Tolerability Issues Research Articles

36 WHAT DO OLDER ADULTS AND HEALTH CARE PROFESSIONALS LOOK FOR IN A FOOD PRODUCT?

Abstract Background The Mediterranean diet (Medi-diet) has proven benefits for healthy ageing but isn’t the habitual diet of most middle-aged or older adults in Ireland; there can be accessibility and tolerability issues with high amounts of fresh fruit and vegetables. Providing key Medi-diet nutrients in a food product is a novel approach to this challenge. This research aims to explore what ‘younger-old’ adults and healthcare professionals (HCPs) would value in such a novel food product. Methods Semi-structured 1:1 interviews and Focus Groups (FGs) were conducted remotely from July 2021 to January 2022. Older adults, defined as over 55’s, were recruited through relevant social, retirement and disease-support groups. Purposive sampling recruited a gender balance and a range of ages and disease profiles. HCPs were recruited through researcher networks and professional associations. Interviews/FGs were recorded, transcribed, and subsequently examined using inductive thematic analysis. Results Older adults (n=47; 50% male) were mostly aged 60-69 years (48.9%). Recruited HCPs (n=26) included dieticians (n=8); geriatricians (n=5); therapists (n=4); and nurses, pharmacists, catering managers (community; residential), and meal delivery service coordinators (n=2 each). Participants supported a food product for older adults requiring a nutrient-dense “boost”, or supplementary fibre or protein, but generally preferred a “food-first” approach, as opposed to a “silver bullet” product. Older adults largely associated functional foods with probiotic products “to repair the gut”, something to have “every now and then”. Product texture and portion size should consider changing dentition and appetite, and consider packaging (dexterity) and preparation ease, but should not stigmatize older adults through targeted branding. Participants felt pre-made soups or cake-type bars would be appealing, but not drinks. Conclusion A novel food product could supplement a balanced diet for older adults, providing high-protein content, and high-fibre for gut health, complimenting an overall lifestyle approach to health improvement and disease prevention.

Identification of potential mutational hotspots in serratiopeptidase to address its poor pH tolerance issue

Serratiopeptidase is the multifunctionality metalloendopeptidase extensively employed in biopharmaceutical and industrial biotechnology. Despite its poor pH tolerance, serratiopeptidase must withstand the highly acidic environment of the gastrointestinal tract to be used as a potent anti-inflammatory and analgesic medication. In earlier studies, post-translational deamination related mutations showed alteration in the net charge of protein’s surface. Therefore, the current study aimed to enhance the acid resistance of serratiopeptidase via implementing computational interventions to screen out the most stable mutational hotspot. The methodology used in this study is as follows: (a) Higher accessibility to surface (b) 4 Å away from active site region to avoid interference with its proteolytic activity, and (c) By converting non-conserved amide residues to acidic residues. A docking study has been conducted to establish the substrate specificity and binding affinity to native and mutant proteins. The docking outcomes were then validated using molecular dynamic simulations to clarify each mutant’s molecular stability and conformation while preserving their activity. The results showed that N412D is the best-screened mutant with negative electrostatic potential that can alter the overall charge on the protein’s surface with increased H+ ions. Alteration in overall charge leads to protein surface more acidic that causes a common ion effect in stomach pH and act as a buffer which could stabilize the serratiopeptidase amid extreme pH. Communicated by Ramaswamy H. Sarma

INHALED IMATINIB FOR PULMONARY ARTERIAL HYPERTENSION CLINICAL TRIAL: DESIGN OF THE IMPACT PHASE 2B/3 STUDY DESIGN

INHALED IMATINIB FOR PULMONARY ARTERIAL HYPERTENSION CLINICAL TRIAL: DESIGN OF THE IMPACT PHASE 2B/3 STUDY DESIGN

Tolerance and european legal values

The article carries out the theoretical and legal analysis of European values. It is emphasized that European values are today the basis of fundamental human rights and freedoms. Among the main of them are: respect for human dignity, fundamental rights and freedoms, democracy, equality, rule of law, tolerance, justice. Together, they are a civilizational identifier of «European identity» and constitute the modern civilizational paradigm of Europe. The main emphasis of the article is on the study of the essence and content of tolerance as one of the main European values. The analysis of scientific positions of specialists of different scientific knowledge allowed to consider tolerance as a universal value that correlates with the legal principle of equality, which embodies the idea of positive perception of otherness and finds its practical expression in tolerance, self-control, non-discrimination. The analysis of universal and regional international legal acts, which became the basis for the formation of the European system of protection of human rights and freedoms in general, including the foundations of the principle of tolerance. It is concluded that Ukraine needs to address the issue of tolerance of «otherness» in various areas, which necessitates the development of its own concept of tolerance, the formation of such legal bases that would ensure individual human rights and freedoms both legislatively and establish effective mechanisms to prevent any – what manifestations of discrimination, xenophobia, various kinds of intolerance. Key words: human rights, legal values, liberal-democratic values, discrimination, tolerance.

Solriamfetol Titration & AdministRaTion (START) in Patients With Narcolepsy

PurposeSolriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved (in the United States and European Union) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75–150 mg/d) or obstructive sleep apnea (OSA) (37.5–150 mg/d). This study characterized real-world titration strategies for patients with narcolepsy (with or without comorbid OSA) initiating solriamfetol therapy. MethodsThis virtual, descriptive study included a retrospective medical record review and qualitative survey. US-based physicians prescribing solriamfetol for EDS associated with narcolepsy or OSA participated. Data are reported for patients with narcolepsy with or without comorbid OSA (OSA alone reported separately). On the basis of medical record review, titration strategies were classified de novo (EDS medication naive), transition (switched or switching from existing EDS medication[s] to solriamfetol), or add-on (adding solriamfetol to current EDS medication[s]). The survey included open-ended questions regarding a hypothetical patient—a 32-year-old woman with narcolepsy (Epworth Sleepiness Scale score of 8) treated with 35 mg/d of amphetamine and 6 g per night of sodium oxybate who experiences non–use-limiting adverse events from amphetamine. FindingsTwenty-six physicians participated: 23 provided data from 70 patients with narcolepsy (type 1, n = 24; type 2, n = 46; mean [SD] age, 40 [11] years; 57% female; 6 with comorbid OSA), and 26 responded to the hypothetical patient scenario. From the medical record review, solriamfetol therapy initiation was de novo for 19 of 70 patients (27%), transition for 31 of 70 patients (44%), and add-on for 20 of 70 patients (29%). Efficacy profile of solriamfetol was the primary reason for de novo (12 of 19 [63%]), transition (18 of 31 [58%]), and add-on (19 of 20 [95%]) initiation. Most (86%) initiated use of solriamfetol at 75 mg/d and were stable at 150 mg/d (76%). Most (67%) had 1 dose adjustment, reaching a stable dose over a median (range) of 14 (1–60) days. Physicians most often considered EDS severity (44%) when titrating. Among transitioning patients, 14 of 22 (64%) using wake-promoting agents discontinued their use abruptly, and 5 of 9 (56%) using stimulants were tapered off. At data collection, 90% continued to take solriamfetol. Regarding the hypothetical patient scenario, most physicians (81%) thought solriamfetol was appropriate, highlighting tolerability issues with current treatment and lack of symptom control as drivers for switching; however, 3 physicians (12%) did not think solriamfetol was appropriate, noting current symptoms were not severe enough and/or symptoms could be managed by increasing sodium oxybate dose; 2 (8%) thought it would depend on other factors. Physicians emphasized managing withdrawal symptoms while maintaining EDS symptom control when titrating off a stimulant and starting solriamfetol therapy. ImplicationsIn a real-world study, physicians initiated solriamfetol therapy at 75 mg/d for most patients with narcolepsy, adjusted dosages once, tapered stimulants, and abruptly discontinued therapy with wake-promoting agents.

Performance of reversible timber connections in Australian light timber framed panelised construction

This paper provides a novel insight into using reversible mass timber connectors in light-timber framed (LTF) construction to create dismountable, panelised LTF construction systems that enable adaptable building design and panel reuse in the context of a circular economy. The study presented in this paper focused on Australian LTF panelised construction:. A total of 10 IdeFix 304 connectors by SIHGA GmbH, and 20 M20 connectors by SHERPA Connection Systems GmbH were installed in Australian machine graded pine and subjected to monotonic tensile and shear loads to assess their feasibility in the given application. Two strength prediction models were evaluated in comparison to experimental results: Formulae given in the manufacturers’ European Technical Assessments (ETAs) and a prediction model adapted from literature. On average, the latter was more accurate in the given configuration. Considering the set goal of repeated assembly and disassembly, the connectors with a tight fit faced tolerance issues due to moisture fluctuations. Furthermore, rupture of the connector was observed in some instances, owed to higher screw withdrawal capacity in Australian timber. A reduction of the number of screws or their length is suggested to achieve a more ductile response with screw withdrawal. Finally, following comparative analysis of experimental tests and prediction models, recommendations were made for future design of novel LTF panel connectors in the context of disassembly and reuse.

To the Issue of Religious Tolerance in Russia at the beginning of the ХХ century: Legal Regulation of Old Believers and Sectarianism

To the Issue of Religious Tolerance in Russia at the beginning of the ХХ century: Legal Regulation of Old Believers and Sectarianism

Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures. A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided. We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200mg/day; lamotrigine, greater than 500mg/day), we encourage consideration of proactive dose reduction at cenobamate 200mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2weeks as dictated by the adverse effects. At cenobamate 200mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy. The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

34433 Evaluation of skin mildness of a nature-based acne cleanser in controlled washing test

Background: Acne care depends on gentle yet effective cleansing; however, patients using acne care products often complain of excessive skin dryness and irritation. We developed a nature-based salicylic acid-containing cleanser with mild surfactants including lauryl glucoside, decyl glucoside and skin-soothing centella asiatica extract for acne treatment. Objective: To assess effects of a nature-based acne cleanser on skin barrier compared with a leading acne cleanser using controlled forearm washing. Methods: Fifty healthy subjects (n = 25 each) participated in a controlled forearm wash test lasting 3 weeks: one arm was treated twice daily with assigned nature-based or leading acne cleanser, the other arm was washed with water only. Noninvasive biophysical assessments of epidermal barrier function were performed by evaporimetry, skin surface hydration by corneometry, SC integrity/cohesion by D-squame, skin pH and microscopic images by videoscope prior to the first washing and on days 7, 14 and 21. Separately, 41 female subjects with mild-moderate facial acne used the nature-based product twice daily for 4 weeks and tolerability was assessed by investigator and subjects. Results: Nature-based and leading acne washes produced mild damage to the forearm epidermal barrier function with no significant difference from water application. A slight nonsignificant decrease in skin hydration was seen with both washes. No significant increase was seen in skin pH; SC cohesion was decreased. No tolerability issues were reported by investigator or subjects. Conclusion: Skin cleansing with nature-based acne cleanser was shown to be gentle, tolerable and effective for moderate/mild grade facial acne.

Biological therapy for young children with atopic dermatitis

Atopic dermatitis is a common inflammatory skin disease that might lead to severe and persistent disease during infancy. Atopic dermatitis is associated with poor school performance, psychiatric disease, and allergic comorbidities.1–3 If atopic dermatitis is inadequately controlled with emollient use and topical anti-inflammatory therapies, systemic medications including ciclosporin, azathioprine, and methotrexate can be used to treat children with moderate-to-severe disease. However, systemic therapies are rarely used in children because the natural disease course often leads to spontaneous improvement, and because their use requires continuous blood monitoring and is associated with tolerance issues and modest efficacy.

Retention of brivaracetam in adults with drug-resistant epilepsy at a single tertiary care center

IntroductionBrivaracetam (BRV) is licensed as an adjunctive treatment for focal epilepsy. We describe our clinical experience with BRV at a large UK tertiary center. MethodsAdults initiated on BRV between July 2015 and July 2020 were followed up until they discontinued BRV or September 2021. Data on epilepsy syndrome, duration, seizure types, concomitant and previous antiseizure medication (ASM) use, BRV dosing, efficacy, and side effects were recorded. Efficacy was categorized as temporary (minimum three months) or ongoing (at last follow-up) seizure freedom, ≥50% seizure reduction, or other benefits (e.g., no convulsions or daytime seizures). Brivaracetam retention was estimated using Kaplan–Meier survival analysis. ResultsTwo-hundred people were treated with BRV, of whom 81% had focal epilepsy. The mean (interquartile range [IQR]) follow-up time was 707 (688) days, and the dose range was 50–600 mg daily. The mean (IQR) of the previous number of used ASMs was 6.9 (6.0), and concomitant use was 2.2 (1.0). One-hundred and eighty-eight people (94%) had previously discontinued levetiracetam (LEV), mainly due to side effects. 13/200 (6.5%) were seizure free for a minimum of six months during treatment, and 46/200 (23%) had a ≥50% reduction in seizure frequency for six months or more. Retention rates were 83% at six months, 71% at 12 months, and 57% at 36 months. Brivaracetam was mostly discontinued due to side effects (38/75, 51%) or lack of efficacy (28/75, 37%). Concomitant use of carbamazepine significantly increased the hazard ratio of discontinuing BRV due to side effects (p = 0.006). The most commonly reported side effects were low mood (20.5%), fatigue (18%) and aggressive behavior (8.5%). These side effects were less prevalent than when the same individuals took LEV (low mood, 59%; aggressive behavior, 43%). Intellectual disability was a risk factor for behavioral side effects (p = 0.004), and a pre-existing mood disorder significantly increased the likelihood of further episodes of low mood (p = 0.019). ConclusionsBrivaracetam was effective at a broad range of doses in managing drug-resistant epilepsy across various phenotypes, but less effective than LEV in those who switched due to poor tolerability on LEV. There were no new tolerability issues, but 77% of the individuals experiencing side effects on BRV also experienced similar side effects on LEV.

Behaviour of the lockbolt demountable shear connector under combined shear and tension loading

A demountable ‘lockbolt’ shear connector (LB-DSC), consisting of a short partially threaded bolt that is locked on a steel flange to eliminate tolerance and initial slip issues and a compatible machined tube that can be fastened/unfastened over the bolt to facilitate the easy and fast disassembly process for reuse of all components, was proposed for use in composite floors or decks of buildings or bridges. This paper focuses on the numerical investigation of the structural behaviour of the LB-DSC under combined tension and shear loading. A detailed finite element method (FEM) model considering material and contact nonlinearity was built and calibrated based on previous standard pushout tests on the LB-DSC. The calibrated FEM model was used to investigate the effects of various parameters on tensile and shear behaviour of the LB-DSC, including the concrete strength of slab, the bolt diameter and strength, the steel tube thickness, and the presence and strength of infill grout. The shear resistance of the connector is significantly reduced when a tensile force more than 20% of the tensile resistance of the connector is applied. Design equations for predicting the tension resistance and tension-shear interaction are proposed to expand the application of the LB-DSCs in sustainable steel–concrete composite construction.

SURPASS-ET: phase III study of ropeginterferon alfa-2b versus anagrelide as second-line therapy in essential thrombocythemia.

Patients diagnosed with high-risk essential thrombocythemia (ET) have limited treatment options to reduce the risk of thrombosis and lessen the progression of the disease by targeting the molecular source. Hydroxyurea is the recommended treatment, but many patients experience resistance or intolerance. Anagrelide is an approved second-line option for ET, but concerns of a higher frequency of disease transformation may affect its role as a suitable long-term option. Interferons have been evaluated in myeloproliferative neoplasms for over 30years, but early formulations had safety and tolerability issues. SURPASS-ET (NCT04285086) is a phase III, open-label, multicenter, global, randomized, active-controlled trial that will evaluate the safety, efficacy, tolerabilityand pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide as second-line therapy in high-risk ET.

Evaluation of the safety, tolerability and plasma vitamin D response to long-term use of patented transdermal vitamin D patches in healthy adults: a randomised parallel pilot study

BackgroundVitamin D delivered transdermally may suppress hyperactivity in nociceptor pain receptors and alter pain intensity, offering a useful addition to localised pain management in varying clinical settings. Currently, little is...

Budget Impact Analysis of Vibegron for the Treatment of Overactive Bladder in the USA.

BackgroundOveractive bladder (OAB) is associated with considerable clinical and economic burden. Treatment of patients with OAB using anticholinergics is limited by tolerability issues and increased anticholinergic burden, which is associated with increased risk of dementia and falls/fractures. This analysis assessed the budget impact of introducing the β3-adrenergic agonist vibegron for the treatment of patients with OAB from US commercial payor and Medicare perspectives.MethodsA budget impact model (BIM) with a 5-year time horizon was developed using a top-down, prevalence-based approach and projected market shares for 1-million-member US commercial and Medicare plans. The BIM included vibegron, mirabegron, and anticholinergics, incorporating changes in clinical outcomes (efficacy, drug–drug interactions, anticholinergic burden (ACB), OAB-related comorbidities, and adverse events (AEs)). Costs per member per month (PMPM) and per treated member per month (PTMPM) were determined. One-way sensitivity analyses quantified the impact of changes in key variables.ResultsThe introduction of vibegron was associated with a modest increase in PMPM cost over 5 years of $0.12 (range for years 1‒5, $0.01‒$0.26) for commercial payors and $0.24 ($0.01‒$0.52) for Medicare (PTMPM cost: $2.70 ($0.17‒$4.85) and $3.15 ($0.19‒$5.82), respectively). Costs were partially offset by savings related to decreased third-line treatment use, yearly decreases in AE and comorbidity incidence, reduced drug–drug interactions, and reduced ACB associated with vibegron introduction. PMPM costs were most sensitive to vibegron market share assumptions, OAB prevalence, and vibegron persistence at 1 month for private payors and Medicare and additionally vibegron persistence at 12 months for Medicare.ConclusionsVibegron may address unmet needs in treating OAB and is a useful addition to health plans while minimizing risks of anticholinergic AEs, ACB, and drug–drug interactions, which may partially offset increased pharmacy costs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-022-01163-5.

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series

Intermittent theta burst stimulation (iTBS) using 600 pulses is an effective and FDA-cleared transcranial magnetic stimulation (TMS) protocol for major depressive disorder (MDD). Prolonged iTBS (piTBS) using 1,800 pulses could increase the effectiveness of TMS for MDD, but its real-world effectiveness is still debated.We assessed the safety, tolerability, and preliminary effectiveness of a 3x daily piTBS 1,800 pulses protocol delivered over 2 weeks in 27 participants. Only four participants (18.2%) achieved response, two of them achieving remission (9.1%). Five participants (18.5%) experienced tolerability issues. Future studies should focus on the neurophysiological effects of TBS protocols to determine optimal parameters.

Nadishodhan pranayama-a cleansing technique: A review article

Practicing yoga like pranayama is becoming more and more important, as well as increased and more well-liked by the scientific community, as a result of the growing interest of the public in health and alternative therapies. One popular yogic breathing technique Nadishodhan Practicing yoga like pranayama is becoming more and more important, as well as increased Pranayama (NSP) is a well-known yogic breathing method that involves breathing through one nostril at a time while physically closing the other. This study attempted to compile published primary scientific information on the advantages of NSP and describe the impacts of independent NSP on numerous physiological, psychological, and general health issues in different populations. The following terms were entered into Google Scholar, PubMed/Medline, Cinahl, and Web of Science: Breathing through the NSPs, anulom-vilom/anuloma-viloma pranayama, and nada-shodhan/nada-shodhan pranayama. This review report includes 48 studies in total. The autonomic nervous system, the cardiopulmonary system, respiratory function, cognitive functioning, spatially memory as well as improved frontal and vertex function, problem-solving skills, motor memory recall, helps with depression and anxiety and other physiological characteristics were reviewed in this research for strong evidence of good effects. There is evidence that NSP Pranayama Studies on this yogic breathing have not found any negative side effects or tolerance issues.

A fault tolerant optimal relay node selection algorithm for Wireless Sensor Networks using modified PSO

Wireless Sensor Networks (WSNs) have energy-constraints that restricts to achieve prolonged network lifetime. To optimize energy consumption of sensor nodes, clustering is one of the efficient techniques for minimization of energy conservation in WSNs. This technique sends the collected data towards the SINK based on cluster head (CH) nodes that leads to the saving of energy. WSNs have been faced a crucial issue of fault tolerance and the overall data communication is collapsed due to the failure of cluster head. Various fault-tolerance clustering methods are available for WSNs, but they are not selected the backup nodes properly. The backup nodes’ closeness or location to the other remaining nodes is not considered in these methods. They may increase network overhead with the backup nodes accessibility. A fault-tolerance cluster-based routing method is presented in this paper that aims on providing fault tolerance for relay selection in addition to the data aggregation method for clustered WSNs. The proposed method utilizes backup mechanism & the Particle Swarm Optimization (PSO) to achieve this. Based on the distance from sink, residual energy, and link delay parameters, the CHs are chosen and the network is categorized into the clusters. The Backup CHs are selected by estimating the centrality among the nodes. As a part of intra-cluster communication for reducing the aggregation overhead among CHs, the Aggregator (AG) nodes are deployed in every cluster. So that they act as the bridge between the member nodes and CHs. These AG nodes aggregates the information from member nodes and deliver it to the CHs. The PSO with modified fitness function is used to identify the best relays between AG and member nodes. The proposed mechanism is compared with existing techniques such as EM-LEACH AI-Sodairi and Ouni (2018), QEBSR Rathee et al. (2019), QOS-IHC Singh and Singh (2019), and ML-SEEP Robinson et al. (2019). The simulation results proved that the proposed mechanism reduces overhead by 55% and improve the energy consumption & throughput by 40% & 60% respectively.

HUMANIS? IDEOLOGY OR THE VALUE OF RELIGIOUS HUMANISM: RESEARCH ON FIGURES DAMIEN DEMATRA

Human values ??have an important role in realizing a safe, peaceful, and serene life in society. This can be achieved when everyone implements a humanist ideology or a view of human values ??in everyday life. The focus of this research is to describe Damien Dematra's social ideology, to describe his social background, and to describe Dematra's social position in society. This research uses qualitative research, data collection techniques use interviews, data analysis techniques use interactive techniques, and the validity of the data used is theory and source triangulation. The results showed that Dematra's social ideology was a humanist person. This is evidenced by his attitude, thoughts, and activities which are dedicated to humanity and world peace. Dematra's social background is a multitalent person or Dematra usually finds himself as an artist. This can be seen from the various fields that he has done, such as photographers, businessmen, painters, novelists, screenwriters for films and TV series, directors, actors and producers. Most of the professional fields that Dematra does have received recognition or awards from both international and domestic. Not only that, Dematra's work, which has contributed greatly to humanity and world peace, has received recognition and respect from the Keraton Surakarta and Keraton Cirebon. Dematra received a knighthood from the Keraton Sultanate of Surakarta and Keraton Kasepuhan Cirebon. Every work produced by Dematra always gives a message of the value of humanity and peace. This is the basis for Dematra's work to be recognized, accepted, and even given respect or appreciation for its great contribution to humanity and peace. Dematra's social position in society also plays an important role in realizing human values ??and peace in Indonesia and the world. Dematra plays an active role as the coordinator and founder of the Pluralism Concern Movement. Pluralism Concern Movement is a non-governmental organization concerned with issues of pluralism, diversity and tolerance in society. There is a relationship between social position, social background, and Dematra's social ideology, this connection refers to one thing, namely the humanist ideology. Keywords: humanist, ideology, humanity

S286: LONG-TERM EFFICACY AND SAFETY RESULTS FROM AN ONGOING OPEN-LABEL PHASE 2 STUDY OF PARSACLISIB FOR THE TREATMENT OF AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

Background: AIHA is a rare condition caused by autoantibody-mediated hemolysis of red blood cells. Few therapies beyond steroids and rituximab are available. Aims: To report updated results from an ongoing multicenter, phase 2, open-label study of the phosphoinositide 3-kinase-δ inhibitor parsaclisib in patients (pts) with AIHA (NCT03538041). Methods: Pts ≥18 years old with warm AIHA (wAIHA), cold agglutinin disease (CAD), or mixed-type AIHA; hemoglobin (Hgb) 7–10 g/dL; and failure of ≥1 standard therapy were eligible. After informed consent, pts were treated with oral parsaclisib for 12 wk at a starting dose of 1.0 mg once daily (QD; cohort 1) or 2.5 mg QD (cohort 2). Increases to 2.5 mg QD were allowed in cohort 1 after 6 wk if no clinical response was achieved and/or transfusion was required; reductions to 1.0 mg QD were permitted in cohort 2 for tolerability issues. Concomitant corticosteroids (≤20 mg/d prednisone) were allowed. After 12 wk of treatment, pts responding on parsaclisib could continue into an extension period. Primary endpoints were efficacy (proportion of pts with complete response [CR; Hgb ≥12 g/dL] or partial response [PR; Hgb 10–12 g/dL or ≥2 g/dL increase from baseline, inclusive of CRs] at any visit from Wk 6–12) and safety (treatment-emergent adverse events [TEAEs]). Results: As of Aug 5, 2021, 25 pts enrolled and received parsaclisib (cohort 1, n=10 [8 with dose increase]; cohort 2, n=15); 20 pts (80%) completed 12 wk of treatment. Sixteen (64%), 6 (24%), and 3 (12%) pts had wAIHA, CAD, and mixed AIHA, respectively. Mean (SD) age was 61.6 (17.0) years; 14 pts (56%) were female and 23 (92%) were White. Mean (SD) Hgb at baseline was 8.9 (0.8) g/dL, and 9 pts (36%) had transfusions in the past year. Mean parsaclisib exposure was 334 (range, 7–819) days. Overall, 8 pts (32%) achieved CR and 16 (64%) had PR at any visit from Wk 6–12. Among pts with wAIHA (n=16), 14 pts (88%) completed 12 wk of treatment; 8 (50%) and 12 (75%) achieved CR and PR, respectively, at any visit from Wk 6–12. Seventeen pts entered the extension period (12 with wAIHA). Increase in Hgb was sustained in the total cohort and among pts with wAIHA during the initial 12-wk treatment and extension periods (Figure). During the 12-wk treatment period, TEAEs occurred in 21 pts (84%) overall. Six pts (24%) had grade (Gr) ≥3 TEAEs, with only neutropenia occurring in >1 pt (n=2 [8%]); 2 pts (8%) had serious AEs (SAEs). Seven pts (28%) had treatment-related AEs, with only pruritic rash reported in >1 pt (n=2 [8%]). Three pts discontinued during the 12-wk treatment period (AE [n=1; thrombocytopenia], lack of efficacy [n=1], withdrawal by subject [n=1]), and 2 pts were of unknown status. During the extension period, 15/17 pts (88%) experienced ≥1 TEAE. Gr ≥3 AEs and SAEs were each reported in 9 pts (53%). Six pts (35%) had treatment-related AEs, with diarrhea and rash reported in >1 pt (n=2 [12%] each). One Gr 3 TEAE (psoriasis) and 3 SAEs (diarrhea [Gr 2], cytomegalovirus reactivation [Gr 2], psoriasis [Gr 3]) were deemed treatment related. Two (12%) pts had TEAEs leading to parsaclisib discontinuation. One fatal TEAE (acute respiratory failure in the extension period) was deemed unrelated to parsaclisib. Image:Summary/Conclusion: Parsaclisib was generally well tolerated and resulted in Hgb improvements as early as Wk 2 that increased over 12 wk of treatment and were sustained through the extension period. Parsaclisib may be an effective oral treatment for AIHA, and a randomized, controlled phase 3 trial in wAIHA is now recruiting (NCT05073458).