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Bruno Bordoni,1 Luca Mapelli,1 Anastasia Toccafondi,1 Francesca Di Salvo,1 Gianmarco Cannadoro,1 Matteo Gonella,1 Allan R Escher,2 Nuccia Morici1 1Dipartimento di Cardiologia, Fondazione Don Carlo Gnocchi IRCCS, Istituto di Ricovero e Cura, S Maria Nascente, Milano, 20100, Italy; 2Department of Anesthesiology/Pain Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USACorrespondence: Bruno Bordoni, Email bordonibruno@hotmail.comAbstract: Myocardial infarction (MI) is one of the leading causes of death worldwide. There can be many reasons that cause MI, such as a sedentary lifestyle, a disordered diet, harmful habits such as smoking and alcoholism, concomitant congenital or acquired systemic pathologies. Patients who survive the acute event suffer a functional alteration of multiple body systems. The various cardiology associations recommend starting a rehabilitation process, pursuing the main objective of improving the patient’s health status. A negative consequence that can be linked to MI is the dysfunction of the main breathing muscle, the diaphragm. The diaphragm is essential not only for respiratory mechanisms but also for adequate production of cardiac pressures. Post-MI patients present a reduction in the performance of the diaphragm muscle, and this condition can become a risk factor for further relapses or for the onset of heart failure. The article reviews the rehabilitation path for post-MI patients, to highlight the absence given to the diaphragm in the recovery of the patient’s health status. The text reviews the post-MI diaphragmatic adaptation to highlight the importance of including targeted training for the diaphragm muscle in the rehabilitation process.Keywords: myocardial infarction, diaphragm, cardiovascular disease, breathing, physiotherapy, cardiac rehabilitation

Bay-scale empirical evaluations of how bivalve aquaculture alters plankton composition, and subsequently ecological functioning and higher trophic levels, are lacking. Temporal, inter- and within-bay variation in hydrodynamic, environmental, and aquaculture pressure complicate plankton monitoring design to detect bay-scale changes and inform aquaculture ecosystem interactions. Here, we used flow cytometry to investigate spatio-temporal variations in bacteria and phytoplankton (< 20 μm) composition in four bivalve aquaculture embayments. We observed higher abundances of bacteria and phytoplankton in shallow embayments that experienced greater freshwater and nutrient inputs. Depleted nutrient conditions may have led to the dominance of picophytoplankton cells, which showed strong within-bay variation as a function of riverine vs marine influence and nutrient availability. Although environmental forcings appeared to be a strong driver of spatio-temporal trends, results showed that bivalve aquaculture may reduce near-lease phytoplankton abundance and favor bacterial growth. We discuss confounding environmental factors that must be accounted for when interpreting aquaculture effects such as grazing, benthic-pelagic coupling processes, and microbial biogeochemical cycling. Conclusions provide guidance on sampling considerations using flow cytometry in aquaculture sites based on embayment geomorphology and hydrodynamics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sharpe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To evaluate the extent to which postoperative complications impact patient health-related quality of life (HRQoL) and survival after pancreatic surgery., Background: Pancreatectomy is frequently associated with severe postoperative morbidity, which can affect patient recovery. Few and conflicting data are available regarding the effect of post-pancreatectomy complications on patient-reported HRQoL., Methods: This is an observational cohort study including consecutive patients enrolled in a prospective clinical trial (NCT04431076) who underwent elective pancreatectomy (2020-2022). Before surgery and on postoperative days 15, 30, 90, and 180, patients completed the PROMIS-29 profile and Duke Activity Status Index questionnaires to assess their HRQoL and functional capacity. Mean differences in HRQoL scores were obtained using multivariable linear regression adjusting for preoperative scores and confounders., Results: Of 528 patients, 370 (70%) experienced morbidity within 90 days, and 154 (29%) had severe complications (Clavien-Dindo grade >2). Delayed gastric emptying had the greatest impact on HRQoL, showing decreased mental health up to POD90 and physical health up to POD180 compared with uncomplicated patients. An inverse relationship between complication severity grade and HRQoL was evident for most domains, with Clavien-Dindo grade 3b to 4 patients showing worse HRQoL and functional capacity scores up to 6 months after surgery. In 235 pancreatic cancer patients, grade 3b and 4 complications were associated with reduced disease-specific survival (median 25 vs 41 mo, P <0.001)., Conclusions: In patients undergoing pancreatic resection, postoperative complications significantly impact all domains of patient quality of life with a dose-effect relationship between complication severity and impairment of HRQoL and functional capacity., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Clozapine is effective in treatment-resistant schizophrenia but with adverse effects including sedation. Excessive daytime sleepiness, a symptom of hypersomnolence, is the most frequently reported subjective side-effect. The aim of this systematic review was to synthesise the literature evaluating the impact of clozapine on the objective assessment of hypersomnolence in people with schizophrenia. We systematically searched databases for articles evaluating hypersomnolence with electrophysiological or psychomotor/cognitive measures in clozapine-treated patients with schizophrenia. Objective assessment of hypersomnolence was evaluated in six studies. All studies using polysomnography (PSG) found significantly longer total sleep time and shorter sleep onset latency in patients treated with clozapine at initiation of clozapine. The study with the multiple sleep latency test (MSLT) also found a shorter sleep onset latency. These observations did not persist 4-6 weeks after treatment initiation. Further investigations are needed. Longer total sleep time should be investigated with standardised long-term PSG to investigate excessive sleep quantity. Shorter sleep onset latency should be investigated with the MSLT or the maintenance of wakefulness test to investigate the excessive propensity to fall asleep or ability to stay awake. Lastly, sleep inertia should be investigated specifically in the morning., (© 2024 European Sleep Research Society.)

Introduction: Heart transplantation (HTx) serves as the gold-standard therapy for end-stage heart failure, yet patients often experience physical deconditioning and cognitive impairments post-surgery. Cardiac rehabilitation (CR) has shown promise in the HTx context. However, uncertainty surrounds the impact of biological sex. Accordingly, the aim of this paper was to investigate the impact of biological sex in a cohort of patients with HTx early admitted to a residential CR program., Methods: This was a retrospective analysis involving patients who underwent HTx at Niguarda Hospital and who subsequently participated in a CR program at IRCCS Fondazione Don Gnocchi, Milan, Italy, between 2010 and 2022. The primary endpoint was time to event (in months), with an event defined as a composite outcome of whichever occurred first of death, allograft rejection, or cardiac allograft vasculopathy up to 30 months follow-up., Results: In a total of 129 patients, 60 % male, and 40 % female, baseline characteristics presented comparably between the sexes. At 6 months, no significant sex differences were observed for the primary composite outcome. However, at 30 months, females exhibited a significantly lower incidence of the primary composite outcome and an increased survival rate. Multivariable analysis confirmed a protective effect of female sex against mortality (F vs. M, HR 0.164, 95 % CI 0.038-0.716, P = 0.0161)., Conclusions: Despite limitations, our findings emphasize that sex affects post-HTx long-term follow-up following CR discharge, with more favorable outcomes for female recipients. In an era of tailored management algorithms, it is imperative to take into account the gender gap even in cardiac rehabilitation., Competing Interests: The authors of this manuscript have no conflicts of interest to disclose., (© 2024 The Authors.)

Background: A highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database., Methods: First, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) "Suicide/Self-injury" and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect., Results: Four cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt., Conclusions: ETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julie Macey declares participation on a Data Safety Monitoring Board and Advisory Board for Vertex Pharmaceuticals. The other authors have nothing to declare., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Purpose: In the last decade trastuzumab biosimilars became more and more frequent. Among their uses, from several years, they have been available in Europe for the treatment of HER2-positive metastatic breast cancer, as an alternative to Herceptin®., Methods/patients: This meta-analysis aimed to analyze the available literature with particular focus on phase 3 randomized clinical trials (RCTs) comparing adverse events between trastuzumab biosimilar and originator. A systematic review was conducted in Pubmed and Scopus to include all phase 3 RCTs related to trastuzumab in patients with HER2-positive breast cancer and published up to July 31, 2023. Of the 508 records identified, 14 articles were meta-analyzed for safety information, including serious treatment emergent adverse events, death-related adverse events, neutropenia, leukopenia, infections, increased ALT, increased AST, anti-drug antibody, and neutralizing antibody., Results: Included patients had an early breast cancer (N=2,877) or a metastatic breast cancer (N=2,603). No significant difference in death-related adverse events was found for trastuzumab biosimilar and originator when evaluated for an early breast cancer in the neoadjuvant phase (Risk Ratio [RR], 1.30; 95% confidence interval [CI], 0.47-3.59; I2 = 0%; p = 0.57) and overall (RR, 0.43; 95%CI, 0.11-1.66; I2 = 20%; p = 0.26), and for metastatic breast cancer (RR, 0.61; 95%CI, 0.30-1.26; I2 = 0%; p = 0.85)., Conclusions: No difference was also observed for all other safety outcomes as in accordance with clinical studies necessary for the registration and approval of a biosimilar at a European level., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: How epilepsy surgery influences the bidirectional relationship of epilepsy and depression remains poorly defined., Method: For a better understanding of this question, we conducted a systematic review and meta-analysis of risk ratio on depression prevalence before and after epilepsy surgery, using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Three databases were comprehensively screened for all studies assessing depression before and after resective surgery in adult epileptic patients until 8 October 2022. Studies were included if depression was assessed before and after epilepsy surgery regardless of the time of follow-up. A total of 1917 studies were screened for eligibility and 91 full-texts up for inclusion; 35 studies were finally included, 25 studies and 2563 patients were included in main meta-analysis and 10 for exploratory analysis. Risk of bias was assessed using Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) from Cochrane. To derive the pooled depression rates before and after surgery, a meta-analysis with inversed-variance was performed using random-effects logistic models with Peto's correction and a 95% CI. Heterogeneity was assessed with Cochran's Q-test along with its derived measure of inconsistency I 2 ., Results: Overall, the depression rates before and after resective epilepsy surgery were 0.70 (0.53 to 0.91) 95% CI, suggesting that the rate of depression at last follow-up evaluation tends to decrease after Resective Epilepsy Surgery (RES). Subgroup analysis suggest a positive long-term effect appears with a significant lower rates of depression already 6 months (0.61 (0.38 to 0.98)), after surgery which is maintained over time after 1 year (0.53 (0.31 to 0.90)), and after 2 years (0.62 (0.42 to 0.92))., Conclusion: This important finding should be taken in consideration before resective surgery for drug-resistant epilepsies. However, prospective studies should be conducted to characterise which patient, at the individual level, might be at risk of de novo or worsening of depression., Prospero Registration Number: CRD42022355386., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, is a systemic vasculitis characterized by eosinophil-rich, necrotizing granulomatous inflammation primarily affecting the respiratory tract with necrotizing vasculitis of small- to medium-sized arteries. In this case series, we retrospectively evaluated the efficacy and safety of mepolizumab in seven patients diagnosed with EGPA who presented to the Department of Allergy and Clinical Immunology at Cleveland Clinic Abu Dhabi. The variables assessed before and after mepolizumab treatment included Birmingham Vasculitis Activity Score (BVAS), prednisolone dose, Asthma Control Test (ACT) score, and blood eosinophil count (BEC). We found a significant reduction in BVAS and prednisolone dosage with clinical improvements in asthma symptoms after treatment with mepolizumab. Our case series, the first from the Middle East on the use of mepolizumab in EGPA, demonstrates that mepolizumab is a safe and effective treatment for patients with EGPA., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Abuzakouk et al.)

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance., (© 2024. The Author(s).)

Background and Aim: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts., Methods: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting., Results: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts., Conclusions: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence., (© 2024. The Author(s).)

Objectives: In France, decisions for pricing and reimbursement for medicinal products are based on appraisals performed by the National authority for health ( Haute Autorité de Santé (HAS)). During the appraisal process, additional real-world evidence can be requested as "Post-Registration Studies" (PRS) when there are uncertainties in evidence that could be resolved by additional data collection. To facilitate PRS planning, a retrospective exploratory analysis was conducted to identify the characteristics of medicinal products associated with a PRS request., Methods: This analysis encompassed all appraisals finalized between January 1, 2016 and December 31, 2021 and compared products for which the appraisal led to a PRS request with those that did not., Results: Six hundred positive opinions for reimbursement were identified, with a PRS request present in 17 percent (n = 103) of cases. The independent characteristics associated with a PRS request were a mild or moderate clinical benefit score, a major to moderate or minor clinical added value score, previous availability under an early access program, and certain therapeutic areas (neurology, pulmonology, and endocrinology). These findings suggest two different profiles of PRS requests: (i) products for which there is uncertainty in the size of the clinical benefit and (ii) innovative products for which a substantial benefit is expected but uncertainties persist., Conclusions: These results will assist health technology developers to better anticipate data generation to promptly address uncertainties identified by HAS. It may also help HAS and other assessment agencies to work together to improve postlaunch evidence generation according to the characteristics of the medicinal products.

Background: The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011., Objectives: This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal., Methods: A cross-sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months., Results: A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment., Conclusion: Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders., (© 2023 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Daridorexant (dari), as the first dual orexin receptor antagonist (DORA) marketed in Europe, offers a novel therapeutic approach to insomnia. However, data regarding its real-world safety are scarce. Thus, this study was aimed at assessing its safety profile using a large-scale pharmacovigilance database. Dari-related adverse drug reaction (ADR) reports from the Food and Drug Administration Adverse Event Reporting System were scrutinized, and ADRs were selected using reporting odds ratio (ROR) as a measure of disproportionality. Frequencies of events related to dari were compared to all other drugs (reference group, RG1) and only to other DORAs (RG2). Only significant disproportionalities to both RGs were evaluated in-depth. A total of 845 dari-related reports were selected; nightmares ( n = 146; dari vs. RG1: ROR = 113.74; 95%CI [95.13, 136]; dari vs. RG2: ROR = 2.35; 95 CI% [1.93, 2.85]), depression ( n = 22; dari vs. RG1: 2.13; [1.39, 3.25]; dari vs. RG2: ROR = 2.31; 95 CI% [1.45, 3.67]), and hangover ( n = 20; dari vs. RG1: ROR = 127.92; 95 CI% [81.98, 199.62]; and dari vs. RG2: 3.38; [2.04, 5.61]) were considered as safety signals. These data provide valuable insights into the real-world safety profile of daridorexant, supporting the existence of safety signals related to nightmares, depression, and hangovers.

The design mebendazole (MBZ) multicomponent systems is important to obtain new materials that incorporate the API (active pharmaceutical ingredient) with better thermal stability, avoiding the interconversion of desmotropes. Interestingly, the presence of water molecules in the mebendazolium mesylate monohydrate prevents the formation of the R 2 2 (8) supramolecular synthon, found in all mebendazolium salts with polyatomic counterions. Here, we designed a new mebendazolium mesylate anhydrous salt based on statistical scrutiny of all mebendazole crystal structures identified in the literature and an exhaustive analysis of the conformational and geometrical requirements for the supramolecular assembly. The synthesis of this new salt and its solid-state characterization through single-crystal X-ray diffraction and complementary techniques are presented. As expected, mebendazole recrystallization in methanol with methanesulfonic acid - a Food and Drug Administration accepted coformer - in the absence of water yields a mesylate anhydrous salt with 1 : 1 stoichiometry. This new salt crystallizes in the P 2 1 2 1 2 1 (19) space group. The main intermolecular interactions found in the crystal structure are the hydrogen bonds that form a R 2 2 (8) supramolecular motif that assembles the ionic pairs. Additional non-classical H-bond, as well as π⋯π and carbonyl⋯cation interactions, contribute to the final stabilization of the crystal packing. This new salt is stable up to 205 °C when it undergoes the endothermic loss of the ester moiety to yield 2-amino-5-benzoylbenzimidazole. Moreover, preliminary dissolution experiments in aqueous 0.1 mol L -1 HCl suggest an apparent solubility of mebendazolium mesylate anhydride 2.67 times higher than that of the preferred for pharmaceutical formulations MBZ form C., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Limited data comparing recovery of health-related quality of life (HRQoL) after laparoscopic (LDP) versus open distal pancreatectomy (ODP) are available. The aim of this study was to assess the impact of laparoscopy on postoperative HRQOL after DP using the Patient-Reported Outcomes Measurement Information System (PROMIS)., Methods: Data from consecutive patients who underwent DP (2020-2022) enrolled in a prospective clinical trial were reviewed. Patients completed PROMIS-29 plus 2 profile preoperatively, at postoperative day (POD) 15, 30, 90, and 180. Linear regression analysis adjusting for confounders including preoperative PROMIS scores, age, gender, ASA score, diagnosis, and multivisceral resection was used to estimate mean between-group differences (MD) in postoperative PROMIS domains T scores., Results: Overall, 202 patients (118 laparoscopic, 86 open) underwent DP (median age 66 years, pancreatic cancer 41%, multivisceral resection 10%, median LOS 6 days). At POD15, LDP was associated with higher physical function (MD 5.6) and participation in social roles and activities scores (MD 3.8), reduced fatigue (MD - 2.7) and sleep disturbance (MD - 3.8) compared to ODP. At POD30, LDP patients had higher physical function (MD 5.2) and participation in social roles and activities scores (MD 6.0), reduced fatigue (MD - 3.5), and anxiety (MD - 4.0) compared to ODP. No between-group differences were found in HRQoL domains at POD90 and 180. Six months after surgery, the proportions of patients who had not recovered to preoperative physical function, participation in social roles and activities, fatigue, pain interference, sleep disturbance, cognitive function, depression, and anxiety were 31%, 31%, 28%, 20%, 15%, 14%, 8%, and 7%, respectively., Conclusions: According to PROMIS, LDP resulted in improved physical and social functioning and reduced anxiety and fatigue up to 30 days after surgery compared to ODP. At 6 months after surgery, recovery of physical domains is still incomplete in up to 30% of patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Heart transplant (HTx) is gold-standard therapy for patients with end-stage heart failure. Cardiac rehabilitation (CR) is a multidisciplinary intervention shown to improve cardiovascular prognosis and quality of life. The aim in this randomized controlled trial is to explore the safety and efficacy of cardiac telerehabilitation after HTx. In addition, biomarkers of rehabilitation outcomes will be identified, as data that will enable treatment to be tailored to patient phenotype., Methods: Patients after HTx will be recruited at IRCCS S. Maria Nascente - Fondazione Don Gnocchi, Milan, Italy (n = 40). Consenting participants will be randomly allocated to either of two groups (1:1): an intervention group who will receive on-site CR followed by 12 weeks of telerehabilitation, or a control group who will receive on-site CR followed by standard homecare and exercise programme. Recruitment began on 20th May 2023 and is expected to continue until 20th May 2025. Socio-demographic characteristics, lifestyle, health status, cardiovascular events, cognitive function, anxiety and depression symptoms, and quality of life will be assessed, as well as exercise capacity and muscular endurance. Participants will be evaluated before the intervention, post-CR and after 6 months. In addition, analysis of circulating extracellular vesicles using Surface Plasmon Resonance imaging (SPRi), based on a rehabilomic approach, will be applied to both groups pre- and post-CR., Conclusion: This study will explore the safety and efficacy of cardiac telerehabilitation after HTx. In addition, a rehabilomic approach will be used to investigate biomolecular phenotypization in HTx patients., Trial Registration Number: ClinicalTrials.gov Identifier: NCT05824364., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce., Objectives: This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings., Methods: We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients ≥18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors., Results: Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45])., Conclusions: In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups., (© 2023 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.)

Introduction: In 2021, the massive Covid-19 vaccination campaign in France was accompanied by an intensified pharmacovigilance monitoring of their potential adverse drug reactions. The importance of this reporting might have led to an important selective reporting and overloading of Pharmacovigilance Centres, delaying the recording of some reports in the national pharmacovigilance database. In this context, we aimed to evaluate the impact of the Covid-19 vaccination campaign in France and related reports on spontaneous reporting of adverse drug reactions that were not related to the Covid-19 vaccine., Methods: We performed time-series analyses considering the monthly number of adverse drug reactions reported between January 1, 2018 and April 30, 2022 using the French Pharmacovigilance database. The impact of the Covid-19 vaccination campaign on the monthly reporting not Covid-19 vaccine related was estimated using interrupted time-series. January 2021, marking the start of the campaign, was the intervention date in the models. Analyses were run globally first considering all adverse drug reaction reports, and second according to notifier type and to case seriousness., Results: We included 170,294 reports registered in the French Pharmacovigilance database between January 1, 2018 and April 30, 2022 that were not Covid-19 vaccine-related. Among these, 77,067 (45.3%) were serious and 146,683 (86.1%) had been reported by health care professionals. The campaign start was associated with a nearly 35.0% decrease in average monthly reporting that was not Covid-19 vaccine-related, with a significant level decrease in the monthly number of reports of -658.0 (p < 10 -3 ) immediately after the vaccination campaign start and a subsequent slope decrease of -50.0 (p < 10 -3 ). This decrease was mainly due to a significant level and slope decrease (level: -739.2 p < 10 -3 ; slope: -39 [p < 10 -2 ]) for health care professional reports. A similar level decrease was found for the monthly number of both serious and non-serious reports (-402.3, p < 10 -3 ; and -311.9, p = 10 -2 , respectively). According to the ATC 1 level, the decrease in the monthly number of reports showed similar patterns for all drugs. However, a potential increase in the number of serious reports suspecting antineoplastic and immunomodulating drugs (ATC L) or drugs targeting blood was observed (ATC B)., Conclusion: Our study showed a significant impact of the Covid-19 campaign vaccination in the reporting of adverse drug reactions that were not Covid-19 vaccine-related, of roughly 35%. This leads to a loss of information regarding the monitoring of drug safety that could have impacted the system capacity to detect safety signals for drugs other than Covid-19 vaccines., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To contribute evidence for the reliability, construct validity, and responsiveness of the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) profile questionnaire as a measure of recovery after pancreatic surgery., Background: PROMIS questionnaires have been recommended to evaluate postdischarge recovery after surgery. Evidence supporting their measurement properties in pancreatic surgery is missing., Methods: An observational validation study designed according to the COSMIN checklist was conducted including data from a prospective clinical trial. Patients undergoing pancreatectomy completed PROMIS-29 preoperatively and on postoperative days (PODs) 15, 30, 90, and 180. Reliability was assessed by internal consistency using Cronbach α. Construct validity was assessed by known-groups comparison. Responsiveness was evaluated hypothesizing that scores would be higher (1) preoperatively versus POD15, (2) on POD30 versus POD15, (3) on POD90 versus POD30, and (4) on POD180 versus POD90., Results: Overall, 510 patients were included in the study. Reliability was good to excellent (α values ranged from 0.82 to 0.97). Data supported 4 of 5 hypotheses tested for construct validity for 5 domains (physical function, anxiety, depression, fatigue, and ability to participate in social roles) at most time points. Responsiveness hypotheses 1, 2, and 3 were supported by the data for physical function, fatigue, sleep disturbance, pain interference, and ability to participate in social roles domains., Conclusions: PROMIS had excellent reliability, discriminated between most groups expected to have different recovery trajectories and was responsive to the expected trajectory of recovery up to 90 days after surgery. Our findings support the use of PROMIS-29 profile as a patient-reported outcome measure of postdischarge recovery after pancreatectomy., Competing Interests: C.L. was awarded the Society of American Gastrointestinal Endoscopic Surgeons (SAGES) 2022 Medical Student Summer Research Award to collaborate on this project. G.G.’s research fellowship, unrelated to this study, was funded by Fondazione Umberto Veronesi. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Two 1D coordination polymers (CPs) with general formula [M( L )(H 2 O)(AcO)] n , (M = Co ( 1 ) or Cd ( 2 ), AcO = acetate anion and L denotes l-phenylalanine based ligand), were synthesized and fully characterized by various spectroscopies (UV-vis, FTIR, and NMR), thermal techniques, magnetic measurements (for 1 ), and single-crystal and powder X-ray diffraction studies. They can be described as "ribbon-like" 1D polymers constructed through a zigzag arrangement. The polymeric structure is developed due to the coordination mode adopted by the amino acid ligand, classified as μ 3 - N 1 O 1 :O 1 :O 2 , which simultaneously links three metal centers. This moiety also plays an important role as a magnetic coupler between metal centers in the cobalt system, which shows a weak antiferromagnetic interaction. Both CPs have also been used in the catalytic oxidation of cyclohexene with molecular oxygen (O 2 ) as an oxidant. Under mild conditions, both compounds demonstrated remarkable catalytic activity, with the cobalt system being more efficient than the cadmium analogue (conversion: 73 and 58% and selectivity for the major product, 2-cyclohexanone: 63 and 55%, for 1 and 2 , respectively). Leaching experiments and the results obtained using a radical quencher are consistent with a radical-mediated mechanism for the Co compound. The presence of the superoxide radical was also confirmed using EPR spectroscopy and DMPO as a spin trap, which was further validated by DFT calculations. The activity observed for the Cd analogue is attributed to the organic scaffold assisted by the templating effect of the metal ion.

Cannabidiol is the first cannabis-derived drug approved for the treatment of Lennox-Gastaut syndrome, Dravet syndrome, and Tuberous Sclerosis Complex. In the current study, we performed a descriptive analysis followed by a disproportionality analysis of potential adverse events caused by CBD extracted from the VigiBase ® database. Furthermore, the biological plausibility of the association between CBD and the serotonin 5-HT 1A receptor as a possible cause of adverse events was analyzed and discussed. Data were extracted from the VigiBase ® database using the VigiLyze ® signal detection and signal management tool. Adverse events in VigiBase ® reports were coded using MedDRA, version 19 of Preferred Terms (PTs). Data were uploaded into SPSS software and analyzed via a disproportionality analysis. Statistically significant disproportionality signals for CBD were found for "weight decreased" (5.19 (95% CI: 4.54-5.70)), "hypophagia" (3.68 (95% CI: 3.22-5.27)), and "insomnia" (1.6 (95% CI: 1.40-1.83)). Positive IC025 values were found for "weight decreased" (2.2), "hypophagia" (1.3), and "insomnia" (0.5), indicating a surplus of reported cases. CBD's interactions with 5-HT 1A serotonin receptors may offer a potential biological explanation for the occurrence of insomnia in patients. It is noteworthy that the risk profiles mentioned in the information for prescribing CBD as an antiepileptic agent by regulatory agencies showed disparities specifically related to the adverse event "insomnia".

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Cardiovascular comorbidities are not contraindications of bevacizumab for metastatic colorectal cancer., Objective: We aimed to evaluate the impact of cardiovascular comorbidities before bevacizumab treatment on overall survival and cardiovascular safety in older patients with metastatic colorectal cancer., Methods: A 2009-2015 cohort of patients with metastatic colorectal cancer aged ≥ 65 years administered first-line bevacizumab was extracted from the French healthcare reimbursement claims database. Baseline heart failure, hypertension, and venous/arterial thromboembolic events were identified. The 36-month overall survival rate was evaluated using the Kaplan-Meier method, and the impact of cardiovascular comorbidities on the 36-month overall survival using a time-dependent, multivariable, Cox proportional hazards model. The 36-month cumulative incidence of cardiovascular events, and the impact of cardiovascular comorbidities on the likelihood of cardiovascular events were evaluated using the Fine and Gray model, with death as a competing risk., Results: We included 9222 patients (56.4% male; median age 73 years). Two-thirds (66.7%) had baseline cardiovascular comorbidities. The median 36-month overall survival was 20.4 [95% confidence interval (CI) 19.9-21.0] and 21.8 [95% CI 21.1-22.6] months in patients with and without cardiovascular comorbidities, respectively. Age ≥ 75 years, dependency in activities of daily living, radiotherapy, and another targeted therapy were identified as death risk factors, but not cardiovascular comorbidities. At 36 months, cardiovascular events had occurred in 60.2% [95% CI 58.9-61.4] and 44.1% [95% CI 42.3-45.9] of patients with and without cardiovascular comorbidities. Baseline venous thrombosis, female, three or more cardiovascular medications, another targeted therapy, and more than six bevacizumab injections were identified as risk factors for cardiovascular events., Conclusions: In clinical practice, cardiovascular comorbidities before administering bevacizumab to older patients with metastatic colorectal cancer impacted the cardiovascular safety, but not overall survival. Unless they limit functional independency, older patients with cardiovascular comorbidities should be treated with bevacizumab under close monitoring., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Aim: Disproportionality analysis is traditionally used in spontaneous reporting systems to generate working hypotheses about potential adverse drug reactions: the so-called disproportionality signals. We aim to map the methods used by researchers to assess and increase the validity of their published disproportionality signals., Methods: From a systematic literature search of published disproportionality analyses up until 1 January 2020, we randomly selected and analyzed 100 studies. We considered five domains: (1) rationale for the study, (2) design of disproportionality analyses, (3) case-by-case assessment, (4) use of complementary data sources, and (5) contextualization of the results within existing evidence., Results: Among the articles, multiple strategies were adopted to assess and enhance the results validity. The rationale, in 95 articles, was explicitly referred to the accrued evidence, mostly observational data (n = 46) and regulatory documents (n = 45). A statistical adjustment was performed in 34 studies, and specific strategies to correct for biases were implemented in 33 studies. A case-by-case assessment was complementarily performed in 35 studies, most often by investigating temporal plausibility (n = 26). Complementary data sources were used in 25 articles. In 78 articles, results were contextualized using accrued evidence from the literature and regulatory documents, the most important sources being observational (n = 45), other disproportionalities (n = 37), and case reports (n = 36)., Conclusions: This meta-research study highlighted the heterogeneity in methods and strategies used by researchers to assess the validity of disproportionality signals. Mapping these strategies is a first step towards testing their utility in different scenarios and developing guidelines for designing future disproportionality analysis., (© 2023. The Author(s).)

Aim of the Study: Post-mRNA coronavirus diseases 2019 (COVID-19) vaccines myocarditis emerged as a rare adverse effect, particularly in adolescents and young adults, and was labeled as such for both vaccines in the summer of 2021. This study aims to summarize the timeline and process of signal detection, substantiation, and quantification of myocarditis cases related to mRNA vaccines in France., Methods: The intensive monitoring plan for COVID-19 vaccine safety was based on case-by-case analysis of all cases collected in the French spontaneous reporting database (Base nationale de pharmacovigilance, BNPV). Cases were evaluated by drug safety medical professionals and discussed at a national level for signal detection purposes. Reported cases were compared to the number of vaccine-exposed persons up to September 30th, 2021. Reporting rates (Rr) of myocarditis per 100,000 injections were calculated and stratified according to age, gender, and injection rank of BNT162b2 and mRNA-1273 vaccines. Poisson distribution was used to compute Rrs 95% Confidence Interval (95% CI)., Results: The case-by-case analysis detected a possible cluster of myocarditis in April 2021 (5 cases, 4 after the 2nd injection). In June 2021, the signal was substantiated with 12 cases (9 related to BNT162b2, and 3 to mRNA-1273). As of September 2021, almost 73 million BNT162b2 and 10 million mRNA-1273 doses had been injected. The Rr per 100,000 injections was 0.5 (0.5-0.6) for BNT162b2 and 1.1 (95% CI 0.9-1.3) for mRNA-1273. The difference among vaccines was more pronounced after the second injection, particularly in men aged 18-24 years (4.3 [3.4-5.5] for BNT162b2 vs. 13.9 [9.2-20.1] for mRNA-1273) and aged 25-29 years (1.9 [1.2-2.9] vs. 7.0 [3.4-12.9])., Conclusion: The study highlighted the role of the spontaneous reporting system in the detection, assessment, and quantification of myocarditis related to m-RNA vaccines. It suggested from September 2021 that mRNA-1273 was reasonably related to a higher risk of myocarditis than BNT162b2 in people under 30, particularly after the second injection., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, tozinameran/BNT162b2 (Comirnaty®, Pfizer-BioNTech) and elasomeran/mRNA-1273 (Spikevax®, Moderna), were approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the end of 2020, less than a year after the start of the coronavirus disease 2019 (COVID-19) pandemic. In France, the health authorities have requested an intensive vaccination campaign, accompanied by a reinforced and active pharmacovigilance surveillance. This surveillance and analysis of real-life data, based on spontaneous reports received by the French Network of Regional PharmacoVigilance Centers (RFCRPV), has enabled to identify numerous pharmacovigilance signals. Some of them, such as myocarditis and heavy menstrual bleeding, have been confirmed as adverse effects of these vaccines., Method: We propose a descriptive review of the main pharmacovigilance signals identified by the RFCRPV concerning vaccines from the mRNA platform., Results: Most pharmacovigilance signals were common to both mRNA vaccines: myocarditis, menstrual disorders, acquired haemophilia, Parsonage-Turner syndrome, rhizomelic pseudo-polyarthritis and hearing disorders. Other signals were more specific, such as arterial hypertension with tozinameran or delayed reaction site injection with elasomeran., Conclusion: This non-exhaustive review illustrates the experience of RFCRPV in identifying and monitoring pharmacovigilance signals related to mRNA vaccines in France during the COVID-19 pandemics, and the crucial role of pharmacological and clinical expertise in this area. It also highlights the predominant contribution of spontaneous reporting in the generation of pharmacovigilance signals, particularly for serious and rare adverse events not detected before marketing., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Perineural invasion (PNI) is a common feature in pancreatic ductal adenocarcinoma (PDAC) and correlates with an aggressive tumor behavior already at early stages of disease. PNI is currently considered as a "present vs. absent" feature, and a severity score system has not yet been established. The aim of the present study was thus to develop and validate a score system for PNI and to correlate it with other prognostic features. In this monocentric retrospective study, 356 consecutive PDAC patients (61.8% upfront surgery patients, 38.2% received neoadjuvant therapy) were analyzed. PNI was scored as follows: 0: absent; 1: the presence of neoplasia along nerves < 3 mm in caliber; and 2: neoplastic infiltration of nerve fibers ≥ 3 mm and/or massive perineural infiltration and/or the presence of necrosis of the infiltrated nerve bundle. For every PNI grade, the correlation with other pathological features, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed. Uni- and multivariate analysis for DFS and DSS were also performed. PNI was found in 72.5% of the patients. Relevant trends between PNI score and tumor differentiation grade, lymph node metastases, vascular invasion, and surgical margins status were found. The latter was the only parameter statistically correlated with the proposed score. The agreement between pathologists was substantial (Cohen's K 0.61). PNI severity score significantly correlated also with decreased DFS and DSS at univariate analysis (p < 0.001). At multivariate analysis, only the presence of lymph node metastases was an independent predictor of DFS (HR 2.235 p < 0.001). Lymph node metastases (HR 2.902, p < 0.001) and tumor differentiation grade (HR 1.677, p = 0.002) were independent predictors of DSS. Our newly developed PNI score correlates with other features of PDAC aggressiveness and proved to have a prognostic role though less robust than lymph nodes metastases and tumor differentiation grade. A prospective validation is needed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Artificial intelligence (AI) based tools offer new opportunities for pharmacovigilance (PV) activities. Nevertheless, their contribution to PV needs to be tailored to preserve and strengthen medical and pharmacological expertise in drug safety., Areas Covered: This work aims to describe PV tasks in which the contribution of AI and intelligent automation (IA) tools is required, in the context of a continuous increase of spontaneous reporting cases and regulatory tasks. A narrative review with expert selection of pertinent references was performed through Medline. Two areas were covered, management of spontaneous reporting cases and signal detection., Perspective: The use of AI and IA tools will assist a large spectrum of PV activities, both in public and private PV systems, in particular for tasks of low added value (e.g. initial quality check, verification of essential regulatory information, search for duplicates). Testing, validating, and integrating these tools in the PV routine are the actual challenges for modern PV systems, to guarantee high-quality standards in terms of case management and signal detection.