Cooperative amyloid fibre binding and disassembly by the Hsp70 disaggregase.

Although amyloid fibres are highly stable protein aggregates, a specific combination of human Hsp70 system chaperones can disassemble them, including fibres formed of α-synuclein, huntingtin, or Tau. Disaggregation requires the ATPase activity of the constitutively expressed Hsp70 family member, Hsc70, together with the J domain protein DNAJB1 and the nucleotide exchange factor Apg2. Clustering of Hsc70 on the fibrils appears to be necessary for disassembly. Here we use atomic force microscopy to show that segments of in vitro assembled α-synuclein fibrils are first coated with chaperones and then undergo bursts of rapid, unidirectional disassembly. Cryo-electron tomography and total internal reflection fluorescence microscopy reveal fibrils with regions of densely bound chaperones, preferentially at one end of the fibre. Sub-stoichiometric amounts of Apg2 relative to Hsc70 dramatically increase recruitment of Hsc70 to the fibres, creating localised active zones that then undergo rapid disassembly at a rate of ~ 4 subunits per second. The observed unidirectional bursts of Hsc70 loading and unravelling may be explained by differences between the two ends of the polar fibre structure.

Multicenter Study on Physician-Modified Endografts for Thoracoabdominal and Complex Abdominal Aortic Aneurysm Repair.

BACKGROUND: Physician modified endografts (PMEGs) have been widely used in the treatment of complex abdominal aortic aneurysm and thoracoabdominal aortic aneurysm, however, previous data are limited to small single center studies and robust data on safety and effectiveness of PMEGs are lacking. We aimed to perform an international multicenter study analyzing the outcomes of PMEGs in complex abdominal aortic aneurysms and thoracoabdominal aortic aneurysms. METHODS: An international multicenter single-arm cohort study was performed analyzing the outcomes of PMEGs in the treatment of elective, symptomatic, and ruptured complex abdominal aortic aneurysms and thoracoabdominal aortic aneurysms. Variables and outcomes were defined according to the Society for Vascular Surgery reporting standards. Device modification and procedure details were collected and analyzed. Efficacy outcomes included technical success and safety outcomes included major adverse events and 30-day mortality. Follow-up outcomes included reinterventions, endoleaks, target vessel patency rates and overall and aortic-related mortality. Multivariable analysis was performed aiming at identifying predictors of technical success, 30-day mortality, and major adverse events. RESULTS: Overall, 1274 patients were included in the study from 19 centers. Median age was 74 (IQR, 68-79), and 75.7% were men; 45.7% were complex abdominal aortic aneurysms, and 54.3% were thoracoabdominal aortic aneurysms; 65.5% patients presented electively, 24.6% were symptomatic, and 9.9% were ruptured. Most patients (83.1%) were submitted to a fenestrated repair, 3.6% to branched repair, and 13.4% to a combined fenestrated and branched repair. Most patients (85.8%) had ≥3 target vessels included. The overall technical success was 94% (94% in elective, 93.4% in symptomatic, and 95.1% in ruptured cases). Thirty-day mortality was 5.8% (4.1% in elective, 7.6% in symptomatic, and 12.7% in ruptured aneurysms). Major adverse events occurred in 25.2% of cases (23.1% in elective, 27.8% in symptomatic, and 30.3% in ruptured aneurysms). Median follow-up was 21 months (5.6-50.6). Freedom from reintervention was 73.8%, 61.8%, and 51.4% at 1, 3, and 5 years; primary target vessel patency was 96.9%, 93.6%, and 90.3%. Overall survival and freedom from aortic-related mortality was 82.4%/92.9%, 69.9%/91.6%, and 55.0%/89.1% at 1, 3, and 5 years. CONCLUSIONS: PMEGs were a safe and effective treatment option for elective, symptomatic, and ruptured complex aortic aneurysms. Long-term data and future prospective studies are needed for more robust and detailed analysis.

Hydrogen Is the Superior Nebulization Gas for Desorption and Electrospray Ionization.

A previous comparative study between helium and nitrogen as nebulizing and desolvation gases in electrospray ionization (ESI) and desorption electrospray ionization (DESI) found that the signal responses of compounds of varying sizes and polarities were improved. Here, an expanded selection of nebulizing gases was evaluated to investigate mechanisms of improvement. The set of nebulizing gases included hydrogen, helium, nitrogen, argon, and carbon dioxide. Results indicate that the signal enhancements are achieved by gases lighter than nitrogen and that the previously described helium effects can be improved by using the more economical and sustainable hydrogen as a nebulizing gas. Additionally, H2 and He reduce the desorption footprint, which could be potentially useful in increasing the resolution of chemical imaging microscopy, especially since, despite the smaller footprint obtained using helium and hydrogen, higher signals are obtained compared to nitrogen.

Angiogenesis related genes in Takayasu Arteritis (TAK): robust association with Tag SNPs of IL-18 and FGF-2 in a South Asian Cohort.

We performed genetic association study for genes encoding angiogenic and angiostatic proteins in patients with Takayasu arteritis (TAK). A total of 96 SNPs involving 60 genes were studied. Genotyping was performed in Fluidigm 96.96 Dynamic Array chip. All statistical analysis for SNP evaluation was performed using PLINK software. Initial analyses revealed five SNPs from three genes [IL-18 (encodes Interleukin-18), FGF2 (encodes Fibroblast Growth Factor-2), and ANGPT1 (encodes Angiopoietin-1)] as significantly different between controls and cases (uncorrected p < 0.05). After permutation-based analysis, two tag SNPs on the promoter region of IL-18 (rs187238 and rs1946518) and one 3'UTR tag SNP (rs1476217) of FGF2 were significantly associated with susceptibility to TAK, with p and OR (95% CI) of 0.0006 and 1.64 (1.25-2.17), 0.03 and 1.28 (1.02-1.64) & 0.016 and 1.33 (1.05-1.67), respectively; while, the two tag SNPs of ANGPT1 gene (rs6469101 and rs16875900) showed a trend (p = 0.055 & p = 0.051, respectively after permutation based correction). There is robust linkage disequilibrium between the two tag SNPs of IL-18 gene as validated by 1000 genome data of South Asian population; the eQTL effects of these tag SNPs of IL-18 and FGF2 genes on adjacent genes further suggest that these tag SNPs act as genetic risks for development of TAK in South Asians, with possible functional implications towards future biomarker development. Genotype phenotype study by genetic model-based analysis also revealed associations between genotype subsets and clinical features like fever, visual loss, left subclavian and coronary artery involvement in our TAK patients.

The "Bundle Wire" Technique: A Novel Approach to Cannulating Challenging Target Vessels Using Multiple Fine Atraumatic Guidewires That Together Serve as a Stiff Guidewire.

PURPOSE: To present a novel technique that enables safe and effective cannulation of target vessels with challenging anatomy during fenestrated/branched endovascular aortic repair (F/B-EVAR). TECHNIQUE: Following deployment of the F/B-EVAR endograft, the target vessels (TVs) are cannulated. The bundle wire technique provides a solution to challenging TVs and uses multiple fine atraumatic guidewires that together serve as a stiff guidewire. The technique can be executed in 2 ways using: (1) one 0.018 inch and one 0.014 inch guidewire or (2) three 0.014 inch guidewires. We demonstrate the technique in a case of a complex abdominal aortic aneurysm treated using branched EVAR in which the left renal artery with severe ostial stenosis was catheterized using the bundle wire technique. CONCLUSIONS: The bundle wire technique offers a technically feasible and economically viable solution for facilitating catheter and bridging stent delivery in anatomically challenging TVs during F/B-EVAR. It is a useful addition to the therapeutic armamentarium available to physicians for accessing demanding TVs.

Ecology and Diversity of Arbuscular Mycorrhizal Fungi (AMF) in Rice (Oryza sativa L.) in South India: An Ecological Analysis of Factors Influencing AMF in Rice Fields.

AIMS: This study examined the diversity of arbuscular mycorrhizal fungi (AMF), mean spore density (MSD), and root colonization in relation to factors such as agroclimatic zones, rice varieties, soil types, and rice varieties in paddy fields of South India. The aim was to understand how these factors influence AMF, facilitating their effective use as a biological tool in agriculture. METHODS AND RESULTS: AMF were identified through light microscopy of spores, while MSD and percentage-root-length colonization (PRLC) were measured using standard methods. Correlation and principal component analyses were performed to explore the interrelationships between AMF characteristics and various environmental, soil, and plant variables. Sixteen AMF species were identified across 29 rice varieties from three agroclimatic zones, six soil orders, and 18 soil series over two seasons. Notably, 70% of chemicalized rice fields lacked AMF spores, and only 50% exhibited root colonization. This study offers new insights into the role of AMF in rice cultivation. CONCLUSIONS: The AMF diversity and root colonization in relation to environmental variables underscores their significant impact on AMF in particular crop fields.

A critical review of soil algae as a crucial soil biological component of high ecological and economic significance.

Aero-terrestrial algae are ecologically and economically valuable bioresources contributing to carbon sequestration, sustenance of soil health, and fertility. Compared to aquatic algae, the literature on subaerial algae is minimal, including studies of distinctive habitats such as forest soils, agricultural fields, deserts, polar regions, specific subaerial zones, artificial structures, and tropical soils. The primary goal here was to identify the gaps and scope of research on such algae. Accordingly, the literature was analyzed per sub-themes, such as the "nature of current research data on terrestrial algae," "methodological approaches," "diversity," "environmental relationships," "ecological roles," and "economic significance." The review showed there is a high diversity of algae in soils, especially members belonging to the Cyanophyta (Cyanobacteria) and Chlorophyta. Algal distributions in terrestrial environments depend on the microhabitat conditions, and many species of soil algae are sensitive to specific soil conditions. The ecological significance of soil algae includes primary production, the release of biochemical stimulants and plant growth promoters into soils, nitrogen fixation, solubilization of minerals, and the enhancement and maintenance of soil fertility. Since aero-terrestrial habitats are generally stressed environments, algae of such environments can be rich in rare metabolites and natural products. For example, epilithic soil algae use wet adhesive molecules to fix them firmly on the substratum. Exploring the ecological roles and economic utility of soil and other subaerial algae could be helpful for the development of algae-based industries and for achieving sustainable soil management.

Treatments for Moderate-to-Severe Acne Vulgaris: A Systematic Review and Network Meta-analysis.

BACKGROUND: Multiple treatment options exist for the management of moderate-to-severe acne. However, the comparative effectiveness (efficacy/safety) of moderate-to-severe acne treatments has not been systematically examined. METHODS: A systematic literature review (SLR) was conducted to identify randomized controlled trials of ≥4 weeks of treatment (topical, oral, physical, or combinations) for moderate-to-severe facial acne in patients aged ≥9 years. Efficacy outcomes included: percentage of patients achieving ≥2-grade reduction from baseline and “clear” or “almost clear” for global severity score (treatment success); absolute change in inflammatory (ILs reduction); and noninflammatory lesion counts (NILs reduction). A random-effects network meta-analysis (NMA) was conducted for the efficacy outcomes. Treatments were ranked with posterior rank plots and surface under cumulative ranking values.  Results: Eighty-five studies were included in the SLR/NMA. Topical triple-agent fixed-dose combination (FDC) gel (clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1%) and combinations of double-agent fixed-dose topical treatments with oral antibiotics (TOA3) consistently ranked in the top 3 treatments. Topical triple-agent FDC gel was numerically superior to TOA3 for treatment success (log-odds ratios: 1.84 [95% credible interval (CrI) 1.36 to 2.29]) and 1.69 (95% CrI: 1.01 to 2.32) vs placebo/vehicle). TOA3 was numerically superior to topical triple-agent FDC gel for reduction of ILs (mean difference: -8.21 [-10.33 to -6.13]) and -10.40 [-13.44 to -7.14] vs placebo/vehicle) and NILs (mean difference: -13.41 [-16.69 to -10.32] and -17.74 [-22.56 to -12.85] vs placebo/vehicle). CONCLUSIONS: Based on this SLR/NMA, topical triple-agent FDC gel was the most efficacious and safe treatment for moderate-to-severe acne. J Drugs Dermatol. 2024;23(4):     doi:10.36849/JDD.8148.

Surface-Enhanced Raman Spectroscopy Using a Silver Nanostar Substrate for Neonicotinoid Pesticides Detection.

Surface-enhanced Raman spectroscopy (SERS) has been introduced to detect pesticides at low concentrations and in complex matrices to help developing countries monitor pesticides to keep their concentrations at safe levels in food and the environment. SERS is a surface-sensitive technique that enhances the Raman signal of molecules absorbed on metal nanostructure surfaces and provides vibrational information for sample identification and quantitation. In this work, we report the use of silver nanostars (AgNs) as SERS-active elements to detect four neonicotinoid pesticides (thiacloprid, imidacloprid, thiamethoxam and nitenpyram). The SERS substrates were prepared with multiple depositions of the nanostars using a self-assembly approach to give a dense coverage of the AgNs on a glass surface, which ultimately increased the availability of the spikes needed for SERS activity. The SERS substrates developed in this work show very high sensitivity and excellent reproducibility. Our research opens an avenue for the development of portable, field-based pesticide sensors, which will be critical for the effective monitoring of these important but potentially dangerous chemicals.

Bayesian design of multi-regional clinical trials with time-to-event endpoints.

Sponsors often rely on multi-regional clinical trials (MRCTs) to introduce new treatments more rapidly into the global market. Many commonly used statistical methods do not account for regional differences, and small regional sample sizes frequently result in lower estimation quality of region-specific treatment effects. The International Council for Harmonization E17 guidelines suggest consideration of methods that allow for information borrowing across regions to improve estimation. In response to these guidelines, we develop a novel methodology to estimate global and region-specific treatment effects from MRCTs with time-to-event endpoints using Bayesian model averaging (BMA). This approach accounts for the possibility of heterogeneous treatment effects between regions, and we discuss how to assess the consistency of these effects using posterior model probabilities. We obtain posterior samples of the treatment effects using a Laplace approximation, and we show through simulation studies that the proposed modeling approach estimates region-specific treatment effects with lower mean squared error than a Cox proportional hazards model while resulting in a similar rejection rate of the global treatment effect. We then apply the BMA approach to data from the LEADER trial, an MRCT designed to evaluate the cardiovascular safety of an anti-diabetic treatment.

Optimization of environmental and the other variables in the application of arbuscular mycorrhizal fungi as an ecotechnological tool for sustainable paddy cultivation: a critical review.

Arbuscular mycorrhizal fungi (AMF) are effective natural alternatives to assist plants in improving crop productivity and immunity against pests and diseases. However, a comprehensive idea of the variables under which they show optimum activity, especially concerning particular soil, climate, geography, and crop characteristics, has yet to be adequately standardized. Since paddy is the staple food for half of the world's population, such standardization is highly significant globally. Research concerning determinants affecting AMF functioning in rice is limited. However, the identified variables include external variables such as abiotic, biotic, and anthropogenic factors and internal variables such as plant and AMF characteristics. Among the abiotic factors, edaphic factors like soil pH, phosphorus availability, and soil moisture significantly affect AMF functioning in rice. In addition, anthropogenic influences such as land use patterns, flooding, and fertilizer regimes also affect AMF communities in rice agroecosystems. The principal objective of the review was to analyse the existing literature on AMF concerning such variables generally and to assess the specific research requirements on variables affecting AMF in rice. The ultimate goal is to identify research gaps for applying AMF as a natural alternative in the sustainable agriculture of paddy with optimum AMF symbiosis enhancing rice productivity.

Content validation of a daily patient-reported outcome measure for assessing symptoms in patients with Small Intestinal Bacterial Overgrowth.

PURPOSE: The aim of this study was to generate evidence supporting the development and content validity of a new PRO instrument, the Small Intestinal Bacterial Overgrowth (SIBO) Symptom Measure (SSM) daily diary. The SSM assesses symptom severity in SIBO patients, with the ultimate goal of providing a fit for purpose PRO for endpoint measurement. METHODS: Qualitative research included 35 SIBO patients in three study stages, using a hybrid concept elicitation (CE)/cognitive interview (CI) method with US patients, ≥ 18 years. Stage 1 included a literature review, clinician interviews, and initial CE interviews with SIBO patients to identify symptoms important to patients for inclusion in the SSM. Stage 2 included hybrid CE/CI to learn more about patients' SIBO experience and test the draft SSM. Finally, stage 3 used CIs to refine the instrument and test its content validity. RESULTS: In stage 1 (n = 8), 15 relevant concepts were identified, with items drafted based on the literature review/clinician interviews and elicitation work. Within stage 2 (n = 15), the SSM was refined to include 11 items; with wording revised for three items. Stage 3 (n = 12) confirmed the comprehensiveness of the SSM, as well as appropriateness of the item wording, recall period, and response scale. The resulting 11-item SSM assesses the severity of bloating, abdominal distention, abdominal discomfort, abdominal pain, flatulence, physical tiredness, nausea, diarrhea, constipation, appetite loss, and belching. CONCLUSIONS: This study provides evidence supporting the content validity of the new PRO. Comprehensive patient input ensures that the SSM is a well-defined measure of SIBO, ready for psychometric validation studies.

Post-Hoc Exploratory Pooled Analysis of the Impact of IDP-126 Gel on QoL in Moderate-to-Severe Acne.

BACKGROUND: Acne has psychosocial effects on patient's quality of life (QoL). This post hoc exploratory analysis of pooled phase 3 data assessed the impact of investigational IDP-126 gel (for moderate to severe acne) on the Acne-Specific Quality of Life Questionnaire (Acne-QoL; exploratory endpoint in the trials).  Methods: A post hoc exploratory analysis using pooled data (N=309; age ≥13 years) was conducted to assess if 1) changes from baseline to week 12 in Acne-QoL domain scores significantly differ by treatment; 2) differences were clinically meaningful, and 3) relative importance of acne severity as measured by the Evaluator's Global Severity Score (EGSS) or lesion counts explains the changes in QoL (Acne-QoL).  Results: Acne-QoL domain scores significantly (P<0.001, each) improved for patients treated with IDP-126 Gel vs vehicle in all four domains (role-emotional [least squares mean difference {LSMean} 4.1], self-perception [LSMean 3.8], acne symptoms [LSMean 2.6], and role-social [LSMean 2.0]). The proportion of responders was significantly higher (P<0.05, each) in the IDP-126 Gel group vs vehicle across Acne-QoL domains, self-perception (odds ratio [OR]: 4.32), acne symptoms (OR: 3.90), role-social (OR: 3.59), and role-emotional (OR: 2.50). Across all Acne QoL domains, the improvement on the EGSS endpoint (53.8-63.3%) was more likely to influence QoL improvements than the inflammatory (20.1-33.4%) and non-inflammatory lesion (9.5-18.7%) counts.  Conclusions: This post hoc exploratory analysis of pooled phase 3 data (moderate to severe acne) suggests that treatment with IDP 126 Gel led to statistically significant and clinically meaningful improvements in QoL and improvement in QoL was primarily influenced by EGSS.J Drugs Dermatol. 2023;22(10):1033-1039      doi:10.36849/JDD.7812.

A System for Accurate Deployment of Unconstrained Triple-Fenestrated Aortic Arch Endografts.

PURPOSE: To achieve accurate rotational orientation and the axial position of unconstrained triple-fenestrated physician-modified endografts upon deployment in the aortic arch during total arch thoracic endovascular aortic repair (TA-TEVAR). MATERIALS AND METHODS: Following a detailed study of reconstructed computerized tomography angiography images of patients' arch anatomy, customized, sealable fenestrations with radio-opaque margins are created onsite on Valiant Captivia (Medtronic) endografts, transposing the arch branch ostial anatomic interrelationship onto the endograft precisely. Radio-opaque figure-of-8 markers, indicating the 12 o'clock (superior) position, are attached to the endograft on the surface and brought up to the surface under the endograft cover during resheathing. Resheathing without any twist in the endograft is achieved by lining up the welds in each endograft stent segment in a straight line. The fluoroscopic working view for arch endograft delivery and deployment is the left anterior oblique view that is orthogonal to the plane of the arch, which, in turn, is the right anterior oblique view in which parts of a stiff indwelling guidewire in the ascending and descending aorta precisely overlap. During introduction in the working view, the endograft delivery system is rotated in the descending thoracic aorta so that the 12 o'clock figure-of-8 markers are viewed on the edge and situated at the outer aortic curvature; continued advancement into the arch without any further rotation will ensure superior orientation of the figure-of-8 markers and, consequently, correct endograft rotational orientation. Proper axial endograft positioning requires locating the left common carotid artery (LCCA) fenestration just proximal to a taut externalized LCCA-femoral guidewire loop marking the posterior limit of the LCCA ostium. After endograft deployment during rapid cardiac pacing, the target arch branches are cannulated through their respective fenestrations using hydrophilic 0.035-inch guidewires that are externalized via distal sheaths to create femoral-arch branch (through-and-through) loops over which covered fenestrated stents are introduced and deployed. RESULTS: This technique was used successfully in 31 consecutive patients undergoing TA-TEVAR; systemic blood pressure was obtained in all arch branches immediately after endograft deployment, indicating adequate blood flow. All arch branches were successfully cannulated and stented. CONCLUSION: This system enables accurate deployment of unconstrained triple-fenestrated arch endografts simply and reliably during TA-TEVAR.

Suprachoroidal Injection of Triamcinolone Acetonide Injectable Suspension for the Treatment of Macular Edema Associated With Uveitis in the United States: A Cost-Effectiveness Analysis.

OBJECTIVES: Suprachoroidal injection of triamcinolone acetonide is the first Food and Drug Administration-approved treatment for macular edema associated with uveitis. A cost-effectiveness analysis was performed comparing this treatment with best supportive care (BSC) for the management of this indication from US Medicare and commercial payer perspectives. METHODS: A patient-level simulation was developed per the patient characteristics and changes in best-corrected visual acuity letter scores observed in a phase III study of triamcinolone acetonide (PEACHTREE). The wholesale acquisition cost of triamcinolone acetonide was $1650/injection; suprachoroidal injection cost was assumed at $200/injection. Healthcare costs were informed by a US claims-based analysis. Mortality risk associated with severe vision loss and blindness was modeled by applying a hazard ratio to all-cause mortality rates of the US general population. Health-related quality of life weights, obtained from a regression model fitted to the Visual Function Questionnaire-25 data from PEACHTREE, were applied based on the best-corrected visual acuity scores of both eyes. Costs (2020 US dollar) and benefits were discounted at 3% annually. Incremental cost-effectiveness ratios were estimated over a 10-year horizon. RESULTS: In the base-case, the incremental cost-effectiveness ratio comparing triamcinolone acetonide with BSC was $28 479 per quality-adjusted life-year gained. The wholesale acquisition cost for triamcinolone acetonide for suprachoroidal use was ∼68%, ∼56%, and ∼27% below the willingness-to-pay thresholds of $150 000, $100 000, and $50 000 per quality-adjusted life-year gained, respectively. Results were robust in sensitivity and scenario analyses. CONCLUSIONS: Triamcinolone acetonide for suprachoroidal use is cost-effective compared with BSC for patients with macular edema associated with uveitis.

Spiking Neural Networks for Structural Health Monitoring.

This paper presents the first implementation of a spiking neural network (SNN) for the extraction of cepstral coefficients in structural health monitoring (SHM) applications and demonstrates the possibilities of neuromorphic computing in this field. In this regard, we show that spiking neural networks can be effectively used to extract cepstral coefficients as features of vibration signals of structures in their operational conditions. We demonstrate that the neural cepstral coefficients extracted by the network can be successfully used for anomaly detection. To address the power efficiency of sensor nodes, related to both processing and transmission, affecting the applicability of the proposed approach, we implement the algorithm on specialised neuromorphic hardware (Intel ® Loihi architecture) and benchmark the results using numerical and experimental data of degradation in the form of stiffness change of a single degree of freedom system excited by Gaussian white noise. The work is expected to open a new direction of SHM applications towards non-Von Neumann computing through a neuromorphic approach.

MuLV-related endogenous retroviral elements and Flt3 participate in aberrant end-joining events that promote B-cell leukemogenesis.

During V(D)J recombination of immunoglobulin genes, p53 and nonhomologous end-joining (NHEJ) suppress aberrant rejoining of DNA double-strand breaks induced by recombinase-activating genes (Rags)-1/2, thus maintaining genomic stability and limiting malignant transformation during B-cell development. However, Rag deficiency does not prevent B-cell leukemogenesis in p53/NHEJ mutant mice, revealing that p53 and NHEJ also suppress Rag-independent mechanisms of B-cell leukemogenesis. Using several cytogenomic approaches, we identified a novel class of activating mutations in Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase important for normal hematopoiesis in Rag/p53/NHEJ triple-mutant (TM) B-cell leukemias. These mutant Flt3 alleles were created by complex genomic rearrangements with Moloney leukemia virus (MuLV)-related endogenous retroviral (ERV) elements, generating ERV-Flt3 fusion genes encoding an N-terminally truncated mutant form of Flt3 (trFlt3) that was transcribed from ERV long terminal repeats. trFlt3 protein lacked most of the Flt3 extracellular domain and induced ligand-independent STAT5 phosphorylation and proliferation of hematopoietic progenitor cells. Furthermore, expression of trFlt3 in p53/NHEJ mutant hematopoietic progenitor cells promoted development of clinically aggressive B-cell leukemia. Thus, repetitive MuLV-related ERV sequences can participate in aberrant end-joining events that promote development of aggressive B-cell leukemia.

Clinical and angiographic outcomes of Mycophenolate versus Methotrexate in South Asian patients of Takayasu arteritis: Results from an open-label, randomised controlled trial.

OBJECTIVE: To compare the clinical and angiographic responses of Mycophenolate Mofetil (MMF) versus Methotrexate (MTX) in Takayasu arteritis (TAK). METHODS: This was a open label, outcome assessor blinded trial. Adult patients of TAK with active disease were randomized 1:1 to MMF 1g twice daily or MTX 20 mg once weekly, by computer generated program. All patients were started on 0.5 mg/kg of steroids with a predetermined tapering protocol. Primary outcome was treatment response as defined by Indian Takayasu arteritis score at 9 months. Secondary end points included time to first failure and angiographic progression. RESULTS: A total of 52 patients (26 in each arm) were recruited. The rate of responders was 71.43% (15/21) in the MMF arm and 63.64% (14/22) in the MTX arm (p=0.58). The median time to 1st failure was 9 months (Range: 3-9) and 4.5 months (range: 3-9) in the MMF and MTX arm respectively (p=0.052). In both groups, 15 % of patients (n=3) had progressive disease in angiography. CONCLUSION: The results showed numerically better outcomes towards MMF, with a longer time to first failure than Methotrexate(9 months versus 4.5 months, p=0.052). No significant difference was seen in the angiographic outcomes.

Clinical course of 602 patients with Takayasu's arteritis: comparison between Childhood-onset versus adult onset disease.

OBJECTIVES: To describe the clinical profile of Asian Indian patients with Takayasu's arteritis (TAK) and to compare clinical features and outcome of childhood-onset Takayasu's arteritis (cTAK) with adult-onset TAK (aTAK). METHODS: Data related to clinical features and response to treatment of patients with cTAK (age of onset <16 years) and aTAK from a large observational cohort in our tertiary care teaching hospital were noted and compared. RESULTS: Altogether, 602 patients (cTAK = 119; aTAK = 483) were studied. Patients with cTAK had a blunted female: male ratio; but fever, elevated acute phase reactants, involvement of abdominal aorta or its branches, hypertension, abdominal pain, elevated serum creatinine and cardiomyopathy were more common in cTAK as compared with aTAK. Patients with aTAK were more likely to have aortic-arch disease and claudication than cTAK. During follow-up, complete remission was more common in cTAK (87% vs 66%; P < 0.01), but subsequent relapses were equally common (30% vs 27%; P = 0.63). Independent associations of disease duration at presentation with disease extent [Disease Extent Index in TAK (DEI.Tak)] and damage [TAK Damage Score (TADS)] were observed (P ≤ 0.01). Moreover, 54% of patients with symptom duration of >5 years at presentation still continued to have elevated CRP suggesting continued and active inflammation warranting escalation or inititation of immunosuppression. CONCLUSION: Patients with cTAK are more likely to have arterial disease below the diaphragm, systemic inflammation and achieve remission. Disease of the aortic arch is more common in patients with aTAK. Longer duration of symptoms prior to initiation of immunosuppression, thereby leading to extensive disease and damage, reflects ongoing disease activity as the rule rather than exception in untreated TAK.

Coronary artery disease management and cost implications with fractional flow reserve guided coronary intervention in Indian patients with stable ischemic coronary artery disease.

OBJECTIVES: To study the safety of stent avoidance, frequency of change in management decisions, and its cost implications while using a fractional flow reserve (FFR)-guided treatment strategy for intermediate-grade coronary artery stenosis. BACKGROUND: The impact of FFR in guiding management decisions and its cost implications has not been studied after imposition of a ceiling on stent prices by the Government of India. METHODS: In 400 patients with 477 intermediate-grade coronary lesions for whom coronary intervention was planned, functional assessment using FFR was done. Incidence of the primary composite endpoint (major adverse cardiac event [MACE], cardiac death, myocardial infarction, objective evidence of ischemia, and target vessel revascularization) in the stent avoided subset was compared with the stented group at follow-up. Micro-costing analysis was done using a computed model with current stent and FFR wire prices. RESULTS: The overall incidence of MACE was 4.9%, 0.9% in the stent-avoided subset and 6.9% in stented group (p = 0.04, comparing the latter two) at a median follow-up of 21 months (interquartile range 12-31 months). Serious adverse events occurred only in 1% of patients receiving adenosine. The average cost saving was Indian rupees (INR) 51,847 [United States Dollar (USD) 746] per patient, resulting in total savings of INR 15,813,379 (USD 227,530). Cost savings persisted but were lower by 36% (INR 18,613/USD 268 per patient) after the ceiling of stent prices. CONCLUSION: FFR-guided percutaneous coronary intervention (PCI) strategy is safe and cost-effective in countries where majority of patients self-finance their health care, resulting in stent and PCI avoidance in approximately one in three patients referred for coronary angioplasty.