Inadequate Response Research Articles

S113 Combined Effect of Obeticholic Acid and Bezafibrate in Patients With Primary Biliary Cholangitis and Inadequate Response or Intolerance to Ursodeoxycholic Acid: 6-Month Results From a Phase 2 Trial

S113 Combined Effect of Obeticholic Acid and Bezafibrate in Patients With Primary Biliary Cholangitis and Inadequate Response or Intolerance to Ursodeoxycholic Acid: 6-Month Results From a Phase 2 Trial

S1428 Efficacy and Safety of Subcutaneous Guselkumab Rescue Therapy in Patients With Moderately to Severely Active Crohn’s Disease and Inadequate Response to Ustekinumab: Phase 2 GALAXI 1 Study Long-Term Extension Results

S1428 Efficacy and Safety of Subcutaneous Guselkumab Rescue Therapy in Patients With Moderately to Severely Active Crohn’s Disease and Inadequate Response to Ustekinumab: Phase 2 GALAXI 1 Study Long-Term Extension Results

Efficacy and safety of filgotinib in patients with rheumatoid arthritis: week 156 interim results from a long-term extension study

BackgroundJanus kinase inhibitors are an effective option for achieving sustained remission or low disease activity in patients with rheumatoid arthritis (RA) following inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs....

A comparative analysis of generative artificial intelligence responses from leading chatbots to questions about endometriosis

IntroductionThe use of generative artificial intelligence (AI) has begun to permeate most industries, including medicine, and patients will inevitably start using these large language model (LLM) chatbots as a modality for education. As healthcare information technology evolves, it is imperative to evaluate chatbots and the accuracy of the information they provide to patients and to determine if there is variability between them. ObjectiveThis study aimed to evaluate the accuracy and comprehensiveness of three chatbots in addressing questions related to endometriosis and determine the level of variability between them. Study DesignThree LLMs, including Chat GPT-4 (Open AI), Claude (Anthropic), and Bard (Google) were asked to generate answers to 10 commonly asked questions about endometriosis. The responses were qualitatively compared to current guidelines and expert opinion on endometriosis and rated on a scale by nine gynecologists. The grading scale included the following: (1) Completely incorrect, (2) mostly incorrect and some correct, (3) mostly correct and some incorrect, (4) correct but inadequate, (5) correct and comprehensive. Final scores were averaged between the nine reviewers. Kendall's W and the related chi-square test were used to evaluate the reviewers’ strength of agreement in ranking the LLMs’ responses for each item. ResultsAverage scores for the 10 answers amongst Bard, Chat GPT, and Claude were 3.69, 4.24, and 3.7, respectively. Two questions showed significant disagreement between the nine reviewers. There were no questions the models could answer comprehensively or correctly across the reviewers. The model most associated with comprehensive and correct responses was ChatGPT. Chatbots showed an improved ability to accurately answer questions about symptoms and pathophysiology over treatment and risk of recurrence. ConclusionThe analysis of LLMs revealed that, on average, they mainly provided correct but inadequate responses to commonly asked patient questions about endometriosis. While chatbot responses can serve as valuable supplements to information provided by licensed medical professionals, it is crucial to maintain a thorough ongoing evaluation process for outputs to provide the most comprehensive and accurate information to patients. Further research into this technology and its role in patient education and treatment is crucial as generative AI becomes more embedded in the medical field.

Pathologic Validation of Deauville Score-Based Disease on F-18 FDG PET/CT after First-Line Treatment in Patients with Lymphoma.

PET/CT-based Deauville scoring (DS) is routinely used for lymphoma response assessment. However, pathological correlation of DS is not yet precisely documented. In the present study we aimed to pathological confirm the PET/CT-based Deauville scoring (DS) in lymphoma after first-line chemotherapy. Participants undergoing PET/CT for response assessment following first-line treatment were recruited prospectively. DS ≥ 4 lesions were interpreted as PET-positive, while DS ≤ 3 as PET-negative. Participants with a PET-positive lesion or suspicious of inadequate response (DS ≤ 3) were recruited for metabolic core-needle biopsy. True-negative and benign histopathology were kept on follow-up for three months. Histopathological, clinical and imaging findings were assessed for diagnostic performance. Procedure-related complications were also noted. In all, 148/480 participants were PET-positive, and 332/480 were PET-negative. 138/148 PET-positive and 12/332 PET-negative lesions were recruited for biopsy. Biopsy was performed in 147/150 participants (PET-positive 135; PET-negative 12). Three patients with inaccessible lesions were excluded. The diagnostic yield of the procedure was 97.3% (143/147). Histology revealed lymphoma in 106 participants (including 70% of total DS-4, 100% of DS-5a and 73.9% of DS-5b lesions), with three false-negative lesions. DS ≤ 3 lesions were true-negative except one diagnosed with lymphoma (8.3%) on follow-up. Non-lymphomatous malignancies (n = 5), granulomas (n = 12), non-specific inflammation (n = 9) and no residual disease (n = 11) were diagnosed in the rest. No major procedure-related adverse event was noted. A DS-5a lesion suggests residual disease; hence, a biopsy can be prevented unless Richter's transformation is suspected. DS-4 and DS-5b lesions require a biopsy before changing the treatment plan, as a certain number of participants had non-lymphomatous F-18 FDG-avid lesions.

ISSUES OF ROUTING PATIENTS WITH AUTOIMMUNE HEPATITIS

Autoimmune hepatitis is a chronic, immune-mediated liver disease characterized by an increased level of immunoglobulins G and/or gamma globulins, the presence of autoantibodies and a typical histological picture. Diagnosis of autoimmune hepatitis causes difficulties due to various variants of the course, wide variability of the clinical picture, which leads to a large number of missed cases of the disease. Treatment of аutoimmune hepatitis is aimed at reducing the activity of an inadequate response of the immune system against cells of its own body and achieving complete remission of the disease. The timeliness of starting treatment is directly related to the prognosis of the disease. These features of the disease necessitate proper patient routing and shortening their path to specialists with knowledge and experience in managing this category of patients.

S575 Dupilumab Efficacy in Children With Eosinophilic Esophagitis and Prior Use of or Prior Inadequate Response, Intolerance, or Contraindication to Swallowed Topical Corticosteroids: Results From the Phase 3 EoE KIDS Study

S575 Dupilumab Efficacy in Children With Eosinophilic Esophagitis and Prior Use of or Prior Inadequate Response, Intolerance, or Contraindication to Swallowed Topical Corticosteroids: Results From the Phase 3 EoE KIDS Study

Invoking time limits for managing responses in US Senate Judiciary Committee lower court nomination hearings

This study uses Conversation Analysis to investigate an interactional practice in US Senate Judiciary Committee (SJC) lower court nomination hearings. Drawing from 13 hr and 36 min of data from Q&A rounds across 12 SJC hearings during 2020 and 2022, I document how senators’ invocations of the hearing’s time limits function as a resource for managing judicial nominees’ responses to their questions. I examine senators’ time invocations (TIs) in two main sequential areas: (1) When designing questions, and (2) when pursuing or challenging nominees’ responses. As a feature of question design, TIs help senators ‘move things along’ during their brief questioning time, as well as pin nominees to respond in ways preferable to the question. As a feature of pursuits or challenges, TIs help senators manage nominees’ off-topic, evasive, or unsound responses, thus ascribing different levels of accountability onto both nominees (for their inadequate responses to senators’ initial questions) and senators themselves (for the sequential and affiliative consequences associated with doing pursuing/challenging). Seven extracts are presented from a collection of 82 cases. Findings reveal how time limits can be leveraged by senators to advance various goals in this highly constrained and institutionalized context, including exhibiting and implicitly legitimizing partisan bias.

Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment

BackgroundTreatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively.ResultsWe identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10−7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10−6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively.ConclusionsWe report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

Efficacy and safety of filgotinib in patients with moderately active rheumatoid arthritis and an inadequate response to methotrexate.

Clinical trials restricted to moderately active RA are limited. Filgotinib is approved for treating moderate to severe active RA. This post hoc analysis assessed efficacy and safety of filgotinib in moderately active RA. In FINCH 1, patients with active moderate to severe RA and inadequate response to methotrexate received filgotinib 200 mg or 100 mg (FIL200/FIL100) once daily, adalimumab 40 mg every 2 weeks, or placebo, all with methotrexate (n = 1,755). This subgroup analysis was conducted in patients with a moderate baseline Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP; >3.2 to ≤ 5.1; n = 425 [24.2%]). A higher proportion of patients achieved DAS28-CRP <2.6, Clinical Disease Activity Index (CDAI) remission (≤2.8), low disease activity (LDA) (DAS28-CRP ≤3.2 or CDAI ≤10), and American College of Rheumatology (ACR20/50/70) responses with FIL200 and FIL100 vs placebo at Weeks 12 and 24. Week 12 ACR20 response rates (primary end point) were 77.9%, 67.8%, and 43.8%, respectively. ∼75% of patients achieved DAS28-CRP LDA by week 24 with either filgotinib dose. FIL200 and FIL100 elicited greater improvements in patient-reported outcomes than placebo. The efficacy of filgotinib, maintained through week 52, was comparable to that of adalimumab. Frequency of adverse events (AEs) was similar with filgotinib and adalimumab. Infections were the most common AEs; incidence rates were 40-53% in active treatment groups. In this subpopulation with moderately active RA, the efficacy and safety of filgotinib were similar to those in the overall FINCH 1 population (patients with active moderate to severe RA). NCT02889796.

Efficacy and speed of effect after the first dose of aspirin in children with congenital heart disease.

Many paediatric studies report that patients must be established on aspirin therapy for a minimum of 5 days to achieve adequate response. This is not always practical especially in critical settings. Prospective identification of patients that are unresponsive to aspirin sooner could potentially prevent thrombotic events. The aim of this study was to investigate prospectively if the first dose of aspirin is effective in decreasing platelet aggregation, and thromboxane formation and if this can be measured after 2 hours in paediatric cardiology patients. A secondary aim was to identify a cut-off for a novel marker of aspirin responsiveness the maximum amplitude with arachidonic acid, which could potentially dramatically reduce the blood volume required. Third, we aimed to prospectively identify potentially non-responsive patients by spiking a sample of their blood ex vivo with aspirin. The majority (92.3%) of patients were responsive, when measured 2 hours post first dose of aspirin. Non-response or inadequate response (7.7%) can also be identified at 2 hours after taking the first dose of aspirin. Additionally, we have shown a novel way to reduce blood sample volume requirements by measurement of the maximum amplitude with arachidonic acid as a marker of response, particularly for monitoring. These findings of rapid efficacy in the majority of patients offer assurance in a sound, practical way to attending clinicians, patients, and families.

Ubrogepant users' real-world experience: Patients on ubrogepant, characteristics and outcomes (UNIVERSE) study.

To assess the real-world effectiveness of ubrogepant by evaluating self-reported satisfaction with pain relief, ability to think clearly, and return to normal function in individuals who had used ubrogepant to treat a migraine episode within the preceding 14 days. Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine in adults. Few studies have evaluated the real-world effectiveness of ubrogepant. The UNIVERSE study was an observational, cross-sectional survey conducted between February 2021 and April 2021 in US adult Migraine Buddy application (app) users currently treated with ubrogepant. Individuals who were 18 years of age or older and reported at least one dose of ubrogepant in the previous 14 days completed a 30-question survey in the app. The survey assessed respondent demographics, migraine history, acute treatment patterns, and treatment satisfaction with ubrogepant. Respondents also reported prior acute medication use and reasons for switching to ubrogepant. Of the 1303 ubrogepant users contacted, 302 (23.2%; 50 mg, 120 participants; 100 mg, 182 participants) were included in this study. The mean (standard deviation) age was 41.9 (11.2) years, and 90.1% (272/302) were female. Satisfaction with migraine relief at 2, 4, and 24 h post-dose was reported by 75.8% (229/302), 83.4% (252/302), and 78.5% (237/302) of participants, respectively. Satisfaction with the ability to think clearly after taking ubrogepant was reported by 85.1% (257/302) of participants, and 83.8% (253/302) were satisfied with their ability to return to normal function. Furthermore, 90.7% (274/302) of participants reported that they were likely to continue using ubrogepant to treat their migraine. Most participants (n = 264 [87%]) reported switching to ubrogepant due to inadequate treatment response with their previous treatment. In this subgroup, comparable outcomes were observed with respect to satisfaction with migraine relief, ability to think clearly, and return to normal function. Ubrogepant demonstrated real-world effectiveness in the acute treatment of migraine, as evidenced by high levels of treatment satisfaction and a strong indication of their intent to continue using the medication.

A Retrospective Study on Insulin Resistance in Adults with Autoimmune Thyroiditis in Turkish Population: a Clinical and Molecular Docking Study

Background/Purpose: This study aims to retrospectively analyze existing data to assess the prevalence and intensity of insulin resistance among adults with autoimmune thyroiditis, a condition marked by the body's immune response against its thyroid gland, including Hashimoto's thyroiditis. Insulin resistance, characterized by the body's inadequate response to insulin, complicates blood sugar regulation. This research seeks to explore historical health records of individuals diagnosed with autoimmune thyroiditis to identify potential correlations with insulin resistance. Methods: Our approach involves a comprehensive review of previous medical records, with a focus on evaluating insulin levels, HbA1c values (an indicator of blood sugar regulation), and other pertinent health markers in patients with autoimmune thyroiditis. Data analysis was conducted using SPSS version 26, a software extensively employed in social sciences for statistical computations. The distribution normality was verified through the Shapiro-Wilks test and Box Plot diagrams. Correlation between variables was determined using either Pearson or Spearman's correlation analysis. Results: Our statistical analysis uncovered a significant correlation between higher Insulin Resistance (HOMA-IR) scores and increased levels of blood glucose and insulin, with p-values indicating strong positive relationships (p

Exploring cariprazine as a treatment option for varied depression symptom clusters.

Major depressive disorder (MDD) is among the most prevalent psychiatric conditions and a leading cause of disability worldwide. MDD presents a diverse range of symptoms that significantly impact personal, societal, and economic dimensions. Despite the availability of numerous antidepressant treatments (ADTs) targeting different molecular mechanisms, a substantial proportion of patients experience inadequate response, presenting a considerable challenge in MDD management. As a result, adjunctive strategies, particularly involving atypical antipsychotics, are often employed to enhance treatment efficacy. Cariprazine, a D2/D3 partial agonist, is distinguished from other atypical antipsychotics by its selective action on the D3 receptor and its modulation of 5-HT1A, 5-HT2A, and alpha 1B receptors. This distinctive pharmacological profile warrants investigation into its potential effectiveness and tolerability across various symptom domains of MDD, including pleasure, interest, and motivation; mood and suicidality; sleep and appetite; fatigue; psychomotor activity and anxiety; and cognitive function. Preliminary evidence from animal studies and clinical trials suggests that cariprazine may improve motivation, anhedonia, and cognitive function symptoms. Cariprazine shows promise in alleviating mood-related symptoms, though its impact on anxiety and its effects on agitation and psychomotor retardation remains uncertain. Cariprazine may be particularly beneficial for patients with MDD exhibiting anhedonia, cognitive deficits, and possibly fatigue and hypersomnia. Evaluating cariprazine's efficacy across these symptom domains could reveal patterns that support more personalized treatment approaches for depression. Further research is essential to elucidate the role of cariprazine as an adjunctive therapy for adults with major depressive disorder who have an inadequate response to antidepressant monotherapy.

What is confirmed in the treatment of sepsis? : An update

Sepsis is defined as "being evoked as a life-threatening organ dysfunction caused by an inadequate host response to infection". The most recent German S3 guidelines were published in 2018 and the Surviving Sepsis Campaign (SSC) last published the current recommendations for the treatment of sepsis and septic shock in 2021. This article explores and discusses which evidence in the treatment of sepsis and septic shock has been confirmed. Discussion of the 2018 German S3 guidelines, supplementation of the content of the 2021 international guidelines and recent research results since 2021. The primary objective for managing sepsis and septic shock still includes rapid identification, early initiation of anti-infective treatment, and focus cleansing when feasible. In addition, the focus is on hemodynamic stabilization, including the early use of vasopressors for prevention of hypervolemia and, if necessary, the use of organ support procedures. Supportive treatment, such as the administration of corticosteroids and the use of apheresis, can be advantageous in specific scenarios. The focus is increasingly shifting towards post-intensive care unit (ICU) follow-up care, improving the quality of life after surviving sepsis and the close involvement of relatives of the patient. Despite the fact that considerable progress has been made in understanding the pathophysiology and treatment of sepsis, the early administration of anti-infective agents, focus control, nuanced volume therapy and the use of catecholamines continue to be fundamental to sepsis management. New recommendations emphasize the early use of vasopressors (primarily norepinephrine) and the administration of corticosteroids, especially in cases of septic shock and pneumonia.

Simultaneous Metastatic Involvement of Bilateral Testes and Left Spermatic Cord in Prostate Cancer Detected on 68Ga-PSMA-11 PET/CT.

Bilateral testicular involvement in prostate cancer is quite rare. It is often associated with widespread systemic disease and inadequate response to systemic therapy. We present a case of metastatic prostate cancer with bilateral testicular metastases and simultaneous involvement of the left spermatic cord detected on 68Ga-PSMA-11 PET/CT and confirmed on the histopathology of bilateral orchiectomy done for achieving the androgen deprivation status. Early detection of such unusual sites of metastases has poorer prognostic outcome and management implications.

Quieter Nurse Call System to Reduce Alarm Noise in Hospitals.

Healthcare staff are typically exposed to hundreds of alarms each shift; researchers believe that the number of alarms may be more than 1000 alarms per shift. This may lead to staff becoming desensitised to the alarm, leading to a delayed or inadequate response to the alarm, known as alarm fatigue. Clinical-grade wireless smartphones are now carried by clinical staff to receive calls and notifications from a nurse call system.

TMX1, a disulfide oxidoreductase, is necessary for T cell function through regulation of CD3ζ.

T cell-targeted therapies are commonly used to manage T cell hyperactivity in autoimmune disorders, graft-versus-host diseases (GVHD), and transplant rejections. However, many patients experience significant side effects or inadequate responses to current treatments, highlighting the urgent need for alternative strategies. In this study, we searched for regulators of T cells through proximity labeling with APEX2 to detect proteins interacting with CD8α, a coreceptor of the T-cell receptor (TCR). This screen revealed TMX1, an ER resident transmembrane disulfide oxidoreductase, is essential for T cell cytotoxicity and NFAT, NFκB, and AP1 signaling but not cell proliferation. TMX1 deletion decreases surface TCR expression and destabilizes CD3ζ, a subunit of TCR complex; however, overexpression of CD3ζ rescues the phenotype, suggesting that TMX1 is not required for CD3ζ function. Mechanistically, TMX1 was found to directly engage the CxxC motif of CD3δ, which has been reported to be essential for proper TCR assembly and function. We hypothesize that the loss of TMX1 interaction with CD3δ leads to impaired TCR assembly and subsequent CD3ζ destabilization. These findings identify TMX1 as a novel regulator of T-cell receptor assembly and a potential target for immunosuppressive therapy.

Clinical outcomes of tocilizumab therapy in polyarticular and systemic juvenile idiopathic arthritis: a single-center analysis (2018-2022)

AbstractThis single-center retrospective study aimed to evaluate the safety and efficacy of Tocilizumab (TOC) in children with polyarticular (pJIA) and systemic juvenile idiopathic arthritis (sJIA) who exhibited inadequate responses to disease-modifying antirheumatic drugs (DMARDs) and biological modifiers (bDMARDs). Conducted at the Department of Pediatric Rheumatology, National Institute of Geriatrics, Rheumatology, and Rehabilitation in Warsaw, Poland, between 2018 and 2022, the study enrolled 29 patients diagnosed with JIA based on International League of Associations for Rheumatology (ILAR) criteria. The cohort comprised 13 sJIA and 16 pJIA patients, aged 2-18 years, receiving TOC treatment for 24 months. Safety and efficacy assessments included analysis of medical documentation, laboratory tests (CRP, ESR, WBC), and Juvenile Disease Activity Score (JADAS) 71 at baseline, 3, 6, 12, and 24 months post-treatment initiation. Significant reductions in CRP and ESR levels were observed within three months, with sustained improvement in JADAS71 scores over the 24-month treatment period. A substantial majority, 73.07% of patients, achieved inactive disease status or low disease activity, highlighting T0C’s effectiveness. Adverse effects were manageable, predominantly involving mild to moderate infections, with no serious adverse events or instances of macrophage activation syndrome (MAS). The study also noted a steroid-sparing effect of TOC, with a reduction in glucocorticoid usage among the cohort. Tocilizumab demonstrates substantial efficacy in reducing disease activity and improving clinical outcomes in patients with pJIA and sJIA, coupled with a favorable safety profile. These findings reinforce the role of TOC as a critical component of the therapeutic arsenal for JIA, offering hope for improved quality of life and disease management in this patient population.

Long-term efficacy of mepolizumab on eosinophilic granulomatosis with polyangiitis: a retrospective study

Aim: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Patients with EGPA are treated with systemic glucocorticoids and immunosuppressive drugs to induce and maintain remission. However, most patients relapse after tapering glucocorticoids, and there are refractory cases with inadequate response to glucocorticoids. Mepolizumab, a humanized anti-IL-5 antibody, is approved for relapsing or refractory EGPA. Furthermore, recent studies have reported the efficacy of benralizumab, a humanized anti-IL-5 receptor α antibody, in EGPA. Here, we investigate the efficacy of biologics on consecutive cases of EGPA. Methods: We retrospectively collected patients with EGPA treated with mepolizumab in addition to glucocorticoids at the Department of Pulmonary Medicine in Kagoshima University Hospital and Imakiire General Hospital. In this study, we compared the effects of biologics on inflammatory parameters between pre- and post-treatment of biologics in patients with EGPA. Results: Ten patients were included in the study. All patients were treated with mepolizumab, and one was switched to benralizumab later. Treatment with biologics markedly reduced EGPA relapse from 70% (pre-treatment) to 20% (post-treatment), Birmingham Vasculitis Activity Score from 8.4 to 4.0, peripheral blood eosinophil counts from 470.3 /µL to 40.5 /µL, and glucocorticoid doses from 7.3 mg/dL to 1.6 mg/dL. In contrast, lung function and fractional exhaled nitric oxide levels were not affected by treatment with biologics. Furthermore, the duration of biologics was positively correlated with symptom improvement. Conclusions: Treatment with mepolizumab for EGPA was effective in glucocorticoid sparing, symptom reduction, and relapse prevention. Mepolizumab is expected to reduce the risk of glucocorticoid-related adverse events. Therefore, continued administration as well as early intervention with mepolizumab for EGPA might be important to conserve future medical resources and control the disease.