Mixed Phenotype Research Articles

Efficacy of the ABC Pathway for Integrated Care Across Phenotypes of Patients with Atrial Fibrillation: A Latent-Class Analysis Report from the mAFA-II Clinical Trial

Abstract Background The mAFA-II cluster randomised trial demonstrated the efficacy of a mobile health-technology implemented ‘Atrial fibrillation Better Care’ (ABC) pathway (mAFA intervention) for integrated care management of patients with AF. Objective To evaluate the effect of mAFA intervention across phenotypes of patients with AF. Design We conducted a latent-class analysis (LCA) according to eight variables, including age and comorbidities. Participants The mAFA-II trial enrolled AF patients between June 2018 and August 2019 across 40 centres in China. Main Measures We evaluated the interaction between the groups identified through LCA, and the effect of mAFA intervention on the risk of the primary composite outcome of all-cause death, stroke/thromboembolism, and rehospitalisations. Results were expressed as adjusted hazard ratio (aHR) and 95% confidence intervals (95% CI). Key Results Across the 3324 patients included in the trial (mean age 68.5 ± 13.9 years, 38.0% females), we identified three phenotypes: (i) low morbidity phenotype (n = 1234, 37.1%), (ii) hypertensive/coronary artery disease (CAD) phenotype (n = 1534, 46.2%), and (iii) mixed morbidity phenotype (n = 556, 16.7%). The effect of mAFA intervention on the primary outcome appeared greater in the low morbidity phenotype (aHR, 0.08; 95% CI 0.02–0.33) compared to the hypertensive/CAD (aHR, 0.30; 95% CI 0.16–0.58) and the mixed morbidity phenotype (aHR, 0.68; 95% CI 0.37–1.24), with a statistically significant interaction (pint = 0.004). Conclusions In patients with AF, the ABC pathway improved prognosis across different comorbidity phenotypes, although with some differences in the magnitude of risk reduction. Patients with more complex phenotypes require further efforts to improve their outcomes, considering their high baseline risk of adverse events. Trial Registration WHO International Clinical Trials Registry Platform (ICTRP) Registration number: ChiCTR-OOC-17014138.

Incidence and clinical characteristics of cardiac amyloidosis in Tuscany and Umbria

Abstract Background Recent advances in imaging and increased disease awareness have led to a significant rise in newly diagnosed cases of cardiac amyloidosis (CA) over the past decade. However, there remains a lack of epidemiological data regarding the true incidence of the disease. Purpose To determine the incidence and clinical characteristics of newly diagnosed cases of CA in a large Italian population. Methods Subjects with suspected CA underwent diagnostic work-up in 20 Centers in Tuscany and Umbria regions within the Cardiac Amyloidosis RegistRY (CARRY), between January 1st 2022 and December 31st 2022. Results A total of 551 subjects were enrolled in the registry, with complete data on the final diagnosis available for 448 individuals. CA was diagnosed in 179 patients (40%), with 28 (16%) classified as light chain CA (AL-CA), 114 (64%) wild-type transthyretin CA (ATTR-CA), 12 (7%) variant ATTR-CA, and 25 (13%) undetermined CA. Considering a reference population in Tuscany and Umbria in 2022 (4,518,388, according to the Italian National Institute of Statistics), this yields an estimated cumulative incidence of 39.6 cases per million inhabitants per year. Alternative diagnoses in the remaining patients mostly included hypertensive heart disease (n=157, 58%), hypertrophic cardiomyopathy (n=25, 9%), moderate-to-severe valvular heart disease (n=11, 4%), or a mixed phenotype (n=72, 27%). The primary referral pathway for the suspicion of CA was cardiological (n=345, 77%), followed by incidental finding during screening visits (n=58, 13%), and haematology referral (n=33, 7%). Patients with confirmed CA were older (81 [75-85] vs. 77 [72-83] years, p<0.001), and more frequently reported musculoskeletal red flags of CA, such as carpal tunnel syndrome (85 [48%] vs. 53 [20%] years, p<0.001), and spontaneous tendon rupture (39 [22%] vs. 18 [7%] years, p<0.001). Median time to diagnosis from clinical suspicion was 73 (37-140) days for CA and 84 (36-156) days for alternative diagnoses (p=0.564). Conclusions The diagnosis of CA is on the rise globally, with an estimated incidence of 39.6 new cases per million inhabitants per year in two large regions of Italy. These findings should inform policymakers in redefining the status of CA as a rare disease, potentially influencing patient care and treatment costs.

Clinical and genetic profiles of patients with hereditary and wild type transthyretin amyloidosis: the transthyretin cardiac amyloidosis registry in the state of Sao Paulo, Brazil REACT-SP

Abstract Introduction Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. Purpose We designed the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo (REACT-SP), aiming to describe the demographic, genetic, clinical, and diagnostic test results and treatment of patients with ATTR. Methods We present data on physical signs and symptoms, cardiac and neurological assessments, and genetics in patients enrolled in the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo, Brazil. Results Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Sixteen different mutations were detected, the most common being Val50Met (48.3%) and V142Ile (40.8%). Overall, more than half of the patients presented cardiological involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p<0.001). The neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p<0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between the forms of amyloidosis. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. The median time between the onset of symptoms and diagnosis was 1,853 (IQR 1277–2997) days, which was longer in ATTRv patients than in ATTRwt patients (p<0.001). Sinus rhythm was reported in 74.2%, atrial fibrillation in 17.0%, low voltage in 28.6%, repolarization abnormalities in 39.8%, and pseudo infarction in 27.4%. Echocardiography showed median Left Ventricular Ejection Fraction (LVEF) was 60%, Interventricular Septum (IVS) 14 mm, Posterior Wall Thickness (PWT) 13 mm, Left Atrium (LA) 41 mm, Left Ventricular Diastolic Diameter (LVDD) 45 mm, Left Ventricular Systolic Diameter (LVSD) 30 mm, basal Right Ventricular Diastolic Diameter (RVDD) 35 mm and Left Ventricle (LV) longitudinal strain 9.1%. There was some degree of LV diastolic dysfunction in 38.4%, apical sparing in 31.3%, and thrombus or masses in 1.0%. Late Gadolinium Enhancement (LGE) was absent in 29% and was subendocardial in 35.5%, transmural in 13.7%, mesocardial in 13.7%, and epicardial in 8.2%. Conclusions This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.

Long-term effects of patisiran on survival and cardiac parameters in patients with transthyretin-mediated cardiac amyloidosis: post hoc analysis of APOLLO-B and cardiac subpopulation of APOLLO OLE

Abstract Introduction Transthyretin-mediated (ATTR) amyloidosis is a progressive, fatal disease in which the most serious manifestations are polyneuropathy and cardiomyopathy. Patients with hereditary ATTR (ATTRv; v for variant) amyloidosis commonly develop a mixed phenotype, and patients with wild-type ATTR amyloidosis predominantly have cardiomyopathy, although polyneuropathy may coexist. Patisiran, an RNAi therapeutic that rapidly knocks down TTR, has shown long-term benefit on measures of polyneuropathy in the APOLLO open-label extension (OLE) study in patients with ATTRv amyloidosis. Purpose To evaluate the long-term benefit of patisiran on survival, hospitalisations and cardiac parameters in a pooled cohort of patients with ATTR amyloidosis and evidence of cardiac involvement, across the patisiran clinical programme (Phase [Ph] 2 launched in 2012). Methods Post hoc analysis of pooled data from cardiac subpopulations of patients with ATTRv amyloidosis and polyneuropathy from 5-year Global OLE (Ph 2 OLE and Ph 3 APOLLO; patients with baseline left ventricular [LV] wall thickness ≥13 mm; absence of history of aortic valve disease or hypertension), and Ph 3 APOLLO-B (patients with wild-type or ATTRv cardiac amyloidosis). Patients received patisiran or placebo every 3 weeks for 18 months in APOLLO and 12 months in APOLLO-B; all patients received patisiran thereafter. Analyses included Kaplan-Meier estimates and Cox regression of survival and all-cause hospitalisations, and summary statistics of cardiac biomarkers and echocardiographic parameters by initial treatment arm. Results Pooled analysis included 496 patients (initial arm placebo, n=214; initial arm patisiran, n=282). Compared with placebo, patients initially receiving patisiran had better long-term survival and fewer hospitalisations (hazard ratio [95% confidence interval] over 84 months for all-cause mortality and all-cause hospitalisations: 0.59 [0.37–0.93] [Figure 1] and 0.77 [0.60–0.99], respectively). At baseline, NT-proBNP and troponin I levels, peak longitudinal strain and LV wall thickness were comparable between patisiran vs placebo-treated patients. Placebo-treated patients showed worsening of all these parameters whilst on placebo; the rates of worsening decreased once the patients initiated patisiran. In contrast, patients who initially received patisiran demonstrated relative stability over 84 months in the Global OLE and significant benefit compared with those initially treated with placebo. Conclusion Long-term benefit of patisiran in patients with cardiomyopathy was observed on survival, hospitalisations, cardiac biomarkers and echocardiographic parameters. Outcomes were significantly more favourable for those initially randomised to patisiran than placebo, highlighting the impact of initiating treatment early in the course of disease.

Hereditary Transthyretin Amyloidosis Polyneuropathy.

In the last decade, we have witnessed dramatic improvements in the diagnosis, workup, management, and monitoring of patients with hereditary transthyretin amyloidosis (ATTRv). Updated imaging techniques (e.g., 99mTc-PYP scan) are increasingly being used in place of tissue biopsies for confirmation of disease. Novel treatments now include antisense oligonucleotide and RNA interference drugs, whereas new applications such as CRISPR and amyloid antibodies are being studied for potential use in the future. These treatments have dramatically improved quality of life and increased survival in patients with ATTRv. Despite these breakthroughs, many challenges remain. Some of these challenges include early recognition and diagnosis of ATTRv, monitoring and initiation of treatment in asymptomatic or paucisymptomatic carriers, adequate treatment in people with mixed phenotype (i.e., cardiac and neurological), and the emergence of new phenotypes in people living longer with the disease (i.e., central nervous system and ocular complications). Research in those areas of deficit is ongoing, and in the future, we may have preventive therapies, better biomarkers, more efficient therapies for organs that we cannot currently target, and enhanced diagnostic techniques with the help of novel imaging techniques and artificial intelligence. In this review, we will summarize the current knowledge about polyneuropathy related to ATTRv and its management, discuss methods to improve early diagnosis and monitoring, and discuss emerging trends.

Arrhythmias May Hide a Genetic Cardiomyopathy in Left Ventricular Hypertrabeculation in Children: A Single-Center Experience.

Left ventricular hypertrabeculation (LVHT) is a myocardial disorder with different clinical manifestations, from total absence of symptoms to heart failure, arrhythmias, sudden cardiac death (SCD), and thromboembolic events. It is challenging to distinguish between the benign and pathological forms of LVHT. The aim of this study was to describe the arrhythmic manifestations of LVHT in a large group of pediatric patients and to correlate them with genetic results or other clinical markers. We retrospectively enrolled 140 pediatric patients with diagnosis of LVHT followed at our Institution from 2013 to 2023. Data regarding family history, instrumental exams, cardiac magnetic resonance, genetic testing and outcomes were collected. Most of them had isolated LVHT (80.7%); in other patients, mixed phenotypes (hypertrophic or dilated cardiomyopathy or congenital heart disease) were present. Arrhythmias were found in 33 children (23.6%): 13 (9.3%) supraventricular tachyarrhythmias; 14 (10%) ventricular arrhythmias (five frequent PVCs (premature ventricular contractions), eight patients with ventricular tachycardia (VT), one ventricular fibrillation (VF)); two (1.4%) sinus node disfunctions; two (1.4%) complete atrio-ventricular blocks (AVB), three (2.1%) paroxysmal complete AVB, one (0.7%) severe I degree AVB. Three patients received an ICD (implantable cardioverter defibrillator). Comparison between LVHT patients with (33 pts) and without (107 pts) arrhythmias as regards genetic testing showed a statistical significance for the presence of class 4 or 5 genetic variants and arrhythmic manifestation (p = 0.037). In our pediatric cohort with LVHT, good outcomes were observed, but arrhythmias were not so rare (23.6%); no SCD occurred.

9390 Does Znt8a Have An Association With The Duration Of Diabetes? Case Series And Literature Review

Abstract Disclosure: N.M. Rivera Vargas: None. C.S. Botero Suarez: None. S.K. Suryanarayanan: None. S. Saad-Omer: None. Context: Latent autoimmune Diabetes of adults (LADA) is a form of autoimmune diabetes with features of Type 2 Diabetes but positive autoantibodies resembling Type 1 Diabetes. Latent autoimmune diabetes in adults (LADA), has a mixed phenotype with positive islet-cell antibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), protein tyrosine phosphatase autoantibodies (IA2A), insulin autoantibodies (IAA), or zinc transporter-8 autoantibodies (ZnT8A). Since the discovery of ZnT8A, the relevance and clinical utility of this marker has sparked interest. Although ZnT8A is used as a complementary diagnostic aid in children, its utility in adults seems to be unclear. Objective: We report a case series of 26 subjects referred to the Orlando VA Endocrine clinic with measured ZnT8A. We hypothesize that higher ZnT8A will be found in adult autoimmune diabetes with newly diagnosed diabetes rather than those with a longer duration of diabetes. We also explore the association between ZnT8A and family history, duration of diabetes, diabetes complications, and C-peptide levels. Method: A case series of 26 adult patients with diabetes mellitus with a positive ZnT8A (≥15 U/mL). We reviewed medical records of these cases to include ZnT8A levels, years of diabetes diagnosis, C-peptide levels, and diabetes complications. Patients were classified into subgroups based on ZnT8A levels into < 350 U/mL or ≥ 350 U/mL. Results: The 26 patients reviewed had a mean (SD) age of 46 (13) years. The mean (SD) duration of diabetes was 16 (12) years, and HbA1C was 8.4 (1.1) %. Poisson regression analysis showed a statistically significant inverse relationship between ZnT8A and years of diabetes (regression coefficient: -0.028; 95% confidence interval: -0.03 to -0.25; p-value <0.001). Diabetic ketoacidosis was present in 35% of subjects, while diabetic neuropathy was noted in 58% of subjects with positive ZnT8A. Patients with a high ZnT8Ab above 350 U/mL displayed a weak trend towards a lower C-peptide mean (p-value 0.42), and lower prevalence of DKA (p-value 0.42) which was not statistically significant. Conclusion: In this case series of patients with adult-onset diabetes, there seems to be a statistically significant inverse relationship between ZnT8A levels and duration of diabetes suggesting a reduction of ZnT8A levels over time. Although limited by a small number of subjects, this may suggest the need for screening with autoantibodies in the setting of diabetes earlier in the disease process. Presentation: 6/2/2024

Hematopoietic stem cell transplantation activity in China 2022-2023. The proportions of peripheral blood for stem cell source continue to grow: a report from the Chinese Blood and Marrow Transplantation Registry Group.

Over past two years, a total of 39,918 hematopoietic stem cell transplantation (HSCT) cases were reported, with 18,194 and 21,714 transplants performed in 2022 and 2023, respectively. Autologous HSCT accounted for 6562 cases (31%) in 2022, while allogeneic HSCT comprised 12,632 cases (69%). In 2023, the number of allogeneic HSCTs exceeded 15,000, maintaining a 69% share. Participation in the 2022 and 2023 surveys included 193 and 212 transplantation teams, respectively, from 27 provinces, municipalities, or autonomous regions. The leading indication of HSCT was acute leukemia, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed phenotype acute leukemia, with a total of 17,421 cases. AML was the most common disease (10,339, 38%) for allogeneic HSCT, which was followed by ALL (5925 cases, 21%). Peripheral blood emerged as the primary source of stem cell grafts, utilized in 54% of matched sibling donor transplants and 77% of haploidentical donor transplants. The BuCy-based conditioning regimen was the most prevalent, used in 53% of allogeneic HSCT cases in the past two years. This survey offers a comprehensive overview of the current HSCT landscape and serves as a valuable resource for clinical practice.

Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia

Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.

Basophil activation test is a complementary tool in the diagnosis of immediate reactions to platinum salts and taxanes.

Delabelling pathways offer confirmatory diagnosis and can prevent unnecessary second-line therapies or drug desensitization procedures after chemotherapeutic hypersensitivity reactions (CHT-HSRs). However, these pathways rely on risky invivo tests. Data on whether invitro tests could be helpful are scarce. We assessed the role of basophil activation test (BAT) in the diagnosis of HSRs to platin salts (PSs) and taxanes (TXs) in a well-defined population featuring varied endophenotypes and severities of HSRs. We conducted a 3-year-long multicentric, prospective study with 121 suspected-immediate CHT-HSR patients. The allergy workup included clinical history (initial reaction based on Type I, cytokine release syndrome, and mixed phenotype's symptoms and if unable to fit in any of these, as "indeterminate"), skin testing (ST), and drug provocation testing (DPT), provided risk assessment was favorable. Final diagnosis classified patients as "hypersensitive," "non-hypersensitive," or "inconclusive." We performed BAT using CD63 and CD203c as activation markers in patients and controls. Patients underwent DPT regardless of BAT results to prevent bias. ST positivity significantly correlated with skin involvement, Type I phenotype, cancer recurrence, and lifetime exposures before reactions. DPTs were negative in all indeterminate phenotype patients (p = .02) and those considered low-risk, whereas they were negative in 62% moderate-risk patients. 55% were confirmed as hypersensitive (mainly Type I reactions, p < .0001), 24% as non-hypersensitive (mainly TXs and indeterminate phenotypes), and 21% as inconclusive. BAT showed 79% sensitivity in Type I IgE-mediated reactions to PSs with a high correlation to ST. BAT is a promising tool for delabelling and endotyping CHT-HSRs, especially Type I reactions to PSs, possibly identifying patients at risk of positive DPT. ST seems useful in confirming CHT-HSRs, especially PS-induced reactions, and DPT remains the gold standard, being essential even in moderate-risk patients.

Detection of tumour heterogeneity in patients with advanced, metastatic castration-resistant prostate cancer on [68Ga]Ga-/[18F]F-PSMA-11/-1007, [68Ga]Ga-FAPI-46 and 2-[18F]FDG PET/CT: a pilot study.

In metastatic castration-resistant prostate cancer (mCRPC), some patients show low/absent PSMA expression in tumour lesions on positron emission tomography (PET) scans, indicating heterogeneity and heightened risk of non-response to PSMA-RLT (radioligand therapy). Imaging cancer-associated fibroblasts and glucose uptake may further characterise tumour heterogeneity in mCRPC patients. Here, we aimed to evaluate tumour heterogeneity and its potential implications for management in mCRPC patients assessed for PSMA-RLT using [68Ga]Ga-FAPI-46, 2-[18F]FDG and [68Ga]Ga-/[18F]F-PSMA-11/-1007 PET. Patients with advanced, progressive mCRPC underwent clinical [68Ga]Ga-/[18F]F-PSMA-11/-1007, 2-[18F]FDG and [68Ga]Ga-FAPI-46 PET/CT to evaluate treatment with PSMA-directed RLT. Tumour detection/semiquantitative parameters were compared on a per-lesion/-region basis. Two phenotypes were defined: Criteria for the mixed phenotype were: (a) PSMA-negative findings for lymph node metastases ≥ 2.5cm, any solid organ metastases ≥ 1.0cm, or bone metastases with soft tissue component ≥ 1.0cm, (b) low [68Ga]Ga-/[18F]F-PSMA-11/-1007 uptake and/or (c) balanced tumour uptake of all radioligands. The PSMA-dominant phenotype was assigned if the criteria were not met. In ten patients, 472 lesions were detected on all imaging modalities (miTNM regions: M1b: 327 (69.3%), M1a: 95 (20.1%), N1: 26 (5.5%), M1c: 18 (3.8%), T: 5 (1.1%) and Tr: 1 (0.2%). [68Ga]Ga-/[18F]F-PSMA-11/-1007 (n = 453 (96.0%)) demonstrates the highest detection rate, followed by [68Ga]Ga-FAPI-46 (n = 268 (56.8%))/2-[18F]FDG (n = 241 (51.1%)). Semiquantitative uptake was highest for [68Ga]Ga-/[18F]F-PSMA-11/-1007 (mean SUVmax (interquartile range): 22.7 (22.5), vs. [68Ga]Ga-FAPI-46 (7.7 (3.7)) and 2-[18F]FDG (6.8 (4.7)). Seven/three patients were retrospectively assigned to the PSMA-dominant/mixed phenotype. Median overall survival was significantly longer for patients who underwent [177Lu]Lu-PSMA-617 RLT and were retrospectively assigned to the PSMA-dominant phenotype (19.7 vs. 9.3months). Through whole-body imaging, we identify considerable inter- and intra-patient heterogeneity of mCRPC and potential imaging phenotypes. Regarding uptake and tumour detection, [68Ga]Ga-/[18F]F-PSMA-11/-1007 was superior to [68Ga]Ga-FAPI-46 and 2-[18F]FDG, while the latter two were comparable. Patients who underwent [177Lu]Lu-PSMA-617 RLT based on clinical-decision making had a longer overall survival and could be assigned to the PSMA-dominant phenotype.

In mouse model of mixed granulocytic asthma with corticosteroid refractoriness, Bronchom mitigates airway hyperresponsiveness, inflammation and airway remodeling

BackgroundAsthma is a heterogeneous, inflammatory disease with several phenotypes and endotypes. Severe asthmatics often exhibit mixed granulocytosis with reduced corticosteroid sensitivity. Bronchom is a newly developed Ayurvedic prescription medicine, indicated for the treatment of obstructive airway disorders. The purpose of the present study was to evaluate the in-vivo efficacy of Bronchom in mouse model of mixed granulocytic asthma with steroidal recalcitrance.MethodsHigh-performance thin layer chromatography (HPTLC) and Ultra-high performance liquid chromatography (UHPLC) were employed to identify and quantitate the phytometabolites present in Bronchom. The preclinical effectiveness of Bronchom was assessed in house dust mite (HDM) and Complete Freund’s adjuvant (CFA)-induced mixed granulocytic asthma model in mice. High dose of dexamethasone was tested parallelly. Specific-pathogen-free C57BL/6 mice were immunized with HDM and CFA and nineteen days later, they were intranasally challenged with HDM for four consecutive days. Then the mice were challenged with nebulized methacholine to evaluate airway hyperresponsiveness (AHR). Inflammatory cell influx was enumerated in the bronchoalveolar lavage fluid (BALF) followed by lung histology. Additionally, the concentrations of Th2 and pro-inflammatory cytokines was assessed in the BALF by multiplexed immune assay. The mRNA expression of pro-inflammatory cytokines and Mucin 5AC (MUC5AC) was also evaluated in the lung.ResultsHPTLC fingerprinting and UHPLC quantification of Bronchom revealed the presence of bioactive phytometabolites, namely, rosmarinic acid, gallic acid, methyl gallate, piperine, eugenol and glycyrrhizin. Bronchom effectively reduced AHR driven by HDM-CFA and the influx of total leukocytes, eosinophils and neutrophils in the BALF. In addition, Bronchom inhibited the infiltration of inflammatory cells in the lung as well as goblet cell metaplasia. Further, it also suppressed the elevated levels of Th2 cytokines and pro-inflammatory cytokines in the BALF. Similarly, Bronchom also regulated the mRNA expression of pro-inflammatory cytokines as well as MUC5AC in mice lungs. Reduced effectiveness of a high dose of the steroid, dexamethasone was observed in the model.ConclusionsWe have demonstrated for the first time the robust pharmacological effects of an herbo-mineral medicine in an animal model of mixed granulocytic asthma induced by HDM and CFA. The outcomes suggest the potential utility of Bronchom in severe asthmatics with a mixed granulocytic phenotype.

Genetic evidence for predisposition to acute leukemias due to a missense mutation (p.Ser518Arg) in ZAP70 kinase: a case-control study

BackgroundThe apparent lack of additional missense mutations data on mixed-phenotype leukemia is noteworthy. Single amino acid substitution by these non-synonymous single nucleotide variations can be related to many pathological conditions and may influence susceptibility to disease. This case-control study aimed to unravel whether the ZAP70 missense variant (rs104893674 (C > A)) underpinning mixed-phenotype leukemia.MethodsThe rs104893674 was genotyped in clients who were mixed-phenotype acute leukemia-, acute lymphoblastic leukemia- and acute myeloid leukemia-positive and matched healthy controls, which have been referred to all major urban hospitals from multiple provinces of country- wide, IRAN, from February 11’ 2019 to June 10’ 2023, by amplification refractory mutation system-polymerase chain reaction method. Direct sequencing for rs104893674 of the ZAP70 gene was performed in a 3130 Genetic Analyzer.ResultsWe found that the AC genotype of individuals with A allele at this polymorphic site (heterozygous variant-type) contribute to the genetic susceptibility to acute leukemia of both forms, acute myeloid leukemia and acute lymphoblastic leukemia as well as with a mixed phenotype. In other words, the ZAP70 missense variant (rs104893674 (C > A)) increases susceptibility of distinct cell populations of different (myeloid and lymphoid) lineages to exhibiting cancer phenotype. The results were all consistent with genotype data obtained using a direct DNA sequencing technique.ConclusionOf special interest are pathogenic missense mutations, since they generate variants that cause specific molecular phenotypes through protein destabilization. Overall, we discovered that the rs104893674 (C > A) variant chance in causing mixed-phenotype leukemia is relatively high.

Comparison of clinical and serological features in thrombotic antiphospholipid syndrome patients, with and without associated systemic lupus erythematosus, followed for up to 42 years: A single centre retrospective study.

To assess the impact of concomitant systemic lupus erythematosus (SLE) on the clinicopathological manifestations of thrombotic antiphospholipid syndrome (APS). This single-centre, retrospective study compared clinical and antiphospholipid antibody (aPL) data from 118 patients, 58 with SLE-associated APS (SLE-APS), and 60 with primary APS. Median follow-up was 13.9 (IQR 7.7-19.3) and 8.6years (3.5-10.6) for the SLE-APS cohort and PAPS cohort, respectively. Age at diagnosis of APS was lower in the SLE-APS cohort (mean 35.9 vs PAPS: 46.7years; p < 0.05). Distribution of aPL subtypes was similar across cohorts. 198 thrombotic events were identified overall (index plus recurrent), with venous thromboembolism (VTE) and arterial thrombosis each occurring in just over half of patients in both cohorts. Microvascular thrombosis (12.1% vs 0%), and a mixed (any combination of venous, arterial and microvascular) thrombotic phenotype (19.0% vs 6.7%, p = 0.05) were more prevalent in SLE-APS patients. Recurrent thrombosis incidence rates (∼0.5 events/10-patient years), and Kaplan-Meier recurrence-free survival after index thrombosis, were similar. In the PAPS cohort, only: (i) triple-aPL-positivity was associated with a significantly higher recurrent thrombosis event rate (incidence rate ratio 2.22, p = 0.03) and lower recurrence-free survival after first thrombosis (log-rank test p = 0.01); (ii) lupus anticoagulant (LA)-positivity was associated with higher prevalance of arterial thrombosis (RR 2.69, p = 0.01), and lower prevlance of VTE (RR 0.48, p < 0.001), versus LA-negativity. Concomitant SLE does not appear to modify long-term recurrent thrombosis risk, or aPL phenotypes, in patients with APS. Triple-aPL-positivity and LA-positive status may have less influence on thrombotic outcomes in patients with SLE-APS compared to PAPS.

Disparities in Acute Lymphocytic Leukemia Outcomes Among Young Adults.

Age is a strong prognostic factor in acute lymphocytic leukemia (ALL), with children doing better than adults with the same disease. One hypothesis for this age-based disparity is differences in treatment regimens. Optimizing care for adolescents and young adults (AYA) with ALL has not been well defined and disparities in care exist. We conducted a retrospective study of all veterans with ALL diagnosed between the ages of 18 and 45 since the year 2000 to evaluate disparities among prognostication methods, treatment regimens, and accrual to clinical trials with regard to age and race/ethnicity and how these factors influence overall survival. Electronic medical record data from the VA Informatics and Computing Infrastructure (VINCI) were used to identify 6,724 patients with an ICD-9 or 10 code for ALL. All patients were chart checked to confirm an ALL diagnosis between the ages of 18 and 45 and excluded if they were diagnosed before 2000, had childhood ALL, or if induction protocol was not recorded. A total of 252 patients were included in the final analysis. Multivariate analysis was performed with controls for age, ALL subtype (B, T, mixed phenotype), Ph status, cytogenetic risk (based on modified Medical Research Council-Eastern Cooperative Oncology Group (MRC-ECOG) study), obesity (body mass index (BMI) > 30), and race. Patients treated with pediatric regimens, including pediatric-inspired regimens, have statistically significant (P = 0.009) survival gains, with a hazard ratio (HR) of 0.52 after controlling for age, obesity, ALL subtype, cytogenetic risk and race. White patients had significantly improved OS compared to people of color (HR 0.57, P = 0.02) after controlling for the aforementioned covariates. Black patients were far less likely (23%) to receive a transplant than non-Black patients (46%). Only 7% of patients were treated on a clinical trial. These data demonstrate that treatment with a pediatric regimen significantly improves overall survival in patients up to the age of 45 and suggests ongoing shortcomings in treatment for young adults with ALL, especially 30 to 45 years old, including persistently high use of adult induction regimens, low rates of referral to clinical trials, and significant racial disparities in bone marrow transplants for Black patients.

Association of blood inflammatory phenotypes and asthma burden in children with moderate-to-severe asthma

BackgroundUnderlying immunological mechanisms in children with moderate-to-severe asthma are complex and unclear. We aimed to investigate the association between blood inflammatory parameters and asthma burden in children with moderate-to-severe asthma.MethodsBlood inflammatory parameters (eosinophil(E) and neutrophil(N) counts and inflammatory mediators using multiplex immunoassay technology) were measured in children (6–17 years) with moderate-to-severe asthma from SysPharmPediA cohort across four European countries. Based upon low(L)/high(H) blood(B) eosinophil (LBE/HBE: &lt;/≥0.3×109/L, respectively) and neutrophil counts (LBN/HBN: &lt;/≥4×109/L, respectively), mixed(HBE-HBN), eosinophilic(HBE-LBN), neutrophilic(LBE-HBN), and paucigranulocytic(LBE-LBN) phenotypes were defined. Inflammatory mediator profiles and burden of disease (asthma control status, exacerbations and school days missed in the past year) were compared between phenotypes using adjusted logistic regression models.ResultsAmong 126 included children (41% girls and mean(sd) age of 11.94(2.76)), 22%, 44%, 11%, and 23% were classified as mixed, eosinophilic, neutrophilic, and paucigranulocytic phenotypes respectively. Neutrophilic children had lowest lung function (FEV1%predicted pre-salbutamol) compared to other groups. Children with mixed asthma were most often uncontrolled and had highest asthma-related school absence in the past year. Interleukin-6(IL-6) and matrix metalloproteinase-9(MMP-9) levels were significantly higher in patients with mixed or neutrophilic asthma, while tissue inhibitor of metalloproteinase-2(TIMP-2) was lower in patients with neutrophilic asthma compared to eosinophilic or paucigranulocytic asthma. Interleukin-5(IL-5) was increased in eosinophilic group compared to neutrophilic and paucigranulocytic groups, irrespective of the chosen cut-off for eosinophilia.ConclusionDifferences in asthma burden-related clinical expression and distinct blood inflammatory mediator profiles were found between phenotypes, highlighting implications for optimizing personalized treatment and management strategies in children with moderate-to-severe asthma.

Clinical outcomes and phenotypes of respiratory failure in older subjects admitted to an acute care geriatric hospital ward.

Respiratory failure (RF) is frequent in hospitalized older patients, but was never systematically investigated in large populations of older hospitalized patients. We conducted a retrospective administrative study based on hospitalizations of a Geriatrics Unit regarding 2014, 2015, and 2016. Patients underwent daily screening for hypoxia. Hospital discharge records were coded through a standardized methodology. RF, defined as documented hypoxia on room air, was always coded, whenever present. We investigated how RF affected clinical outcomes, whether RF grouped into specific comorbidity phenotypes, and how phenotypes associated with the outcomes. RF was coded in 48.6% of the 1,810 hospitalizations. RF patients were older and more frequently had congestive heart failure (CHF: 49 vs 23%), chronic obstructive pulmonary disease (COPD: 27 vs 6%), pneumonia (14 vs 4%), sepsis (12 vs 7%), and pleural effusion (6 vs 3%), than non-RF patients. RF predicted longer length of stay (a-Beta 2.05, 95% CI 1.4-2.69; p < 0.001) and higher in-hospital death/intensive care units (ICU) need (aRR 7.12, 5-10.15; p < 0.001) after adjustment for confounders (linear and Poisson regression with robust error variance). Among RF patients, cerebrovascular disease, cancer, electrolyte disturbances, sepsis, and non-invasive ventilation predicted increased, while CHF and COPD predicted decreased in-hospital death/ICU need. The ONCO (cancer) and Mixed (cerebrovascular disease, dementia, pneumonia, sepsis, electrolyte disturbances, bedsores) phenotypes displayed higher in-hospital death/ICU need than CARDIO (CHF) and COPD phenotypes. In this study, RF predicted increased hospital death/ICU need and longer hospital stay, but also reflected diverse underlying conditions and clinical phenotypes that accounted for different clinical courses.

Integrating mechanistic-based and classification-based concepts into perioperative pain management: an educational guide for acute pain physicians

Chronic pain begins with acute pain. Physicians tend to classify pain by duration (acute vs chronic) and mechanism (nociceptive, neuropathic and nociplastic). Although this taxonomy may facilitate diagnosis and documentation,...

Clinical and molecular insights into A97S variants in hereditary transthyretin amyloid polyneuropathy in South China

Objective This study aims to delineate the clinical profiles of the hereditary transthyretin amyloid polyneuropathy (ATTRv-PN) patients with A97S variant from southern China and the molecular characteristics of this mutant protein. Methods Fifteen ATTRv-PN patients with heterozygous A97S and one patient with homozygous A97S were included in the study. Serum TTR tetramer concentration was quantified through ultra-performance liquid chromatography. Stabilities of A97S-TTR were assessed through in vitro urea-mediated tryptophan fluorescence experiments, and nephelometry was employed in drug response assessment. Results All patients were late-onset (≥50 years) with a mean age of onset at 59.26 ± 5.06 years old. Patients displayed a mixed phenotype featuring sensory-motor neuropathy with autonomic dysfunction and cardiac involvement, such as palpitations and chest pain. Electrophysiological studies showed generally axonal impairment of sensory and motor nerves. Tafamidis-treated patients showed significantly higher TTR tetramer concentrations, approaching healthy controls’ levels. In vitro assessment showed that A97S-TTR was more kinetically stable than the V122I-TTR, and tetramer stabilisers inhibited A97S-TTR amyloid formation by more than 70%. Conclusion This study provides valuable insights into the clinical and molecular characteristics of ATTRv-PN patients with A97S from South China, particularly regarding the differences in disease progression and stability features.

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found unique structural variabilities in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structure’s impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies.