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This research note describes a pilot study that examined the meaning of caring from the perspectives of patients undergoing physical therapy. METHODS: A phenomenological methodology was used to explore the essential meaning of caring behaviors from the experiences of patients undergoing physical therapy. Patients were asked to describe caring interactions they have experienced with their physical therapists. RESULTS: The responses of the participants were inductively analyzed for themes and sub-themes that explained physical therapy caring. Based on that analysis, a central theme of mindful caring emerged from participants' responses. The theme of mindful caring reflected the physical therapist and patient relationship. Further analysis uncovered four sub-themes that gave a clearer picture of caring behaviors experienced by the participants. These included personal values, patient empowerment, open communication and exceptional service. CONCLUSION: The results of this pilot study demonstrate the dimensions of caring in healthcare practice from the unique perspectives of patients. [ABSTRACT FROM AUTHOR]

Highly pathogenic influenza A virus (HPIAV) H5N1 within the genetic clade 2.3.4.4b has emerged in wild birds in different regions of the world, leading to the death of >70 million birds. When these strains spread to pinniped species a remarkable mortality has also been observed. A detailed genetic characterization of HPIAV isolated from pinnipeds is essential to understand the potential spread of these viruses to other mammalian species, including humans. To gain insight into these matters a detailed phylogenetic analysis of HPIAV H5N1 2.3.4.4b strains isolated from pinniped species was performed. The results of these studies revealed multiple transmission events from birds to pinnipeds in all world regions. Different evolutionary histories of different genes of HPIAV H5N1 2.3.4.4b strains gave rise to the viruses infecting pinnipeds in different regions of the world. European strains isolated from pinnipeds represent a completely different genetic lineage from strains isolated from South American ones. All strains isolated from pinnipeds bear characteristics of a highly pathogenic form for of avian influenza in poultry. Amino acid substitutions, previously shown to confer an adaptive advantage for infecting mammals, were observed in different genes in all pinniped species studied., 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. The funding institutions has no role in the decision of publishing of this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction and Objectives: New drugs for metastatic castrate resistant prostate cancer (mCRPC) were approved, first in the pos-docetaxel and then in the pre-docetaxel setting. We aim to assess the real daily practice benefit of abiraterone (Abi), enzalutamide (Enz) and cabazitaxel (Cab) in patients with mCRPC, compare it with RCT results and compare Abi vs Enz., Materials and Methods: We retrospectively collected the data of all consecutive mCRPC patients treated with Abi, Enz or Cab in the six major oncological hospitals in the north of Portugal until December 2020., Results: A total of 470 treatments pre-docetaxel (163 Abi and 307 Enz) and 373 pos-docetaxel (160 Abi, 148 Enz and 59 Cab) were included, with median follow-up time of 35 months. Mean age was 73.1, 84.4% had ECOG status < 2, ISUP grade was ≥ 4 in 59% and 28.0% had oligometastatic disease. In first line, for Abi and for Enz respectively, the proportion of patients with PSA reduction > 50% was 64.4% and 80.4% (P < .001), the mean duration of treatment (DT) was 10 and 14 months (P = .037) and the median overall survival (OS) was 25 months and 30 months (P = .17). In second line the results for Abi, Enz and Cab were respectively: proportion of patients with PSA reduction > 50% was 40.4%, 57.4% and 24.6% (p for Abi vs Enz=0.004); DT was 7, 8, and 3 months (p for Abi vs Enz = 0.27); OS was 17, 22 and 10 months (p for Abi vs. Enz = 0,07)., Conclusion: These drugs have good efficacy in real-world evidence, similar to those reported in randomized clinical trials, with the expected exception of lower OS due to the inclusion of a broader sample of patients. Our results add to the evidence that Enz might have better efficacy in this setting compared with Abi., Competing Interests: Disclosure The following authors declare to have received remuneration from consulting and lectures of the following companies: Francisco Botelho: Astellas, Janssen-Cilag, Bayer, MSD Isaac Braga: Astellas, Janssen-Cilag, Bayer Frederico Teves: Astellas, Ipsen, Janssen-Cilag, Bayer, Glaxo, Jaba-Recordatti, Medtronic Ricardo Leão: Roche, Janssen-Cilag, Ipsen. Carlos Silva: Astellas, Janssen-Cilag, Astra Zéneca, Menarini, Ferring, Pfizer, Glaxo, Bayer. Luís Pacheco-Figueiredo: Astellas. The remaining authors have no confit of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Bariatric surgery induces several micronutrient deficiencies that require supplementation. For iron, parenteral infusions are usually preferred over oral supplementation. Ferric carboxymaltose infusion has been associated with hypophosphataemia, mostly transient and asymptomatic. However, in some cases, ferric carboxymaltose-induced hypophosphataemia may persist for weeks to months and may induce muscle weakness, osteomalacia and bone fractures. The aim of this study was to identify possible predictors of a clinically relevant decrease in serum phosphate after ferric carboxymaltose infusion in patients with previous Roux-en-Y gastric bypass., Methods: Patients with previous Roux-en-Y gastric bypass who received ferric carboxymaltose infusions between January 2018 and September 2019 and had recorded phosphataemia before and after ferric carboxymaltose infusion at the Lausanne University Hospital, Lausanne, Switzerland, were studied retrospectively. A multiple linear regression model was built with delta phosphataemia as the outcome to investigate the factors related to magnitude of serum phosphate lowering., Results: Seventy-seven patients (70 females and 7 males) with previous Roux-en-Y gastric bypass were studied. Mean age (SD) was 43.2 (10.7) years and median BMI was 30.9 kg/m2 (IQR 27.9-36.4). Sixty-eight patients (88.3%) received an infusion of 500 mg ferric carboxymaltose and 9 patients (11.7%) received 250 mg ferric carboxymaltose. Forty-nine patients (63.6%) developed hypophosphataemia (<0.8 mmol/l) after ferric carboxymaltose infusion. Median plasma phosphate significantly decreased by 0.33 mmol/l (IQR 0.14-0.49) (p<0.0001). Multiple linear regression identified the ferric carboxymaltose dose as the only risk factor significantly associated with the magnitude of serum phosphate lowering, with an additional mean loss of 0.26 mmol/l with a 500 mg infusion compared to a 250 mg infusion (p = 0.020)., Conclusion: Ferric carboxymaltose infusions substantially decreased plasma phosphate levels in patients with previous Roux-en-Y gastric bypass. Compared to a dose of 250 mg, infusion of a dose of 500 mg ferric carboxymaltose decreased the plasma phosphate further in this population.

Introduction: In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily "OFF"-time relative to placebo in adults with Parkinson's disease (PD) and motor fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize "OFF"-times around nighttime sleep and to explore the effects of opicapone 50 mg., Methods: "OFF" before sleep (OBS), "OFF during the nighttime sleep period" (ODNSP), early morning "OFF" (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits., Results: At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (-0.9 vs. -0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (-1.0 vs. -0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (-12.8 % vs. -4.5 %, P < 0.05)., Conclusion: "OFF"-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period "OFF" episodes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R. A. Hauser has received speaking fees from Acorda, Amneal Pharmaceuticals, Cerevel, Inhibikase, Kyowa Kirin, Neurocrine Biosciences Ltd., Sunovion and Supernus; has received consulting fees from AbbVie Ltd., Acsel Health, Amneal Pharmaceuticals, Avanex Ltd., Biogen Ltd., BlueRock Therapeutics, EPI-Q, Forsee Pharmaceuticals, Global Kinetics, Inhibikase, Jazz Pharmaceuticals Ltd., KeifeRX, Krog and Partners, Kyowa Kirin, Magnolia Innovation, MDCE Suzhou, MedRhythms, Medsphere Ltd., Merz Ltd., Neurocrine Ltd., Neuroderm, Ovid Therapeutics, PD Neurotechnology Ltd., Pharma Two B, Regenxbio, Revance Ltd., Sage Therapeutics Ltd., Scion NeuroStim, Stoparkinson, Sunovion, Supernus Pharmaceuticals, Tolmar, Tremor Research Group, Tris Pharma Ltd., UCB, and Vivifi Biotech Ltd. R. A. Hauser serves on a scientific advisory board for Stoparkinson and Inhibikase. R. A. Hauser holds stock in Revance Therapeutics Ltd. and has stock options in Enterin, Inhibikase, and Axial Therapeutics. R. A. Hauser has received intellectual property interests from a PD Diary through his University. R. A. Hauser acknowledges a Center of Excellence grant from the Parkinson Foundation. R. A. Hauser's University has received research support from Annovis Bio Inc., Artizan Biosciences, Parkinson's & Movement Disorder Alliance, Inhibikase Therapeutics, AbbVie Inc., Aeon Biopharma, Biogen MA, Bukwang Pharmaceutical Co. Ltd., Cavion Inc., Cerevance Inc., Cerevel Therapeutics, Cynapsus Therapeutics, Enterin Inc., Genentech, Global Kinetics Corporation, Hoffman-La Roche Inc., Impax Laboratories, Integrative Research Laboratories Sweden, Lundbeck Inc., Michael J. Fox Foundation for Parkinson's Research, National Parkinson's Foundation, Neuraly Inc., Neurocrine Biosciences, Neuroderm, Pharma Two B Ltd., Revance Therapeutics, Sage Therapeutics, Sanofi Pharmaceuticals, Scion NeuroStim, SunPharma, and UCB BioPharma. A. Videnovic has served as a consultant to Alexion Pharmaceuticals. P. Soares-da-Silva and J. F. Francisco Rocha are employees of BIAL–Portela & C(a) SA. G. Liang, K. Olson, E. Jen, and O. Klepitskaya are employees of Neurocrine Biosciences., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cirrhosis is a major health concern worldwide with a complex pathophysiology affecting various biological systems, including all aspects of haemostasis. Bleeding risk is mainly driven by portal hypertension, but in end-stage liver disease it is further increased by alterations in haemostatic components, including platelet function, coagulation, and fibrinolysis. Concurrently, patients with cirrhosis are prone to venous thromboembolic events (VTE) because of the altered haemostatic balance, in particular an increase in thrombin generation. In patients with cirrhosis, vitamin K antagonists (VKA) and low molecular weight heparins (LMWH) are currently the standard of care for VTE prevention, with VKA also being standard of care for stroke prevention in those with atrial fibrillation. However, direct oral anticoagulants (DOAC) could have specific advantages in this patient population. Clinical experience suggests that DOAC are a safe and possibly more effective alternative to traditional anticoagulants for the treatment of VTE in patients with compensated cirrhosis. In addition, emerging data suggest that primary prophylactic treatment with anticoagulants may improve clinical outcomes in patients with cirrhosis by reducing the risk of hepatic decompensation. The selection of the most appropriate DOAC remains to be clarified. This review focuses on the rationale for the use of DOAC in patients with cirrhosis, the specific effects of the different DOAC (as assessed by in vitro and in vivo pharmacokinetic and pharmacodynamic studies), as well as clinical outcomes in patients with cirrhosis on DOAC., (© 2024 The Authors.)

The presence of endocrine-disrupting compounds (EDCs) in water poses a significant threat to human and animal health, as recognized by regulatory agencies throughout the world. The Yeast Estrogen Screen (YES) assay is an excellent method to evaluate the presence of these compounds in water due to its simplicity and capacity to assess the bioaccessible forms/fractions of these compounds. In the presence of a compound with estrogenic activity, Saccharomyces cerevisiae cells, containing a lacZ reporter gene encoding the enzyme β-galactosidase, are induced, the enzyme is synthesised, and released to the extracellular medium. In this work, a YES-based approach encompassing the use of a lacZ reporter gene modified strain of S. cerevisiae, microcarriers as solid support, and a fluorescent substrate, fluorescein di-β-d-galactopyranoside, is proposed, allowing for the assessment of EDCs' presence after only 2 h of incubation. The proposed method provided an EC50 of 0.17 ± 0.03 nM and an LLOQ of 0.03 nM, expressed as 17β-estradiol. The assessment of different EDCs provided EC50 values between 0.16 and 1.2 × 10 3  nM. After application to wastewaters, similar results were obtained for EDCs screening, much faster, compared to the conventional 45 h spectrophotometric procedure using a commercial kit, showing potential for onsite high-throughput screening of environmental contamination., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Rapid and sustained clinical responses are critical in improving long-term outcomes in epilepsy. While a 50 % reduction from baseline in standardized seizure frequency (SSF) is often cited as a measure of clinically meaningful efficacy, sustained response (SR) is an alternative method that allows the assessment of onset and durability of the response. Time to sustained response in SSF of ≥ 50 %, ≥ 75 %, ≥ 90 %, and 100 % was assessed for pooled data from 3 similar randomized clinical trials of adjunctive eslicarbazepine acetate (ESL). Patients with focal seizures on stable doses of 1-2 antiseizure medications were randomized to placebo, ESL 800 mg/day, or ESL 1200 mg/day. SR50, SR75, SR90, and SR100 were defined as a ≥ 50 %, ≥ 75 %, ≥ 90 %, and 100 % reduction, respectively, in SSF compared to baseline occurring anytime during the 12-week maintenance period, sustained through the end of the maintenance period. Safety signals were assessed for patients with SR50 onset within the first 2 weeks of the maintenance period (early responders) and any point following the first 2 weeks (later responders). A total of 1221 patients were included in this analysis. SR50 was achieved as early as Day 1 (placebo, 4.7 %; ESL 800 mg/day, 8.8 %; ESL 1200 mg/day, 10.4 %). After 84 days, SR50 was achieved by 32.1 % of the placebo group, 46.9 % of the ESL 800 mg/day group (p = 0.0002 vs placebo), and 53.7 % of the ESL 1200 mg/day group (p < 0.0001 vs placebo). Both ESL groups demonstrated earlier SR50 onset compared with placebo (p < 0.0001). Time to SR50 onset was not statistically different between the 800 and 1200 mg/day ESL dose groups. SR75 (p = 0.0001), SR90 (p = 0.0019), and SR100 (p = 0.0014) were achieved significantly earlier in the ESL 1200 mg/day groups vs placebo. SR75 was achieved significantly earlier in the ESL 800 mg/day group vs placebo (p = 0.0188), while achievements of SR90 (p = 0.0525) and SR100 (p = 0.0540) trended toward earlier occurrence. A greater proportion of patients in the ESL groups compared to the placebo group achieved an SR50 during the maintenance period, and those patients in the ESL groups also achieved SR50 and SR75 sooner than placebo treated patients. Additionally, patients treated with the higher ESL dose achieved SR90 and SR100 sooner than those treated with placebo., (Copyright © 2023 Elsevier B.V. All rights reserved.)

By controlling seizures, anti-seizure medications can improve health-related quality of life (HRQOL). Data from a post-hoc pooled analysis of adjunctive eslicarbazepine acetate (ESL) was used to describe HRQOL measures, including overall quality of life, seizure worry, emotional well-being, energy/fatigue, cognitive functioning, medication effects, social function, and overall score over a period of up to one year. Patients who completed a double-blind treatment phase (Part 1) of these trials were eligible to enter the open label extension (OLE; Part 2). Patients who continued into the OLE initiated adjunctive ESL at 800 mg/day for 1 month before investigators could titrate dosages based on efficacy and tolerability. HRQOL was measured at baseline and at the last assessment using the Quality of Life in Epilepsy Inventory (QOLIE-31) in all patients who entered the 1-year OLE and in patients who completed the 1-year OLE. The mean QOLIE-31 scores and mean change in scores were analyzed using paired t-tests. The percentage of patients with improvements in QOLIE-31 scores beyond the minimally important change (MIC) threshold from baseline to end of 1-year OLE is described. Of 1410 patients in the intent-to-treat population, 1120 patients continued to part 2, and 795 patients completed the OLE. In patients who entered the OLE, mean improvements in scores for seizure worry, overall quality of life, emotional well-being, medication side effects, social functioning, and total score were statistically significant. In patients who completed the OLE, the mean change to final assessment was statistically significantly improved for all QOLIE categories. In patients who entered the OLE with a final assessment, the percentage of patients meeting the MIC for social functioning was the highest (46.9%), followed by medication effects (44.9%), and seizure worry (42.9%). Patients who completed the OLE with a final assessment found a similar rank ordering in QOLIE scale improvements compared with those who entered the OLE with a final assessment. For both sets of patient groups, the least number of subjects met MIC criteria for the energy/fatigue QOLIE category. Treatment with therapeutic doses of adjunctive ESL in patients with focal seizures was associated with improvements in HRQOL for a period of up to one year., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SRK has nothing to disclose. DC, DH, and TG are employees of Sunovion Pharmaceuticals, Inc. HG and AP are employees of Bial-Portela & C.(a), S.A., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Polypharmacy in cancer patients is a recognized issue and should be an integral part of comprehensive patient assessment and management. Despite this, a systematic review of concomitant drugs or a search for potential drug-drug interactions (DDIs) is not always performed. Here, we present the results of a medication reconciliation model performed by a multidisciplinary team to identify clinically meaningful potential DDIs (defined by the presence of DDI of major severity or contraindication) in cancer patients undergoing oral antineoplastic drugs., Methods: From June to December 2022, we performed a non-interventional, prospective, cross-sectional, single-center study of adult cancer patients, initiating or undergoing treatment with oral antineoplastic drugs, referred by their oncologists for therapeutic review regarding potential DDIs. DDIs were assessed by a multidisciplinary team of hospital pharmacists and medical oncologists, through research in three different drug databases as well as in the summary of product characteristics. A report detailing all potential DDIs was created for each request and provided to the patient's medical oncologist for further examination., Results: Overall, 142 patients' medications were reviewed. Regardless of the severity or clinical importance, 70.4% of patients had at least one potential DDI. We found 184 combinations of oral anticancer and regular therapy agents with potential DDIs, 55 of whom were considered of major severity by at least one DDI database. As expected, the number of potential DDIs increased with the number of active substances in regular therapy ( p <  0.001), but we did not find an increased relation between age and the total number of potential DDIs ( p =  0.109). Thirty-nine (27.5%) patients had at least one clinically meaningful DDI identified. After adjustment through multivariable logistic regression, only the female sex (odds ratio (OR) 3.01,  p  = 0.029), the number of active comorbidities (OR 0.60,  p  = 0.029), and the presence of proton pump inhibitors in chronic medication (OR 2.99,  p  = 0.033) remained as predictors of potential meaningful DDI., Conclusion: Although drug interactions are a concern in oncology, a systematic DDI review is rarely conducted in medical oncology consultations. The availability of a medication reconciliation service, carried out by a multidisciplinary team with dedicated time for this task, is an added value for safety enhancement in cancer patients., Competing Interests: All declarations of interest are outside the scope of this work and can be consulted at the Portuguese Transparency and Advertising Platform - Infarmed I.P. (https://extranet.infarmed.pt/pmro/Publico/ListagemPublica.aspx), (Copyright © 2023, Rodrigues et al.)

Background: The goal of the present study was to investigate the association between PTSD and the onset of hypertension in previously normotensive individuals in a population living in the stressful environment of the urban slums while controlling for risk factors for cardiovascular disease (CVD)., Methods: Participants were 320 normotensive individuals who lived in slums and were attending a family doctor program. Measurements included a questionnaire covering sociodemographic characteristics, clinical status and life habits, the Posttraumatic Stress Disorder Checklist - Civilian Version, and the Beck Depression Inventory. Incident hypertension was defined as the first occurrence at the follow-up review of the medical records of (1) systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher, (2) the participant started taking antihypertensive medication, or (3) a new diagnosis of hypertension made by a physician. Differences in sociodemographic, clinical, and lifestyle characteristics between hypertensive and non-hypertensive individuals were compared using the χ 2 and t tests. Multivariate Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI)., Results: Six variables - age, educational level, body mass, smoking, diabetes, and PTSD diagnosis - showed a statistically significant ( p ≤ 0.20) association with the hypertensive status. In the Cox regression, only PTSD diagnosis was significantly associated with incident hypertension (multivariate HR = 1.94; 95% CI 1.11-3.40)., Conclusions: The present findings highlight the importance of considering a diagnostic hypothesis of PTSD in the prevention and treatment of cardiovascular diseases.

Background: Most international guidelines suggest that benzodiazepines (BDZs) may be inefficient or iatrogenic in the aftermath of a potentially traumatic event (PTE). The goal of this study was to assess the strength of the evidence on whether the use of BDZs in the aftermath of a PTE negatively affects the incidence and severity of post-traumatic stress disorder (PTSD)., Methods: We systematically scrutinized the ISI Web of Knowledge, MEDLINE, SCOPUS, and PTSDpubs electronic databases in addition to citation searching. We included original studies providing data about the development of PTSD in adults after BDZ administration in the aftermath of a PTE. We screened 387 abstracts and selected eight studies for the qualitative synthesis and seven for the meta-analysis. We performed two separate meta-analyses, one for randomized clinical trials (RCTs) and the other for cohort studies. Heterogeneity between studies was evaluated with Higgins I ² statistic and tested using the χ². This study was registered at PROSPERO (number 127170)., Results: The meta-analysis of the cohort studies showed an increased risk of PTSD in patients who received BDZs compared to those who did not (risk ratio (RR) = 1.53; 95% confidence interval (CI): 1.05-2.23) with a modest heterogeneity among studies ( I 2  = 41.8, p  = 0.143). Regarding the RCTs, the combined measure revealed a tendency toward an increased severity of the PTSD symptoms (standardized mean difference (SMD): 0.24; 95% CI: 0.32-0.79)., Conclusion: The studies reviewed showed a possible harmful effect of BDZs when used immediately after a PTE. However, these conclusions were based on a small number of studies of poor to moderate methodological quality.

Procoagulant platelets are a subtype of activated platelets that sustains thrombin generation in order to consolidate the clot and stop bleeding. This aspect of platelet activation is gaining more and more recognition and interest. In fact, next to aggregating platelets, procoagulant platelets are key regulators of thrombus formation. Imbalance of both subpopulations can lead to undesired thrombotic or bleeding events. COAT platelets derive from a common pro-aggregatory phenotype in cells capable of accumulating enough cytosolic calcium to trigger specific pathways that mediate the loss of their aggregating properties and the development of new adhesive and procoagulant characteristics. Complex cascades of signaling events are involved and this may explain why an inter-individual variability exists in procoagulant potential. Nowadays, we know the key agonists and mediators underlying the generation of a procoagulant platelet response. However, we still lack insight into the actual mechanisms controlling this dichotomous pattern (i.e., procoagulant versus aggregating phenotype). In this review, we describe the phenotypic characteristics of procoagulant COAT platelets, we detail the current knowledge on the mechanisms of the procoagulant response, and discuss possible drivers of this dichotomous diversification, in particular addressing the impact of the platelet environment during in vivo thrombus formation.

Objective: to validate the incidence of inflammatory bowel disease (IBD) reported in Vigo in 2010 within the Epi-IBD study, which was the highest incidence reported so far in Spain., Methods: an epidemiological, prospective, population-based inception cohort study. All incident cases of IBD living in the Vigo area at diagnosis from January 1 to December 31, 2011 were included., Results: one hundred patients were diagnosed (62 % men; median age, 43.27 years): 49 with ulcerative colitis (UC), 34 with Crohn's disease (CD), and 17 with IBD unclassified (IBDU). The incidence (per 100,000 inhabitants/year) was 17.56 (CD: 5.97; UC: 8.60; IBDU: 2.98), similar to that reported in 2010. The incidence in the non-pediatric population was 19.66 (CD: 6.89, UC: 9.52; IBDU: 3.04). CD and UC phenotype was similar in 2010 and 2011., Conclusion: this study supports the increased incidence of EII in the Vigo area reported in 2010.

Type 1 salt-inducible kinases (SIK1) has been shown to act as a mediator during the cellular adaptation to variations in intracellular sodium in a variety of cell types. Type 2 SIK (SIK2) modulates various biological functions and acts as a signal transmitter in various pathways. To evaluate the role of both SIK isoforms in renal and intestinal Na + ,K + -ATPase (NKA) activity, we made use of constitutive sik1 -/- (SIK1-KO), sik2 -/- (SIK2-KO), double sik1 -/- sik2 -/- (double SIK1*2-KO) knockout and wild-type (WT) mice challenged to a standard (0.3% NaCl) or chronic high-salt (HS, 8% NaCl) diet intake for 48 h or 12 weeks. Long-term HS intake in WT was accompanied by 2-fold increase in jejunal NKA activity and slight (~30% reduction) decreases in NKA in the ileum and cecum; none of these changes was accompanied by changes in the expression of α 1 -NKA. The ablation of SIK1 and SIK2 prevented the marked increase in jejunal NKA activity following the long-term HS intake. The ablation of SIK1 and SIK2 in mice on a long-term HS intake impacted differently in the ileum and cecum. The most interesting finding is that in SIK2-KO mice marked reductions in NKA activity were observed in the ileum and cecum when compared to WT mice, both on normal and long-term HS intake. In summary, SIK1 or SIK2 ablation on chronic high-salt intake is accompanied by modulation of NKA along the intestinal tract, which differ from those after an acute high-salt intake, and this may represent an absorptive compensatory mechanism to keep electrolyte homeostasis., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Opicapone is a third generation nitrocatechol catechol-O-methyltransferase inhibitor that has received regional market approval for use as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. This study evaluated the effects of opicapone as adjunct to levodopa in reversing a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson's-like syndrome in cynomolgus monkeys in during opicapone preclinical development program. A Parkinson's-like syndrome was induced in cynomolgus monkeys by daily administrations of MPTP. Evaluation of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity. MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (PPMRS scores of 10-15) and decreased locomotor activity (13% of pre-MPTP values). Opicapone treatment alone, for 14 days, did not change Parkinson's-like symptoms nor decreased subject's locomotor behaviour. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS and improved locomotor behaviour reaching statistical significance for levodopa/benserazide doses of 18/4.5 mg/kg and those effects were enhanced in opicapone treated subjects. Opicapone treated subjects as compared vehicle-treated, had markedly reduced erythrocyte catechol-O-methyltransferase activity, significantly increased plasma levodopa levels (1.8-fold higher AUC) with no statistically significant changes in C max and significantly reduced 3-OMD AUC and C max values (7.8- and 6.8-fold respectively). Opicapone potentiated the improvements in Parkinson's-like symptoms produced by levodopa/benserazide combinations with concomitant increase in plasma levodopa exposure, reduction of plasma 3-O-methyldopa levels and erythrocyte catechol-O-methyltransferase activity, results that were later demonstrated in 2 large Phase 3 studies in Parkinson's disease patients., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the safety and tolerability of eslicarbazepine acetate (ESL), a once-daily oral anti-seizure drug (ASD), in older and younger adult patient populations., Methods: Two post-hoc pooled data analyses were performed: one from three Phase III studies in patients with focal (partial-onset) seizures who were taking 1-3 concomitant ASDs; the other from five Phase II studies in patients from non-epilepsy populations not taking other ASDs chronically and/or at a clinically-effective anti-seizure dose. The frequencies of treatment-emergent adverse events (TEAEs) were calculated for the older (≥60 years) and younger (18-59 years) adults separately., Results: In the focal seizures study pool, 4.1 % of patients (58/1431) were aged ≥60 years. The overall frequency of TEAEs was 77.5 % in older ESL-treated patients and 72.6 % in younger ESL-treated patients (p = 0.495). For patients who received placebo, the overall frequency of TEAEs was 50.0 % in the older adults and 57.5 % in the younger adults (p = 0.531). The overall placebo-adjusted frequency of TEAEs was 27.5 % in older adults and 15.1 % in younger adults. The placebo-adjusted frequencies of the TEAEs dizziness, somnolence, headache, nausea, diplopia, blurred vision, and ataxia were ≥5 % higher, and frequencies of vomiting and vertigo were ≥2 % higher in older than younger adults. The overall frequency of TEAEs leading to discontinuation was 15.0 % in older ESL-treated patients and 17.6 % in younger ESL-treated patients (p = 0.647); the frequency increased with increasing ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 5.6 % in older adults and 6.6 % in younger adults (p = 0.847). In the non-epilepsy study pool, 30.2 % of patients (515/1705) were aged ≥60 years. The overall frequency of TEAEs was 56.9 % in older ESL-treated patients and 58.8 % in younger ESL-treated patients. The placebo-adjusted frequencies were 14.9 % in older and 15.1 % in younger ESL-treated patients. The placebo-adjusted frequencies of the TEAEs nausea, vomiting, fatigue, and vertigo were ≥2 % higher in older adults, whereas somnolence was ≥2 % higher in younger adults. The overall frequency of TEAEs leading to discontinuation was 18.3 % in older ESL-treated patients and 12.1 % in younger ESL-treated patients (p = 0.003); frequencies were not related to ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 8.0 % in older adults and 5.6 % in younger adults (p = 0.407)., Conclusion: Analyses of adverse event data support the safety and tolerability of ESL in adults aged ≥60 years. In the limited number of older patients with focal seizures taking ESL plus concomitant ASDs (n = 40), the frequency of TEAEs was generally higher than in younger adults. However, in the non-epilepsy patient group (in which the number of older patients was ten times larger; 427 patients taking ESL without concomitant ASDs), no marked age-related TEAE differences were observed, suggesting that increased ASD load associated with adjunctive therapy may complicate treatment selection in older patients, due to risk of increased adverse events. As is common practice for all ASDs, balancing clinical response and tolerability is needed in this vulnerable group of patients., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of "extra-target" RAS suggests the need for RAS screening in all three DAA target regions., Competing Interests: Declaration of competing interest We declare that no public or private company has had any role in the study design, data collection, experimental work, data analysis, decision to publish, or preparation of the manuscript. Roche Diagnostics S.L. provided support in the form of a salary for one of the authors [Josep Gregori], but the company did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No other Competing Interests to declare. Thus, our adherence to Antiviral Research policies on sharing data and materials is not altered., (Copyright © 2019 Elsevier B.V. All rights reserved.)