Tolerability Issues Research Articles

Characteristics of 2-drug regimen users living with HIV-1 in a real-world setting: A large-scale medical claim database analysis in Japan.

BackgroundRegimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear.MethodsThis retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings.ResultsThere were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44–64] vs 42 years [IQR 35–50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5–8] vs 5 [IQR 4–6]), more co-medications (median 6 [IQR 4–11] vs 3 [IQR 2–7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%).ConclusionThe profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.

Adolescents and young adults with rhabdomyosarcoma treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) protocols: a cohort study

Adolescent and young adult patients with rhabdomyosarcoma often have poorer outcomes than do children. We aimed to compare the findings of adolescent and young adult patients with children enrolled in two prospective clinical protocols. This retrospective observational analysis was based on data from the European paediatric Soft tissue sarcoma Study Group (EpSSG) rhabdomyosarcoma 2005 trial (phase 3 randomised trial for localised rhabdomyosarcoma, open from April, 2006, to December, 2016) and the EpSSG MTS 2008 protocol (prospective, observational, single-arm study for metastatic rhabdomyosarcoma, open from June, 2010, to December, 2016), which involved 108 centres from 14 different countries in total. For this analysis, patients were categorised according to their age into children (age 0-14 years) and adolescents and young adults (age 15-21 years). For the analysis of adherence to treatment and toxicity, only patients with high-risk localised rhabdomyosarcoma included in the randomised part of the rhabdomyosarcoma 2005 study were considered. The primary outcome of event-free survival (assessed in all participants) was defined as the time from diagnosis to the first event (eg, tumour progression, relapse) or to the latest follow-up. Secondary outcomes were overall survival, response to chemotherapy, and toxicity. Our analysis included 1977 patients, 1720 children (median age 4·7 years; IQR 2·6-8·4) and 257 adolescents and young adults (16·6 years; 15·8-18·0). 1719 patients were from the EpSSG rhabdomyosarcoma 2005 study (1523 aged <15 years and 196 aged 15-21 years) and 258 patients were from the EPSSG MTS 2008 study (197 aged <15 years and 61 aged 15-21 years). Adolescent and young adult patients were more likely than were children to have metastatic tumours (61 [23·7%] of 257 vs 197 [11·5%] of 1720; p<0·0001), unfavourable histological subtypes (119 [46·3%] vs 451 [26·2%]; p<0·0001), tumours larger than 5 cm (177 [68·9%] vs 891 [51·8%]; p<0·0001), and regional lymph node involvement (109 [42·4%] vs 339 [19·7%]; p<0·0001). Adolescent and young adult patients had lower 5-year event-free survival (52·6% [95% CI 46·3-58·6] vs 67·8% [65·5-70·0]; p<0·0001) and lower 5-year overall survival (57·1% [50·4-63·1] vs 77·9% [75·8-79·8]; p<0·0001) than did children. The multivariable analysis confirmed the inferior prognosis of patients aged 15-21 years (hazard ratios 1·48 [95% CI 1·20-1·83; p=0·0002] for poorer event-free survival and 1·73 [1·37-2·19; p<0·0001] for poorer overall survival). Modifications of administered chemotherapy occurred in 13 (15·3%) of 85 adolescents and young adults, and in 161 (21·4%) of 754 children. Grade 3-4 haematological toxicity and infection were observed more frequently in children than in adolescent and young adult patients. This study found better outcomes for adolescent and young adult patients than those reported in epidemiological studies (eg, the EUROCARE-5 study reported 5-year overall survival of 39·6% for patients aged 15-19 years in the 2000-07 study period), suggesting that adolescent and young adult patients, at least up to age 21 years, can be treated with intensive paediatric therapies with no major tolerability issues and should be included in paediatric rhabdomyosarcoma trials. However, the inferior outcomes in adolescent and young adult patients compared with those in children, despite receiving similar therapy, suggest that a tailored and intensive treatment strategy might be warranted for these patients. Fondazione Città della Speranza.

Effects of biaxial residual stress components on mixed-mode fatigue crack propagation behavior in friction stir welded 7075-T6 aluminium alloy panel

Residual stress in friction stir weld (FSW) joint significantly affects fatigue performance. It can often combine critically with the applied load cause premature fatigue failure. Research on the residual stress effects on fatigue behavior is required to assess the damage tolerance issues in FSW joints. In this study, the effect of biaxial residual stress components (longitudinal residual stress and transverse residual stress) on mixed-mode crack propagation behavior in FSWed 7075-T6 fuselage panel was studied. Residual stress profiles across the welded plate were measured by X-ray diffraction technique. Fatigue crack propagation for mode mixity angles of 30°, 45° and 60° were carried out. The stress intensity factors (SIFs) at the crack tip were evaluated by finite element method and used to study the effect of biaxial residual stress and the individual component on mixed-mode crack behaviors. The results show that the variation of crack path is strongly linked with the residual stress component as well as the initial oblique crack angle. SIF components are affected by the individual residual stress component. Both two components are required to study the mixed-mode crack propagation in FSWs.

Evaluating the pharmacokinetics of extended release viloxazine in the treatment of children with attention-deficit/hyperactivity disorder

ABSTRACT Introduction Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and impacts function negatively in multiple settings. Current treatments include stimulants, which inhibit the reuptake of dopamine and norepinephrine, a nonstimulant norepinephrine reuptake inhibitor (NRI) atomoxetine, and alpha-2 agonists clonidine extended release (ER) and guanfacine ER. Despite the effectiveness of these medications some patients do not respond to available drugs or may experience tolerability issues that hinder their use. Areas covered Viloxazine, a serotonin norepinephrine modulating agent, was used outside of the United States (U.S.) as an effective antidepressant for several decades, but its use fell out of favor due to the need for multiple daily dosing. An ER viloxazine formulation was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD. The efficacy, pharmacokinetics and metabolism of viloxazine and viloxazine ER are reviewed. Expert opinion Viloxazine ER is the first nonstimulant approved to treat ADHD in more than a decade. Although they have not been directly compared, the effect size of viloxazine ER is less than has been observed for stimulants. However, its pharmacokinetic properties and tolerability make viloxazine ER a useful addition to the collection of FDA approved ADHD treatments.

Lessons Learned through the Muslim Youngsters’ Creative Process of Digital Storytelling (DST) on Peace

The heterogeneous, rich and unique social cultural background of Indonesiahas routinely become a hidden agenda of hate speech, intolerance, cultural conflicts, and group friction leading to disharmony. Educational intervention is believely needed to address the issue of tolerance. This article aims to investigate ten young students’ experiences with their narration during the creative process of peace-themed Digital Storytelling (DST). By employing a narrative research paradigm, the study reveals the students’ thoughts during the creative DST process. The students’ statements, picture selection, and syntax served as the primary data. Applying Braun and Clark’s thematic analysis, the parameters of peaceful literacy included the commitment to one nation, tolerance, non-violence, and acceptance of various cultures and traditions. The results of this study on the students’ narratives indicated that these young people were peaceful literary agents who use their voices to speak about the importance of upholding cultural traditions, and respecting and accepting others. The study offers a novelty in terms of methods by using a narrative design to narrate the youngsters’ voice related to peace literacy, and in empirical contribution as the supplement to support the national curriculum as well as the implementation of peace-themed peace literacy in educational context.

Patient preferences for treatment and outcomes in hormone-sensitive prostate cancer (HSPC).

e18757 Background: Treatment options for patients with HSPC have broadened, and data regarding patient preferences for therapies can aid in therapeutic decision-making. This study evaluated the impact of attributes associated with therapies for US patients with locally advanced prostate cancer (LAPC) or metastatic HSPC (mHSPC) from the perspective of patient preferences. Methods: An online discrete choice experiment (DCE) was developed for patients with LAPC or mHSPC. The DCE included 12 questions designed to systematically require tradeoffs between treatment attributes of efficacy (5-year overall survival [OS]), tolerability (fatigue, skin rash, neurotoxicity, and common chemotherapy-related toxicity), and convenience (administration factors [route, frequency, and setting], concomitant use of steroids, and monitoring requirements). Respondents could choose androgen deprivation therapy (ADT) alone or with hypothetical therapies that improved 5-year OS but had additional adverse events (AEs). Attribute-specific importance weights measuring their relative impact on treatment choices were estimated using a mixed-logit model, which also controlled for heterogeneity in preferences. Results: From September 3 to October 14, 2021, 82 respondents (mean age 61 years) completed the survey (LAPC, n = 40; mHSPC, n = 42), with 61 (74.4%) receiving ADT at the time of the survey. Respondents reported treatment efficacy (36% [95% confidence interval (CI) 22, 49]) as the most important aspect of treatment choice, followed by changes in chemotherapy-related toxicity (13% [95% CI 3, 22]) and the need for concomitant steroid use (12% [95% CI 5, 19]). Respondents considered monitoring requirements (8% [95% CI 5, 19]) to be more important than fatigue (5% [95% CI 2, 13]). Administration factors were comparable in importance to therapy AEs (Table). Respondents preferred, by at least 10 percentage points, adding therapies to ADT that could improve 5-year OS, at the detriment of additional AEs. Conclusions: After efficacy, convenience was considered to impact treatment choices at a rate comparable to tolerability issues, potentially influenced by perceived COVID-19 exposure risks. Patients with LAPC and mHSPC prioritize efficacy despite the detriment of additional AEs.[Table: see text]

Olanzapine/Samidorphan: A New Combination Treatment for Schizophrenia and Bipolar I Disorder Intended to Reduce Weight Gain.

Olanzapine is a second-generation antipsychotic with established efficacy in several psychiatric disease states, but its use is limited because of weight gain and metabolic side effects. Samidorphan is a novel opioid antagonist that binds to mu-opioid, kappa-opioid, and delta-opioid receptors and is hypothesized to reduce cravings for high-calorie foods thus attenuating antipsychotic-induced weight gain. The combination product olanzapine/samidorphan was approved by the US Food and Drug Administration in June 2021 for the treatment of schizophrenia and bipolar I disorder; this article reviews the pharmacological properties of oral olanzapine/samidorphan and its clinical efficacy and tolerability with a focus on mitigation of olanzapine-induced weight gain in these patient populations. In clinical trials, the combination of olanzapine/samidorphan was associated with significantly less weight gain and smaller increases in waist circumference as compared with olanzapine monotherapy. Olanzapine/samidorphan demonstrated similar efficacy as olanzapine monotherapy and was well tolerated. Weight gain and metabolic side effects associated with olanzapine monotherapy can result in tolerability issues and potentially medication nonadherence. Olanzapine/samidorphan is an effective treatment for schizophrenia and bipolar I disorder with less weight gain than olanzapine monotherapy.

AB0350 ASSESSMENT OF REAL-LIFE PATIENT HANDLING EXPERIENCE OF AVT02 ADMINISTERED SUBCUTANEOUSLY VIA AUTOINJECTOR IN PATIENTS WITH MODERATE-TO-SEVERE ACTIVE RHEUMATOID ARTHRITIS: AN OPEN-LABEL, SINGLE-ARM CLINICAL TRIAL, THEN AN EXTENSION PHASE OF AVT02 ADMINISTERED WITH A PRE-FILLED SYRINGE (ALVOPAD-PEN)

BackgroundAVT02 is an investigational biosimilar to adalimumab. It is approved in Europe, Canada, and the UK. It is not approved by the US Food and Drug Administration (FDA).ObjectivesTo assess the real-life patient handling of an autoinjector (AI) in adult patients with moderate-to-severe active rheumatoid arthritis (RA) who self-inject AVT02 subcutaneously (s.c.).MethodsThis open-label study enrolled 107 adalimumab-naïve subjects with moderate-to-severe active RA to self-inject AVT02 with the proposed AI 40 mg s.c. in Week 1, and every other week thereafter through Week 8. In an optional extension phase through Week 56, subjects were switched from AVT02 AI to pre-filled syringe and followed for safety and efficacy. The primary endpoint was the percentage of successful self-injections as reported by both the trial site and by subjects using standardized questionnaires at Week 8. Additional endpoints included ease of use and robustness of the AI at Week 8, and efficacy in RA, assessment of serum trough levels of AVT02, and detection of antidrug antibodies (ADA) throughout the study.ResultsThe AI success rate was 100% as reported by both the trial site and by subjects. No handling events were noted through Week 8. Approximately 80% (78.1–84.9%) of subjects found the AI ‘very easy’ to use and, in general, less difficulty was reported as the study progressed. The first 110 AIs used were inspected for robustness and none showed any sign of damage or malfunction.All subjects who completed Week 8 (n = 106) took part in and completed the optional extension phase through Week 56.At Week 8, 49.1%, 5.7% and 0.9% subjects achieved ACR20, -50 and -70 responses, respectively. Improvement was also reported for the SDAI, DAS28 CRP and HAQ, with scores consistently decreasing through Week 8. In the extension phase, 70.8%, 47.2% and 13.2% subjects achieved ACR20, -50 and -70 responses at Week 56. Improvement was also reported for the SDAI, DAS28 CRP and HAQ, with scores consistently decreasing through Week 56.From Baseline through Week 8 the mean serum concentrations of investigational AVT02 increased consistently at each visit, reaching a peak at Week 24. There was no significant difference in serum concentrations of AVT02 based on injection subsite (abdomen or thigh).ADAs were detected in 65.1% of subjects through Week 8, reducing to 49.1% by Week 56. Of ADA-positive subjects, most were also positive for neutralizing antibodies through Week 8 (62.3%) increasing through Week 56 (90.4%). Subjects who were ADA-positive had lower serum concentrations of study drug compared with the overall population at Week 8 and Week 56 as expected.There were no clinically relevant safety or tolerability issues. Overall, treatment-emergent adverse events reported in at least 5% of subjects at the PT level were anaemia and influenza (6 subjects [5.6%)] reported 6 events each), and no local ISRs were reported.ConclusionThe fully successful self-injection with the AI in this study supported the use of the device while administering AVT02. Furthermore, subjects typically found the AI easy to use, with ease of use increasing as time progressed.The ACR20, -50, and -70, SDAI, DAS28 CRP and HAQ results supported the use of AVT02 to treat adult patients with moderate-to-severe RA, with the treatment effect persisting beyond Week 8 and through Week 56.The safety and immunogenicity profiles were as expected for adalimumab.ClinicalTrials.gov Identifier: NCT04224194Disclosure of InterestsNemanja Damjanov: None declared, Heimo Stroissnig Employee of: Alvotech, Matjaz Steiger Employee of: Alvotech, Joanna Sobierska Employee of: Alvotech, Eric Guenzi Employee of: Alvotech, Hendrik Otto Employee of: Alvotech, Abid Sattar Employee of: Alvotech, Halimu N. Haliduola Employee of: Alvotech, Elin Edwald Employee of: Alvotech, Fausto Berti Employee of: Alvotech

Topical Endoxifen for Mammographic Density Reduction-A Randomized Controlled Trial.

Although breast cancer incidence is increasing, there are few primary preventive initiatives. Tamoxifen can reduce breast cancer incidence but is rarely used for primary prevention due to adverse events and tolerance issues. We tested if endoxifen, a tamoxifen metabolite, applied directly to the skin of the breast, could reduce mammographic density, a proxy for therapy response. Ninety women were randomized to placebo, 10 and 20 mg of topical Z-endoxifen for 6 months. Mammographic density and symptoms were measured at baseline and study exit. Despite a high discontinuation rate, driven by skin rashes, we found a significant mammographic density decrease, a dose-dependent increase in the concentration of plasma Z-endoxifen but no systemic side effects. Topical application of tamoxifen metabolites has the potential to decrease breast cancer incidence without major systemic side effects. However, endoxifen may not be suitable for topical administration and is unlikely to be used for breast cancer prevention.

Robustness and reliability assessment of Single-Sided Spot Welding as a process for sheet to closed profile joining for Body in White vehicle structures

The application of high performance steels in combination with rolled profiles, hydro-formed or tailored tubes (TT) can create a stiffer and safer vehicle structure. However, it presents some challenges regarding the joining process, once accessibility to both sides of the surface to be joined is limited. The Single-Sided Spot Welding (SSSW) is an alternative to Resistance Spot Welding (RSW), as it only requires access to just one side of the joint to weld it. In order to validate SSSW as a robust and reliable welding process for automotive manufacturing, this work encompassed experiments comparing SSSW and RSW under manufacturing conditions and tolerance problems, such as sheets and electrode misalignment, gaps or shunt current conditions, using DX54D steel sheets, and steel profiles made of press-hardened 22MnB5 and S355J2 + N. The experimental parameters in this study were current, electrode force, geometry and misalignment angle. The performed tests were lap shear tensile strength, analyses of weld nugget quality and the measurement of spot diameters by chisel testing. The obtained results show that SSSW can meet RSW requirements regarding mechanical properties and quality standards, overcoming the set manufacturing tolerance issues, without reducing the spot diameter and with similar mechanical properties of RSW joints.

Culture and Ethics of Communication in the Distance Educational Process when Training Nuclear Specialists

The paper considers the problems of formation of culture and ethics of communication in the distance learning process when training nuclear specialists, the basic principles and methods of communication of students online, analyzes the issues of ethics and communicative tolerance of students.

Religious Tolerance in the Constitution and Guarantees for the Protection of Human Rights

Protection of human rights is an absolute guarantee that must be fulfilled by the rule of law. Article 1 Paragraph 3 of the 1945 Constitution of the Republic of Indonesia mandates that " The State of Indonesia shall be a state based on the rule of law. " it shows Indonesia recognizes and protects human rights, one of which is the right or freedom to believe in a particular religion. The purpose of this study is to figure out how the regulation of religious tolerance ruled in the Constitution of the Republic of Indonesia/ Undang-Undang Dasar Negara Republik Indonesia Tahun 1945. This research is descriptive research by describing, and analyzing, the issues of tolerance and human rights. The approach used is a legal approach by tracing all relevant laws and regulations. The data collection technique used in this study is a library research technique, which is a data collection technique by reviewing journals, laws and regulations, and other related materials related to the regulation of religious tolerance in Indonesia. That guarantees for the protection of human rights as mandated by the constitution can create religious tolerance among people of different religions in the plurality of Indonesian society. Religious tolerance in Indonesia will create inter-religious harmony to maintain peace, order, tranquility, and the prosperity of the people, nation and state of Indonesia.

Functionality, satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: a post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials

BackgroundTriptans are the first-line option for the acute treatment of migraine attacks; however, triptans are contraindicated in people with certain underlying cardiovascular risk factors and are associated with inadequate efficacy or poor tolerability in some individuals. Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine.MethodsThis post hoc analysis of the phase 3 ACHIEVE trials examined the impact of ubrogepant on the Functional Disability Scale (FDS), satisfaction with medication, and Patient Global Impression of Change (PGIC) in participants who were self-reported triptan insufficient responders (TIRs), defined as those who are unable to take triptans due to contraindications, tolerability issues, or insufficient efficacy. Responder definitions for the FDS, satisfaction measures, and PGIC were based on qualitative interpretation of the respective response options for the pooled ubrogepant 50 mg and placebo groups.ResultsIn the pooled analysis population (n = 1799), 451 (25%) participants were TIRs, with most (80%) reporting insufficient efficacy with triptan use. A significantly higher proportion of TIRs treated with ubrogepant vs placebo reported being able to function normally from 2 to 8 h post dose (P < 0.05). Notably, significance was demonstrated at the time of the primary outcome assessments (2 h post dose), where rates of normal function were 38% for ubrogepant vs 29% for placebo (P = 0.048). A greater proportion of TIRs in the ubrogepant arm vs the placebo arm were satisfied with treatment at 2 (33% vs 21%, P = 0.006) and 24 h (58% vs 28%, P < 0.001) and indicated that their migraine improved at 2 h vs placebo (30% vs 18%, P = 0.006). Results were generally similar in the insufficient efficacy subpopulation of TIRs as in the overall TIRs group. Ubrogepant was safe and well tolerated in TIRs, with no new safety signals identified.ConclusionsIn people with migraine who are TIRs, individuals treated with ubrogepant had favorable 2-h outcomes, as measured by the FDS, satisfaction with medication, and PGIC, compared with placebo.Trial registrationClinicalTrials.gov: NCT02828020 (ACHIEVE I), registered July 11, 2016; NCT02867709 (ACHIEVE II), registered August 16, 2016.

Gendering Islamophobia at the crossroad of conflicting rights

The presence of Muslims in the European public spheres has raised a hoist of debates concerning issues of neutrality, tolerance, and secularism. All over Europe, Muslims are the target of specific forms of hostility, a phenomenon rising substantial questions about the real inclusivity of European democratic spaces. The category of ‘Islamophobia’ has emerged as a valid heuristic tool to identify specific processes of racialization of religion. However, its validity has been fiercely questioned, and the use of this term has been defined as a pretext to bar the way to any form of criticism and objection to Islam. This paper will use the case of Islamophobia to reflect on the new set of conflicts between freedom of religion and freedom of speech, in the perspective of constructing post secularist, pluralistic public spheres. This paper adopts gender as a privileged lens to identify the mechanisms of essentialization and reification at work in the case of Islam

Assessment of Cardiac Contribution to Exercise Intolerance in Pediatric Bilateral Lung Transplant Recipients

<h3>Purpose</h3> Exercise intolerance is common among lung transplant (LTx) recipients. However, there is limited data in pediatrics. Since the heart and lungs work in concert with each other, we aim to assess the cardiac contribution to exercise intolerance in pediatric LTx recipients by examining the prevalence of traditional cardiac risk factors (CRFs) and their performance on cardiopulmonary exercise testing (CPET). <h3>Methods</h3> All pediatric LTx recipients followed at a single center who had a resting echocardiogram (echo), were able to exercise, and had a routine CPET in the last 2 years were included. CRFs including hypertension, hyperlipidemia, diabetes mellitus (DM), body mass index (BMI), activity level, and smoking history were assessed. CPET-derived maximal oxygen consumption (VO2_max) and % predicted peak VO2 (ppVO2_max) were used to assess exercise tolerance. Left ventricular (LV) systolic and diastolic function were also assessed on resting echo. <h3>Results</h3> 11 bilateral LTx patients (7M, 4F, and median age 21 years, range 17-28 years) formed the cohort. Median time since LTx is 6 years, range 2-10 years. The majority of patients (8, 73%) had multiple CRFs: 7 (64%) had hypertension, 7 (64%) hyperlipidemia, 6 (55%) DM, 2 with BMI ≥25 kg/m², and 6 (55%) sedentary lifestyle. None had a smoking history. On resting echo, all had normal LV systolic function. 5 (45%) had LV diastolic dysfunction. On CPET, 9 (82%) had abnormal ppVO2_max ≤85%, even with maximal patient effort. None had ischemia. Surprisingly, only 2 of the 9 had a pulmonary limitation to exercise with abnormal breathing reserve (<25%) to account for abnormal ppVO2_max. 6 had a cardiac limitation to exercise attributed to inability to augment stroke volume (decreased % predicted peak O2 pulse). 1 had an abnormal respiratory exchange ratio (RER <1.10), with a normal % predicted peak O2 pulse and a chronotropic deficit (achieving 60% predicted peak heart rate). Of note, 2 patients had normal exercise tolerance with ppVO2_max >85%. <h3>Conclusion</h3> Despite maximal effort, low exercise tolerance is common among pediatric LTx recipients. The high prevalence of CRFs, diastolic dysfunction, and inability to augment stroke volume suggest a potential cardiac contribution to exercise intolerance for this cohort. Further studies are needed to define potential cardiac issues in exercise tolerance in pediatric LTx recipients.

New Generation Gepants: Migraine Acute and Preventive Medications.

Migraine is a debilitating disease whose clinical and social impact is out of debate. Tolerability issues, interactions, contraindications, and inefficacy of the available medications make new options necessary. The calcitonin-gene-related peptide (CGRP) pathway has shown its importance in migraine pathophysiology and specific medications targeting this have become available. The first-generation CGRP receptor antagonists or gepants, have undergone clinical trials but their development was stopped because of hepatotoxicity. The new generation of gepants, however, are efficacious, safe, and well tolerated as per recent clinical trials. This led to the FDA-approval of rimegepant, ubrogepant, and atogepant. The clinical trials of the available gepants and some of the newer CGRP-antagonists are reviewed in this article.

Ketamine Improves Desensitization of µ-Opioid Receptors Induced by Repeated Treatment with Fentanyl but Not with Morphine.

The issue of tolerance to continuous or repeated administration of opioids should be addressed. The ability of ketamine to improve opioid tolerance has been reported in clinical studies, and its mechanism of tolerance may involve improved desensitization of μ-opioid receptors (MORs). We measured changes in MOR activity and intracellular signaling induced by repeated fentanyl and morphine administration and investigated the effects of ketamine on these changes with human embryonic kidney 293 cells expressing MOR using the CellKey™, cADDis cyclic adenosine monophosphate, and PathHunter® β-arrestin recruitment assays. Repeated administration of fentanyl or morphine suppressed the second MOR responses. Administration of ketamine before a second application of opioids within clinical concentrations improved acute desensitization and enhanced β-arrestin recruitment elicited by fentanyl but not by morphine. The effects of ketamine on fentanyl were suppressed by co-treatment with an inhibitor of G-protein-coupled receptor kinase (GRK). Ketamine may potentially reduce fentanyl tolerance but not that of morphine through modulation of GRK-mediated pathways, possibly changing the conformational changes of β-arrestin to MOR.

Effects of Hepatic Impairment on the Pharmacokinetic Profile and Safety of Lobeglitazone.

In this open-label, single-dose, parallel-group study, we compared the pharmacokinetic profile and safety of lobeglitazone, a thiazolidinedione acting as an agonist for peroxisome proliferator-activated receptors, in patients with hepatic impairment (HI) and healthy matched controls for age, sex, and body weight. After a single oral dose of lobeglitazone (0.5 mg), the lobeglitazone (parent drug) and M7 (major metabolite) plasma concentrations and pharmacokinetic parameters were analyzed and compared between the HI patient groups and healthy matched control groups. The geometric mean ratio (GMR; 90% confidence interval [CI]) for maximum concentration (Cmax ) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf ) of lobeglitazone was 1.06 (0.90-1.24) and 1.07 (0.82-1.40), respectively, for mild HI vs control A. The GMR (90%CI) of Cmax and AUCinf was 0.70 (0.56-0.88) and 1.00 (0.72-1.37), respectively, for moderate HI vs control B. For M7, the GMR (90%CI) of Cmax and AUCinf was 1.09 (0.75-1.57) and 1.18 (0.71-1.97), respectively, for mild HI vs control A and 1.50 (0.95-2.38) and 1.79 (1.06-3.04), respectively, for moderate HI vs control B. Notable adverse events or tolerability issues were not observed. Lobeglitazone may be safely used in patients with mild or moderate HI without dose adjustment.

Toleranz

Abstract Tolerance. An Ethical Challenge for Education Tolerance is outlined as willingness to accept characteristics of humans, behaviour, or beliefs and attitudes that are different from one’s own, although one might not agree with them or disapprove them. In education, different theoretical perspectives and methodological approaches can be taken that address different meanings of the concept. An overview is presented, and it is discussed in more detail how research on expertise can help to overcome ethical challenges that are related to issues of tolerance. Examples from a series of empirical studies are provided.

How to Predict Parturition in Cattle? A Literature Review of Automatic Devices and Technologies for Remote Monitoring and Calving Prediction.

Simple SummaryCattle farming is progressively facing an increase in the number of animals that farmers must care for, resulting in decreasing time for observation of the single cow. A large amount of the scientific literature has been published concerning remote automatic devices and machine learning technologies for continuous monitoring of animal behavior and health status, including sensors for calving prediction This review summarizes the current status of the art concerning available automatic devices for the identification of the beginning of calving.Cattle farming is facing an increase in number of animals that farmers must care for, together with decreasing time for observation of the single animal. Remote monitoring systems are needed in order to optimize workload and animal welfare. Where the presence of personnel is constant, for example in dairy farms with great number of lactating cows or with three milking/day, calving monitoring systems which send alerts during the prodromal stage of labor (stage I) could be beneficial. On the contrary, where the presence of farm personnel is not guaranteed, for example in smaller farms, systems which alert at the beginning of labor (stage II) could be preferred. In this case, time spent observing periparturient animals is reduced. The reliability of each calving alarm should also be considered: automatic sensors for body temperature and activity are characterized by a time interval of 6–12 h between the alarm and calving. Promising results have been shown by devices which could be placed within the vaginal canal, thus identifying the beginning of fetal expulsion and optimizing the timing of calving assistance. However, some cases of non-optimal local tolerability and cow welfare issues are reported. Future research should be aimed to improve Sensitivity (Se), Specificity (Sp) and Positive Predictive Value (PPV) of calving alert devices in order to decrease the number of false positive alarms and focusing on easy-to-apply, re-usable and well tolerated products.