Stringent Definition Research Articles

Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials.

Background: Kidney outcomes have been variably defined using non-standardized composite endpoints in key heart failure (HF) trials, thus introducing complexity in their interpretation and cross-trial comparability. We examined the effects of steroidal mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, and sodium-glucose cotransporter-2 (SGLT2) inhibitors on composite kidney endpoints using uniform definitions in 6 contemporary HF trials. Methods: Individual participant-level data from trials of steroidal MRAs (EMPHASIS-HF, TOPCAT Americas), ARNI (PARADIGM-HF, PARAGON-HF), and SGLT2 inhibitors (DAPA-HF, DELIVER) were included. The standardized composite kidney endpoint was defined as a sustained decline (a reduction in estimated glomerular filtration rate (eGFR) confirmed by a subsequent measurement at least 30 days later) in eGFR by 40%, 50%, or 57%, end-stage kidney disease, or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Results: Among 28,690 participants across the 6 trials (median age 69 years [IQR, 62-76]; 9,656 [33.7% ] women), the proportion experiencing the composite kidney endpoint with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this endpoint with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% and 10.0%. The steroidal MRAs doubled the risk of the composite kidney endpoint when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. ARNI appeared to consistently reduce the occurrence of the composite kidney endpoints irrespective of specific eGFR threshold applied. The potential benefits of SGLT2-inhibitors on the composite kidney endpoints appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant. Conclusions: When applying standardized stringent kidney endpoint definitions, steroidal MRAs, ARNI, and SGLT2-inhibitors have either neutral or beneficial effects on kidney outcomes in HF. Applying less stringent definitions increased event rates but included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.

On the Combinatorial Acceptability Entropy Consensus Metric for Multi-Criteria Group Decisions

AbstractIn group decisions, achieving consensus is important, because it increases commitment to the result. For cooperative groups, Combinatorial Multicriteria Acceptability Analysis (CMAA) is a group decision framework that can achieve consensus efficiently. It is based on a novel Combinatorial Acceptability Entropy (CAE) consensus metric. As an output measure, the CAE metric is unique in its ability to identify the evaluations that have the greatest impact on consensus and to prevent premature consensus. This paper is intended to complement the original CMAA publication by providing additional insights into the CAE consensus metric. The design requirements for the CAE algorithm are presented, and it is shown how these requirements follow from the properties of cooperative decisions. The CAE-based consensus-building algorithm is contrasted both qualitatively and quantitatively with a representative example of the conventional input distance and input averaging approach to multi-criteria consensus-building. A simulation experiment illustrates the ability of the CAE-based algorithm to converge quickly to the correct decision as defined for cooperative decisions. The metric is able to meet a new, more stringent definition of hard consensus. The CAE approach highlights the need to distinguish between competitive and cooperative group decisions. Attention in the literature has been paid almost exclusively to the former type; the CAE approach demonstrates the greater efficiency and effectiveness that can be achieved with an approach that is designed specifically for the latter.

Retrospective analysis of hospital electronic health records reveals unseen cases of acute hepatitis with unknown aetiology in adults in Oxfordshire

BackgroundAn outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children during 2022 was subsequently linked to infections with adenovirus-associated virus 2 and other ‘helper viruses’, including human adenovirus. It is possible that evidence of such an outbreak could be identified at a population level based on routine data captured by electronic health records (EHR).MethodsWe used anonymised EHR to collate retrospective data for all emergency presentations to Oxford University Hospitals NHS Foundation Trust in the UK, between 2016–2022, for all ages from 18 months and older. We investigated clinical characteristics and temporal distribution of presentations of acute hepatitis and of adenovirus infections based on laboratory data and clinical coding. We relaxed the stringent case definition adopted during the AS-Hep-UA to identify all cases of acute hepatitis with unknown aetiology (termed AHUA). We compared events within the outbreak period (defined as 1st Oct 2021—31 Aug 2022) to the rest of our study period.ResultsOver the study period, there were 903,433 acute presentations overall, of which 391 (0.04%) were classified as AHUA. AHUA episodes had significantly higher critical care admission rates (p < 0.0001, OR = 41.7, 95% CI:26.3–65.0) and longer inpatient admissions (p < 0.0001) compared with the rest of the patient population. During the outbreak period, significantly more adults (≥ 16 years) were diagnosed with AHUA (p < 0.0001, OR = 3.01, 95% CI: 2.20–4.12), and there were significantly more human adenovirus (HadV) infections in children (p < 0.001, OR = 1.78, 95% CI:1.27–2.47). There were also more HAdV tests performed during the outbreak (p < 0.0001, OR = 1.27, 95% CI:1.17–1.37). Among 3,707 individuals who were tested for HAdV, 179 (4.8%) were positive. However, there was no evidence of more acute hepatitis or increased severity of illness in HadV-positive compared to negative cases.ConclusionsOur results highlight an increase in AHUA in adults coinciding with the period of the outbreak in children, but not linked to documented HAdV infection. Tracking changes in routinely collected clinical data through EHR could be used to support outbreak surveillance.

Incidence and prevalence of eating disorders among U.S. military service members, 2016-2021.

Despite unique experiences that may increase eating disorder risk, U.S. military service members are an understudied population. The current study examined incidence and prevalence of eating disorder diagnoses in U.S. military personnel. This retrospective cohort study utilized Military Health System Data Repository (MDR) data on eating disorder diagnoses (2016-2021). Active duty, Reserve, and National Guard U.S. military service members who received care via TRICARE Prime insurance were identified by ICD-10 eating disorder diagnostic codes. During the 6-year surveillance period, 5189 Service members received incident eating disorders diagnoses, with a crude overall incidence rate of 6.2 cases per 10,000 person-years. The most common diagnosis was other/unspecified specified eating disorders, followed by binge-eating disorder, bulimia nervosa, and anorexia nervosa. There was an 18.5% overall rise in total incident cases across the surveillance period, but this trend was not statistically significant (p = 0.09). Point prevalence significantly increased across the 6-year timeframe for total eating disorders (p < 0.001). Period prevalence for 6-year surveillance period was 0.244% for total eating disorders, 0.149% for other/unspecified eating disorder, 0.043% for bulimia nervosa, 0.038% for binge-eating disorder, and 0.013% for anorexia nervosa. Overall crude incidence estimates for total eating disorders were higher than reported in prior research that included only active duty Service members and required an eating disorder diagnosis code in the first or second diagnostic position of the medical record. Comprehensive and confidential studies are needed to more thoroughly characterize the nature and scope of eating disorder symptomatology within U.S. military personnel. U.S. military service members are a vulnerable population with regard to eating disorder symptoms. Previously reported incidence and prevalence estimates using data from the Military Health System may have been underestimated due to overly stringent case definitions. Given personal and occupational barriers (e.g., career consequences), confidential studies of military personnel may provide more complete data on the scope of eating disorders to inform screening and clinical practice guidelines for military populations.

Chronic widespread pain and cause of death: a 25-year follow-up study.

Chronic widespread pain (CWP) has been suggested as a risk factor for mortality in cardiovascular diseases and malignancies. Different definition of CWP makes it difficult to compare previous studies. The aim was to study whether mortality and certain causes of death were increased among people with CWP and whether the definition of CWP influenced outcome. This 25-year follow-up study included 2425 people from the general population, at baseline divided into 3 pain groups: CWP, chronic regional pain, and no chronic pain (NCP). Chronic widespread pain was defined according to the ACR1990 (CWPACR1990) and the more stringent WP2019 (CWPWP2019) criteria. Causes of death were derived from official national register. Mortality, adjusted for age, sex, socioeconomic status, and smoking habits were analyzed with Cox regression. Overall mortality was not higher in people with CWPACR1990 (hazard ratio [HR] 1.08, P = 0.484) compared with NCP but significantly higher when using CWPWP2019 (HR 1.32, P = 0.033). People with CWPWP2019 had a higher mortality in diseases of the circulatory system (HR 1.32, P = 0.033) but not for neoplastic diseases. CWPACR1990 showed an increased mortality in malignancies of digestive organs. An increased mortality in influenza, pneumonia, acute kidney failure, and chronic kidney disease was observed for the CWPWP2019 definition. The more stringent WP2019 definition of CWP showed an excess risk for death, especially within diseases of the circulatory system. The results suggest that WP2019 defines a more vulnerable group in the population. Chronic widespread pain should be acknowledged in the clinic as a risk factor for increased mortality.

Comparison of the five different definitions of equol producers: The relationship between blood and urine equol concentrations and blood parameters in 466 healthy men and women

Background and aimsNo studies have compared various definitions of “equol producers” until now. Therefore, we aimed to explore the accuracy of five different definitions of equol producers (EQP) and their associations with health benefits. MethodsThis is a cross-sectional study of 466 healthy Japanese men and women aged between 22 and 88 years. Equol producer proportions were calculated from their serum and urine isoflavone concentrations using five commonly used definitions. We then examined their accuracy, and associations with the blood parameters. ResultsProportions of equol ranged from 29 % in the most stringent definition to 47.6 % in the most sensitive definition. EQP identified under all definitions had significantly low serum PSA11PSA: prostate specific antigen. levels compared to nonequol producers (NEQP). The most stringent definition, which is defined as the urinary equol level of 1.0 μM and above, corresponded to the highest median serum equol level and was associated with better health outcomes. Male EQP identified by this definition seemed to have reduced risk of LDL22LDL: low density lipoprotein-hypercholesterolemia by 50 %, and female EQP identified by this definition seemed to have lower risk of high hs-CRP,33CRP: C-reactive protein compared to NEQP. Both the first and second stringent definition, which is defined as the serum equol level of 1.0 ng/mL and above, was associated with lower thyroid stimulating hormone level. ConclusionsMore stringent definitions were associated with better parameters in general. Combined with the dietary inquires, a reliable definition for equol producer is crucial to evaluate the health benefits of equol.

Defining success after surgical treatment of stress urinary incontinence

BackgroundA consensus standardized definition of success after stress urinary incontinence surgical treatment is lacking, which precludes comparisons between studies and affects patient counseling. ObjectivesTo identify optimal patient-centric definition(s) of success after stress urinary incontinence surgical treatment and to compare the identified “more accurate” treatment success definitions with a commonly used composite definition of success (ie, no reported urine leakage, negative cough stress test result, and no retreatment). Study DesignWe evaluated 51 distinct treatment success definitions for participants enrolled in a previously conducted randomized trial of stress urinary incontinence treatments concomitantly performed with sacrocolpopexy (NCT00934999). For each treatment success definition, we calculated the mean (SD) of participant-assessed symptom improvement and participant-assessed surgical success scores with an 11-point Likert scale among those achieving success and failure. The “more accurate” treatment success definition(s) were identified by measuring the magnitude of the mean difference of participant assessments with Hedges g values. The treatment success definitions with the highest Hedges g values were considered “more accurate” treatment success definitions and were then compared with the composite definition of success. ResultsThe percentage of participants who had treatment success (6.4% to 97.3%) and Hedges g values (–4.85 to 1.25) varied greatly according to each treatment success definition. An International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form score of 5 or less, Urogenital Distress Inventory-6 score of 33.3 or less, and a no/mild stress urinary incontinence response on Urogenital Distress Inventory-6 question 3 had the highest Hedges g values and were considered the top 3 “more accurate” treatment success definitions. Paradoxically, treatment success definitions that required a negative cough stress test result or no persistent urinary leakage greatly reduced the ability to differentiate participant-assessed symptom improvement or surgical success. When the “more accurate” treatment success definitions were compared with the composite definition, patients with failed treatment according to the composite definition had lower Urinary Impact Questionnaire-7 scores, and a higher proportion of complete/somewhat satisfaction and very good/perfect bladder condition survey responses. Additionally, the composite definition had considerably fewer favorable outcomes for participants than did the top 3 “more accurate” treatment success definitions. ConclusionsSuccessful outcomes of stress urinary incontinence surgical treatments for women undergoing concurrent sacrocolpopexy varied greatly depending on the definition used; however, stringent definitions (requiring complete dryness) and objective testing (negative cough stress test result) had decreased, rather than increased, participant-assessed symptom improvement and surgical success scores. The “more accurate” treatment success definitions better differentiated participant-assessed symptom improvement and surgical success than the composite definition. The composite definition disproportionally misidentified participants who reported minor symptoms or complete/somewhat satisfaction with their outcome as having treatment failures and yielded a considerably lower proportion of women who reported favorable outcomes than did the top 3 “more accurate” treatment success definitions.

Vaccination patterns and up-to-date status of children 19–35 months, 2011–2021

IntroductionBeing up-to-date with all recommended vaccines is needed to protect children from vaccine preventable diseases. Understanding vaccination patterns is needed to develop messaging and strategies to increase vaccination uptake and confidence. MethodsData from the 2011 to 2021 National Immunization Surveys was used to assess trends and disparities in vaccination patterns, zero vaccination status, and up-to-date status of U.S. children by 19–35 months. ResultsFrom 2011 to 2021, adherence to the recommended schedule using the stringent definition increased from 35.7 % to 52.2 % (p < 0.01), adherence to the alternate schedule decreased from 28.2 % to 15.1 % (p < 0.01), and proportion of children who were not up-to-date decreased from 49.0 % to 33.3 % (p < 0.01). However, the proportion of children who had zero vaccinations did not change from 2011 (0.9 %) to 2021 (0.9 %; p = 0.08). In 2021, children 19–23 months were less likely to follow the recommended schedule than children 24–29 months (49.2 % compared to 56.4 %, p < 0.01). Adherence to the recommended schedule among children 19–23 months decreased in 2021 compared to 2020 overall and for some subpopulations (e.g. those with non-Hispanic (NH) Black parents (33.2 % compared to 44.9 %, p < 0.01). Furthermore, it was lowest among children of NH Black parents living at or below the federal poverty level (31.2 %) compared to their respective NH White counterparts (43.6 %, p < 0.01). ConclusionsWhile there were overall increases in adherence to the recommended schedule from 2011 to 2021, a sustained catch-up program is needed to prevent missed vaccinations and achieve equitable vaccination coverage for all children.

Local sign stability and its implications for spectra of sparse random graphs and stability of ecosystems

Abstract We study the spectral properties of sparse random graphs with different topologies and type of interactions, and their implications on the stability of complex systems, with particular attention to ecosystems. Specifically, we focus on the behaviour of the leading eigenvalue in different type of random matrices (including interaction matrices and Jacobian-like matrices), relevant for the assessment of different types of dynamical stability. By comparing numerical results on Erdós-Rényi and Husimi graphs with sign-antisymmetric interactions or mixed sign patterns, we propose a sufficient criterion, called strong local sign stability, for stability not to be affected by system size, as traditionally implied by the complexity-stability trade-off in conventional models of random matrices. The criterion requires sign-antisymmetric or unidirectional interactions and a local structure of the graph such that the number of cycles of finite length do not increase with the system size. Note that the last requirement is stronger than the classical local tree-like condition, which we associate to the less stringent definition of local sign stability, also defined in the paper.&amp;#xD;In addition, for strong local sign stable graphs which show stability to linear perturbations irrespectively of system size, we observe that the leading eigenvalue can undergo a transition from being real to acquiring a nonnull imaginary part, which implies a dynamical transition from nonoscillatory to oscillatory linear response to perturbations. Lastly, we ascertain the discontinuous nature of this transition.

Alienated Heroines in Basil, Lady Audley’s Secret, and East Lynne: A Jaeggian Reading

Abstract While the term ‘alienation’ is frequently mentioned in criticism of sensation fiction, there is a lack of a stringent definition of this term. This article aims to address this gap with a focused examination of the depiction of alienation in three sensation novels, Lady Audley’s Secret (1862) by M. E. Braddon, East Lynne (1861) by Mrs Henry Wood, and Basil (1852) by Wilkie Collins. Borrowing a critical framework from contemporary philosopher Rahel Jaeggi, the article sees alienation as an obstructed relation of ‘appropriation’. According to Jaeggi, to appropriate is, briefly, to take oneself and one’s world at one’s own command. The relation of appropriation bespeaks a more profound relationship between the self and the world than ownership. Previous studies of sensation heroines often associate their alienation with their desires for material property. With Jaeggi’s critical framework, however, this article moves forward by identifying a parallel between the heroines’ troubled desires for material possessions and their problematic relationships in life. Through a Jaeggian lens, all three texts illustrate the heroines’ dispossession of the self and dispossession of property as profoundly, even structurally, linked. A Jaeggian reading of the novels also provides new insights into the genre’s ideological function, particularly in relation to the limited social roles and precarious hold on the material world faced by ambitious Victorian women.

Understanding the Nuances of First-Generation College Students: How the Culture of College Factors Into Academic Success

Abstract: The designation of first-generation college students in educational research has been operationalized inconsistently since its inception. This variation makes understanding and generalizing about this complex group problematic. We explore the inconsistencies in definitions of first-generation students using a culture of college resilience framework and argue that substantial differences in these definitions exist across the literature, which scholars should consider when conducting research on first-generation students. The need for a more stringent definition of what constitutes a first-generation college student is discussed at length. We propose a familial educational capital model that centers on risk and protective factors across social class and familial education. We offer recommendations for researchers, administrators, and other key stakeholders to consider how to operationalize this diverse group more mindfully. Finally, we provide other recommendations to address educational inequalities more effectively for this group.

Persistent esophageal changes after histologic remission in eosinophilic esophagitis

BackgroundEosinophilic esophagitis (EoE) is characterized by persistent or relapsing allergic inflammation, and both clinical and histologic features of esophageal inflammation persist over time in most individuals. Mechanisms contributing to EoE relapse are not understood and therefore chronic EoE-directed therapy is required to prevent long-term sequelae. ObjectiveWe investigated if with EoE patients in histologic remission have persistent dysregulation of esophageal gene expression. MethodsEsophageal biopsies from pediatric (n=51) and adult (n=52) subjects with EoE in histopathologic remission (<15 eos/HPF) and control (n=48 pediatric, n=167 adult) subjects from multiple institutions were subjected to molecular profiling by the EoE Diagnostic Panel (EDP), a set of 94 esophageal transcripts differentially expressed in active EoE. ResultsDefining remission as <15 eosinophils/HPF, we identified 511 and 32 differentially expressed genes in pediatric and adult EoE patients compared to control individuals, respectively (FDR < 0.05). Using the stringent definition of remission (0 eos/HPF), the adult and pediatric cohorts continued to have 18 and 25 differentially expressed genes (FDR ≤ .05). Among 6 shared genes between adults and children, CDH26 was upregulated in both children and adults; immunohistochemistry demonstrated increased cadherin 26 staining in the epithelium of EoE patients in remission compared to non-EoE controls. In the adult cohort, POSTN expression correlated with the Endoscopic Reference Score (Spearman r= 0.35, p= 0.011), specifically correlating with the rings EREFS subscore (r= 0.53, p=0.004). ConclusionWe have identified persistent EoE-associated esophageal gene expression in patients with deep remission. These data suggest potential inflammation-induced epigenetic mechanisms may influence gene expression during remission in EoE and provide insight into possible mechanisms that underlie relapse in EoE.

Pharmacokinetics of Long-Acting Methylphenidate: Formulation Differences, Bioequivalence, Interchangeability.

A literature search was conducted in EMBASE, Medline, and Cochrane Library with no time limits. Study characteristics, non-compartmental pharmacokinetic parameters, and bioequivalence data were extracted for analysis. Thirty-three studies were identified with primary pharmacokinetic data after the administration of ER MPH, of which 10 were direct comparative studies (i.e., at least 2 formulations tested within a single setting) and 23 were indirect comparisons (i.e., different experimental settings). Two formulations were consistently reported as bioequivalent across the regulatory bodies using criteria from their guidance documents, although inconsistencies have been observed. However, when additional kinetic criteria (discussed in this manuscript) were imposed, only one study met the more stringent definition of bioequivalence. Various clinical factors also had inconsistent effects on the pharmacokinetics and interchangeability of the different formulations, which were associated with a lack of standardization for assessing covariates across the regulatory agencies. Additional pharmacokinetic parameters and consistency in guidelines across the regulatory bodies may improve bioequivalence assessments. Based on our findings, more research is also required to understand whether bioequivalence is an appropriate measure for determining MPH interchangeability. This critical review is suitable for formulation scientists, clinical pharmacologists, and clinicians.

Characteristics of difficult-to-treat axial spondyloarthritis: Results of a real-world multicentric study

ObjectiveThe EULAR task force recently published the difficult-to-treat RA (D2T RA) definition, however, a definition of D2T axSpA is still lacking and limitations in this definition exist. The objectives were to study the characteristics of D2T axSpA patients using the EULAR definition and to study a subgroup of patients with a predefined more stringent definition including a temporal criterion. MethodsA multicentric retrospective study was performed. D2T axSpA was defined as failure of≥2 b/tsDMARDs with different mechanism of action. Very D2T axSpA was defined as failure of≥2 b/tsDMARDs in less than 2 years of follow-up. D2T and Very D2T axSpA patients were compared to non-D2T (nD2T) axSpA patients. ResultsThree hundred and eleven axSpA patients were included: 88 D2T axSpA (28.3%) and 223 non-D2T (nD2T) axSpA (71.7%). Peripheral involvement was more prevalent in the D2T group (34.9 vs. 21.4%; P=0.015). BASDAI level at baseline was higher in the D2T group (63.7±16.5 vs. 58.8±14.7; P=0.015). Fibromyalgia was found to be more frequent in the D2T group vs nD2T group (P<0.001). Twelve patients (3.8%) were categorized as very D2T axSpA. Compared to nD2T, Very D2T patients had a higher CRP level at baseline (42.0±31.3 vs. 17.8±23.1; P=0.010). IBD prevalence at baseline was higher in the very D2T group (41.7 vs. 3.1%; P<0.001). None of the very D2T patients presented a fibromyalgia. ConclusionD2T axSpA was associated with higher disease activity, peripheral involvement, extra-musculoskeletal manifestations and fibromyalgia. Very D2T patients represented a minim proportion of patients after applying a more stringent definition including a temporal criterion of 2 years and might be independent from fibromyalgia.

Association of Bioimpedance Parameters with Increases in Blood Pressure during Hemodialysis.

Intradialytic hypertension, defined as an increase in BP from pre- to post-hemodialysis (HD), affects 5%-15% of patients receiving maintenance HD and is associated with cardiovascular and all-cause mortality. Hypervolemia is believed to be a major etiological factor, yet the association of more objective biomarkers of volume status with intradialytic hypertension is not well described. In a post hoc analysis of the Frequent Hemodialysis Network Daily Trial ( n =234), using data from baseline, 1-, 4-, and 12-month visits ( n =800), we used random-effects regression to assess the association of bioimpedance estimates of volume (vector length) with post-HD systolic BP (continuous) and any increase in systolic BP (categorical) from pre- to post-HD. We adjusted models for randomized group; age; sex; self-reported race; Quételet (body mass) index; vascular access; HD vintage; hypertension; history of heart failure; diabetes; residual kidney function (urea clearance); pre-HD systolic BP; ultrafiltration rate; serum-dialysate sodium gradient; and baseline values of hemoglobin, phosphate, and equilibrated Kt/V urea. The mean age of participants was 50±14 years, 39% were female, and 43% were Black. In adjusted models, shorter vector length (per 50 Ω/m) was associated with higher post-HD systolic BP (2.9 mm Hg; 95% confidence interval [CI], 1.6 to 4.3) and higher odds of intradialytic hypertension (odds ratio 1.66; 95% CI, 1.07 to 2.55). Similar patterns of association were noted with a more stringent definition of intradialytic hypertension (>10 mm Hg increase from pre- to post-HD systolic BP), where shorter vector length (per 50 Ω/m) was associated with a higher odds of intradialytic hypertension (odds ratio 2.17; 95% CI, 0.88 to 5.36). Shorter vector length, a bioimpedance-derived proxy of hypervolemia, was independently associated with higher post-HD systolic BP and risk of intradialytic hypertension.

Tazemetostat in Combination with R-CHOP in Patients with High-Risk, Frontline Follicular Lymphoma (Epi-RCHOP): A Phase II Study from the Lysa

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or with R/R FL who have no satisfactory alternative treatment options. We previously reported that the RP2D of TAZ in combination with R-CHOP was 800mg BID in the phase 1 part of Epi-RCHOP study (NCT02889523). Here, we report results of the phase 2 part evaluating TAZ with R-CHOP + rituximab maintenance in a cohort of previously untreated high-risk FL patients. Methods: patients were eligible if aged 18-80 years, had histologically confirmed FL grade 1-3A, high-risk FLIPI (score of 3-5) and were in need of treatment according to GELF criteria. Induction treatment consisted in 6 cycles of RCHOP every 21 days and TAZ 800mg BID every day, starting on day 2 of cycle 1, plus 2 additional 21 days cycles of rituximab+TAZ (cycle 7 and 8). Responses were assessed at end of induction (EOI), and responders then received maintenance 1 (TAZ 6 mo + rituximab 12 mo) and maintenance 2 (12 mo of rituximab alone).The primary efficacy endpoint was PET-based complete response rate based on local assessment at the end of induction or at permanent treatment discontinuation, as determined by Cheson IWG 2014 Lugano Classification (Deauville scale 1-3); in addition bone marrow biopsy (BMB) was mandatory at EOI if involved at baseline and complete metabolic response (CMR) patients with missing assessment at EOI classified as partial responders. Sample size calculation was made with the expectation of an increase of 13% in CR, with an H0 hypothesis of 67% and an H1 assumption of 80%, leading to a theorical sample size of 62 pts, assuming a drop out of 10%. Initial assumption was that CR rate should be &amp;gt;76.4% to consider the combination eligible for further clinical evaluation in high risk FL patients. Results: As of June 14, 2022, 62 patients were enrolled between Aug2020 and Apr2022 across 20 centers (including a drop-out of 12 patients, 70 were enrolled in France, 4 in Belgium). Disease characteristics included: males 61.3%, median age 64.5 years, FLIPI 3/4/5 in 61.3%/32.3%/6.5%, EZH2 mutated 17.3% (n=9/46 assessed had EZH2 mutation; 16 undertermined), BM involvement 68.3%, circulating FL cells in 21%, and increased LDH in 50%. Fifty eight (93%) patients completed induction and initiated maintenance 1, 44 (71%) initiated maintenance 2. Fourteen patients permanently discontinued treatment: 4 before EOI not related to PD (2 COVID19 disease, 1 late onset neutropenia and 1 stopped therapy but accepted FU), and 9 after EOI (5 PD, 2 COVID19 disease, 1 neutropenia, 1 paralytic ileus and 1 patient's refusal). At EOI, 79% (95%CI 66.8; 88.3%) achieved complete metabolic response (CMR) and 16.2% PMR for an overall metabolic response rate of 95.2%, however, according to the stringent protocol definition, 16 patients who achieved CMR had no BMB assessment at EOI and were downgraded to PR leading to 53.2% CR and 41.9% PR rate at EOI. Complete response rates were significantly higher in EZH2 mutants (8/9 CMR 88.9%) versus 17/37 (45.9%) in EZH2 wild-type (WT) patients (Fisher exact test p=0.027). Figure 1 shows the AEs reported by more than 10% of patients. The most common grade 3-4 TEAEs were neutropenia (53.2%, only 3.2% febrile), thrombocytopenia (17.7%), anemia (16.1%). Serious AEs occurred in 14 patients, the two most frequent being Covid19 disease (6.5%) and gastrointestinal hypomotility (6.5%). This latter AE was the most frequent non-hematologic event (40.3%), followed by peripheral neuropathy (35.5%). After amending vincristine dose (Oct2020), 30 digestive AEs were reported (16 related to TAZ, mostly grade 1-2, only 1 grade 3, no sequelae). No SPM was observed. With a median follow-up of 19 months, 7 relapses (5 EZH2 WT and 2 undetermined) including 5 needing subsequent treatment and 2 deaths occurred (1 Covid19 disease, 1 after PD). Median PFS and median DOR were not reached and appeared to be similar irrespective of EZH2 status, 18-months PFS and OS rates were 89.3% and 98.3% respectively. Conclusions: Although the primary endpoint was not met due to missing BM assessments, TAZ + RCHOP combination demonstrated a promising complete metabolic response rate of 79% in this high-risk frontline FL population, with a manageable safety profile, after vincristine dose was reduced.

Association between major histocompatibility complex haplotypes and susceptibility of unvaccinated and vaccinated cattle to paratuberculosis

Bovine Johne’s disease (BJD) or paratuberculosis is caused by Mycobacterium avium spp. paratuberculosis (MAP) and is a worldwide problem among domestic and wild ruminants. While vaccines are available, natural differences in background immunity between breeds within species and between individuals within herds suggest that genetic differences may be able to be exploited in marker-assisted selection as an aid to disease control. The major histocompatibility complex (MHC) is an important component in immune recognition with considerable genetic variability. In this study, associations between the MHC and resistance to BJD were explored in dairy cattle across two herds in which some of the cattle had been vaccinated with Silirum® (n = 540 cows). A BJD susceptible animal was exposed to MAP and became infected, while a resistant animal was exposed but did not become infected. There are different ways to define both exposure and infection, with different levels of stringency, therefore many classifications of the same set of animals are possible and were included in the analysis. The polymorphic regions of major histocompatibility complex class I (MHC I) and class II (MHC II) genes were amplified from the genomic DNA by PCR and sequenced, targeting exons 2 and 3 of the classical and non-classical MHC I genes and exon 2 from the DRB3, DQA1, DQA2 + 3 and DQB MHC II genes. The frequencies of MHC I and MHC II haplotypes and alleles were determined in susceptible and resistant populations. In unvaccinated animals, seven MHC I haplotypes and seven MHC II haplotypes were associated with susceptibility while two MHC I and six MHC II haplotypes were associated with resistance (P < 0.05). In vaccinated animals, two MHC I and three MHC II haplotypes were associated with susceptibility, while one MHC I and two MHC II haplotypes were associated with resistance (P < 0.05). The alleles in significant haplotypes were also identified. Case definitions with higher stringency resulted in fewer animals being included in the analyses, but the power to detect an association was not reduced and there was an increase in strength and consistency of associations. Consistent use of stringent case definitions is likely to improve agreement in future association studies.

Grey zones in respiratory cytology: Atypical or suspicious for malignancy and neoplasms of unknown malignant potential.

The purpose of pulmonary cytology is two-fold. First, to establish whether a pulmonary nodule is benign or malignant. Second, pulmonary cytology should classify the type of pathologic process present. When a pulmonary nodule is characterized as malignant, it is of high importance to further classify the malignancy as to type, with non-small cell carcinomas being sub-divided into adenocarcinomas, squamous cell carcinomas, and other types of non-small cell carcinoma. The World Health Organization Reporting System for Lung Cytopathology (WHORSLC) provides an important framework for reporting and classifying material obtained by cytologic techniques, including sputum analysis, bronchial brushings, bronchial washings, and fine-needle aspiration. The system contains five categories for specimen reporting. Clinicians prefer definitive diagnoses separating specimens into definitively benign or definitively malignant categories. The WHORSLC recognizes that it is not invariably possible for cytopathologists to separate specimens into definitively benign or definitively malignant categories. The five categories of the WHORSLC recognize the spectrum of cytologic changes running from clearly benign to clearly malignant, which cytopathologists must place into diagnostically useful and reproduceable categories. The intermediate categories of "atypical" and "suspicious for malignancy" provide structured categories with stringent definitions, estimated malignancy risks, and suggested management and follow-up recommendations. In this way, the categories "atypical" and "suspicious for malignancy" aid in maintaining the high diagnostic accuracy of the "benign" and "malignant" categories.

Characteristics Of Difficult-To-Treat Psoriatic Arthritis: A Comparative Analysis

ObjectiveThe EULAR task force recently published the difficult-to-treat rheumatoid arthritis (D2T RA) criteria, however, a definition of D2T patients in psoriatic arthritis (PsA) is still lacking. To date, we have little data concerning D2T PsA, especially in real-world. One of the limitations of the D2T RA EULAR definition is the absence of a temporal criterion. The primary endpoint of this work was to study the characteristics of D2T PsA patients using the EULAR definition. The second objective was to study a sub-group of patients with a predefined more stringent definition including a temporal criterion. MethodsA retrospective study was performed in a tertiary center. D2T PsA was defined as failure of ≥ 2 b/tsDMARDs with different mechanism of action. Very D2T PsA was defined as failure of ≥ 2 b/tsDMARDs in less than 2 years of follow-up. D2T and Very D2T PsA patients were compared to nD2T PsA patients using statistical tests. Results150 PsA patients were included (from 2004 to 2015): 49 D2T PsA and 101 nD2T PsA. D2T PsA was associated with a higher prevalence of axial involvement (p=0.030), axial and/or peripheral structural damage (p=0.007) at baseline and more bDMARDs discontinuation due to poor dermatological control (p=0.005). There was no significant difference regarding comorbidities such as obesity, smoking status, fibromyalgia or depression. In multivariate analysis, peripheral structural damage at baseline was found to be a predictive factor for D2T PsA with an OR of 2.57 (1.16 to 5.69; p=0.020).17 PsA (11.3%) patients were categorized as Very D2T PsA. When compared to nD2T group, proportion of obesity was higher (p=0.015) and axial involvement was more prevalent in the Very D2T group (p=0.020). ConclusionD2T PsA patients had a higher prevalence of axial involvement, peripheral structural damage and therapeutic discontinuation due to poor dermatological control whereas Very D2T PsA patients were more likely obese with axial involvement. Very D2T PsA represent a minim proportion among patients when applying a more stringent definition. Pending the PsA D2T definition by the European and American societies, this study highlights some characteristics that may help practitioners better identify D2T patients.

Polygenic risk scores of lithium response and treatment resistance in major depressive disorder

Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate the genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) and non-TRD within ~4500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores (PRS) of antidepressants and lithium response for individuals with MDD and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1778 ECT-treated MDD cases, nearly all (94%) used antidepressants before their first ECT and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We did not observe a significant difference in the mean PRS of antidepressant response between TRD and non-TRD; however, we found that TRD cases had a significantly higher PRS of lithium response compared to non-TRD cases (OR = 1.10–1.12 under various definitions). The results support the evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.