Baseline Severity Research Articles

Clinical Manifestations.

It is unclear whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) represent the two ends of a clinical continuum or exist as distinct syndromic entities with specific pathologic/prognostic correlates. We aimed to characterize the main clinical features along the spectrum of progressive non-fluent speech-language disorders (nf-SLD) and explore the existence of data-driven symptom clusters with etiological/prognostic value. We included 98 participants presenting with progressive motor speech impairment and/or agrammatism, of which 43 had an autopsy-confirmed neuropathological diagnosis. Speech pathologists rated motor speech features indicative of dysarthria and AOS. Quantitative measures of expressive/receptive agrammatism were obtained and compared with healthy controls. Baseline and longitudinal disease severity was assessed with the Clinical Dementia Rating sum-of-boxes (CDR-SB). We explored the clustering tendency of the data to form robust symptom clusters and used principal component analysis to extract data-driven clinical components. The longitudinal CDR-SB change was estimated with linear mixed-effects models. Ninety-one participants fitted previously reported clinical profiles (69 AOS+agrammatism, 18 PPAOS and 4 PAA), while 7 remained unclassifiable and were characterized by nonfluent speech and dysarthria in the absence of apraxia of speech or agrammatism. None of the baseline clinical features discriminated between FTLD subgroups. The Hopkins statistic ruled out the existence of syndromic clusters in the whole sample. Three data-driven components explained 71% of the variance ([i]severity-agrammatism, [ii]AOS, and [iii]dysarthria). The component characterized by prominent dysarthria was more specific to patients with Progressive Supranuclear Palsy while the component characterized by severity-agrammatism predicted a faster CDR-SB increase. Our results suggest that nf-SLD represents a clinical continuum. Splitting this continuum into different clinical phenotypes based on its major clinical features does not improve clinical-pathological correlations, stressing the need for new clinical and biological markers. The term nf-SLD could be used to group together these speech-language phenotypes strongly associated with FTLD.

Post Hoc Analysis of a Phase 2/3 Study in Japanese Patients with iTTP Treated with Caplacizumab

Introduction Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disease caused by a severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13). Caplacizumab is a von Willebrand factor-directed antibody fragment designed to treat iTTP in conjunction with therapeutic plasma exchange (TPE) and immunosuppressive therapy. Caplacizumab was approved in Europe in 2018, in the United States in 2019, and in Japan in 2022. Methods In the open-label, Phase 2/3 study (NCT04074187), Japanese patients ≥18 years old with a clinical diagnosis of iTTP and ≤1 prior TPE received caplacizumab in combination with TPE and immunosuppression for ≥30 days post-TPE and were followed for 4 weeks after the end of treatment. Patients with persistent ADAMTS13 deficiency (eg, <10%) were allowed treatment extension of up to 8 weeks. This post hoc analysis assessed outcomes including patient characteristics, time to platelet count recovery, time to normalization of all 3 organ damage markers (lactate dehydrogenase, cardiac troponin I, and serum creatinine), safety, time to recovery of ADAMTS13 activity, ADAMTS13 activity at end of treatment, and incidence of ADAMTS13 inhibitor elevation during treatment stratified by iTTP severity. Very severe iTTP at baseline was defined as follows: French severity score ≥3 or severe neurological involvement (eg, coma, seizures, focal deficit), or cardiac involvement (cardiac troponin level >2.5×ULN). Results Overall, 21 patients were enrolled and treated with ≥1 dose of caplacizumab (modified intent-to-treat population [mITT] and safety population). Of these,19 patients had confirmed iTTP (less severe iTTP, n=8; very severe iTTP, n=11; Table). Median (95% confidence interval [CI]) time to platelet count response and median (range) days of TPE was 3.28 (1.69-4.01) and 5.5 (3-15) days in patients with less severe iTTP and 3.49 (1.76-3.98) and 6.0 (4-20) days in patients with very severe iTTP, respectively. Median (95% CI) time to normalization of all 3 organ damage marker levels was 1.73 (0.79-2.94) days in patients with less severe iTTP and 8.66 (2.65-12.55) days in patients with very severe iTTP, which may reflect the fact that patients with very severe iTTP had worse organ damage at baseline. The number of patients experiencing recurrence, ≥1 major thromboembolic event, or TTP-related death in patients with less severe and very severe iTTP was 1 for each subgroup. Two patients in each disease severity subgroup had ≥1 treatment-emergent serious adverse event. Of the 19 patients with confirmed iTTP, median (95% CI) time to recovery of ADAMTS13 activity to ≥10, ≥20, and ≥60% was 14.57 (5.95-24.76),18.49 (5.95-31.75), and 47.51 (18.49-60.94) days, respectively. Patients with ADAMTS13 inhibitor levels ≥2 BU/mL at baseline (n=7) took approximately twice as long to recover ADAMTS13 activity to ≥10, ≥20, and ≥60% versus patients with baseline inhibitor levels <2 BU/mL. Median (range) ADAMTS13 activity level at the end of caplacizumab treatment was 62.0% (29.0%-101.0%). ADAMTS13 inhibitor elevation occurred in 9 patients (Figure). Among them, 7 patients extended caplacizumab treatment. Only 1 patient with inhibitor re-increase experienced a recurrence 2 days after discontinuing caplacizumab due to an adverse event. Conclusions These results suggest that caplacizumab in conjunction with TPE and immunosuppression is effective for patients with iTTP regardless of their baseline severity and may reduce the risk of recurrence due to inhibitor re-increase.

Partitioning of Circulating Monocyte Subsets in Immune Thrombocytopenia

Introduction Immune thrombocytopenia (ITP) is an autoimmune disease characterized by accelerated platelet destruction with impaired platelet production leading to a platelet count decreased +/- bleeding manifestations, mostly caused by antiplatelet autoantibodies. The role of monocytes in ITP pathophysiology is not clearly established. Circulating monocyte subpopulations were identified phenotypically by flow cytometry and defined according to the surface expression of CD14 and of CD16 into classical (cMo), intermediate (iMo) and nonclassical (ncMo) monocytes. A new subpopulation, defined by the expression of the slan marker, has recently been described and represents a fraction of ncMo (ncMo slan +). Objectives The 1 st objective of the study was to analyze the partitioning of peripheral blood monocyte subsets by flow cytometry in ITP patients compared to a group of healthy blood donors (HD). Our second objective was to further characterize different phenotypic profiles of monocytes among ITP patients based on baseline characteristics, severity and treatment(s). Methods From April 2019 to January 2023, peripheral blood samples from ITP patients and HD were collected on EDTA and stained with the following antibodies: anti-CD45, CD2, CD56, CD24, CD14, CD16 and anti-slan. Acquisition analysis was performed either with a Navios or a DxFLEX cytometer. All files were analyzed with the previously described exclusion strategy of non-monocytes populations, using Kaluza™ analysis software, to characterize cMo, iMo, ncMo and ncMo slan + subsets. ITP patients were included regardless of their ITP status and/or phase of the disease. Results In total, 56 peripheral blood samples from 46 ITP patients and from 19 HD were analyzed. ITP patients had a median age of 50.5 years [19-91], 54.3% were females, whereas the median age of HD was 36 years [21-65] with 42.1% of females. ITP was defined as primary in 82.6% of the cases with a median disease duration of 3 years (<3 months or newly-diagnosed in 26.8% and >12 months or chronic ITP in 60.7%). Nine patients had undergone splenectomy (19.6%) at time of analysis. The platelet count was <50 x 10 9/L in 60.7% of ITP patients and absolute monocyte count ≥ 1 x 10 9/L was found in 21.4%. Regarding ITP treatment, 14 patients (25%) were receiving glucocorticoids (GC) at time of analysis whereas 9 (16.1%) had been exposed to GC within the previous month. Eleven patients (19.6%) had received intravenous immunoglobulin within a month prior to the analysis, 20 (35.7%) were on thrombopoietin receptor agonists, 9 (16.1%) had received rituximab in the previous year, 4 (7.1%) received another immunosuppressive therapy and 6 (10.7%) received another treatment. Eighteen patients (32.1%) were considered as “treatment-free” as they had not received any treatment for their ITP in the previous month or rituximab in the previous year. The latter group of “untreated” patients displayed a significant increase of the iMo relative fraction when compared to HD (4.92% vs 3.18%, p=0.018). There was no significant difference between the two groups regarding other monocytic subpopulations, including cMo, ncMo, ncMo slan+, the absolute and relative counts of monocytes. As for the treatment effect, the ongoing intake of GC therapy did not have a significant impact on monocytosis but was strongly associated with an increased proportion of cMo (94.2% vs 85.0%, p < 0.0001; Figure 1) and a decreased proportion of ncMo (2.31% vs 9.85%, p<0.0001) and ncMo slan+ (3.12% vs 7.46%, p<0.0001), mimicking the cMo accumulation characteristic of chronic myelomonocytic leukemia. Splenectomy and other treatments did not significantly interfere neither with monocyte count nor with the monocyte subpopulation partitioning. When excluding patients receiving GC, splenectomized patients had a higher monocyte count compared to non-splenectomized patients (1.0 vs 0.5G/L, p=0.008), with no difference in monocyte subset repartition. Conclusion Using multiparameter flow cytometry analysis, we demonstrated the expansion of iMo in untreated ITP patients. GC treatment led to the accumulation of cMo with reduced ncMo proportion, hence should be considered when interpreting the monocyte subset partitioning. These data suggest a potential role of monocytes in ITP pathogenesis and clinical response to GC therapy.

Tolerability and Outcomes of Bruton Tyrosine Kinase Inhibitors for Chronic Lymphocytic Leukemia in Patients with Severe Renal Dysfunction

Introduction: There is limited data on the outcomes and tolerability of Bruton Tyrosine Kinase (BTK) inhibitors for chronic lymphocytic leukemia (CLL) in patients with severe renal dysfunction, particularly older adults. The most commonly prescribed BTK inhibitor, ibrutinib, is believed to be safe for mild to moderate renal dysfunction. However, severe renal failure has been excluded from prospective studies, and there is no guidance on dosing under the FDA label. Furthermore, ibrutinib itself can cause kidney injury and worsen existing renal dysfunction. This national Veterans Affairs (VA) analysis aims to review the safety and tolerability of BTK inhibitors in severe renal impairment. Methods: An electronic query of the VA Corporate Data Warehouse and retrospective chart review were performed to identify patients with CLL treated with a BTK inhibitor between 2013-2022 and who had severe chronic kidney disease defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m 2 overlapping with their treatment period. Isolated acute kidney injuries lasting < 1 month were excluded. Fisher's exact test was utilized to evaluate categorical variables, logistic regression for binary outcomes, and log-rank and Cox regression for time-to-event analyses. Results: A total of 115 patients across 68 VA medical centers received 124 lines of BTK inhibitors with an eGFR < 30 (Table 1). The median duration of follow-up from the start of therapy was 26 months (range, 0.5 - 94). The median age was 74, and 98% were male, reflecting the U.S. veteran population. 64% had an eGFR < 30 at the start of therapy, with 18% requiring dialysis, while the remaining 36% experienced progressive renal dysfunction during treatment. The oral BTK agents prescribed were ibrutinib ( n = 103), acalabrutinib ( n = 18), and zanubrutinib ( n = 3). Most BTK inhibitors (n = 94 of 124 lines, 76%) were initiated at the FDA-label dose. 46 (37%) later required dose reduction, primarily due to drug toxicity ( n = 37). The most common reasons for dose reduction were cytopenia ( n = 10), failure to thrive ( n = 6), bleeding ( n = 5), and worsening renal function ( n = 5). Discontinuation of therapy for toxicity occurred in 50% (ibrutinib), 39% (acalabrutinib), and 33% (zanubrutinib). The most common reasons for discontinuation were infection ( n = 15), bleeding ( n = 10), arrhythmia ( n = 9), and disease progression ( n = 9). Among patients who received ibrutinib ( n = 103), the median progression-free survival (PFS) and overall survival (OS) were 45 and 49 months, respectively. In multivariate Cox regression, covariates associated with shorter PFS included the baseline severity of renal failure (HR 1.85, 95% CI 1.21 - 2.88), cirrhosis (HR 6.36, 95% CI 1.45 - 19.76), and heart failure (HR 4.20, 95% CI 1.82 - 9.47). Younger age, dialysis, and absence of atrial fibrillation at the start of therapy were protective in univariate but not multivariate models. Heart failure and cirrhosis retained their prognostic impact on OS in multivariate modeling. Factors including race, rural residence, obesity, IGHV status, and TP53 deletion were not significantly associated with survival in this cohort. The median duration of therapy of ibrutinib was 33 months. Ibrutinib dose reductions at initiation or during treatment were associated with a longer duration of therapy (Figure 1). Of note, dose reductions did not significantly reduce the response rate to ibrutinib or worsen survival. Interestingly, 11 patients had CLL-related kidney dysfunction. However, kidney function did not improve after treatment with a BTK inhibitor in any of the 115 patients. Progression of renal impairment was observed in 51 patients (50%) on ibrutinib, 8 (44%) on acalabrutinib, and none on zanubrutinib. The etiology of worsening renal function was uncertain for the majority of patients. Conclusion: The clinical outcomes of BTK inhibitors in patients with CLL and severe renal dysfunction have not been well-described. In our real-world data analysis, these agents appear to be a reasonable therapeutic option in severe renal impairment, including in older adults and those on dialysis. Lab monitoring is needed, given the risk of worsening renal function. Dose modifications may help improve tolerability without reducing efficacy. Unfortunately, severe renal dysfunction is unlikely to improve with CLL treatment, even in CLL-related kidney failure.

Exploring Factors Linked to Home-Reported Acute Pain Events and Pain Crises in Sickle Cell Disease (SCD) through Flare Tracking in the Ascend Study

Introduction: Pain is a prominent symptom in sickle cell disease (SCD) and often broadly categorized as persistent chronic pain or more intense acute pain episodes compared to regular chronic pain experiences. Many research studies focus solely on pain events requiring healthcare utilization, neglecting those experienced at home, which may cloud the understanding of an individual's daily experience in managing their symptoms. Capturing home-reported evidence is crucial for comprehending SCD's impact on patients and potential effects of medical interventions. Objective: The objective of the Ascend Study was to collect individuals' experiences with pain events in SCD, employing a flexible, home-reported outcomes data collection methodology in Folia Health's mobile and web-based platform. Methods: The Advarra IRB-approved study recruited individuals with any genotype of SCD in the U.S., aged 13 and above, and caregivers of children aged 4 to 12. E-consent and data collection occurred through the Folia platform, where participants selected and tracked relevant symptoms (including, but not limited, to pain-specific symptoms) and treatments, along with health-related quality of life, over the course of 3 months per participant. Baseline severity scores were collected on a 1 to 10 Likert scale for symptoms that were pre-selected by participants at the start of the study. Participants also directly reported potential acute pain events and pain crises experienced in monthly surveys. Detailed flare tracking was set up for four symptom types (chronic pain, acute pain, pain crises, pain and discomfort), enabling structured follow-up questions on select pain flare events. Flare tracking was activated if participants reported a 2-point increase in severity compared to self-identified baselines or opted to track a pain symptom outside of their pre-selected routine. Overall pain burden was collected by participants who routinely tracked all of these various pain experiences, comprising the Ascend Study's home-reported pain hierarchy (Figure A). Results: 89% (n=59) of tracking participants reported experiencing a potential pain crisis for at least 1 month through monthly surveys. Analysis using the flare threshold applied to all pain symptoms tracked (sensitivity 77.5%; specificity 44.9%) identified 2,660 potential pain flare events. Among participants, 86% (n=57) experienced at least one flare event based on the flare threshold. On average, each participant had 24.9 flare days. Flare events identified by the threshold included 9 pain types tracked on a 1-10 Likert scale and 26 pain types tracked as binary “yes/no.” A total of 812 potential pain flare events reported by 46 participants prompted flare tracking follow-up questions (Table 1). Increases in chronic pain were more common than new types. 74% of these participants (n=34) opted to provide additional information through flare tracking in 282 pain flare events. Real-time flare tracking was reported in 85% of flare tracking events. From follow-up responses, most common classifications of pain were stabbing(188, 30.3%), pulsing or throbbing(144, 23.2%), and dull or aching(143, 23.0%). The back (155, 15.7%) and leg (268, 27.2%) were the most prevalent pain locations, with weather (177) and seasonal change (92) identified as potential triggers. Top flare descriptors included ‘can't do normal activities’ (84, 24.4%) and ‘not getting better with home pain meds’ (78, 22.7%). Conclusion: The Ascend Study provides detailed insights into SCD acute pain experiences, showing a high percentage of real-time flare tracking. Chronic pain flares were frequently reported, back and leg pain being the most prevalent locations, and seasonal changes identified as potential triggers. While the flare threshold analysis identified many potential pain flare events, the method's sensitivity might lead to lower specificity for pain flare events and the inclusion of potentially non-flare events. Findings provide valuable insights into the acute pain experiences of individuals with SCD, emphasizing the significance of capturing home-reported evidence to improve patient care and SCD therapies.

2789. Cefepime Versus Non-Cefepime/Non-Carbapenem Therapy for Blood Stream Infections Caused by Non-ESBL-Producing Serratia Marcescens: A Subgroup Analysis of The Carbapenem-Serratia Multicenter Retrospective Cohort Study

Abstract Background Serratia Marcescens causes serious infections. Carbapenems were prescribed due to the bacterium’s ability to develop inducible AmpC-mediated resistance. Recent IDSA guidance recommends ceftriaxone and in high-burden cases, cefepime. Evidence on the role of cefepime in the treatment of Serratia bacteremia is scarce. We aim to evaluate the outcomes of patients who received cefepime-containing empiric and/or definitive therapy (CFCT) to those receiving non-cefepime therapy (NCFCT). Methods This is a sub-analysis of a retrospective study of 7 Massachusetts acute care hospitals from January 1, 2015, to October 31, 2022. We included hospitalized adults (≥18 years) with Serratia Marcescens bacteremia. IRB approval was obtained. Demographics, clinical course characteristics, and choice of antibiotic therapy were collected. Primary outcome was 30-day mortality, and secondary outcome was composite antimicrobial failure (see Definitions in Table 1). Chi Square and Mann-Whitney U tests were computed using SPSS statistical package. Results The original Carbapenem-Serratia study had 73 out of 128 patients who met the inclusion criteria (Figure 1). The non-carbapenem group (n=56) was further studied for the purpose of this subanalysis and was divided into CFCT (n=15) and NCFCT (n=41). The two subgroups were similar in baseline comorbidities, severity measures, and sources of bacteremia (Table 1). Neither 30-day mortality nor the composite outcome of antimicrobial failure were significantly different with relative risks of 0.94 (95% CI 0.16 to 5.3, P=0.948) and 1.21 (95% CI 0.27 to 5.4, P=0.800), respectively. Study exclusion flow-chart with subanlaysis. ESBL phenotypically defined by ceftriaxone resistance (MIC <1). Characteristics and outcomes of patient with Serratia bacteremia treated with a cefepime versus non-cefepime nor carbapenem therapy regimen. * Immunocompromised patients are those receiving immunosuppressants, chemotherapy, or transplants, having HIV with CD4+ T cell count <200 cells/mm3, neutropenia with ANC < 500 cells/mm3, or corticosteroid use with prednisone or equivalent >10 mg for ≥ 14 days. † Hospital-acquired bacteremia is diagnosed when a positive blood culture obtained from patients hospitalized for 48 hours or longer. Healthcare-associated bacteremia was defined as a positive blood culture is obtained within 48 hours of hospital admission and the patient fulfills specific pre-defined criteria utilized in prior studies. Community-acquired bacteremia refers to positive a blood culture obtained within 48 hours after hospital admission in patients who do not fit the criteria for healthcare-associated infections. ‡ Deep seated complicated infection included Infective endocarditis, septic arthritis, osteomyelitis, or epidural abscess § Empiric antibiotic therapy: Antibiotics administered before antimicrobial susceptibility testing (AST) results, with a minimum 48-hour of uninterrupted duration and appropriate dosing. || Definitive antibiotic therapy (i.e., antibiotics administered after the AST results, also with a minimum of 48-hour duration). ¶ Duration of total definitive antibiotic therapy was counted from day of AST results until last day of definitive antimicrobial therapy. # Microbiological failure, microbiological relapse, in- hospital mortality, 30-day mortality, infection-related hospital readmission, or recurrent Serratia bateremia within 30 days. Microbiological failure refers to the growth of Serratia after 48 hours of definitive antibiotic therapy, while microbiological relapse is the regrowth of Serratia after a negative blood culture (Kunz Coyne et al., 2023). Note: Two patients had recurrence of Serratia bacteremia within 30 days, neither were resistant to third generation cephalosporins. Δ Infection-related re-admission was defined when a patient is readmitted not solely for a procedure or surgery, and they experience fever, worsening leukocytosis, or required escalation of antimicrobial therapy from the definitive therapy of the index admission. Conclusion Averting cefepime in the antimicrobial therapy of Serratia bacteremia is not associated with a significant increase in 30-day mortality or the composite outcome of antimicrobial failure. When applicable, a narrower beta-lactam therapy such as ceftriaxone may be appropriate. Limitations include a small sample size, with higher risk for type II error, and overlap in definitive antibiotic therapy. Further prospective studies are needed to confirm these findings, especially in patients with deep-seated infections. Disclosures All Authors: No reported disclosures

Clinical dimensions along the non-fluent variant primary progressive aphasia spectrum.

It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analysed speech, language and disease severity features in a comprehensive cohort of patients with progressive motor speech impairment and/or agrammatism to ascertain evidence of naturally occurring, clinically meaningful non-overlapping syndromic entities (e.g. PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with aetiologic/prognostic value could be identified. We included 98 participants, 43 of whom had an autopsy-confirmed neuropathological diagnosis. Speech pathologists assessed motor speech features indicative of dysarthria and apraxia of speech (AOS). Quantitative expressive/receptive agrammatism measures were obtained and compared with healthy controls. Baseline and longitudinal disease severity was evaluated using the Clinical Dementia Rating Sum of Boxes (CDR-SB). We investigated the data's clustering tendency and cluster stability to form robust symptom clusters and employed principal component analysis to extract data-driven latent clinical dimensions (LCD). The longitudinal CDR-SB change was estimated using linear mixed-effects models. Of the participants included in this study, 93 conformed to previously reported clinical profiles (75 with AOS and agrammatism, 12 PPAOS and six PAA). The remaining five participants were characterized by non-fluent speech, executive dysfunction and dysarthria without apraxia of speech or frank agrammatism. No baseline clinical features differentiated between frontotemporal lobar degeneration neuropathological subgroups. The Hopkins statistic demonstrated a low cluster tendency in the entire sample (0.45 with values near 0.5 indicating random data). Cluster stability analyses showed that only two robust subgroups (differing in agrammatism, executive dysfunction and overall disease severity) could be identified. Three data-driven components accounted for 71% of the variance [(i) severity-agrammatism; (ii) prominent AOS; and (iii) prominent dysarthria]. None of these data-driven LCDs allowed an accurate prediction of neuropathology. The severity-agrammatism component was an independent predictor of a faster CDR-SB increase in all the participants. Higher dysarthria severity, reduced words per minute and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression. Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum. In our cohort, splitting the nfvPPA spectrum into separate clinical phenotypes did not improve clinical-pathological correlations, stressing the need for new biological markers and consensus regarding updated terminology and clinical classification.

Sex-related differences in patient characteristics, and efficacy and safety of advanced therapies in randomised clinical trials in psoriatic arthritis: a systematic literature review and meta-analysis

Sex-related differences in clinical manifestations and disease outcomes exist in psoriatic arthritis, however, there is limited information on sex-related differences in randomised controlled trials of psoriatic arthritis. We aimed to compare patient characteristics and efficacy and safety of advanced therapies (including biological and targeted synthetic therapies) between male and female patients with psoriatic arthritis participating in randomised controlled trials. In this systematic review and meta-analysis, we searched Medline, Embase, and Central databases, and conference abstract archives, from their inception to June 10, 2022, for randomised controlled trials that assessed the efficacy of advanced therapies in psoriatic arthritis. Two reviewers extracted information on participants' characteristics and rates of American College of Rheumatology (ACR) 20 and ACR50 response and minimal disease activity (MDA) by sex. Random-effects models were used to calculate pooled effects of ACR20, ACR50, and MDA in male versus female patients by drug class. We included 54 trials (11 514 [50·9%] of 22 621 participants were female and 11 107 [49·1%] were male). Sex-disaggregated results were reported in a minority of studies (nine [17%] of 54 reported baseline characteristics by sex, 18 [33%] reported efficacy by sex, and two [4%] reported safety endpoints by sex). At baseline, male patients had lower baseline tender joint count (mean difference -3·01 [95% CI -3·83 to -2·18], health assessment questionnaire scores (-0·28 [-0·33 to -0·24]), pain scores (-4·58 [-6·86 to -2·30]), patient global assessment (-3·22 [-5·27 to -1·17]), and physician global assessment (-1·34 [-2·08 to -0·08]) than did female patients. Male patients had higher baseline psoriasis area and severity index scores (mean difference 1·95 [95% CI 0·78 to 3·11]) and C-reactive protein concentrations (2·57 [0·40 to 4·74]) than did female patients. ACR20 response by sex varied across drug classes, with higher rates in males than females with interleukin (IL)-17 inhibitors (odds ratio [OR] 1·70 [95% CI 1·38-2·11]), IL-23 inhibitor (1·46 [1·20-1·78]), IL-12 and IL-23 inhibitor (2·67 [1·39-5·09]), and tumour necrosis factor (TNF) inhibitors (1·55 [1·11-2·18]), but no difference with JAK and TYK2 inhibitors (1·10 [0·87-1·38]). Similarly, ACR50 response rates were higher in male patients versus female patients in all drug classes, with exception of JAK and TYK2 inhibitors (TNF inhibitors, OR 2·17 [95% CI 1·62-2·90]; IL-17 inhibitors, 1·93 [1·56-2·38]; IL-23 inhibitor, 1·71 [1·25-2·34]; IL-12 and 23 inhibitor, 2·43 [1·14-5·20]; and JAK and TYK2 inhibitors, 1·09 [0·73-1·62]). Male patients were more likely to reach MDA with most drug classes, including IL-17 inhibitors (OR 1·99 [95% CI 1·50-2·63]), IL-23 inhibitors (1·79 [1·29-2·50]), TNF inhibitors (2·62 [1·54-4·44]), and JAK and TYK2 inhibitors (1·77 [1·15-2·73]). Risk of bias was low for most studies. Biological sex of patients with psoriatic arthritis influences their response to advanced therapies, but the effect varies by drug class. Selective reporting might have influenced these results. Future trials should report baseline characteristics and endpoint results by sex. Canadian Rheumatology Association.

A comparison of self- and observer-rated scales for detecting clinical improvement during repetitive transcranial stimulation (rTMS) treatment of depression

Clinical outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) for treatment of Major Depressive Disorder (MDD) vary widely, and no single mood rating scale is standard for assessing rTMS outcomes. This study of 708 subjects undergoing clinical rTMS compared the performance of four scales in measuring symptom change during rTMS treatment. Self-report and observer ratings were examined weekly with the Inventory of Depressive Symptomatology 30-item (IDS), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item (POMS), and Hamilton Depression Rating Scale 17-item (HDRS). While all scales were correlated and detected significant improvement, the degree of improvement over time as well as response (33–50%) and remission (20–24%) rates varied significantly. Higher baseline severity was associated with lower likelihood of remission, and greater improvement by sessions 5 and 10 predicted response across all scales. Use of only a single scale to assess outcome conferred 14–36% risk of failing to detect response/remission indicated by another scale. The PHQ was most likely to indicate improvement and least likely to miss response or remission. These findings indicate that assessment of symptom burden during rTMS treatment may be most accurately assessed through use of multiple instruments.

Deucravacitinib, an Oral, Selective, Allosteric Tyrosine Kinase 2 Inhibitor, in Moderate to Severe Plaque Psoriasis: Efficacy by Baseline Body Surface Area (BSA) Involvement and Baseline Psoriasis Area and Severity Index (PASI)

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. In the phase 3 POETYK PSO-1 (NCT03624127) and PSO-2 (NCT03611751) trials, deucravacitinib was significantly more efficacious than placebo and apremilast. This analysis evaluated deucravacitinib efficacy by two measures of baseline disease severity, BSA involvement and PASI scores.
 Methods: Patients were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily in both trials, which included 16-week placebo-controlled and 24-week apremilast-controlled periods from Day 1. Of patients randomized to deucravacitinib, those in PSO-1 were treated continuously for 52 weeks; in PSO-2, Week 24 PASI 75 responders were rerandomized to continued deucravacitinib or placebo. Patients randomized to placebo crossed over to deucravacitinib at Week 16 and were treated through Week 52. Efficacy outcomes, including ≥75%/≥90%/100% reductions from baseline in PASI (PASI 75/90/100) and static Physician Global Assessment score of 0 (clear) or 1 (almost clear) (sPGA 0/1), were evaluated using nonresponder imputation in disease severity subgroups defined by baseline BSA involvement (10%-<15%, 15%-<20%, 20%-<30%, ≥30%) and PASI score (12-<15, ≥15). Results are reported through Week 24 in the pooled PSO-1/PSO-2 population (apremilast-controlled) and through Week 52 in the PSO-1 population (continuous deucravacitinib treatment).
 Results: In the pooled PSO-1/PSO-2 population (N=1686), 391 (23.2%) had baseline BSA involvement of 10%-<15% (deucravacitinib, n=194), 371 (22.0%) had 15%-<20% (deucravacitinib, n=183), 391 (23.2%) had 20%-<30% (deucravacitinib, n=198), and 533 (31.6%) had ≥30% (deucravacitinib, n=268). For baseline PASI scores, 387 (23.0%) had a score of 12-<15 (deucravacitinib, n=183) and 1298 (77.0%) had a score of ≥15 (deucravacitinib, n=660). Deucravacitinib-treated patients had comparable PASI 75 response rates across all subgroups at Week 16 (BSA subgroups, 50.5%-58.2%; PASI subgroups, 48.6%-57.0%) and at Week 24 (BSA subgroups, 62.0%-64.1%; PASI subgroups, 59.9%-63.8%), with superior responses versus those in patients receiving placebo or apremilast evaluated in each subgroup. Similar findings were observed for all other efficacy measures. In PSO-1, efficacy was maintained through Week 52 with continuous deucravacitinib treatment across BSA (PASI 75, 67.1%-75.7%; sPGA 0/1, 52.1%-61.2%) and PASI subgroups (PASI 75, 65.6%-73.1%; sPGA 0/1, 54.7%-58.8%).
 Conclusion: Deucravacitinib was efficacious in patients with moderate or severe plaque psoriasis regardless of extent of baseline BSA involvement or PASI scores.

Impact of sleep disruption on BDD symptoms and treatment response

BackgroundBody dysmorphic disorder (BDD) is severe, undertreated, and relatively common. Although gold-standard cognitive behavioral therapy (CBT) for BDD has strong empirical support, a significant number of patients do not respond. More work is needed to understand BDD's etiology and modifiable barriers to treatment response. Given its high prevalence and impact on the development, maintenance, and treatment of related, frequently comorbid disorders, sleep disruption is a compelling, but not-yet studied factor. MethodsData were drawn from a randomized controlled trial of guided smartphone app-based CBT for BDD. Included participants were offered 12-weeks of treatment, immediately (n = 40) or after a 12-week waitlist (n = 37). Sleep disruption and BDD symptom severity were assessed at baseline, week-6, and week-12. ResultsHypotheses and analysis plan were pre-registered. Two-thirds of patients reported significant insomnia symptoms at baseline. Baseline severity of sleep disruption and BDD symptoms were not related (r = 0.02). Pre-treatment sleep disruption did not predict BDD symptom reduction across treatment, nor did early sleep improvements predict greater BDD symptom improvement. Early BDD symptom improvement also did not predict later improvements in sleep. LimitationsLimitations include the small sample, restricted ranges of BDD symptom severity and treatment response, and few metrics of sleep disruption. ConclusionsAlthough insomnia was disproportionately high in this sample and both BDD symptoms and sleep improved in treatment, results suggest sleep and BDD symptoms may function largely independent of one another. More work is encouraged to replicate and better understand findings as well as potential challenges and benefits of addressing sleep in BDD.

Machine learning vs. traditional regression analysis for fluid overload prediction in the ICU

Fluid overload, while common in the ICU and associated with serious sequelae, is hard to predict and may be influenced by ICU medication use. Machine learning (ML) approaches may offer advantages over traditional regression techniques to predict it. We compared the ability of traditional regression techniques and different ML-based modeling approaches to identify clinically meaningful fluid overload predictors. This was a retrospective, observational cohort study of adult patients admitted to an ICU ≥ 72 h between 10/1/2015 and 10/31/2020 with available fluid balance data. Models to predict fluid overload (a positive fluid balance ≥ 10% of the admission body weight) in the 48–72 h after ICU admission were created. Potential patient and medication fluid overload predictor variables (n = 28) were collected at either baseline or 24 h after ICU admission. The optimal traditional logistic regression model was created using backward selection. Supervised, classification-based ML models were trained and optimized, including a meta-modeling approach. Area under the receiver operating characteristic (AUROC), positive predictive value (PPV), and negative predictive value (NPV) were compared between the traditional and ML fluid prediction models. A total of 49 of the 391 (12.5%) patients developed fluid overload. Among the ML models, the XGBoost model had the highest performance (AUROC 0.78, PPV 0.27, NPV 0.94) for fluid overload prediction. The XGBoost model performed similarly to the final traditional logistic regression model (AUROC 0.70; PPV 0.20, NPV 0.94). Feature importance analysis revealed severity of illness scores and medication-related data were the most important predictors of fluid overload. In the context of our study, ML and traditional models appear to perform similarly to predict fluid overload in the ICU. Baseline severity of illness and ICU medication regimen complexity are important predictors of fluid overload.

Antibiotics With or Without Rifaximin for Acute Hepatic Encephalopathy in Critically Ill Patients With Cirrhosis: A Double-Blind, Randomized Controlled (ARiE) Trial.

Critically ill patients with cirrhosis admitted to the intensive care unit (ICU) are usually on broad-spectrum antibiotics because of suspected infection or as a hospital protocol. It is unclear if additional rifaximin has any synergistic effect with broad-spectrum antibiotics in ICU patients with acute overt hepatic encephalopathy (HE). In this double-blind trial, patients with overt HE admitted to ICU were randomized to receive antibiotics (ab) alone or antibiotics with rifaximin (ab + r). Resolution (or 2 grade reduction) of HE, time to resolution of HE, in-hospital mortality, nosocomial infection, and changes in endotoxin levels were compared between the 2 groups. A subgroup analysis of patients with decompensated cirrhosis and acute-on-chronic liver failure was performed. Baseline characteristics and severity scores were similar among both groups (92 in each group). Carbapenems and cephalosporin with beta-lactamase inhibitors were the most commonly used ab. On Kaplan-Meier analysis, 44.6% (41/92; 95% confidence interval [CI], 32-70.5) in ab-only arm and 46.7% (43/92; 95% CI, 33.8-63) in ab + r arm achieved the primary objective ( P = 0.84).Time to achieve the primary objective (3.65 ± 1.82 days and 4.11 ± 2.01 days; P = 0.27) and in-hospital mortality were similar among both groups (62% vs 50%; P = 0.13). Seven percent and 13% in the ab and ab + r groups developed nosocomial infections ( P = 0.21). Endotoxin levels were unaffected by rifaximin. Rifaximin led to lower in-hospital mortality (hazard ratio: 0.39 [95% CI, 0.2-0.76]) in patients with decompensated cirrhosis but not in patients with acute-on-chronic liver failure (hazard ratio: 0.99 [95% CI, 0.6-1.63]) because of reduced nosocomial infections. Reversal of overt HE in those on ab was comparable with those on ab + r.

Aortic stenosis rapid progression is associated with premature cardiac damage independently of baseline severity

Abstract Background Aortic stenosis (AS) is one of the major valvular heart diseases in developed countries. Degenerative fibrocalcific AS is a progressive disease of the valve and, ultimately, the myocardium. AS is a potentially fatal disease characterized not only by a narrowing of the aortic orifice but also by gradual cardiac damage (CD) that may extend beyond the left ventricle (LV). However, the presence and extent of extra-aortic cardiac damage did not reflect the baseline hemodynamic severity of AS in retrospective studies. Purpose This study aims to determine the rate of AS progression and its impact on cardiac damage and survival. Methods We retrospectively identified 914 patients (age 76 ± 8 years, 52% female, median follow-up time 6.8 years) with AS who had undergone > 1 echocardiogram. Bayesian hierarchical nonlinear models were used to predict aortic peak velocity as a function of time and estimate individual AS acceleration rates. Then, patients were clustered into rapid (RP) and slow progressors (SP) using machine learning algorithms. Results APV was best modeled by a logistic function of time. 483 patients were clustered as RP (53 %) and 431 as SP (47 %), with acceleration rate coefficients estimated at 0.14 ± 0.02 years-1 and 0.09 ± 0.02 years-1, respectively (p < 0.01). No association between progression rate and clinical variables was found. Compared with SP, RP had significantly higher 5-year incidences of LV damage, combined left atrium and mitral valve damage and combined tricuspid valve damage and pulmonary hypertension (all p ≤ 0.01). No statistically significant differences were seen for right ventricle damage between RP and SP, as the number of events was low. After multivariate adjustment for age, gender, comorbidities and baseline AS severity, RP remained an independent predictor for all extra-aortic cardiac damages except for the RV dysfunction. Importantly, baseline AS severity was not predictive of AS-related CD. RP was associated with higher mortality (HR 1.28, p = 0.02), persisting after adjustment for demographics, comorbidities, AS severity, and time-dependent aortic valve replacement (AVR) (HR = 1.36, p < 0.01). Conclusions RP may impair cardiac adaption to rapidly changing loading conditions, which induces premature cardiac damage that may not be reversible in the late stages of AS, when guideline-triggered interventions are currently delivered.

Measurement ofHead Kinematics Using Instrumented Mouthguards During Introductory Boxing Courses inU.S. Military Academy Cadets.

Use of wearable impact sensor devices to quantitatively measure head impact exposure remains largely unstudied in military-style martial arts training and combat sports, particularly at the beginner levels. The baseline frequency and severity of head impact exposure during introductory military-style martial arts trainings, such as combatives training, is valuable information for developing future programs of instruction and exposure monitoring programs. The purpose of this study was to describe head impact exposures experienced during introductory combatives training (a boxing course) at U.S. Military Academy. This study used instrumented mouthguards to measure head impact exposure in U.S. Military Academy cadets during a compulsory boxing course. Summary exposures from a preliminary dataset are presented. Twenty-two male subjects (19.9±1.1 years, 86.6±11.7kg) participated in 205 analyzed player-bouts (full contact sparring sessions) with 809 video verified impacts (average 3.9 impacts per player-bout). The mean peak linear acceleration was 16.5 ±7.1G, with a maximum of 70.8G. There was a right-skewed distribution, with 640/809 (79.1%) events falling between 10 and 20 G. The mean peak angular acceleration was 1.52±0.96krad/s2, with a maximum of 8.85krad/s2. Compared to other high-risk sports at Service Academies, head impacts from beginner boxing were of similar magnitude to those reported for Service Academy football and slightly lower than those reported for Service Academy rugby. Based on these preliminary data, the risk profile for introductory military-style martial arts training, such as boxing or combatives, may be similar to other contact sports like football and rugby, but further research is required to confirm these findings and understand the effects of the exposures in a shorter duration.

Low Dose Risperidone Prophylaxis for The Prevention of Delirium in The Intensive Care Unit: A Randomized, Placebo Controlled Trial

Background Delirium is common among patients in intensive care units. Antipsychotics have been shown to reduce the incidence of delirium in post-operative patients. We set out to compare the efficacy of risperidone to placebo in preventing delirium in critically ill patients admitted to a medical ICU. Methods This double-blind, randomised controlled trial compared prophylactic low-dose risperidone to placebo in critically ill patients. Patients were screened daily for delirium using a validated screening tool (CAM-ICU), and the incidence of delirium was compared between groups. Results Forty-five patients were recruited. Baseline demographic characteristics, diagnosis and severity of illness were not statistically significantly different between groups. There was no significant difference in the incidence of delirium, adverse events or complications. Conclusion In this study, low-dose risperidone did not prevent the incidence of delirium. As delirium is a heterogeneous syndrome, a single intervention may not be effective across subtypes and aetiologies (ISRCTN17375500) Key Message Prophylactic risperidone did not reduce the incidence of delirium in ICU patients in this small study. As delirium is a heterogeneous syndrome, a single intervention may not be effective across subtypes and aetiologies.

A Mini Review of the Impact of Baseline Disease Severity on Clinical Outcomes: Should We Compare Atopic Dermatitis Clinical Trials?

Based on clinical trials of systemic treatments in adults with moderate-to-severe atopic dermatitis (AD) reported between 2014 and 2023, we used linear regression to investigate relationships between baseline Eczema Area and Severity Index (EASI) scores and (1) study start date, (2) EASI response, and (3) rescue medication rates. Analysis 1 was conducted with all patients from monotherapy and combination therapy trials; analyses 2 and 3 used monotherapy trial placebo arms. Across 32 trials with a baseline inclusion criterion of EASI ≥ 16, baseline mean EASI scores decreased with study start date. The lowest and highest baseline mean EASI scores were 25.1 and 33.6 (median 21.1 and 30.5), reported for the WW001 Phase 2 trial of rademikibart (formerly CBP-201; start date, July 2020) and the SOLO1 Phase 3 trial of dupilumab (start date, December 2014), respectively. In placebo arms, lower baseline EASI scores tended to be associated with greater percent reductions in EASI scores at Week 16 and less rescue medication usage. The WW001 trial placebo arm had the lowest baseline EASI score (mean 25.2; median 22.1), lowest rescue medication rate (14.3%), and a large reduction in least squares mean EASI scores (- 39.7%) at Week 16. In summary, baseline mean EASI scores have decreased across clinical trials conducted during the last decade. Less severe AD at baseline tended to be associated with greater placebo response and less use of rescue medications in placebo arms. Intertrial differences in variables, such as baseline AD severity, limit the validity of indirectly comparing clinical trials.

Plasma Cartilage Acidic Protein 1 Measured by ELISA Is Associated With the Progression to Total Joint Replacement in Postmenopausal Women.

To investigate the association of plasma cartilage acidic protein 1 (CRTAC1), a novel biochemical marker of osteoarthritis (OA), and total joint replacement (TJR) in postmenopausal women. The association of plasma CRTAC1 with the incidence of TJR was investigated in a prospective cohort including 478 postmenopausal women. A total of 38 women underwent a TJR for OA during a median follow-up of 18 years. Every one of the TJR cases were age- and BMI (kg/m2)-matched with 2 controls with no TJR from the same cohort. Plasma CRTAC1 was measured before TJR. The association between CRTAC1 and TJR incidence was investigated by conditional logistic regression. Increased CRTAC1 was associated with a higher risk of TJR with an odds ratio (OR) of 1.80 (95% CI 1.11-2.92) for 1 SD increase, which remained significant after adjusting for Western Ontario and McMaster Universities Osteoarthritis Index, knee OA baseline severity (Kellgren-Lawrence grade), hip OA, and hip bone mineral density. Urinary crosslinked C-telopeptide of type II collagen (CTX-II) was also associated with a higher risk of TJR with an adjusted OR of 1.83 (95% CI 1.11-3.00). When CRTAC1 and CTX-II were included in the same model, both markers were significantly associated with TJR with similar ORs. CRTAC1 is a new risk indicator of TJR for OA in postmenopausal women. Combined with knee and hip OA and CTX-II, it may help to identify subjects at risk for TJR.

Longitudinal Analysis of Prophylactic Anticoagulation in Primary Nephrotic Syndrome: Low Incidence of Thromboembolic Complications

Introduction: Thromboembolic events (TEEs) are a serious and potentially fatal complication of nephrotic syndrome (NS). Despite this, there is a lack of evidence examining the benefits of prophylactic anticoagulation (PAC) in NS. It was our objective to review the risk factors, rates of TEEs, and patterns of PAC in patients with primary NS, with the aim to provide a pragmatic approach to PAC in primary NS. Methods: This is a retrospective longitudinal cohort study of adult patients with primary NS. Included were as follows: biopsy-proven minimal change disease and focal segmental glomerulosclerosis (described as a combined podocytopathy cohort) plus membranous nephropathy (MN) over an 8-year period from a single centre. Anticoagulation practice, TEEs, and longer term outcomes were recorded. Results: Fifty-four patients with MN and 48 patients with podocytopathies were included. Baseline demographics and severity of NS were comparable. Those with MN were more likely to develop TEE 12 (22%) versus 4 (8%) (p = 0.027) though this difference was predominantly seen at index diagnosis. Only 2 patients developed TEEs during active incident NS. Rates of PAC were similar when comparing MN (53%) and podocytopathies (58%). Those with a serum albumin <20 g/L and HAS-BLED score <3 were most likely to receive PAC (22/30, 73% in MN vs. 21/30, 70% in podocytopathy). Warfarin was the most common agent used in MN cohort 18/26 (69%) versus prophylactic dose low-molecular-weight heparin in the podocytopathy cohort 12/28 (43%). Discussion/Conclusion: PAC practices applied in this cohort of patients were pragmatic and effective, with low TEE rates during active NS.

Working memory training for reward processing in university students with subsyndromal depression: The influence of baseline severity of depression

Previous studies have tentatively suggested that working memory training (WMT) has the potential to improve reward processing, but it is not known how long this improvement lasts, whether there is a lag effect, or whether it is reflected in neurophysiological indicators. In this study, 40 university students with subsyndromal depression were randomly assigned to a training group or a control group and completed a 20-day working memory training task and a simple memory task, respectively. All participants completed the Temporal Experience of Pleasure Scale (TEPS) and a doors task with electroencephalogram (EEG) signals recorded simultaneously on a pre- and post-test and a 3-month follow-up. The reward-related positivity (RewP) amplitude, theta power, and their differences between conditions (i.e., ΔRewP and Δtheta power, respectively) in the doors task were the primary outcomes, and the score on TEPS was the secondary outcome. The results indicated no group-related effects were demonstrated in primary and secondary outcomes at post-test and 3-month follow-up. Furthermore, the differences in the pre- and post-test in Δtheta power were moderated by the baseline severity of depression. This was primarily driven by the fact that the change values in the control group increased with the severity of depression, while the change values in the training group had high homogeneity. Our findings did not provide support for the effect of WMT on reward processing across the whole sample, but without intervention, there would be high heterogeneity in the change in the cognitive control ability to loss feedback, which is detrimental to individuals with high depression severity.