Prognostic Value of a 6-Minute Walk Test in Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: The 6-minute walk test (6MWT) represents a comprehensive functional assessment that is commonly used in patients with heart failure; however, data are lacking in patients with transthyretin cardiac amyloidosis (ATTR-CA). OBJECTIVES: This study aimed to assess the prognostic importance of the 6MWT in patients with ATTR-CA. METHODS: A retrospective analysis of patients diagnosed with ATTR-CA at the National Amyloidosis Centre who underwent a baseline 6MWT between 2011 and 2023 identified 2,141 patients, of whom 1,118 had follow-up at 1 year. RESULTS: The median baseline 6MWT distance was 347 m (Q1-Q3: 250-428 m) and analysis by quartiles demonstrated an increased death rate with each distance reduction (deaths per 100 person-years: 6.3 vs 9.2 vs 13.6 vs 19.0; log-rank P < 0.001). A 6MWT distance of <350 m was associated with a 2.2-fold higher risk of mortality (HR: 2.15; 95% CI: 1.85-2.50; P < 0.001), with a similar increased risk across National Amyloidosis Centre disease stages (P for interaction = 0.761) and genotypes (P for interaction = 0.172). An absolute (reduction of >35 m) and relative worsening (reduction of >5%) of 6MWT at 1 year was associated with an increased risk of mortality (HR: 1.80; 95% CI: 1.51-2.15; P < 0.001 and HR: 1.89; 95% CI: 1.59-2.24; P < 0.001, respectively), which was similar across the aforementioned subgroups. When combined with established measures of disease progression (N-terminal pro-B-type natriuretic peptide progression and outpatient diuretic intensification), each incremental increase in progression markers was associated with an increased death rate (deaths per 100 person-years: 7.6 vs 13.9 vs 22.4 vs 32.9; log-rank P < 0.001). CONCLUSIONS: The baseline 6MWT distance can refine risk stratification beyond traditional prognosticators. A worsening 6MWT distance can stratify disease progression and, when combined with established markers, identifies patients at the highest risk of mortality.

Toward robust and privacy-enhanced facial recognition: A decentralized blockchain-based approach with GANs and deep learning.

In recent years, the extensive use of facial recognition technology has raised concerns about data privacy and security for various applications, such as improving security and streamlining attendance systems and smartphone access. In this study, a blockchain-based decentralized facial recognition system (DFRS) that has been designed to overcome the complexities of technology. The DFRS takes a trailblazing approach, focusing on finding a critical balance between the benefits of facial recognition and the protection of individuals' private rights in an era of increasing monitoring. First, the facial traits are segmented into separate clusters which are maintained by the specialized node that maintains the data privacy and security. After that, the data obfuscation is done by using generative adversarial networks. To ensure the security and authenticity of the data, the facial data is encoded and stored in the blockchain. The proposed system achieves significant results on the CelebA dataset, which shows the effectiveness of the proposed approach. The proposed model has demonstrated enhanced efficacy over existing methods, attaining 99.80% accuracy on the dataset. The study's results emphasize the system's efficacy, especially in biometrics and privacy-focused applications, demonstrating outstanding precision and efficiency during its implementation. This research provides a complete and novel solution for secure facial recognition and data security for privacy protection.

Stratifying Disease Progression in Patients With Cardiac ATTR Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive cardiomyopathy. The clinical course varies among individuals and there are no established measures to assess disease progression. OBJECTIVES: The goal of this study was to assess the prognostic importance of an increase in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outpatient diuretic intensification (ODI) as markers of disease progression in a large cohort of patients with ATTR-CA. METHODS: We evaluated landmark survival analysis based on worsening of NT-proBNP and requirement for ODI between time of diagnosis and a 1-year visit, and subsequent mortality in 2,275 patients with ATTR-CA from 7 specialist centers. The variables were developed in the National Amyloidosis Centre (NAC) cohort (n = 1,598) and validated in the external cohort from the remaining centers (n = 677). RESULTS: Between baseline and 1-year visits, 551 (34.5%) NAC patients and 204 (30.1%) patients in the external validation cohort experienced NT-proBNP progression (NT-proBNP increase >700 ng/L and >30%), which was associated with mortality (NAC cohort: HR: 1.82; 95% CI: 1.57-2.10; P < 0.001; validation cohort: HR: 1.75; 95% CI: 1.32-2.33; P < 0.001). At 1 year, 451 (28.2%) NAC patients and 301 (44.5%) patients in the external validation cohort experienced ODI, which was associated with mortality (NAC cohort: HR: 1.88; 95% CI: 1.62-2.18; P < 0.001; validation cohort: HR: 2.05; 95% CI: 1.53-2.74; P < 0.001). When compared with patients with a stable NT-proBNP and stable diuretic dose, a higher risk of mortality was observed in those experiencing either NT-proBNP progression or ODI (NAC cohort: HR: 1.93; 95% CI: 1.65-2.27; P < 0.001; validation cohort: HR: 1.94; 95% CI: 1.36-2.77; P < 0.001), and those experiencing both NT-proBNP progression and ODI (NAC cohort: HR: 2.98; 95% CI: 2.42-3.67; P < 0.001; validation cohort: HR: 3.23; 95% CI: 2.17-4.79; P < 0.001). CONCLUSIONS: NT-proBNP progression and ODI are frequent and consistently associated with an increased risk of mortality. Combining both variables produces a simple, universally applicable model that detects disease progression in ATTR-CA.

Ratiometric Fluorescence and Chromogenic Probe for Trace Detection of Selected Transition Metals.

The design and development of a fluorescence sensor aimed at detecting and quantifying trace amounts of toxic transition metal ions within environmental, biological, and aquatic samples has garnered significant attention from diagnostic and testing laboratories, driven by the imperative to mitigate the health risks associated with these contaminants. In this context, we present the utilization of a heterocyclic symmetrical Schiff Base derivative for the purpose of fluorogenic and chromogenic detection of Co2+, Cu2+ and Hg2+ ions. The characterization of the ligand involved a comprehensive array of techniques, including physical assessments, optical analyses, NMR, FT-IR, and mass spectrometric examinations. The mechanism of ligand-metal complexation was elucidated through the utilization of photophysical parameters and FT-IR spectroscopic analysis, both before and after the interaction between the ligand and the metal salt solution. The pronounced alterations observed in absorption and fluorescence spectra, along with the distinctive chromogenic changes, following treatment with Co2+, Cu2+ and Hg2+, affirm the successful formation of complexes between the ligands and the treated metal ions. Notably, the receptor's complexation response exhibited selectivity towards Co(II), Cu(II), and Hg(II), with no observed chromogenic changes, spectral variations, or band shifts for the various tested metal ions, including Na+, Ag+, Ni2+, Mn2+, Pd2+, Pb2+, Cd2+, Zn2+, Sn2+, Fe2+, Fe3+, Cr3+ and Al3+. This absence of interaction between these metal ions and the ligand could be attributed to their compact or inadequately conducive conduction bands for complexation with the ligand's structural composition. To quantify the sensor's efficacy, fluorescence titration spectra were employed to determine the detection limits for Co2+, Cu2+ and Hg2+, yielding values of 2.92 × 10-8, 8.91 × 10-8, and 4.39 × 10-3 M, respectively. The Benesi-Hildebrand plots provided association constant values for the ligand-cobalt, ligand-copper, and ligand-mercury complexes as 0.74, 2.52, and 13.89 M-1, respectively.

Cardiopulmonary Exercise Testing in Evaluating Transthyretin Amyloidosis.

Importance: Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with transthyretin (ATTR) amyloidosis. Objective: To use CPET to characterize the spectrum of functional phenotypes in patients with ATTR amyloidosis and assess their association with the cardiac amyloid burden as well as the association between CPET parameters and prognosis. Design, Setting and Participants: This single-center study evaluated patients diagnosed with ATTR amyloidosis from May 2019 to September 2022 who underwent CPET at the National Amyloidosis Centre. Of 1045 patients approached, 506 were included and completed the study. Patients were excluded if they had an absolute contraindication to CPET or declined participation. The mean (SD) follow-up period was 22.4 (11.6) months. Main Outcomes and Measures: Comparison of CPET parameters across disease phenotypes (ATTR with cardiomyopathy [ATTR-CM], polyneuropathy, or both [ATTR-mixed]), differences in CPET parameters based on degree of amyloid infiltration (as measured by cardiovascular magnetic resonance [CMR] with extracellular volume mapping), and association between CPET parameters and prognosis. Results: Among the 506 patients with ATTR amyloidosis included in this study, the mean (SD) age was 73.5 (10.2) years, and 457 participants (90.3%) were male. Impairment in functional capacity was highly prevalent. Functional impairment in ATTR-CM and ATTR-mixed phenotypes (peak mean [SD] oxygen consumption [VO2], 14.5 [4.3] mL/kg/min and 15.7 [6.2] mL/kg/min, respectively) was observed alongside impairment in the oxygen pulse, with ventilatory efficiency highest in ATTR-CM (mean [SD] ventilatory efficiency/volume of carbon dioxide expired slope, 38.1 [8.6]). Chronotropic incompetence and exercise oscillatory ventilation (EOV) were highly prevalent across all phenotypes, with both the prevalence and severity being higher than in heart failure from different etiologies. Worsening of amyloid burden on CMR was associated with decline in multiple CPET parameters, although chronotropic response and EOV remained abnormal irrespective of amyloid burden. On multivariable Cox regression analysis, peak VO2 and peak systolic blood pressure (SBP) were independently associated with prognosis (peak VO2: hazard ratio, 0.89 [95% CI, 0.81-0.99; P = .03]; peak SBP: hazard ratio, 0.98 [95% CI, 0.97-0.99; P < .001]). Conclusions and Relevance: In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment between all disease phenotypes. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic of this population. CPET parameters were associated with amyloid burden by CMR and with peak VO2, and SBP, which have been shown to be independent predictors of mortality. These findings suggest that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and predicting outcomes, and potentially offers a more comprehensive method of evaluating functional capacity for future prospective studies.

Multiorgan Dysfunction and Associated Prognosis in Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart failure; however, their significance in ATTR-CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR-CA using blood biomarkers and assess the association between blood biomarkers and prognosis. METHODS AND RESULTS: This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR-CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C-reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR-CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio [HR], 1.19 [95% CI, 1.04-1.37]; P=0.01), high urea (HR, 1.23 [95% CI, 1.04-1.45]; P=0.01), hyperbilirubinemia (HR, 1.32 [95% CI, 1.13-1.57; P=0.001), increased alkaline phosphatase (HR, 1.20 [95% CI, 1.01-1.42; P=0.04), hyponatremia (HR, 1.65 [95% CI, 1.28-2.11]; P<0.001), and troponin-T >56 ng/L (HR, 1.72 [95% CI, 1.46-2.03]; P<0.001) were all independently associated with mortality in the overall population. The association between biomarkers and mortality varied across the spectrum of genotypes and left ventricular ejection fraction, with anemia remining independently associated with mortality in p.(V142I) hereditary ATTR-CA (HR, 1.58 [95% CI, 1.17-2.12]; P=0.003) and in a subgroup of the overall population with a left ventricular ejection fraction ≤40% (HR, 1.39 [95% CI, 1.08-1.81]; P=0.01). CONCLUSIONS: Cardiac and noncardiac biomarker abnormalities were common and reflect the complex and multifaceted nature of ATTR-CA, with a wide range of biomarkers remaining independently associated with mortality. Clinical trials are needed to investigate whether biomarker abnormalities represent modifiable risk factors that if specifically targeted could improve outcomes.

Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosis.

ABSTRACT: Amyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry-based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.

Deep phenotyping of p.(V142I)-associated variant transthyretin amyloid cardiomyopathy: Distinct from wild-type transthyretin amyloidosis?

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. A total of 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.(V142I) variant, a powerful risk factor for development of variant ATTR-CM (ATTRv-CM); this equates to 1.6 million carriers in the United States. We undertook deep phenotyping of p.(V142I)-ATTRv-CM and comparison with wild-type ATTR-CM (ATTRwt-CM). METHODS AND RESULTS: A retrospective study of 413 patients with p.(V142I) ATTRv-CM who attended the UK National Amyloidosis Centre (NAC) was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance (CMR) imaging. A total of 413 patients with ATTRwt-CM, matched for independent predictors of prognosis (age, NAC Stage, decade of first presentation), were used as a comparator group. At time of diagnosis, patients with ATTRv-CM had significant functional impairment by New York Heart Association classification (NHYA class ≥ III; 38%) and 6-min walk test distance (median 276 m). Median 5-year survival in ATTRv-CM patients was 31 versus 59 months in matched patients with ATTRwt-CM (p < 0.001). Patients with ATTRv-CM had significant impairment of functional parameters by echocardiography including biventricular impairment, high burden of regurgitant valvular disease and low cardiac output. Multivariable analysis revealed the prognostic importance of right ventricular dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv-CM. CONCLUSION: p.(V142I)-ATTRv-CM has an aggressive phenotype characterized by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR-CM genotypic subgroup.

Albuminuria in transthyretin cardiac amyloidosis: Prevalence, progression and prognostic importance.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative cardiomyopathy that commonly presents with concomitant chronic kidney disease. Albuminuria is common in heart failure and associated with worse outcomes, but its prevalence and relationship to outcome in ATTR-CA remains unclear. METHODS AND RESULTS: A total of 1181 patients with ATTR-CA were studied (mean age 78.1 ± 7.9 years; 1022 [86.5%] male; median estimated glomerular filtration rate 59 ml/min/1.73m2 [interquartile range: 47-74]). Albuminuria was present in 563 (47.7%) patients (499 [88.6%] with microalbuminuria and 64 [11.4%] with macroalbuminuria). Patients with albuminuria had a more severe cardiac phenotype evidenced by higher serum cardiac biomarkers (median N-terminal pro-B-type natriuretic peptide [NT-proBNP]: 4027 ng/L [2173-6889] vs. 1851 ng/L [997-3209], p < 0.001; median troponin T: 69 ng/L [46-101] vs. 48 ng/L [34-68], p < 0.001) and worse echocardiographic indices of systolic (longitudinal strain: -10.0 ± 3.6% vs. -11.6 ± 3.8%, p < 0.001) and diastolic function (E/e': 17.5 ± 6.4 vs. 16.4 ± 6.7, p < 0.001) than those with a normal urinary albumin to creatinine ratio (UACR). Microalbuminuria and macroalbuminuria were independently associated with mortality in the overall population (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.13-1.92, p = 0.005 and HR 1.87, 95% CI 1.15-3.05, p = 0.012, respectively). In a subgroup of patients (n = 349) without concomitant hypertension, diabetes mellitus or chronic kidney disease, albuminuria was also associated with mortality (HR 2.98, 95% CI 1.72-5.17, p < 0.001). At 12 months, 330 patients had a repeat UACR measurement; those in whom UACR increased by 30% or more (n = 148, 44.8%) had an increased risk of mortality (HR 1.84, 95% CI 1.06-3.19, p = 0.030). CONCLUSIONS: Albuminuria is common in patients with ATTR-CA, and more prevalent in those with a more severe cardiac phenotype. Albuminuria at diagnosis and a significant increase in UACR during follow-up are associated with mortality.

A cost effective communication model for requirements elicitation in global software development.

Requirement elicitation stands as a pivotal activity within requirement engineering, gaining even greater significance in the context of global software development. Effective communication among stakeholders assumes paramount importance in this arena. Factors such as time zone disparities, cultural variations, and language differences exert a formidable impact on communication within the sphere of global software development. These dynamics inevitably impinge upon timely coordination, potentially compromising the software's quality. In response, researchers have proffered communication models tailored for requirement elicitation within the ambit of global software development. The purpose of this study is to conduct an in-depth critical review of existing communication models for demand elicitation in global software development. Through this comprehensive review, we aim to discern prevailing publication trends, provide an introductory overview, and illuminate the strengths and limitations inherent in the existing communication models. By identifying these limitations, we seek to advance a novel, low-cost communication approach designed primarily for demand elicitation in global software development. To culminate our endeavor, we will undertake a case study-based experiment, meticulously designed to assess the efficacy and practical utility of the proposed techniques.

Proteomic profile of epidermal mucus from Labeo rohita reveals differentially abundant proteins after Aeromonas hydrophila infection.

We report the proteomic profile of Epidermal Mucus (EM) from Labeo rohita and identified the differentially abundant proteins (DAPs) against Aeromonas hydrophila infection through label-free liquid chromatography-mass spectrometry (LC-MS/MS). Using discovery-based proteomics, a total of 2039 proteins were quantified in nontreated group and 1,328 proteins in the treated group, of which 114 were identified as DAPs in both the groups. Of the 114 DAPs, 68 proteins were upregulated and 46 proteins were downregulated in the treated group compared to nontreated group. Functional annotations of these DAPs shows their association with metabolism, cellular process, molecular process, cytoskeletal, stress, and particularly immune system. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Fisher's exact test between the two groups shows that most of the proteins were immune-related, which were significantly associated with the proteasome, phagosome, and Salmonella infection pathways. Overall, this study shows a basic and primary way for further functional research of the involvement of vitellogenin 2, alpha-2-macroglobulin-like protein, toll-like receptors (TLR-13), calpain, keratin-like proteins, and heat shock proteins against bacterial infection. Nonetheless, this first-ever comprehensive report of a proteomic sketch of EM from L. rohita after A. hydrophila infection provides systematic protein information to broadly understand the biological role of fish EM against bacterial infection.

Bactericidal role of epidermal mucus of freshwater fish treated with Aeromonas hydrophila.

This study explored the bactericidal role of the epidermal mucus (EM) of five freshwater Cyprinid fish species namely Ctenopharyngodon idella, Labeo rohita, Catla catla, Hypophthalmichthys molitrix, and Cirrhinus mrigala after treatment with Aeromonas hydrophila. Extracts of EM (crude and acidic) of each species showed bactericidal activity against various Gram -ve (Pseudomonas aeruginosa, Escherichia coli, Aeromonas hydrophila, Edwardsiella tarda, Salmonella enterica, Klebsiella pneumonia, Serratia marcescens, and Enterobacter cloacae) and Gram +ve (Bacillus wiedmannii and Staphylococcus aureus) bacteria compared with standard antibiotics (Fosfomycin). The zone of inhibition (ZOI) was measured in millimetres against antibiotics (Fosfomycin). Variations in bactericidal activity of EM were observed against bacteria from the same and different fish species. The acidic extract was more effective than the crude extract and showed significantly higher ZOI values against various bacteria and Fosfomycin antibiotics. This result shows that fish EM may perform an important role in fish defence against bacteria. Therefore, this study may hint towards the substitution of synthetic antibiotics with fish EM that may be used as a novel 'bactericidal' in aquaculture as well as in humans against bacterial infections.

Rare Forms of Cardiac Amyloidosis: Diagnostic Clues and Phenotype in Apo AI and AIV Amyloidosis.

BACKGROUND: Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging. METHODS: We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement. RESULTS: Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure (n=8, 62%) or dysphonia (n=7, 54%). The Arg173Pro variant universally caused cardiac and laryngeal involvement (n=7, 100%). AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6±1.9 versus 6.3±1.3 mm versus 7.7±1.2 mm, P=0.004), greater incidence of tricuspid stenosis (4 [31%] versus 0 [0%] versus 0 [0%], P=0.012) and tricuspid regurgitation (6 [46%] versus 1 [8%] versus 2 [15%], P=0.048) than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI (15 [71%] versus 13 [29%], P=0.001). AApoAIV-CA most commonly presented with heart failure (n=12, 80%), and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA (36 mL/[min·1.73 m²] versus 65 mL/[min·1.73 m²] versus 63 mL/[min·1.73 m²], P<0.001). All AApoAIV-CA patients had classical CA features on echocardiography/cardiac magnetic resonance, including an apical-sparing strain pattern, which was less common in AApoAI-CA (15 [100%] versus 7 [54%], P=0.003), whereas cardiac uptake on bone scintigraphy was less common in AApoAIV-CA than AApoAI-CA (all grade 1) (14% versus 82%, P<0.001). Patients with AApoAI and AApoAIV had a good prognosis (median survival >172 and >30 months, respectively), and a lower risk of mortality than matched patients with AL-amyloidosis (AL versus AApoAI: hazard ratio, 4.54 [95% CI, 2.02-10.14]; P<0.001; AL versus AApoAIV: hazard ratio, 3.07 [95% CI, 1.27-7.44]; P=0.013). CONCLUSIONS: Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis.

Variations in the Behaviour, Survival, Haematology, and Biochemistry of Ctenopharyngodon idella (Grass Carp) After Exposure to Commercial Grade Atrazine.

The current study assessed the harmful effects of Atrazine (ATZ) herbicide on haematology and biochemistry of the freshwater fish Ctenopharyngodon idella, a commercially significant fish in Pakistan. C. idella (13 ± 8.4 cm; 132 ± 5.6 g) was exposed to graded levels of ATZ, and its 96-hour LC50 value at 25°C was calculated to be 150.5 µl/L. After exposure to ATZ, fish displayed rapid movements, a loss of balance in position and equilibrium, anxious swimming patterns, colour changes, and increased mucous production. The MCHC, MCH, RBCs, and Hb in C. idella decreased significantly (P < 0.05), whereas the MCV, Ht, and WBCs were significantly increased (P < 0.05). At different time intervals (24, 48, 72, and 96 h) following ATZ administration (50, 100, 150, and 200 µl/L), biochemical analysis significantly decreased (P < 0.05) triglyceride, total protein, cholesterol, and albumin levels, whereas glucose levels significantly increased (P < 0.05). We concluded that ATZ is toxic to C. idella, altering their haematology and blood biochemistry even after only a brief exposure.

Tracking Treatment Response in Cardiac Light-Chain Amyloidosis With Native T1 Mapping.

Importance: Cardiac magnetic resonance (CMR) imaging-derived extracellular volume (ECV) mapping, generated from precontrast and postcontrast T1, accurately determines treatment response in cardiac light-chain amyloidosis. Native T1 mapping, which can be derived without the need for contrast, has demonstrated accuracy in diagnosis and prognostication, but it is unclear whether serial native T1 measurements could also track the cardiac treatment response. Objective: To assess whether native T1 mapping can measure the cardiac treatment response and the association between changes in native T1 and prognosis. Design, Setting, and Participants: This single-center cohort study evaluated patients diagnosed with cardiac light-chain amyloidosis (January 2016 to December 2020) who underwent CMR scans at diagnosis and a repeat scan following chemotherapy. Analysis took place between January 2016 and October 2022. Main Outcomes and Measures: Comparison of biomarkers and cardiac imaging parameters between patients with a reduced, stable, or increased native T1 and association between changes in native T1 and mortality. Results: The study comprised 221 patients (mean [SD] age, 64.7 [10.6] years; 130 male [59%]). At 6 months, 183 patients (mean [SD] age, 64.8 [10.5] years; 110 male [60%]) underwent repeat CMR imaging. Reduced native T1 of 50 milliseconds or more occurred in 8 patients (4%), all of whom had a good hematological response; by contrast, an increased native T1 of 50 milliseconds or more occurred in 42 patients (23%), most of whom had a poor hematological response (27 [68%]). At 12 months, 160 patients (mean [SD] age, 63.8 [11.1] years; 94 male [59%]) had a repeat CMR scan. A reduced native T1 occurred in 24 patients (15%), all of whom had a good hematological response, and was associated with a reduction in N-terminal pro-brain natriuretic peptide (median [IQR], 2638 [913-5767] vs 423 [128-1777] ng/L; P < .001), maximal wall thickness (mean [SD], 14.8 [3.6] vs 13.6 [3.9] mm; P = .009), and E/e' (mean [SD], 14.9 [6.8] vs 12.0 [4.0]; P = .007), improved longitudinal strain (mean [SD], -14.8% [4.0%] vs -16.7% [4.0%]; P = .004), and reduction in both myocardial T2 (mean [SD], 52.3 [2.9] vs 49.4 [2.0] milliseconds; P < .001) and ECV (mean [SD], 0.47 [0.07] vs 0.42 [0.08]; P < .001). At 12 months, an increased native T1 occurred in 24 patients (15%), most of whom had a poor hematological response (17 [71%]), and was associated with an increased N-terminal pro-brain natriuretic peptide (median [IQR], 1622 [554-5487] vs 3150 [1161-8745] ng/L; P = .007), reduced left ventricular ejection fraction (mean [SD], 65.8% [11.4%] vs 61.5% [12.4%]; P = .009), and an increase in both myocardial T2 (mean [SD], 52.5 [2.7] vs 55.3 [4.2] milliseconds; P < .001) and ECV (mean [SD], 0.48 [0.09] vs 0.56 [0.09]; P < .001). Change in myocardial native T1 at 6 months was independently associated with mortality (hazard ratio, 2.41 [95% CI, 1.36-4.27]; P = .003). Conclusions and Relevance: Changes in native T1 in response to treatment, reflecting a composite of changes in T2 and ECV, are associated with in changes in traditional markers of cardiac response and associated with mortality. However, as a single-center study, these results require external validation in a larger cohort.

The Western Himalayan fir tree ring record of soil moisture in Pakistan since 1855.

Data on historical soil moisture is crucial for assessing and responding to droughts that commonly occur in climate change-affected countries. The Himalayan temperate forests in Pakistan are particularly at risk of climate change. Developing nations lack the means to gather surface soil moisture (SSM) information. Tree rings are one way to bridge this gap. Here, we employed dendrochronological methods on climate-sensitive tree rings from Abies pindrow to reconstruct the SSM in the Western Himalayan mountain region of Pakistan from 1855 to 2020. December (r = 0.41), May (r = 0.40), and June (r = 0.65) SSMs were found to be the limiting factors for A. pindrow growth. However, only the June SSM showed reconstruction possibility (coefficient of efficiency = 0.201 and reduction of error = 0.325). Over the studied period, we found 6 years (wet year) when June SSM was above the threshold of 32.04 (mean + 2 δ) and 1 year (dry year) when June SSM was below the threshold of 21.28 (mean - 2 δ). It was revealed that 1921 and 1917 were the driest and wettest SSM of all time, with means of 19.34 and 36.49, respectively. Our study shows that winter soil moisture is critical for the growing season in the context of climate change. Climate change has broad impacts on tree growth in the Western Himalayas. This study will assist various stakeholders in understanding and managing local and regional climate change.

Application of ZnO-NRs@Ni-foam substrate for electrochemical fingerprint of arsenic detection in water.

Arsenic (As3+) is the most carcinogenic and abundantly available heavy metal present in the environment. Vertically aligned ZnO nanorod (ZnO-NR) growth was achieved on metallic nickel foam substrate via a wet chemical route and it was used as an electrochemical sensor towards As(iii) detection in polluted water. Crystal structure confirmation, surface morphology observation and elemental analysis of ZnO-NRs were conducted using X-ray diffraction, field-emission scanning electron microscopy and energy-dispersive X-ray spectroscopy, respectively. Electrochemical sensing performance of ZnO-NRs@Ni-foam electrode/substrate was investigated via linear sweep voltammetry, cyclic voltammetry and electrochemical impedance spectroscopy in a carbonate buffer solution of pH = 9 and at different As(iii) molar concentrations in solution. Under optimum conditions, the anodic peak current was found proportional to the arsenite concentration from 0.1 µM to 1.0 µM. The achieved values for limit of detection and limit of quantification were 0.046 ppm and 0.14 ppm, respectively, which are far lower than the recommended limits for As(iii) detection in drinking water as suggested by the World Health Organization. This suggests that ZnO-NRs@Ni-foam electrode/substrate can be effectively utilized in terms of its electrocatalytic activity towards As3+ detection in drinking water.

Synthesis, in vitro biological assessment, and molecular docking study of benzimidazole-based thiadiazole derivatives as dual inhibitors of α-amylase and α-glucosidase.

The clinical significance of benzimidazole-containing drugs has increased in the current study, making them more effective scaffolds. These moieties have attracted strong research interest due to their diverse biological features. To examine their various biological significances, several research synthetic methodologies have recently been established for the synthesis of benzimidazole analogs. The present study aimed to efficiently and quickly synthesize a new series of benzimidazole analogs. Numerous spectroscopic techniques, including 1H-NMR, 13C-NMR, and HREI-MS, were used to confirm the synthesized compounds. To explore the inhibitory activity of the analogs against α-amylase and α-glucosidase, all derivatives (1-17) were assessed for their biological potential. Compared to the reference drug acarbose (IC50 = 8.24 ± 0.08 µM), almost all the derivatives showed promising activity. Among the tested series, analog 2 (IC50 = 1.10 ± 0.10 & 2.10 ± 0.10 µM, respectively) displayed better inhibitory activity. Following a thorough examination of the various substitution effects on the inhibitory capacity of α-amylase and α-glucosidase, the structure-activity relationship (SAR) was determined. We looked at the potential mechanism of how active substances interact with the catalytic cavity of the targeted enzymes in response to the experimental results of the anti-glucosidase and anti-amylase. Molecular docking provided us with information on the interactions that the active substances had with the various amino acid residues of the targeted enzymes for this purpose.

Conventional heart failure therapy in cardiac ATTR amyloidosis.

AIMS: The aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA). METHODS AND RESULTS: A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population [hazard ratio (HR) 0.77 (95% confidence interval (CI) 0.66-0.89), P < .001] and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) >40% [HR 0.75 (95% CI 0.63-0.90), P = .002]; and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% [HR 0.61 (95% CI 0.45-0.83), P = .002]. No convincing differences were found for treatment with ACEi/ARBs. CONCLUSION: Conventional heart failure medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.

Reducing diagnostic delay in hypophosphatasia: a case series of 14 patients presenting to general rheumatology.

OBJECTIVES: Hypophosphatasia (HPP) is a rare genetic metabolic bone disease that can cause chronic pain and fractures. Its hallmark is a persistently low serum ALP. HPP is now recognised by many osteoporosis specialists, but other specialists, such as rheumatologists and primary care physicians, may be less aware of this condition, causing diagnostic delay and possible harm to these patients. Our objective was to highlight features that can reduce this delay. METHODS: We retrospectively analysed 14 patients that presented with musculoskeletal pain to general rheumatology clinic at St. George's Hospital and were subsequently diagnosed with HPP. RESULTS: Median diagnostic delay was 13 years. All patients had an ALP below reference range for age and gender, with lowest mean ALP of 16 IU/L. All but one patient were women with median age of 51 years. Most common presentation was peripheral joint pain in 85.7% of patients. This was due to early-onset CPPD (calcium pyrophosphate deposition disease) in 71.4% of patients, osteoarthritis in 50%, or bursitis in 50%. Axial pain was reported in 64% of patients due to osteoarthritis or spinal stenosis. Fifty percent of patients had a history of long bone pain. Fifty percent had previous fracture(s). A total of 28.6% of patients had psoriatic arthritis, of which 1 patient had spondyloarthropathy, and 4 patients also had enthesitis. CONCLUSION: Patients with HPP can present to rheumatology with musculoskeletal pain, and if a persistently low ALP is confirmed, this may reduce the diagnostic delay of this rare disease. Similar to other rheumatologic patients, musculoskeletal pain in HPP was noted in peripheral joints and in the spine with almost a third of patients having psoriatic arthritis. Pain was also noted in the long bones, a feature consistent with metabolic bone disease. The diagnosis of HPP was also more likely in those patients with a personal or family history of dental disease or arthritis.