model in this setting.Methods We developed the model on 1020 cancer patients prospectively enrolled to home care palliative care at VIDAS Milan, Italy, between May 2018 and February 2020 and followed-up to June 2020. The model was then validated among two separate samples of 544 home care and 247 hospice patients. Overall survival was considered as the primary outcome to develop and validate the model; Cox and flexible parametric Royston-Parmar regression models were used.Results Through a four-step modelling process, among 68 clinical factors considered, five predictors were included in the predictive model, i.e., rattle, heart rate, anorexia, liver failure, and the Karnofsky performance status. Patient’s survival probability at various time points was estimated. The predictive model showed a good calibration and moderate discrimination (area under the receiver operating characteristic curve between 0.72 and 0.79) in the home care validation set, but model calibration was suboptimal in hospice patients.Conclusions The new multivariable predictive model for palliative cancer patients’ survival (PACS model) includes clinical parameters routinely at patient’s admission to PC and can be easily used to facilitate immediate and appropriate clinical decisions for PC cancer patients in the home setting.

Characteristic functions that are radially symmetric have a dual interpretation, as they can be used as the isotropic correlation functions of spatial random fields. Extensions of isotropic correlation functions from balls into $d$-dimensional Euclidean spaces, $\R^{d}$, have been understood after Rudin. Yet, extension theorems on product spaces are elusive, and a counterexample provided by Rudin on rectangles suggest that the problem is quite challenging. This paper provides extension theorem for multiradial characteristic functions that are defined in balls embedded in $\R^d$ cross, either $\R^{\dd}$ or the unit sphere $\S^{\dd}$ embedded in $\R^{\dd+1}$, for any two positive integers $d$ and $\dd$. We then examine Turning Bands operators that provide bijections between the class of multiradial correlation functions in given product spaces, and multiradial correlations in product spaces having different dimensions. The combination of extension theorems with Turning Bands provides a connection with random fields that are defined in balls cross linear or circular time.

Background: Noncommunicable, chronic diseases need pharmacological interventions for long periods or even throughout life. The temporary or permanent cessation of medication for a specific period, known as a ‘medication holiday,’ should be planned by healthcare professionals. Objectives: We evaluated the association between continuity (adherence or persistence) of treatment and several outcomes in patients with fragility fractures in the context of the development of the Italian Guidelines. Design: Systematic review. Data Sources and Methods: We systematically searched PubMed, Embase, and the Cochrane Library up to November 2020 for randomized clinical trials (RCTs) and observational studies that analyzed medication holidays in patients with fragility fracture. Three authors independently extracted data and appraised the risk of bias of the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Effect sizes were pooled in a meta-analysis using random effects models. Primary outcomes were refracture and quality of life; secondary outcomes were mortality and treatment-related adverse events. Results: Six RCTs and nine observational studies met our inclusion criteria, ranging from very low to moderate quality. The adherence to antiosteoporotic drugs was associated with a lower risk of nonvertebral fracture [relative risk (RR) 0.42, 95% confidence interval (CI) 0.20–0.87; three studies] than nonadherence, whereas no difference was detected in the health-related quality of life. A reduction in refracture risk was observed when continuous treatment was compared to discontinuous therapy (RR 0.49, 95% CI 0.25–0.98; three studies). A lower mortality rate was detected for the adherence and persistence measures, while no significant differences were noted in gastrointestinal side effects in individuals undergoing continuous versus discontinuous treatment. Conclusion: Our findings suggest that clinicians should promote adherence and persistence to antiosteoporotic treatment in patients with fragility fractures unless serious adverse effects occur.

A general strategy for the synthesis of 2-substituted cyclobutanone sulfides via a tandem Brønsted acid-catalyzed nucleophile addition/ring contraction/C3-C4 ring expansion reaction sequence has been exploited. The procedure led to a wide panel of four-membered cyclic ketones in good to excellent yields and with broad substrate scope. Mechanistic aspects and kinetic parameters were investigated by quantum chemical DFT calculations, allowing us to rationalize the different reactivity of 2-aryl- and 2-alkyl-substituted 2-hydroxycyclobutanones towards thiol nucleophiles in reactions mediated by sulfonic acids. NMR and in situ Raman techniques were employed to better understand the reaction kinetics and parameters that affect the desired outcome.

En geoestadística, bajo estacionariedad, kriging simple (KS) es el mejor predictor lineal (MPL) y kriging ordinario (KO) es el mejor predictor lineal insesgado (MPLI). Cuando el proceso estocástico es Normal, KS no es solo un MPL sino un mejor predictor (MP), es decir que bajo la función de pe ́rdida cuadrática, éste coincide con la esperanza condicional del predictor dada la información. En este escenario, el predictor KO sirve como aproximación del MP. Por esta razón, en geoestadística aplicada, es importante probar el supuesto de normalidad. Dada una realización de un proceso espacial, KS será un predictor óptimo si el vector aleatorio subyacente sigue una distribución normal multivariada. Algunas pruebas de normalidad clásicas como Shapiro-Wilk (SW), Shapiro-Francia (SF), o Anderson-Darling (AD) son usadas para evaluar este supuesto. Estas asumen independencia y por ello no son apropiadas en geoestadística (y en general en estadística espacial). Por un lado, las observaciones en geoestadística son espacialmente correlacionadas. Por otro lado la optimalidad del kriging es fundamentada en normalidad multivariada (no en normalidad univariada). En este trabajo se presenta un estudio de simulación para mostrar por qué es inapropiado el uso de pruebas univaridas de normalidad con datos geoestadísticos. También, como solución al problema anterior, se propone una adaptación de la prueba de Mahalanobis al contexto geoestadístico para hacer de manera correcta el test de normalidad en este ambito.

Diagnosing early-stage mycosis fungoides (MF) remains a significant challenge. The International Society for Cutaneous Lymphomas (ISCL) proposed an algorithm for diagnosing early MF incorporating clinical and histopathologic characteristics, as well as immunohistochemistry and molecular studies. Here we aim to examine the diagnostic utility of the ISCL algorithm.In this single-center retrospective review, the ISCL algorithm was applied to 28 patients diagnosed with early-stage MF. Immunohistochemistry and molecular studies were not performed for all patients, so a subgroup analysis was conducted including 18 patients in whom both studies had been performed. We calculated the diagnostic sensitivity of the algorithm. Subsequently, we examined how modifying the algorithm's histopathologic criterion from epidermotropism without spongiosis to epidermotropism influenced its sensitivity.Forty-three percent (12/28) of the cohort and 50% (9/18) of the subgroup met the algorithm's diagnostic threshold. When the algorithm was modified, 71% of the cohort and 89% of the subgroup met the algorithm's threshold.While the ISCL algorithm is useful in diagnosing early-stage MF, its sensitivity remains suboptimal. Further refinement of the algorithm to capture spongiotic subtypes of MF may improve its diagnostic value.

Background Mycosis fungoides with large-cell transformation (MF-LCT) is associated with an aggressive clinical course, yet data comparing treatment outcomes in MF-LCT are sparse. Objective To compare treatment outcomes and to determine disease prevalence and characteristics associated with survival in MF-LCT. Methods A retrospective review was conducted of mycosis fungoides patients from 2012 to 2020 treated at Thomas Jefferson University. Patients with histopathologic diagnosis of MF-LCT were included. Treatment outcomes were assessed by mean changes in the modified Severity Weighted Assessment Tool (mSWAT) and stage. Results Of 171 patients with mycosis fungoides, 23 (13.4%) had histologic diagnosis of MF-LCT. The overall 5-year survival rate for MF-LCT was 74% and was not significantly associated with sex, age, or initial stage at the time of MF-LCT diagnosis. Brentuximab vedotin showed the greatest mean decrease in mSWAT (−20.53) and stage progression (change in Δ stage: –0.4) in MF-LCT compared to oral bexarotene (ΔmSWAT: +4.51; Δstage: +0.27), skin-directed therapy (ΔmSWAT: −5.93; Δstage: −0.08), and chemotherapy (ΔmSWAT: +4.97; Δstage: +0.85). Limitations Single-center retrospective design, and patients often on multiple treatment modalities. Conclusions We report superior treatment outcomes for brentuximab vedotin compared to oral bexarotene, skin-directed therapy, and chemotherapy in MF-LCT in both early and advanced disease.

This study aimed to evaluate the differences of brain connectivity between healthy subjects (HS) and patients with extracranial internal carotid artery (eICA) stenosis before and after carotid endarterectomy (CEA). An exploratory prospective study was designed. The study population consisted of a patient group (PG) of 20 patients with eICA stenosis eligible for CEA, and a control group (CG) of 20 HS, matched for age and sex. The subjects of the PG group underwent Magnetic Resonance Imaging (MRI) for resting-state functional connectivity MRI (rs-fc MRI) analysis within one week from the CEA (pre-CEA) and 12 months following CEA (post-CEA). The CG underwent a single MRI with the same protocol utilized for the PG. Three region-of-interest to region-of-interest (ROI-to-ROI) rs-fc MRI analyses were conducted: analysis 1 to compare pre-CEA PG and CG; analysis 2 to compare pre-CEA PG and post-CEA PG; analysis 3 to compare post-CEA PG and CG. The Functional Network Connectivity multivariate parametric technique was used for statistical analysis, adopting a p-uncorrected (p-unc) 0.05 as connection threshold, and a cluster level False Discovery Rate corrected p (p-FDR) 0.05 as cluster threshold. The clusters were defined by using a data-driven hierarchical clustering procedure. Analysis 1 revealed two clusters of reduced interhemispheric connectivity of pre-CEA PG when compared to CG. Analysis 2 and 3 showed no statistically significant differences. Our exploratory analysis suggests that patients with eICA stenosis have reduced interhemispheric connectivity when compared to a matched control group, and this difference was not evident anymore following endarterectomy.

People often coordinate actions with others, requiring an adjustable amount of self–other integration between actor’s and co-actor’s actions. Previous research suggests that such self–other integration (indexed by the joint Simon effect) is enhanced by agent similarity of the co-actor (e.g., high in intentionality). In this study, we aimed to extend this line of research by testing whether experiencing agency over a co-actor’s actions (vicarious agency) and/or action prediction strengthens the joint Simon effect. For this purpose, we manipulated experienced agency by varying the experienced control over a co-actor’s actions (Experiment 1), and action prediction regarding the co-actor’s actions (Experiment 2). Vicarious agency could effectively be induced, but did not modulate the size of the joint Simon effect. The joint Simon effect was decreased when the co-actor’s actions were unpredictable (vs. predictable) during joint task performance. These findings suggest social agency can be induced and effectively measured in joint action. Action prediction can act as an effective agency cue modulating the amount of self–other integration in joint action.

This paper looks into the relationship between students’ university choices and their secondary school background. The main aim is to assess the role of secondary schools in steering university applications toward local or non-local institutions, also in the light of the tertiary education supply available in students’ areas of residence. With this aim, we classify students’ mobility choices by using a robust definition of local and non-local universities that accounts for the uncertainty in the definition of students’ local areas and their characteristics. In this framework, we apply a multilevel model to jointly consider the high school effect on the probability of students belonging to one specific category of mobility (local, forced non-local, free non-local) conditional upon students’ macro areas of residence, their chosen university and field of study. The findings highlight that high schools have a relevant role in affecting students’ mobility choices, especially when considering local universities. The magnitude of the effect depends on students’ macro area of residence. In particular, this result highlights that schools may pursue specific guidance policies to address students’ choices toward local universities; furthermore, it suggests that their influence on students is stronger in areas hosting the most important universities.

IntroductionThe increased incidence of cutaneous melanoma (CM) and Merkel cell carcinoma (MCC) in patients with hematologic malignancies (HM) is well established. While the risk of CM has been assessed in some subtypes of HM including cutaneous T-cell lymphoma, the incidence in patients with primary cutaneous B-cell lymphoma (PCBCL) has not been interrogated.MethodsHere we evaluated the standardized incidence ratio (SIR) of CM and MCC in 5,179 PCBCL patients compared to approximately 1.5 billion individuals in the general population using the Surveillance, Epidemiology and End Results (SEER) database. Among patients with PCBCL, we identified subgroups that were at increased risk for CM or MCC as a second primary cancer.ResultsWe found 36 cases of CM in the PCBCL cohort (SIR, 1.35; 95% CI, 0.94–1.86), among which SIR was significantly elevated for non-Hispanic White patients compared to the general population (SIR, 1.48; 95% CI, 1.03–2.06). Males had a significantly increased risk of developing CM after a diagnosis of PCBCL (SIR, 1.60; 95% CI, 1.10–2.26). We found that males in the age group of 50–59 were at increased risk for CM development (SIR, 3.02; 95% CI, 1.11–6.58). Males were at increased risk of CM 1–5 years after PCBCL diagnosis (SIR, 2.06; 95% CI, 1.18–3.34). Patients were at greater risk of developing MCC within 1 year of diagnosis of PCBCL (SIR, 23.60; 95% CI, 2.86–85.27), particularly in patients who were over the age of 80 (SIR, 46.50; 95% CI, 5.63–167.96). Males aged 60–69 with PCBCL, subtype marginal zone, were also at increased risk for MCC (SIR, 42.71; 95% CI, 1.08–237.99).ConclusionThere is an increased incidence of CM in White, middle-aged males within 5 years of diagnosis of PCBCL and an increased risk of MCC in elderly patients within 1 year of PCBCL diagnosis. These data suggest that certain subgroups of patients with PCBCL may require more rigid surveillance for CM and MCC.

Supplementary Data from Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma

Supplementary Figure from Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL.Significance:Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival.This article is highlighted in the In This Issue feature, p. 85

Supplementary Table 1A (ST1A). Clinical features of CTCL (MF and SS) patients used in Figure 1B and Figure 4E (denoted with *). Stage 1B and IIB are MF samples and Stage III/IV are SS samples. Supplementary Table 1B (ST1B). Clinical features of SS patients whose CD4+ T cells were used in Figure 1C. Supplementary Table 1C (ST1C). Clinical features of SS patients whose CD4+ T cells were used in Figure 5B and Supplementary Figure 1D-F (denoted with #). Supplementary Table 1D (ST1D). Clinical features of SS patients whose CD4+ T cells were used in Figure 4D and 5A.

Supplementary Figure Legends

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