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Abstract Background Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated. Method Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK. Results A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94–1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10–1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03–2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/μL. Conclusions In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).

Summary: Background: Little is known about the epidemiology and patterns of care of intrahepatic cholangiocarcinoma (iCCA) in daily clinical practice. The aims of this study were to estimate the number of declared cases during the study period 2014–2015 in France from a hospitalization database and to describe the healthcare trajectories of these patients. Methods: A retrospective analysis was carried out using the French nationwide prospective hospitalization database. All pts with a new diagnosis of ''carcinoma of the intrahepatic bile duct'' who had a first hospital stay in the Medicine, Surgery and Obstetrics departments (MSO) between 2014 and 2015 with a 2-year follow-up were included. Data related to the first identified stay (S1) in the MSO and on all subsequent stays in the MSO, aftercare and rehabilitation or home hospitalization were analysed. Findings: A total of 3650 new iCCA cases were identified. At S1 (admission via emergency room (ER) in 28%), the median age of the patients was 73 years, 57% were male and 35% had metastases. Jaundice/anaemia/ascites/cholangitis were reported in 17%/16%/12%/7% of patients, respectively. The care of patients at S1 was mainly provided in general hospitals (CHG, 60%). A total of 896 (24%) patients died during S1. They were more frequently hospitalized via the ER (48% vs 23%), metastatic (52% vs 35%) and symptomatic. Subsequent stays were identified for 2507 (69%) patients. Three healthcare pathways were defined: surgery (n = 519; 14%), chemotherapy (CT) without surgery (n = 812; 22%) and best supportive care (BSC) (n = 2319; 63%). CT, surgery and BSC were most frequently performed in the cancer centres, university hospitals and CHG, respectively. Interpretation: This medico administrative study reveals a higher number of iCCA cases than that previously reported by registries and highlights the severity of this disease. Funding: This study was sponsored by Incyte Biosciences International Sàrl., Geneva, Switzerland. INCYTE validated the design of the study, the analysis, the interpretation of data and the writing of the manuscript which was first written by the 2 experts and CEMKA.

Treatment-free remission (TFR) has become a primary therapeutic goal in CML and is also considered feasible by international guidelines. TKIs dose reduction is often used in real-life practice to reduce adverse events, although its impact on TFR is still a matter of debate. This study aimed to explore the attitude of Italian hematologists towards prescribing TKIs at reduced doses and its impact on TFR. In September 2020, a questionnaire was sent to 54 hematology centers in Italy participating to the Campus CML network. For each patient, data on the main disease characteristics were collected. Most of the hematologists involved (64.4%) believed that low-dose TKIs should not influence TFR. Indeed, this approach was offered to 194 patients. At the time of TFR, all but 3 patients had already achieved a DMR, with a median duration of 61.0 months. After a median follow-up of 29.2 months, 138 (71.1%) patients were still in TFR. Interestingly, TFR outcome was not impaired by any of the variables examined, including sex, risk scores, BCR-ABL1 transcript types, previous interferon, type and number of TKIs used before treatment cessation, degree of DMR or median duration of TKIs therapy. On the contrary, TFR was significantly better after dose reduction due to AEs; furthermore, patients with a longer DMR duration showed a trend towards prolonged TFR. This survey indicates that low-dose TKI treatment is an important reality. While one third of Italian hematologists still had some uncertainties on TFR feasibility after using reduced doses of TKIs outside of clinical trials, TFR has often been considered a safe option even in patients treated with low-dose TKIs in the real-life setting. It should be noted that only 28.9% of our cases had a molecular recurrence, less than reported during standard dose treatment. Consequently, TFR is not impaired using low-dose TKIs.

BackgroundThe anti-CD38 monoclonal antibody daratumumab is the backbone of most anti-multiple myeloma (MM) regimens. To mitigate the risk of infusion-related reactions (IRRs), intravenous daratumumab administration requires 7 hours for the first infusion and 3.5-4 hours thereafter, thus making daratumumab-containing regimens burdensome for patients and health care resources. Preliminary data suggest that a rapid (90-minute) infusion of daratumumab is safe and does not increase IRRs. The rapid schedule was adopted by our centers since 2019.MethodsWe conducted an observational multi-center, real-life study to assess the safety of rapid daratumumab infusion protocol from the third administration in relapsed MM patients receiving daratumumab alone or in combination with lenalidomide-dexamethasone or bortezomib-dexamethasone. The primary endpoint was the safety of the rapid infusion protocol, particularly in terms of IRRs.ResultsA total of 134 MM patients were enrolled. IRRs occurred in 7 (5%) patients and were mostly mild (6/7 of grade 1-2), with only 1 patient experiencing a grade 3 IRR. Due to the IRRs, 5 (3.7%) patients discontinued the rapid infusions and resumed daratumumab at the standard infusion rate, while 1 patient permanently discontinued daratumumab. In 4/7 patients (57%), IRRs occurred while resuming rapid daratumumab infusions after a temporary interruption (2-4 months). No other adverse event was considered related to the rapid infusion protocol.ConclusionsOur findings confirmed the safety of rapid daratumumab infusions starting from the third administration. In case of prolonged daratumumab interruption, it is advisable to resume infusions at the standard rate (3.5 hours) before switching to the rapid infusion.

Introduction: The 21-gene Oncotype DX Breast Recurrence Score® test, (Genomic Health, Redwood City CA) has not been formally evaluated in an older cohort with estrogen receptor (ER)-positive breast cancer (BC) in term of physicians' treatment decisions. We determine the utility of Recurrence Score® (RS) result on adjuvant therapy prescription in elderly patients with resected early BC. Material and methods: PONDx was a multicenter, prospective, observational study, and which investigated the real-life use of the Oncotype DX® test by physicians treating early BC patients in clinical practice. Results: Data from the elderly extracted from 1724 BC patients who underwent Oncotype DX testing were available from 27 reference centers located in 6 regions of Italy (Lombardia, Lazio, Emilia Romagna, Campania, Abruzzo, and Marche). A total of 230 patients (13% of the total population) aged > 70 years were analyzed. The study primarily evaluated the impact of the Oncotype DX test on adjuvant treatment decisions. Physicians chosen chemotherapy plus endocrine therapy in 36% of elderly patients and 46% of those 50–70 years before the Oncotype DX test. After knowing the RS data, these rates fell to 23 and 33% (38 and 28% relative reduction, respectively). Conclusions: 21-gene test may be helpful even in a relatively low-risk group as elderly patients and may avoid the toxicity of adjuvant chemotherapy in a significant amount. If the Oncotype DX test is currently adopted on a large scale among the elderly and may impact the general prognosis of elderly BC patients, it is challenging and still unproven. [ABSTRACT FROM AUTHOR]

Introduction and objectives: Little is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population. Material and methods: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC. Results: 562 patients (95% females, mean age 51 § 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 § 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates. Conclusions: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization. [ABSTRACT FROM AUTHOR]

Using video recounts from revenge porn victims, this study explores whether levels of victim blaming differs for the sharing of self- and stealth-taken sexually explicit images and videos. Building on previous work which has demonstrated victim blame for both self- and stealth generated images in occurrences of revenge porn (Zvi & Schechory-Bitton, 2020), the reported study presents an original and ecologically valid methodological approach whereby 342 (76 male, 266 female) participants (Mage = 39.27, SD = 11.70) from the UK watched videoed accounts of real experiences of falling victim to revenge porn, rather than using text based, often fictional, vignettes to attribute blame which dominate studies in this area. All data was collected in 2019. The results demonstrated that significantly more blame was assigned to victims when participants were indirectly rather than directly asked who was to blame for the occurrence of revenge porn, supporting the notion of an unconscious processing bias in attributing blame. More blame was also assigned to those victims who themselves generated the material compared to when it had been acquired without their awareness by a perpetrator, suggesting the cognitive bias to be in line with a just world hypothesis. Male participants were more likely to blame a victim than were female participants, although sex of victim and mode of shared sexually-explicit material (video or image) did not appear to affect levels of victim-blame. Findings are considered in terms of extant research and the need for future work in the area of victim blame and revenge pornography. [ABSTRACT FROM AUTHOR]

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Objective: The evolution of non-vitamin K antagonist anticoagulants (NOACs) has changed the horizon of stroke prevention in atrial fibrillation (SPAF). All 4 NOACs have been tested against dose-adjusted warfarin in well-designed, pivotal, phase III, randomized, controlled trials (RCTs) and were approved by regulatory authorities for an SPAF indication. However, as traditional RCTs, these trials have important weaknesses, largely related to their complex structure and patient participation, which was limited by strict inclusion and extensive exclusion criteria. In the real world, however, clinicians are often faced with complex, multimorbid patients who are underrepresented in these RCTs. This article is based on a meeting report authored by 12 scientists studying atrial fibrillation (AF) in diverse ways who discussed the management of challenging AF cases that are underrepresented in pivotal NOAC trials. Methods: An advisory board panel was convened to confer on management strategies for challenging AF cases. The article is derived from a summary of case presentations and the collaborative discussions at the meeting. Conclusion: This expert consensus of cardiologists aimed to define management strategies for challenging cases with patients who underrepresented in pivotal trials using case examples from their routine practice. Although strong evidence is lacking, exploratory subgroup analysis of phase III pivotal trials partially informs the management of these patients. Clinical trials with higher external validity are needed to clarify areas of uncertainty. The lack of clear evidence about complex AF cases has pushed clinicians to manage patients based on clinical experience, including rare situations of off-label prescriptions.

Background: The objective of this work is to document performance of automated insulin delivery (AID) during real-life use in type 2 diabetes (T2D)., Methods: A retrospective analysis was performed of continuous glucose monitoring and insulin delivery data from 796 individuals with T2D, who transitioned from 1-month predictive low-glucose suspend (PLGS) use to 3-month AID use, in real-life settings. Primary outcome was change of time in range (TIR = 70-180 mg/dL) from PLGS to AID. Secondary outcomes included time above/below range (TAR/TBR) and total daily insulin (TDI)., Results: Compared with PLGS, AID increased TIR on average from 63.2% to 72.6%, decreased TAR from 36.2% to 26.8%, and increased TDI from 70.2 to 76.3 U (all P < .001), without significant change to TBR. Glycemic improvements were more pronounced in those with worse glycemic control during PLGS use ( P < .001)., Conclusions: Real-life use of AID led to a rapid and sustained improvement of glycemic control in individuals with T2D., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.F. reports receiving patent royalties from Dexcom, Inc handled by the University of Virginia’s Licensing and Ventures Group. B.K. reports receiving research support from Dexcom, Inc and Tandem Diabetes Care handled by the University of Virginia; and patent royalties from Dexcom, Inc handled by the University of Virginia’s Licensing and Ventures Group. Tandem Diabetes Care provided the data analyzed in this work; Tandem Diabetes Care was not involved in the data analysis or interpretation of the results.

Background: The availability of mechanical thrombectomy (MT) is limited. Thus, there are two paradigms for patients living closer to a primary stroke center (PSC) than a comprehensive stroke center (CSC) capable of MT: "Mothership" (direct referral to a CSC) and "Drip-and-Ship" (referral to a PSC for imaging and thrombolysis and transfer to a CSC for thrombectomy or monitoring). We aimed to compare the prognosis of patients at three months between the two paradigms in a rural area., Materials: From September 2019 to March 2021, we prospectively included patients living closer to a PSC than the one CSC, regardless of the type of stroke or reperfusion treatment. The proportion of patients with a good functional outcome (Rankin≤2) at three months was compared between the two initial orientations for all patients and for subgroups: patients with ischemic stroke and patients treated by MT., Results: Among the 206 patients included, 103 were admitted directly to the CSC (82.5% had an ischemic stroke and 24.3% a MT) and 103 initially admitted to a PSC and then transferred to the CSC (100% had an ischemic stroke and 52.4% a MT). The proportion of patients with a good outcome was comparable between the two groups (54.5% vs. 43.7%, P=0.22). Among the 79 patients who underwent MT, the prognosis at three months was better in the Mothership group (49.3% vs. 15.3%, P=0.01)., Conclusion: The functional prognosis is comparable between Mothership and Drip-and-Ship paradigms in our setting, despite a trend towards a better prognosis for the Mothership. As has been shown in urban settings, the mothership paradigm also leads to a better prognosis for patients treated with MT in a rural setting., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Doravirine (DOR) efficacy and safety have been evaluated in adult naive or treated patients starting a DOR-based regimen between September 15, 2019, and December 31, 2020. Medical history and examination, laboratory results, and tolerance were assessed during the 48 weeks of follow-up. Among the 77 patients included, virological control (VC) was noticed for 66 patients at baseline. Median age was 51 years, and 62% were men. The most common reason for initiating a DOR-based therapy was toxicity (44; 67%) and, especially, weight gain. A virological suppression (VS) was maintained in 55 (83%) patients of the VC group and noticed in 9 (82%) of the non-VC patients at week 48, by intention-to-treat analysis. On treatment analysis, 98% and 100% patients achieved VS in the VC and non-VC groups, respectively. The renal and metabolic tolerance were good. DOR-based regimens appear to be a safe and relevant strategy to circumvent drug interactions and drugs with a poor metabolic tolerance profile. [ABSTRACT FROM AUTHOR]

Introduction: Since 2009, multiple randomized trials have shown faster and deeper responses in CML patients treated with new‐generation TKI (NG‐TKI) compared to those treated with imatinib (IM). Are the same results observed in the general population? Materials and Methods: Patients were identified from the three French hematological malignancies population‐based registries. All CML patients (ICD‐O‐3: 9875/3) diagnosed between 2006 and 2016 and resided in registries areas were included. The TKI generation effect on achievement of MMR in first‐line therapy was assessed through a multivariate competitive risk analysis. An alluvial plot described the pathways leading to death. Results: In total, 507 CML patients received TKI in first‐line treatment, 22% were enrolled in a clinical trial. After adjustment, NG‐TKI patients were significantly more likely to achieve MMR during first‐line therapy than IM patients (HR: 1.88 CI95% [1.35–2.61]). At the end of follow‐up, 212 patients were still in first‐line therapy (46 of them died), 203 switched to second‐line (43 subsequently died), 26 were on TFR from first‐line (4 subsequently died), and 20 stopped their treatment (16 subsequently died). Discussion: In this comprehensive real‐life setting, the results were consistent with clinical trials. The results are not sufficient to conclude that a NG‐TKI treatment is superior with regard to these patients, despite indications regarding differences between the TKI generation effect on survival and tolerance. [ABSTRACT FROM AUTHOR]

Most of our interactions with our environment involve manipulating real 3D objects. Accordingly, 3D objects seem to enjoy preferential processing compared with 2D images, for example, in capturing attention or being better remembered. But are they also more readily perceived? Thus far, the possibility of preferred detection for real 3D objects could not be empirically tested because suppression from awareness has been applied only to on-screen stimuli. Here, using a variant of continuous flash suppression (CFS) with augmented-reality goggles ("real-life" CFS), we managed to suppress both real 3D objects and their 2D representations. In 20 healthy young adults, real objects broke suppression faster than their photographs. Using 3D printing, we also showed in 50 healthy young adults that this finding held only for meaningful objects, whereas no difference was found for meaningless, novel ones (a similar trend was observed in another experiment with 20 subjects, yet it did not reach significance). This suggests that the effect might be mediated by affordances facilitating detection of 3D objects under interocular suppression. [ABSTRACT FROM AUTHOR]

Although cladribine induces sustained reductions in peripheral T and B lymphocytes, little is known about its effect on axonal damage reduction in multiple sclerosis (MS), which could be demonstrated by assessing the serum neurofilament light chain (sNfL) levels. We investigated the reduction/reconstitution of different lymphocyte subsets (LS) by verifying the correlation with no evidence of disease activity (NEDA) and the variation in sNfL levels during cladribine treatment. We analysed 33 highly active relapsing MS patients and followed them up for 12 ± 3.3 months; blood samples were collected at treatment start (W0) and after 8, 24 and 48 weeks. Seventeen patients (60.7%) showed NEDA during the first treatment. At week 8, we observed a significant decrease in B memory cells, B regulatory 1 CD19+/CD38+ and B regulatory 2 CD19+/CD25+, a significant increase in T regulatory CD4+/CD25+, a slight increase in T cytotoxic CD3+/CD8+ and a non-significant decrease in T helper CD3+/CD4+. Starting from week 24, the B subsets recovered; however, at week 48, CD19+/CD38+ and CD19+/CD25+ reached values near the baseline, while the Bmem were significantly lower. The T cell subsets remained unchanged except for CD4+/CD25+, which increased compared to W0. The LS changes were not predictive of NEDA achievement. The sNfL levels were significantly lower at week 24 (p = 0.046) vs. baseline. These results could demonstrate how cladribine, by inflammatory activity depletion, can also reduce axonal damage, according to the sNfL levels.

Introduction: Double antiplatelet therapy (DAPT) is indicated for the treatment of coronary artery diseases (CAD). The optimal duration of therapy with DAPT continues to be a subject of debate in the scientific community. To improve adherence to DAPT, the FDC (fixed dose combination) of Acetylsalicylic acid (ASA) and clopidogrel was developed into a single pill instead of two separate pills thus facilitating the dosage and administration of the therapy and increasing compliance. The aim of this study was to assess adherence and persistence over a period of two years in patients treated with DAPT composed of: ASA/clopidogrel, ASA/prasugrel, ASA/ticagrelor and FDC with ASA and clopidogrel in real life and to assess whether the use of ASA and clopidogrel FDC is associated with improved adherence.Materials and Methods: In the following retrospective pharmacological-observational non-interventional study, all patients treated with DAPT in the Hospital of Pescara from January 2010 to October 2019 were considered. Persistence to treatment is defined as the duration of time from initiation to discontinuation of treatment. Adherence was calculated as the ratio between Received Daily Dose (RDD) and Prescribed Daily Dose (PDD).Results: 277 patients treated with ASA/clopidogrel, 77 patients treated with ASA/prasugrel, 57 patients treated with ASA/ticagrelor and 108 patients treated with FDC of ASA/clopidogrel were analysed. Persistence curves at two years showed a statistically significant difference (p < 0.001). Adherence to therapy was optimal with an absolute value at two years of 0.96. Adherence was better in patients treated with ASA/prasugrel with a value of 0.98 and with 97 % of patients with an adherence value greater than or equal to 0.8, while, it was worse in patients treated with FDC ASA/clopidogrel with an absolute value of 0.94 and with 88 % of patients with an optimal adherence value. No statistically significant difference was found between the ASA/clopidogrel FDC in comparison to each component taken as a separate pill (p = 0.0752).Conclusion: DAPT along with ASA/clopidogrel showed a statistically significant better persistence than ASA/ticagrelor and ASA/prasugrel. Whereas, to our knowledge and as per the current literature no statistically significant differences were found, in terms of adherence in real life, between the use of ASA/Clopidogrel FDC and the use of two different pills. [ABSTRACT FROM AUTHOR]

Background: Various studies have assessed omalizumab outcomes in the clinical practice setting but follow‐up and/or number of patients included were limited. We aim to describe the long‐term outcomes of pediatric patients with severe persistent allergic asthma receiving omalizumab in the largest real‐life cohort reported to date. Methods: ANCHORS was a multicenter, observational, retrospective cohort study conducted in 25 Pediatric Allergy and Pulmonology units in Spain. We collected data of patients < 18 years and initiating omalizumab between 2006 and 2018, from the year prior to omalizumab initiation to discontinuation or last available follow‐up. The primary outcome was the evolution of the annual number of moderate‐to‐severe exacerbations compared with the baseline period. Results: Of the 484 patients included, 101 (20.9%) reached 6 years of treatment. The mean ± standard deviation number of exacerbations decreased during the first year of treatment (7.9 ± 6.6 to 1.1 ± 2.0, P <.001) and remained likewise for up to 6 years. The other clinical parameters assessed also improved significantly during the first year and stabilized or continued to improve thereafter. The percentage of patients experiencing adverse events was consistently low, and the main reason for discontinuation was good disease evolution. Conclusion: In this large, long‐term, observational study, moderate‐to‐severe exacerbations decreased significantly from the first year of treatment with omalizumab. The beneficial effect was maintained in the long term, along with a good safety profile. Our results position omalizumab as an effective long‐term treatment in pediatric patients with severe persistent allergic asthma. [ABSTRACT FROM AUTHOR]

The international PRECONNECT Phase IIIb study demonstrated safety and efficacy of trifluridine/tipiracil in the management of patients with metastatic colorectal cancer. Post-hoc analyses in a national context are important because of the differences in disease management across countries. Post-hoc safety and efficacy analyses in the PRECONNECT Italian patient subset were conducted. Patients' quality of life was assessed from baseline to end of treatment. In Italy, 161 patients were enrolled. The median age was 64 years, with a performance status of 0-1. The most common hematological drug-related adverse events ≥grade 3 were neutropenia (41.0%) and anemia (13.7%). The median progression-free survival was reached at 3.0 months, with a disease control rate of 28.6%. The Quality of Life Questionnaire Core 30 score improved in 25.4% of the patients. Safety, efficacy and quality of life results confirmed trifluridine/tipiracil as a feasible and favorable treatment option for metastatic colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Exposure to multiple synthetic chemicals is a permanent feature of modern life. Many of these chemicals are suspected to disrupt endocrine systems of humans and animals. Endocrine disrupting chemicals (EDCs) act at very low concentrations and non-linearly, defying mainstream single-substance chemical regulation. Here we provide an analysis of findings from the first phase of the European Horizon2020-funded "EDC-MixRisk" project as a case of contemporary life-science enterprise, which addresses health-risks related to real-life exposure to mixtures of EDCs. Real-life EDC mixtures were inferred in the project from biological samples taken from pregnant women in a large epidemiological study that followed up their children over several years across major health domains; responses to these mixtures were then experimentally identified, and based on these findings, mixture risk assessment models were developed. The project consequently advocated for European chemical regulation more attentive to real-life exposure. Locating it within historical and sociological analyses of chemical exposure and within the European chemical political context, we argue that scientific uncertainty related to real-life EDC mixture exposure enables a form of epistemological approach and scientific activism, simultaneously in continuity with, and in break from, mainstream toxicology. In a chemically polluted world, this kind of science still occupies a place in the tension between public health and market-oriented regulation. [ABSTRACT FROM AUTHOR]

This research examines how faculty members working in complex sociopolitical context cope with campus diversity. Through 20 focus groups comprised of faculty members representing all of the departments at one academic institution, we investigated the participants' experiences with student diversity. The findings show that the protracted Israeli–Palestinian conflict seeps into classroom interactions. This infiltration of the protracted conflict is particularly salient during escalations of the conflict. The participants feel they are unable to address these difficulties, experience isolation, fear, and a lack of support. The study expands understanding of how employees cope with political tensions in a real‐life setting. [ABSTRACT FROM AUTHOR]

The high cost of fidaxomicin has restricted its use despite the benefit of a lower Clostridioides difficile infection (CDI) recurrence rate at 4 weeks of follow-up. This short follow-up represents the main limitation of pivotal clinical trials of fidaxomicin, and some recent studies question its benefits over vancomycin. Moreover, the main risk factors of recurrence after treatment with fidaxomicin remain unknown. We designed a multicentre retrospective cohort study among four Spanish hospitals to assess the efficacy of fidaxomicin in real life and to investigate risk factors of fidaxomicin failure at weeks 8 and 12. Two-hundred forty-four patients were included. Fidaxomicin was used in 96 patients (39.3%) for a first episode of CDI, in 95 patients (38.9%) for a second episode, and in 53 patients (21.7%) for a third or subsequent episode. Patients treated with fidaxomicin in a first episode were younger (59.9 years vs 73.5 years), but they had more severe episodes (52.1% vs. 32.4%). The recurrence rates for patients treated in the first episode were 6.5% and 9.7% at weeks 8 and 12, respectively. Recurrence rates increased for patients treated at second or ulterior episodes (16.3% and 26.4% at week 8, respectively). Age greater than or equal to 85 years and having had a previous episode of CDI were identified as recurrence risk factors at weeks 8 and 12. We conclude that the outcomes with fidaxomicin in real life are at least as good as those observed in clinical trials despite a more demanding evaluation. Be it 85 years of age or older, and the use after a first episode appears to be independent factors of CDI recurrence after treatment with fidaxomicin. [ABSTRACT FROM AUTHOR]

AIM: To evaluate the real life anatomical and visual outcome after intravitreal anti-VEGF treatment in diabetic macular edema(DME)throughout 24mo. METHODS: Treatment naive central-involved DME patients with intraretinal and/or subretinal fluid and baseline central macular thickness(CMT)over 300 μm in spectral domain optic coherence tomography scans who received intravitreal injections between June 2012 and December 2016 were included in the study. The changes in visual acuity(VA)and CMT, and total number of patient visits and intravitreal injections were assessed in the baseline of 3, 6, 12, 18 and 24mo. RESULTS: Totally 54 eyes of 40 patients were included. VA at baseline improved from 0.67±0.47 LogMAR to 0.59±0.43 LogMAR at 3mo and maintained with 3.5±2.19 injections throughout 12mo. The average number of visits was 9±2.39 and 15.48±4.84 at 12mo and 24mo, respectively. The mean CMT at baseline was 450±153μm and decreased to 385±141μm and 305±111μm at 12 and 24mo, respectively(P CONCLUSION: Pro re nata(PRN)approach in DME treatment may keep the VA stable and reduce macular edema, but probably similar or better treatment effectivity could be obtained with a lower visit burden in proactive regimens.

This article aims to reveal how learners make use of a space for self-directed learning to promote collaborative autonomous learning, drawing on data collected at a Japanese language institution for the Economic Partnership Agreement (EPA) care worker candidates in Osaka. The data analysis shows that, through the activities the learners chose and organized, they imagined an ideal L2 self and created their own L2 world. As soon as the self-directed learning session had started, they created their own group on Facebook and promoted learning activities which were related with their real lives in Japan. These activities on Facebook created a learning space beyond the classroom. These online activities they engaged in eventually returned to the classroom space and led to them increasingly taking ownership of the physical space. This research reveals that an important factor for self-directed learning is providing learners spaces and allowing them to explore the boundaries and possibilities of that space. The learners in this case study used the space to translate their past experiences and present emotions into the second language context, and moreover, to strategize for the future. To encourage collaborative autonomous learning, the activities must be organized around learners’ inner worlds where their emotions, experiences and futures exist.

Abstract Introduction To report the 52-week treatment outcomes with intravitreal injections of aflibercept using a treat-and-extend regimen for treating macular edema secondary to central retinal vein occlusion (CRVO). Methods A retrospective analysis of patients newly diagnosed with CRVO was performed. Patients receiving aflibercept between 1 December 2016 and 31 March 2017 were included in the analysis. Data on age, gender, visual acuity measured on Early Treatment of Diabetic Retinopathy Study charts, presence of macular and peripheral ischemia, anatomical changes observed on spectral domain–optical coherence tomography examination and the number of injections needed were recorded. Results The mean gain in vision was 17.8 ± 19.1 (± standard deviation) letters and 15.1 ± 20.2 letters at weeks 24 and 52 of follow-up, respectively. The proportion of patients who gained ≥ 15 letters in best-corrected visual acuity was 52.9% at week 24 and 50% at week 52. The mean reduction in central subfield macular thickness was 331.5 and 311.6 at weeks 24 and week 52, respectively. For the patients completing 52 weeks of follow-up, the mean number of treatments was 4.9 ± 1.3 injections in the first 26 weeks and 3.2 ± 2.0 injections in the second 26 weeks. Conclusions The Moorfields protocol for treating macula edema in CRVO achieves a quick response to treatment without over- or under-treating patients with a fixed protocol. Overall, our individualized treat-and-extend protocol achieved real-life outcomes approaching those of clinical trials. As there are currently no such trials using this practically useful regimen, our study provides real-world evidence for using a treat-and-extend protocol for aflibercept in CRVO.

To date, therapeutic switches are performed to reduce and prevent toxicity, improve adherence, promote virological control, and save costs. Drug switches are a daily challenge in the management of people living with HIV (PLWH), especially in those with multiple comorbidities and on polypharmacy. The objectives of this prospective analysis were: (I) to evaluate the viro-immunological efficacy of BIC/FTC/TAF in a cohort of PLWH who switched to this regimen from any other previous, at the Infectious and Tropical Diseases Unit of the Padua University Hospital; (II) to assess the impact on body weight, lipids, and renal function parameters at week 48; and (III) to evaluate daily costs changes, adherence, and the rate and causes of discontinuation of the regimen. We included all adult PLWH who switched to BIC/FTC/TAF from 1 February 2020 to 31 October 2021. We collected demographic, clinical, and laboratory data at baseline and week 48 after the switch. In addition, the estimated cART-related cost changes over the follow-up period were calculated. Over the study period, 290 individuals who switched to BIC/FTC/TAF, 76.9% were males, with a median age of 52 years, and 94.8% had an undetectable baseline HIV viremia. After a median time of 35 days (IQR: 1–55), 41 (14.1%) individuals discontinued the regimen. Factors significantly associated with discontinuation were switching from dual regimens, and neurological disorders. At week 48, we detected a significant increase in body weight, BMI, CD4 T-cell count, and CD4/CD8 ratio, and a significant reduction in triglycerides and costs; all patients had undetectable HIV RNA. Our results showed that switching to BIC/FTC/TAF may favor slightly immunological recovery and cost saving (−4.2 EUR/day from baseline to week 48, equivalent to a mean saving of 1533 EUR/year/person). The reduction in triglycerides does not appear to be clinically relevant, even if statistically significant, nor do both the increase in body weight and BMI (+1 kg and +0.29 BMI, respectively) and the increase in CD4 T-cell count (+45 cells/mmc). Further studies are needed to confirm our results.

Background and aim: Bismuth quadruple therapy (BQT) or non-bismuth quadruple therapy (i.e., concomitant therapy) (CT) is the first-line regimens to eradicate H. pylori infection in areas with high prevalence of clarithromycin (CLA) resistance. Guidelines suggest that in areas of high prevalence of H. pylori strains with double resistance (i.e., CLA + metronidazole), BQT should be preferred to CT. The aim of this study was to evaluate the efficacy and safety of BQT administered through the three-in-one pill (Pylera) formulation in a large series of H. pylori–infected patients, naive to treatment in a region with high CLA and dual resistance.Patients and methods: We treated 250 patients (148 F and 102 M, mean age 48.6 years) with H. pylori infection naïve to treatment. Patients received esomeprazole 40 mg bid and Pylera 3 tablets qid for 10 days. Diagnosis of H. pylori infection was through 13C urea breath test (13C UBT), or stool antigen test or histology, as appropriate. The evaluation of eradication was through 13C UBT at least 45 days after the end of therapy. Incidence of treatment-related adverse events (TRAEs) was assessed through a questionnaire at the end of treatment. Compliance was considered good if at least 90% of medication had been taken. Statistical analysis was per intention-to-treat e per protocol (PP). 95% confidence intervals (CIs) were calculated.Results: 1) 13 patients (5.2%) discontinued therapy due to side effects; 2) eradication rates in ITT and PP were 227/250 (90.8%; 95% CI 86.3–93.7%) and 226/237 (95.3%; 95% CI 91–99%), respectively; 3) the prevalence of TRAEs was 26.8%; and 4) adherence to treatment was good with compliance greater than 90%.Conclusion: In this real-life study, we demonstrate that in an area with a high prevalence of H. pylori strains with CLA or CLA + metronidazole resistance, BQT using Pylera is an effective therapeutic strategy with ITT eradication rates higher than 90%; this therapy is associated with good compliance and low incidence of side effects.

Resumen: Introducción: El mepolizumab es un anticuerpo monoclonal que bloquea la interleuquina 5 circulante (IL5). El benralizumab se une a la subunidad alfa del receptor de la IL 5 induciendo la eliminación directa de eosinófilos y basófilos. El propósito fue evaluar su efectividad en nuestra práctica clínica habitual. Métodos: Estudio observacional retrospectivo de una cohorte de pacientes asmáticos graves eosinofílicos tratados con mepolizumab y benralizumab durante al menos 6 meses. El seguimiento se ha realizado en la unidad de asma. Resultados: Se analizaron 25 pacientes en tratamiento con mepolizumab y 13 con benralizumab alcanzando un tiempo de seguimiento de 12 meses en el 73,7% de los mismos (10 en el caso de benralizumab y 18 para mepolizumab). Tras el tratamiento biológico se observa una disminución del 71% en el número de ingresos (p = 0,0027) y del 66% (p = 0,0013) en las visitas a urgencias. Se contabilizaron 31 ciclos de corticoides vs. 15 tras el tratamiento biológico suponiendo un descenso de un 52% (p = 0,0069). El control del asma medido por cuestionario de control (ACT) fue de 10,8 puntos (SD: 4,73) vs. 20,3 puntos (SD: 4,77), (p = 0,001) y el % FEV1 fue del 70,6% (SD: 21.5) vs. 76,2% (SD: 27,2), (p = 0,0437). Conclusiones: Se confirma la efectividad de los fármacos anti-IL5 en vida real mostrando mejoras en exacerbaciones, control y función pulmonar. Abstract: Introduction: Mepolizumab is a monoclonal antibody that inhibits circulating interleukin 5 (IL-5). Benralizumab binds to the alpha subunit of the IL-5 receptor, inducing the direct elimination of eosinophils and basophils. The aim of this study was to evaluate their effectiveness in our routine clinical practice. Methods: A retrospective observational study of a cohort of patients with severe eosinophilic asthma treated with mepolizumab and benralizumab for at least 6 months, and followed up in the asthma unit. Results: We analyzed 25 patients who received mepolizumab and 13 who received benralizumab, 73.7% of whom were followed up for 12 months (10 months for benralizumab and 18 for mepolizumab). After biological treatment, there was a 71% reduction in the number of admissions (p = .0027) and a 66% reduction (p = .0013) in emergency visits. A reduction in corticosteroid use was recorded: 31 cycles of corticosteroids compared to 15 after biological treatment, representing a decrease of 52% (p = .0069). Asthma control measured by the Asthma Control Test was 10.8 (SD: 4.73) vs. 20.3 (SD: 4.77), (p = .001) and FEV1% was 70.6% (SD: 21.5) vs. 76.2% (SD: 27.2), (p = .0437). Conclusions: The effectiveness of anti-IL-5 drugs in real life was confirmed, with improvements in exacerbations, asthma control and lung function.

Background: Ultrasound (US) is useful in monitoring RA patients, with the US7 score allowing grey-scale and power-Doppler (PD) semi-quantitative evaluation of synovitis and teno-synovitis. We evaluated real-life efficacy and safety of Baricitinib, an oral selective JAK1-2 inhibitor, in RA patients using clinical, clinimetric, and US assessments. Methods: Disease activity score in 28 joints calculated with C-reactive protein (DAS28-CRP), disease activity score in 28 joints calculated with erythrocyte sedimentation rate (DAS28-ESR), clinical disease activity index (CDAI), simplified disease activity index (SDAI), visual analogue scale (VAS)-pain, health assessment questionnaire (HAQ), COCHIN scale, adverse events (AE), concomitant medications, laboratory parameters, and US7 were performed/recorded at baseline, 1, 3, and 6 months in RA patients starting Baricitinib. Responder/non-responder status was determined according to the EULAR Response Criteria at 3 months. SDAI clinical remission or low disease activity (LDA) were calculated at 3 and 6 months. Results: In 43 enrolled patients, a significant improvement in disease activity and US7 components (except tendon PD) and a reduction of steroid dosage were observed. Responders at 3 months showed a significantly higher reduction of CDAI, SDAI, COCHIN scale, VAS-pain, and US7 synovialPD, compared with non-responders. At 3 and 6 months, remission/LDA was achieved by 12.8/53.8% and 21.6/51.3% patients, respectively. The csDMARD co-treatment was independently associated with remission/LDA at 3 months. Safety-related drop-outs were in line with literature data. The steroid dosage was associated with AE development at 6 months. Conclusion: The real-life data, also obtained with US evaluation, confirmed the Baricitinib efficacy in RA disease control, as well as the utility of assessment during the follow up of disease activity. [ABSTRACT FROM AUTHOR]

Objective The aim was to report results from PERSIST, a real-life, observational, prospective cohort study of CT-P13, an infliximab (IFX) biosimilar, for treatment of patients with RA, AS or PsA who were biologic naïve or switched from an IFX reference product (IFX-RP; Remicade). Methods Adult patients were recruited during usual care at 38 sites in Europe and Canada and enrolled by their physicians after meeting eligibility criteria according to the country-approved label for CT-P13. Primary outcomes were to determine drug utilization and treatment persistence and to assess safety. Patients were followed for up to 2 years. Data were analysed and reported descriptively. Results Of 351 patients enrolled, 334 were included in the analysis (RA, 40.4%; AS, 34.7%; PsA, 24.9%). The safety analysis set comprised all 328 patients treated with CT-P13. The majority (58.2%) of patients received CT-P13 monotherapy, most (72.6%) by dosing every 6 or 8 weeks. The mean treatment persistence was 449.2 days; 62.3% of patients completed 2 years of treatment. In all, 214 treatment-emergent adverse events (TEAEs) were reported in 38.4% of patients. Most TEAEs were of mild or moderate intensity; 13 were severe. The most commonly reported TEAEs were drug ineffective (9.5%) and infusion-related reactions (5.2%). The most frequently reported infection-related TEAEs were upper respiratory tract infections (3.0%), nasopharyngitis (2.1%) and bronchitis (1.5%). No patients experienced tuberculosis. Conclusion Drug utilization and treatment persistence with CT-P13 were consistent with historical reports of IFX-RP in this patient population. Safety findings did not identify new concerns for CT-P13 in the treatment of patients with RA, AS or PsA. Trial registration ClinicalTrials.gov: NCT02605642. [ABSTRACT FROM AUTHOR]

Background: It is not clear whether mepolizumab is differently effective in allergic and nonallergic severe eosinophilic asthmatics (SEA) in real life. Objective: We tested mepolizumab effectiveness in allergic/nonallergic SEA in real life. A strict criterion to identify the 2 phenotypes was used. Method: We retrospectively considered 134 consecutive patients divided into allergic, with a positivity to at least 1 allergen to prick tests and/or IgE values ≥100 UI/mL (severe allergic eosinophilic asthma [SAEA]; n: 97–72.4%), and nonallergic, with no prick test results and normal IgE levels <100 UI/mL (severe nonallergic eosinophilic asthma [SNAEA]; n: 37–27.6%). They had taken mepolizumab for at least 6 months. Results: After 10.9 ± 3.7 months, improvements in FEV1%, FEF25–75%, exacerbation numbers, blood eosinophil (BE) counts, fractional exhaled nitric oxide (FENO) (ppb), percentages of patients that stopped/reduced short-acting β2-agonists (SABAs) or oral corticosteroid (OC), observed after treatment, were similar in both groups. Only Asthma Control Test (ACT) increases were higher in SNAEA (8 [5–9]) than in SAEA (5 [2.5–8.5]; p = 0.016). However, no differences were found after treatment in percentages of subjects with ACT ≥20, as well as with FEV1 >80%, FEF25–75 >65%, exacerbations ≤2, BE <300 cells/µL, and FENO <25 ppb between SAEA and SNAEA. Besides, no significant relationships were found, comparing SNAEA with SAEA, for FEV1% (β = −0.110; p = 0.266), FEF25–75% (β = −0.228; p = 0.06), BE counts (β = −0.012; p = 0.918), FENO (β = 0.234; p = 0.085), ACT (β = 0.046; p = 0.660), and exacerbations (β = −0.070; p = 0.437). No different associations between lung function and SNAEA occurrence when compared to SAEA condition (FEV1 >80%: OR = 1.04 [95% CI: 0.43–2.55], p = 0.923; FEF25–75 >65%: OR = 0.41 [95% CI: 0.08–2.03], p = 0.272) were detected. Neither all other parameters, such as ACT >20 (OR = 0.73 [95% CI: 0.32–1.63], p = 0.440), presence of exacerbations (OR = 1.35 [95% CI: 0.55–3.27], p = 0.512), SABA discontinuation (OR = 1.16 [95% CI: 0.40–3.39], p = 0.790), and OC cessation/reduction (OR = 3.44 [95% CI: 0.40–29.27], p = 0.258), were differently associated with 1 or the other phenotype. Conclusion: Mepolizumab can be considered as a valid therapeutic choice for either allergic or nonallergic SEA in real life. [ABSTRACT FROM AUTHOR]

Background: Age-adjusted lymphoma incidence rates continue to rise in France since the early 80's, although rates have slowed since 2010 and vary across subtypes. Recent improvements in patient survival in major lymphoma subtypes at population level raise new questions about patient outcomes (i.e. quality of life, long-term sequelae). Epidemiological studies have investigated factors related to lymphoma risk, but few have addressed the extent to which socioeconomic status, social institutional context (i.e. healthcare system), social relationships, environmental context (exposures), individual behaviours (lifestyle) or genetic determinants influence lymphoma outcomes, especially in the general population. Moreover, the knowledge of the disease behaviour mainly obtained from clinical trials data is partly biased because of patient selection.Methods: The REALYSA ("REal world dAta in LYmphoma and Survival in Adults") study is a real-life multicentric cohort set up in French areas covered by population-based cancer registries to study the prognostic value of epidemiological, clinical and biological factors with a prospective 9-year follow-up. We aim to include 6000 patients over 4 to 5 years. Adult patients without lymphoma history and newly diagnosed with one of the following 7 lymphoma subtypes (diffuse large B-cell, follicular, marginal zone, mantle cell, Burkitt, Hodgkin, mature T-cell) are invited to participate during a medical consultation with their hematologist. Exclusion criteria are: having already received anti-lymphoma treatment (except pre-phase) and having a documented HIV infection. Patients are treated according to the standard practice in their center. Clinical data, including treatment received, are extracted from patients' medical records. Patients' risk factors exposures and other epidemiological data are obtained at baseline by filling out a questionnaire during an interview led by a clinical research assistant. Biological samples are collected at baseline and during treatment. A virtual tumor biobank is constituted for baseline tumor samples. Follow-up data, both clinical and epidemiological, are collected every 6 months in the first 3 years and every year thereafter.Discussion: This cohort constitutes an innovative platform for clinical, biological, epidemiological and socio-economic research projects and provides an opportunity to improve knowledge on factors associated to outcome of lymphoma patients in real life.Trial Registration: 2018-A01332-53, ClinicalTrials.gov identifier: NCT03869619 . [ABSTRACT FROM AUTHOR]

Purpose: Intraperitoneal with intravenous chemotherapy (IP/IV) is the recommended option for patients with stage III cancer with optimally debulked (<1 cm residual) disease based on randomized controlled trials and showing important improvements in overall survival and progression free survival. However, its application has not been largely adopted due to its difficult administration that requires a trained nurse staff. The aim of this work was to study the completion and the toxicity of an IP outpatient chemotherapy regimen in optimally debulked stage III ovarian cancer patients. Methods: A single-center, retrospective observational study in women with stage III ovarian cancer following optimal cytoreductive surgery (<1 cm) followed by IP/IV chemotherapy from 2009 to 2017. The IP/IV regimen was as it follows: IV paclitaxel 175 mg/m2 in 3 h, day 1; IP cisplatin (100 mg/m2—until December 2013—or 75 mg/m2), day 2; IP paclitaxel 60 mg/m2, day 8, each 21 days for six cycles. Results: A total of 60 patients received IP/IV regimen. Of these, 41 patients (68.3%) completed the six IP chemotherapy cycles and 51 (84.9%) completed four or more cycles. Most of the adverse events reported were non-hematological and G1-2. There was no difference neither in adherence nor in the frequency of adverse events between both cisplatin groups. Despite a high rate of adverse events, IP chemotherapy can be delivered with a high completion rate and manageable toxicity to patients with optimally debulked ovarian cancer. [ABSTRACT FROM AUTHOR]

The book The Woman from Sarajevo (Gospodjica) is one of the important novels written by Serbian writer Ivo Andric who once lived through the world war and worked in significant department of the country. This novel is not only the product of that period of time but also his only long psychological one which represents his interest in describing the mental states of the main characters. It is a purely psychological study of greed from the point of the pathology and obsession. It also shows his greatness in writing which helps him win the Nobel Prize in literature for his epic force of tracing themes and depicting human destinies drawn from the history of his country. This novel describes the real experience of a single woman named Raica Radakovic from a unique perspective, unfolding the ordinary people's life and fate in historical tide. It depicts Raica's life experience objectively, showing the author's philosophical reflection on people's life and fate, which makes this novel demonstrate its objective and profound artistic style. [ABSTRACT FROM AUTHOR]

Short-term adverse events are common following the BNT162b2 vaccine for SARS-Cov-2 and have been possibly associated with IgG response. We aimed to determine the incidence of adverse reactions to the vaccine and the impact on IgG response. Our study included 4156 health-care professionals who received two doses of the BNT162b2 vaccine 21 days apart and obtained 6113 online questionnaires inquiring about adverse events. The serum response was tested in 2765 subjects 10 days after the second dose. Adverse events, most frequently a local reaction at the site of injection, were reported by 39% of subjects. Multivariate analysis showed that female sex (odds ratio—OR—1.95; 95% confidence interval—CI—1.74–2.19; p < 0.001), younger age (OR 0.98 per year, p < 0.001), second dose of vaccine (OR 1.36, p < 0.001), and previous COVID-19 infection (OR 1.41, p < 0.001) were independently associated with adverse events. IgG response was significantly higher in subjects with adverse events (1110 AU/mL—IQR 345-1630 vs. 386 AU/mL, IQR 261-1350, p < 0.0001), and the association was more pronounced in subjects experiencing myalgia, fever, and lymphadenopathy. We demonstrate that a more pronounced IgG response is associated with specific adverse events, and these are commonly reported by health care professionals after the BNT162b2 vaccine for SARS-Cov-2.

Aims: Hereditary (ATTRv) and wild‐type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR‐ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real‐life population in comparison to the population included in the ATTR‐ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)‐free survival time without cardiac decompensation, heart transplant, or death. Methods and results: From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR‐ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO‐free survival time (n = 98): 1565 (1010–2400) days vs. 771 (686–895) days without treatment (log‐rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N‐terminal pro‐B‐type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P = 0.0132). Conclusion: In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR‐ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real‐life population. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the characteristics and treatment patterns of patients developing a neovascular event (NE) in the anterior chamber secondary to central retinal vein occlusion (CRVO) in an ordinary clinical setting. Methods: In this retrospective real‐life study, data from 243 eyes presenting with CRVO during 2012–2013 were collected. Maximum follow‐up was 5 years. All patients that developed NE were included in the analysis. Results: Of 243 eligible patients, 72 (30%) either presented with or developed NE during the follow‐up. In these 72 patients, 23 (32%) eyes already had evidence of NE at baseline. Twenty‐eight eyes (39%) developed NE after discontinuation of intravitreal therapy for macular oedema (ME). In this subgroup, the NE occurred 15.6 ± 13.8 months after the baseline visit and 4.1 ± 2.6 months after the last injection. Final best‐corrected visual acuity was 8.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the group of patients presenting with NE compared to 8.1 ETDRS letters in the group that developed NE later on. Of the patients presenting with intraocular pressure (IOP) below 30 mmHg, 3/29 (10%) needed subsequent cyclodiode laser therapy compared to 35/43 (81%) patients with a baseline IOP above 30 mmHg (p < 0.001). Conclusions: In a clinical setting, many patients show evidence of NE already at the first visit. A substantial part of patients develops NE a long time after presentation, commonly a few months after discontinuation of intravitreal therapy for ME. The visual prognosis is similar for patients presenting with NE and patients developing NE during follow‐up. A high baseline IOP predicts the need for subsequent pressure‐lowering procedures. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis B (CHB) is a viral infection that can result in life-threatening conditions, such as hepatocellular carcinoma and cirrhosis. Tenofovir, which is used for the treatment of CHB, is a nucleotide analog that inhibits HBV-DNApolymerase and has two formulations: disoproxil and alafenamide. In contrast to tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) penetrates the whole hepatocyte without being eliminated due to its longer plasma half-life and greater plasma stability. As a result, side effects such as proximal renal tubulopathy and loss of bone density are less common in the treatment of TAF and have similar efficacy to TDF. Objectives: The purpose of the study was to evaluate the effectiveness and reliability of TAF using real-life data. Methods: This retrospective cohort study was carried out in secondary or tertiary healthcare centers in southern Turkey. A total of 480 patients aged 18 years and older were administered TAF for an appropriate indication by the infectious diseases and gastroenterology clinics of the healthcare centers participating in this study. The data collected at t = 0, t = 3, and t = 6 months of treatment were analyzed. The chi-square, Mann-Whitney U, Friedman, Wilcoxon, Cochran's Q, and McNemar's tests were used. Results: The mean age of the patients was 47.40 ± 14.5, and 327 of them (68.1%) were male. A total of 78.l% of the 480 patients who underwent the TAF treatment had previous antiviral therapy experience (TDF, n = 340; 70.8 %), and 2l.9% were treatment-naive. The most common reasons for the initiation of TAF treatment were the use of drugs affecting bone mineral density (BMD) (42.9%) and osteoporosis (22.3%). Patients who had taken TDF experienced a significant improvement in glomerular filtration rate (GFR), hip and spine T-scores, and phosphorus levels from t = 0 months to t = 6 months after switching to TAF (P < 0.05). For this group, no statistically significant difference was observed concerning LDL and cholesterol levels from t = 0 months to t = 6 months. Side effects were reported by 5.7% of patients in the third month and 7.l% in the sixth month, with the most common side effect being hair loss (l%). Conclusions: TAF was found to be an effective and safe alternative to TDF with lower incidences of its long-term effects, such as nephrotoxicity and decreased bone density. [ABSTRACT FROM AUTHOR]

Background: Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated.Method: Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK.Results: A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10-1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03-2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/μL.Conclusions: In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851). [ABSTRACT FROM AUTHOR]

Recent major research advancements have significantly expanded our understanding of psoriasis pathophysiology, resulting in the development of highly effective, targeted therapies. Guselkumab is the first interleukin (IL)‐23 inhibitor approved for the treatment of moderate‐to‐severe‐psoriasis, providing a new therapeutical option for psoriasis. The aim of our study was to evaluate the efficacy of guselkumab in psoriatic patients who previously failed anti‐IL‐12/23 and/or anti‐IL‐17 treatment. A 52‐week single‐center retrospective study was performed enrolling moderate‐to‐severe patients attending our Psoriasis Care Center from October 2018 to May 2020. Study population included 13 patients; 46.1% have been previously treated with ustekinumab, while 69.2% have previously failed an anti‐IL‐17 treatment (38.5% secukinumab, 30.8% ixekizumab, and 38.5% both). At baseline, mean Psoriasis Area and Severity Index was 13.2 ± 6.8, reducing up to 0.5 ± 0.7 at week 52 (P <.001). Body surface area reduced from 22.3 ± 10.5 (baseline) to 0.8 ± 1.1 at week 52 (P <.001). No statistically significant differences have been found between patients previously treated with anti‐IL‐12/23 compared to anti‐IL‐17 or both. Only one patient discontinued guselkumab at week 36 due to secondary inefficacy. This is a single institution study with a relatively small sample size. Our real‐life data confirm trial results, showing guselkumab as a safe and effective option in patients with moderate‐to‐severe psoriasis even in those who previously failed ustekinumab and/or anti‐IL‐17 treatment. [ABSTRACT FROM AUTHOR]

Low adherence and persistence values, which indicate real-life efficiency, have been widely reported in patients suffering from COPD (Chronic Obstructive Pulmonary Disease). Poor adherence may be related to treatment dosage, thus, simplifying the dosing regimen might improve adherence. The objective of the present study was either to evaluate adherence and persistence in primary drugs used in COPD treatment after 3 years in real life and assess whether the different dosing regimen affects adherence levels to therapy. A pharmacological, observational, non-interventional, retrospective study was carried out by taking into consideration the drugs dispensed between 1 January 2011 and 31 December 2018 at the hospital pharmacy of Pescara. Adherence was reckoned as the ratio between Received Daily Dose (RDD) and Prescribed Daily Dose (PDD). Treatment persistence was reckoned as the time from the start of treatment until its discontinuation. The evaluation of the two drug used indices was carried out by using three different dose regimens: Defined Daily Dose (DDD), minimum daily dose, maximum daily dose. During the study period, 52,374 patients met the inclusion criteria, and after applying the exclusion criteria, 3432, 3608, and 3594 were eligible for analysis by maximum daily, dose, DDD, and minimum daily dose, respectively. For the majority of active ingredients, adherence data was less than 0.8, that is the cut-off universally accepted as ideal value for adherence. In terms of adherence, a statistically significant difference has been highlighted in active ingredients requiring a single daily inhalation, with respect to active ingredients requiring multiple inhalations. Persistence curves have shown no statistically significant difference. It would be appropriate to promote the use of drugs which require a single daily dose in order to improve adherence in these patients. [ABSTRACT FROM AUTHOR]

Background: Cancer treatments induce symptoms/signs superimposing on individual patient's clinical status, determining heterogenous toxicity syndromes (TS). We reviewed intensive first line triplet chemotherapy-based regimens in metastatic gastro-intestinal cancers (mGI), based on FIr/FOx schedule, fluorouracil and weekly alternating irinotecan/oxaliplatin, to point out limiting TS (LTS) relevance.Methods: Metastatic colo-rectal (mCRC), pancreatic ductal adenocarcinoma (mPDAC), gastric carcinoma (mGC) patients were enrolled by careful decision-making including age, performance status (PS), and comorbidity status in real life phase II studies: FIr-B/FOx adding bevacizumab (B) overall, FIr-C/FOx-C adding cetuximab (C) in KRAS/NRAS wild-type mCRC; FIr/FOx in mPDAC; FD/FOx adding docetaxel (D) in mGC. Toxicity, individual LTS, LT alone (LTS-single site, LTS-ss) or associated to other limiting/G2 toxicities (LTS-multiple sites, LTS-ms) were evaluated, compared by chi-square test. In FIr-C/FOx-C, 5-fluorouracil/irinotecan pharmacogenomic biomarkers, 5-fluorouracil degradation rate (5-FUDR), SNPs ABCB1, CYP3A4, DYPD, UGT1A1 were evaluated, related with LTS.Results: FIr-B/FOx, FIr-C/FOx-C in mCRC, FIr/FOx in mPDAC, FD/FOx in mGC, showed activity, efficacy, toxicities similar to reported triplet regimens. LTS: mCRC FIr-B/FOx 44%, LTS-ms 24%, LTS-ss 20%, in young-elderly 46%, LTS-ms significantly increased vs. LTS-ss; FIr-C/FOx-C 65.5%, significantly increased LTS-ms vs. LTS-ss, in young-elderly 83%; mPDAC FIr/FOx 27.5%, mostly LTS-ms, in young-elderly 38.4% all LTS-ms; mGC FD/FOx 30%, all LTS-ms, in young-elderly 25%. Reduced FUDR, SNPs CYP3A4, UGT1A1, >1 positive pharmacogenomic biomarkers were prevalent in patients with gastrointestinal LTS.Conclusions: LTS is an innovative clinical parameter of toxicity burden, differential treatment-related TS in individual patient. LTS can evaluate pharmacogenomic biomarkers predictive relevance to select mGI patients fit for intensive treatments, at risk of limiting gastrointestinal toxicity.Trial Registrations: The trials were registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34, and Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009- 016793-32.

Satisfactory indoor thermal environments can improve working efficiencies of office staff. To build such satisfactory indoor microclimates, individual thermal comfort assessment is important, for which personal clothing insulation rate (Icl) and metabolic rate (M) need to be estimated dynamically. Therefore, this paper proposes a vision-based method. Specifically, a human tracking-by-detection framework is implemented to acquire each person’s clothing status (short-sleeved, long-sleeved), key posture (sitting, standing), and bounding box information simultaneously. The clothing status together with a key body points detector locate the person’s skin region and clothes region, allowing the measurement of skin temperature (Ts) and clothes temperature (Tc), and realizing the calculation of Icl from Ts and Tc. The key posture and the bounding box change across time can category the person’s activity intensity into a corresponding level, from which the M value is estimated. Moreover, we have collected a multi-person thermal dataset to evaluate the method. The tracking-by-detection framework achieves a mAP50 (Mean Average Precision) rate of 89.1% and a MOTA (Multiple Object Tracking Accuracy) rate of 99.5%. The Icl estimation module gets an accuracy of 96.2% in locating skin and clothes. The M estimation module obtains a classification rate of 95.6% in categorizing activity level. All of these prove the usefulness of the proposed method in a multi-person scenario of real-life applications.

Abstract Background Albinism comprises a group of autosomal recessive diseases that are characterized by poor vision and a variable hypopigmentation phenotype. A comprehensive literature review showed that no tool can assess the burden experienced by individuals who present with albinism, although such a tool is needed and would be beneficial for clinicians and patients alike. Method The questionnaire was devised using standardized methodology for developing and validating questionnaires on the quality of life of subjects according to the following chronological structure: conceptual phase, development phase, and then validation phase. A multidisciplinary working group was assembled, including experts on questionnaire design and development, dermatologists specializing in care for patients with albinism, and representatives of the Genespoir association. Results Based on an initial verbatim report, the workgroup compiled a list of items that were transcribed and reformulated into questions. During the validation phase, principal component analysis (PCA) was conducted on the 24 items, which allowed the questionnaire to be reduced to 20 questions [Q]. The standardized regression coefficients were all greater than 0.5 for their corresponding factors. Based on their normalized regression coefficients, each group of questions was linked to one of the following four dimensions, with each dimension consisting of at least three questions: “Live with” (8 Q), “Daily life” (3 Q), “Resignation” (3 Q), and “Fear of the future” (6 Q). All dimensions correlated well with the overall BoA score. Cronbach’s α was 0.92 for the entire BoA scale, confirming excellent internal coherence. Intradimensional coherences all demonstrated excellent reliability (α > 0.65). The BoA questionnaire was highly correlated with the SF12, RSES and DLQI validated questionnaires. This outcome confirmed the external validity. Conclusion This questionnaire represents the first specific assessment tool for evaluating the burden of albinism. It is easy to use and relatively quick to complete, which will allow the burden to be evaluated over time with a reproducible questionnaire. To ensure that this questionnaire can be used by as many people as possible, cultural and linguistic validation in US English was conducted with the original French version.

Abstract Background This article summarizes a EUFOREA symposium, presented during the European Rhinology Research Forum in Brussels (9–10 November 2017; https://www.rhinologyresearch.eu/) which focused on novel pathways and therapeutic approaches in allergic rhinitis (AR). Main body AR remains under-diagnosed, under-estimated and under-treated. A key component in understanding the AR landscape has been the realization of a significant mismatch between how physicians instruct AR patients to manage their disease and what AR patients actually do in real life. Data from the Allergy Diary (developed by MACVIA ARIA) showed that AR patients take their medication prn, rapidly switch treatments, often experience poor control, use multiple therapies and stop treatment when symptoms are controlled. Better control of AR may be achievable by using an AR treatment which has a rapid onset of action and which effectively targets breakthrough symptoms. Indeed, AR patients report complete symptom relief, lack of breakthrough symptoms, rapid onset of action, safety and use on an ‘as needed’ basis as key targets for new nasal sprays. MP-AzeFlu comprises intranasal azelastine and fluticasone propionate (FP) in a novel formulation delivered in a single device. It is the first AR treatment to break the 5 min onset of action threshold and provides clinically relevant symptom relief in 15 min, much faster than that noted for FP + oral loratadine. MP-AzeFlu also significantly reduces nasal hyperresponsiveness (NHR) which may be responsible for the breakthrough symptoms frequently reported by AR patients. Mechanisms underlying MP-AzeFlu’s effect include inhibition of mast cell degranulation, stabilization of the mucosal barrier, synergistic inhibition of inflammatory cell recruitment and a unique desensitization of sensory neurons expressing the transient receptor potential A1 and V1 channels. Conclusion With the most rapid onset of action and onset of clinically-relevant effect of any AR medication currently available, and proven efficacy in the treatment of NHR, MP-AzeFlu is an AR treatment which provides what patients want, and fits how patients manage their AR in real life.

Jeffrey D Jenks,1,* Helmut JF Salzer,2,3,* Juergen Prattes,4,5,* Robert Krause,4,5,* Dieter Buchheidt,6,* Martin Hoenigl1,3,7,8,* 1Department of Medicine, University of California San Diego, San Diego, CA, USA; 2Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany; 3German Center for Infection Research, Clinical Tuberculosis Center, Leibniz Lung Center, Borstel, Germany; 4Section of Infectious Diseases and Tropical Medicine, Medical University of Graz, Graz, Austria; 5CBmed – Center for Biomarker Research in Medicine, Graz, Austria; 6Department of Hematology and Oncology, Mannheim University Hospital, Heidelberg University, Mannheim, Germany; 7Division of Pulmonology, Medical University of Graz, Graz, Austria; 8Division of Infectious Diseases, Department of Medicine, University of California San Diego, San Diego, CA, USA *All authors contributed equally to this work Abstract: In recent decades, important advances have been made in the diagnosis and treatment of invasive aspergillosis (IA) and mucormycosis. One of these advances has been the introduction of isavuconazole, a second-generation broad spectrum triazole with a favorable pharmacokinetic and safety profile and few drug–drug interactions. Phase III trials in patients with IA and mucormycosis demonstrated that isavuconazole has similar efficacy to voriconazole for the treatment of IA (SECURE trial) and liposomal amphotericin B for the treatment of mucormycosis (VITAL trial with subsequent case–control analysis) and a favorable safety profile with significantly fewer ocular, hepatobiliary, and skin and soft tissue adverse events compared to voriconazole. As a result, recent IA guidelines recommend isavuconazole (together with voriconazole) as gold standard treatment for IA in patients with underlying hematological malignancies. In contrast to liposomal amphotericin B, isavuconazole can be safely administered in patients with reduced renal function and is frequently used for the treatment of mucormycosis in patients with reduced renal function. Updated guidelines on mucormycosis are needed to reflect the current evidence and give guidance on the use of isavuconazole for mucormycosis. Studies are needed to evaluate the role of isavuconazole for 1) anti-mold prophylaxis in high-risk patients, 2) salvage treatment for IA and mucormycosis, and 3) treatment for other mold infections such as Scedosporium apiospermum. Keywords: TDM, plasma level, triazole, SECURE, VITAL, susceptibility, real life

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). Objective: To investigate the effectiveness and safety of rituximab in relapsing–remitting (RR) and progressive MS. Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p <.0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p <.0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose. Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS. [ABSTRACT FROM AUTHOR]