Pharmacological counseling in hepatotoxicity induced by macitentan and selexipag: a case report.

BACKGROUND: Pulmonary arterial hypertension is a progressive, debilitating condition characterized by increased resistance in the pulmonary arterial circulation. Current treatments for pulmonary arterial hypertension include endothelin receptor antagonists such as bosentan, sitaxentan, ambrisentan, macitentan, and oral prostacyclin receptor agonists such as selexipag. Endothelin receptor antagonists have been associated with liver injury, while hepatotoxicity was not reported for selexipag. Although genetic variability has been indisputably associated with variability in drug response, no study has been designed until now to assess its effects on the pharmacokinetics of endothelin receptor antagonists or selexipag. CASE PRESENTATION: We report the case of a 58-year-old female Caucasian patient with a dramatic increase in plasma levels of transaminases after treatment with macitentan and selexipag, drugs whose risk of causing liver injury has so far been considered limited. After therapy discontinuation, plasma levels of transaminases returned to baseline, thus suggesting a role of these drugs in the observed hepatotoxicity. After pharmacological counseling, we decided to introduce ambrisentan for the patient's treatment. After 7 months of treatment, no liver injury has been reported. To evaluate the role of genetic factors in the observed hepatotoxicity, we genotyped the patient for single-nucleotide polymorphisms previously associated with macitentan, ambrisentan, or selexipag metabolism. We found a genetic profile associated with a poor metabolizer (PM) phenotype for CYP2C8 and CYP2C9, key enzymes for elimination of both macitentan and selexipag. The reported results suggest that an allelic profile associated with low activity for CYP2C8 and CYP2C9 enzyme could be a potential risk factor for macitentan and selexipag-induced liver injury and could provide a possible marker for early identification of subjects at higher risk of developing hepatotoxicity. CONCLUSIONS: A multidisciplinary approach based on clinical evaluation, as well as pharmacological counseling and evaluation of the patient's genetic profile, might be useful for identification of patients with a high chance of drug-induced liver injury, avoiding unnecessary risks in therapy selection and prescription.

Assessment of right ventricle in pulmonary arterial hypertension with three-dimensional echocardiography and cardiovascular magnetic resonance.

AIM: To correlate 3-D Echo and CMR RV parameters and to verify whether they are similarly related to the clinical conditions of patients with pulmonary arterial hypertension (PAH), a disease in which the RV plays a crucial prognostic role. METHODS: We enrolled 34 consecutive PAH patients followed by our PAH clinics. All patients underwent a 3-D Echo and CMR assessment of RV volumes and functions in the same day. The presence or absence of correlation between major findings was investigated; functional RV parameters were also analyzed in relation to 6-min walking test (6MWT) results and BNP/Nt-proBNP plasma levels. Twenty-four subjects served as controls. RESULTS: Good agreement was found between 3-D Echo and CMR measures of RV volumes [RV-end-diastolic volume (r = 0.72, P < 0.0001), RV-end-systolic volume (ESV) (r = 0.80, P < 0.0001)] and function [RV-EF (r = 0.73, P < 0.0001), RV-ESV/SV (r = 0.83, P = 0.001)] for all the subjects of the study. These correlations were stronger in PAH patients than in control subjects. Importantly, 3-D Echo and CMR RV-EF and RV to pulmonary arterial coupling (RV-ESV/SV) similarly correlated with BNP/Nt-proBNP levels and with functional capacity measured at 6MWT in the PAH patients group. CONCLUSIONS: 3-D Echo demonstrated a significant agreement with CMR in the assessment of RV volume and function in PAH patients. Both techniques showed a similar correlation with clinical and prognostic parameters. The use of 3-D Echo should be amply boosted in the real-world clinical evaluation of PAH patients.

3D Encapsulation Made Easy: A Coaxial-Flow Circuit for the Fabrication of Hydrogel Microfibers Patches.

To fully exploit the potential of hydrogel micro-fibers in the design of regenerative medicinal materials, we designed a simple, easy to replicate system for cell embedding in degradable fibrous scaffolds, and validated its effectiveness using alginate-based materials. For scaffold fabrication, cells are suspended in a hydrogel-precursor and injected in a closed-loop circuit, where a pump circulates the ionic cross-linking solution. The flow of the cross-linking solution stretches and solidifies a continuous micro-scaled, cell-loaded hydrogel fiber that whips, bends, and spontaneously assembles in a self-standing, spaghetti-like patch. After investigation and tuning of process- and solution-related parameters, homogeneous microfibers with controlled diameters and consistent scaffolds were obtained from different alginate concentrations and blends with biologically favorable macromolecules (i.e., gelatin or hyaluronic acid). Despite its simplicity, this coaxial-flow encapsulation system allows for the rapid and effortless fabrication of thick, well-defined scaffolds, with viable cells being homogeneously distributed within the fibers. The reduced fiber diameter and the inherent macro-porous structure that is created from the random winding of fibers can sustain mass transport, and support encapsulated cell survival. As different materials and formulations can be processed to easily create homogeneously cell-populated structures, this system appears as a valuable platform, not only for regenerative medicine, but also, more in general, for 3D cell culturing in vitro.

Genetics and mathematics: evidence from Prader-Willi syndrome.

Mathematical abilities were tested in people with Prader-Willi syndrome (PWS), using a series of basic mathematical tasks for which normative data are available. The difference between the deletion and the disomy variants of this condition was explored. While a wide phenotypic variation was found, some basic findings emerge clearly. As expected from previous literature, deletion and disomy participants were found to differ in their degree of impairment, with disomy being overall the most spared condition. However, the tasks selectively spared in the disomy condition are not necessarily the easiest ones and those that discriminate less the PWS group from controls. It rather seems that disomy patients are spared, with respect to deletion, in tasks entailing transcoding and comparison of numbers in the Arabic code. Overall a particular difficulty was detected in reliably performing parity judgments. This task has been shown to be very frequently spared after a brain injury, even in severe aphasic conditions. The most interesting result is the sparing in analog number scale, whereby PWS seem, overall, to outperform controls. This finding may help in understanding previously reported, surprising results about cognitive skills in PWS. Elevated performances in PWS may result from life-long hyper-reliance on one visuo-spatial system in presence of underdevelopment of the other.

A dedicated neural mechanism for vowel selection: a case of relative vowel deficit sparing the number lexicon.

We report the case of an Italian speaker (GBC), with classical Wernicke's aphasia following a vascular lesion in the posterior middle temporal region. GBC exhibited a selective deficit in spoken language production affecting vowels more than consonants. In reading from a newspaper, GBC substituted vowels for other vowels from the Italian inventory at a rate of 7/1 compared to consonants. No effects of frequency or grammatical class were found. Vowel errors could also not be accounted for by morphological or known phonological processes. Production of number words, in contrast, was free from phonological errors. While GBC has intact representations of Italian vowels and consonants, his data argue for a separate selection mechanism for vowels that is dissociable from that used for consonants. This case provides neuropsychological evidence for models of word production that distinguish between the abstract phonological properties of a word (e.g., sequencing of phonemic slots, or "CV skeleton") and a separate representation for the specific sounds (melody).

Patients with obesity-related comorbidities have higher disability compared with those without obesity-related comorbidities: results from a cross-sectional study.

The aim of the present study was to describe disability in adult obese patients with obesity-related comorbidities, and to compare it with that of patients without obesity-related comorbidities. Two groups of obese patients were administered a set of 166 International Classification of Functioning, Disability and Health (ICF) categories; on the basis of this set, count-based indexes were developed for each ICF component and difference between patients with and without comorbidities were assessed with independent-sample t-test and Cohen's d as a measure of effect size. ICF categories in which at least 20% of patients reported a problem were considered relevant for describing functioning of obese patients; for each of them, the risk of having obesity-related comorbidities was calculated using odds ratio and 95% confidence interval. A total of 106 inpatients were enrolled in the study: 68 ICF categories reached the 20% threshold, and 31 of them were relevant only among patients with comorbidities. The presence of obesity-related comorbidities was associated with an increased risk of bodily impairments and limitations in performing daily activities. Compared with patients without obesity-related comorbidities, those with comorbidities showed higher disability. Comorbidities contribute to obesity-related disability, and our results support the importance of early rehabilitation interventions to reduce disability.

An ICF-Based Model for Implementing and Standardizing Multidisciplinary Obesity Rehabilitation Programs within the Healthcare System.

INTRODUCTION/OBJECTIVE: In this study, we aimed to design an ICF-based individual rehabilitation project for obese patients with comorbidities (IRPOb) integrated into the Rehab-CYCLE to standardize rehabilitative programs. This might facilitate the different health professionals involved in the continuum of care of obese patients to standardize rehabilitation interventions. METHODS: After training on the ICF and based on the relevant studies, ICF categories were identified in a formal consensus process by our multidisciplinary team. Thereafter, we defined an individual rehabilitation project based on a structured multi-disciplinary approach to obesity. RESULTS: the proposed IRPOb model identified the specific intervention areas (nutritional, physiotherapy, psychology, nursing), the short-term goals, the intervention modalities, the professionals involved and the assessment of the outcomes. Information was shared with the patient who signed informed consent. CONCLUSIONS: The model proposed provides the following advantages: (1) standardizes rehabilitative procedures; (2) facilitates the flow of congruent and updated information from the hospital to outpatient facilities, relatives, and care givers; (3) addresses organizational issues; (4) might serve as a benchmark for professionals who have limited specific expertise in rehabilitation of comorbid obese patients.

When two and too don't go together: a selective phonological deficit sparing number words.

We report the case of an Italian speaker (GBC) with classical Wernicke's aphasia syndrome following a vascular lesion in the left posterior middle temporal region. GBC exhibited a selective phonological deficit in spoken language production (repetition and reading) which affected all word classes irrespective of grammatical class, frequency, and length. GBC's production of number words, in contrast, was error free. The specific pattern of phonological errors on non-number words allows us to attribute the locus of impairment at the level of phonological form retrieval of a correctly selected lexical entry. These data support the claim that number words are represented and processed differently from other word categories in language production.

Obesity-related disability: key factors identified by the International Classification of Functioning, Disability and Health.

PURPOSE: To identify obese patients' disability features considering the level of body impairments, activity limitations and participation restrictions in relation to environmental factors' effect. METHOD: Adult obese inpatients (BMI > 35) were enrolled and were administered a set of 166 ICF categories. Count-based indexes were developed for each ICF component: correlations and regression on performance and capacity indexes were performed. RESULTS: Fifty-one patients (62.7% females, mean age 38.1) entered in the study. Description of ICF-based disability components is reported. Capacity is better correlated with body functions (r = 0.619, P < 0.01) and body structures (r = 0.375, P < 0.01) than performance; on the contrary, environmental barriers are correlated better with performance (r = 0.531, P < 0.01) than with capacity. Impairments in body functions and environmental barriers are the best predictors of limitations both in capacity and in performance. CONCLUSIONS: Through this multidisciplinary approach, supported by ICFs biopsychosocial model, we described functioning and disability in obese patients, highlighting the strong effect of body functions' impairments and the limited one of environmental factors. This approach can guide rehabilitation programmes, the promotion of positive health outcomes and the modification of patients' lifestyle, not only intended as an issue of barriers' elimination, but as the activation and maintenance of environmental facilitators.

Mapping an obesity clinical evaluation protocol to the International Classification of Functioning, Disability and Health.

PURPOSE: To evaluate a multidisciplinary clinical protocol for obesity treatment by mapping it against the International Classification of Functioning, Disability and Health (ICF) and to determine the areas, defined by the ICF, in which no standardized assessment tools are available. METHOD: Assessment instruments used by a multidisciplinary team were linked to ICF categories and compared with a list of ICF categories composed by the ICF checklist and the comprehensive ICF core-set for obesity. Other relevant ICF categories were added, and not relevant ones were deleted when appropriate. RESULTS: Five ICF categories were deleted and 11 were added, and 166 ICF categories were linked to assessment tools and to semi-structured interviews. The majority were linked to assessment tools, but within the domain of the environmental factors all ICF categories were mapped using semi-structured interviews. CONCLUSIONS: Our results show that an extended list of ICF categories is adequate to cover a wide spectrum of clinical and functional information, and it could be employed to describe, disability profiles of obese patients, to develop preventive measures and to identify what factors in the environment need to be changed to improve rehabilitation's outcomes.