iPSC-Derived Neurons from Patients with POLG Mutations Exhibit Decreased Mitochondrial Content and Dendrite Simplification.

Mutations in POLG, the gene encoding the catalytic subunit of DNA polymerase gamma, result in clinical syndromes characterized by mitochondrial DNA (mtDNA) depletion in affected tissues with variable organ involvement. The brain is one of the most affected organs, and symptoms include intractable seizures, developmental delay, dementia, and ataxia. Patient-derived induced pluripotent stem cells (iPSCs) provide opportunities to explore mechanisms in affected cell types and potential therapeutic strategies. Fibroblasts from two patients were reprogrammed to create new iPSC models of POLG-related mitochondrial diseases. Compared with iPSC-derived control neurons, mtDNA depletion was observed upon differentiation of the POLG-mutated lines to cortical neurons. POLG-mutated neurons exhibited neurite simplification with decreased mitochondrial content, abnormal mitochondrial structure and function, and increased cell death. Expression of the mitochondrial kinase PTEN-induced kinase 1 (PINK1) mRNA was decreased in patient neurons. Overexpression of PINK1 increased mitochondrial content and ATP:ADP ratios in neurites, decreasing cell death and rescuing neuritic complexity. These data indicate an intersection of polymerase gamma and PINK1 pathways that may offer a novel therapeutic option for patients affected by this spectrum of disorders.

Multi-mode fiber-based speckle contrast optical spectroscopy: analysis of speckle statistics.

Speckle contrast optical spectroscopy/tomography (SCOS/T) provides a real-time, non-invasive, and cost-efficient optical imaging approach to mapping of cerebral blood flow. By measuring many speckles (n>>10), SCOS/T has an increased signal-to-noise ratio relative to diffuse correlation spectroscopy, which measures one or a few speckles. However, the current free-space SCOS/T designs are not ideal for large field-of-view imaging in humans because the curved head contour cannot be readily imaged with a single flat sensor and hair obstructs optical access. Herein, we evaluate the feasibility of using cost-efficient multi-mode fiber (MMF) bundles for use in SCOS/T systems. One challenge with speckle contrast measurements is the potential for confounding noise sources (e.g., shot noise, readout noise) which contribute to the standard deviation measure and corrupt the speckle contrast measure that is central to the SCOS/T systems. However, for true speckle measurements, the histogram of pixel intensities from light interference follows a non-Gaussian distribution, specifically a gamma distribution with non-zero skew, whereas most noise sources have pixel intensity distributions that are Gaussian. By evaluating speckle data from static and dynamic targets imaged through an MMF, we use histograms and statistical analysis of pixel histograms to evaluate whether the statistical properties of the speckles are retained. We show that flow-based speckle can be distinguished from static speckle and from sources of system noise through measures of skew in the pixel intensity histograms. Finally, we illustrate in humans that MMF bundles relay blood flow information.

Validation of secretory Immunoglobulin A (IgA) for early and efficient diagnosis of Pseudomonas aeruginosa lung infection.

Pseudomonas aeruginosa is a gram-negative bacterium that is considered to be a major causal organism of nosocomial infection. This study brought data-specific evidence to reveal the efficacy of secretory Immunoglobulin A (IgA) measurement in diagnosing pulmonary P. aeruginosa infection and claims its validation as a diagnostic marker. This study has included controls and patients of Pseudomonas and grouped them into four, namely, controls, chronic cases, intermittent cases, and negative group. The last group, that is, the "Negative" group, is the ones who had a history of infection but currently showed negative blood culture. The level of sIgA was quantified in all the patients and the controls and then their status of pulmonary infection was determined by their blood culture. ANOVA and Pearson Chi-Square were employed for showing the association between sIgA and pulmonary infection. The mean value of salivary sIgA has been found the highest in chronic cases followed by Intermittent cases and Negative Infections. The boxplot diagram showed several parameters of sIgA quantification in each group and control. ANOVA and Pearson Chi-square (P<0.005) tests showed a significant association between sIgA level in saliva and pulmonary infection of P. aeruginosa. The ROC curve was plotted to determine the cut-off value of sIgA (sIgA≧13.09 U/ml) for efficient clinical diagnosis of pulmonary P. aeruginosa infection. The study has validated statistically that quantification of salivary sIgA can be used in clinical practice for early diagnosis of pulmonary infection of P. aeruginosa.

Serum Expression Level of MicroRNA-122 and its Significance in different Stages of Hepatitis B Virus Infection.

This study aims to determine the serum expression level of miRNA-122 and its significance in the different stages of Hepatitis B virus infection. The study subjects were recruited and grouped for Hepatitis B associated with Chronic Hepatitis B infection, hepatic sclerosis, hepatocellular carcinoma, and healthy controls were also considered. Venous blood was collected from the participants including the controls and routine blood tests and quantification of miRNA-122 were done and analyzed in each case of hepatitis B infection and compared with that of healthy controls. The miRNA-122 was determined, which came to be highest in patients with Chronic Hepatitis B while patients with hepatic sclerosis and patients with hepatocellular carcinoma showed a subsequent number of copies. The number of copies of miRNA-122 in the CHB, hepatic sclerosis, and HCC group was significantly higher than in the healthy control. The quantification of miRNA-122 and subsequently plotting the ROC curve has shown that miRNA-122 can be considered as a biomarker of hepatitis B for screening and diagnosis purposes.

Meta-analysis and cost-effectiveness analysis of intranasal corticosteroid treatment in allergic rhinitis with ocular symptoms.

BACKGROUND: Intranasal corticosteroid (INCS) has a beneficial effect on ocular symptoms in allergic rhinitis (AR). To our knowledge, the cost-effectiveness of available INCS for AR with ocular symptoms is yet to be demonstrated. OBJECTIVE: To evaluate the cost-effectiveness of INCSs including Budesonide (BANS), Mometasone furoate (MFNS), Triamcinolone (TANS), and Fluticasone furoate (FFNS) on ocular symptoms associated with AR in the Thai context. METHODS: The percentage of effectiveness in improving total ocular symptoms score (TOSS) was derived from the result of a meta-analysis that estimated the SMD of each INCS treatment compared to placebo as clinical input parameters. A cost-effectiveness analysis based on a decision-tree model to assess one-year costs and outcomes from a Thai societal perspective. The outcomes were to compare incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analyses (PSA) were also conducted to capture parameter uncertainties. RESULTS: 13 eligible RCTs with a total of 3,722 patients with SAR were included in the analysis. The percentage of effectiveness of FFNS, MFNS, TANS, and BANS was 59.89%, 45.60%, 24.89%, and 16.00%, respectively. The ICER of FFNS, MFNS, and TANS is THB-6,539.92, 4,593.83, and 1,401.24 compared to BANS. CECA result showed the probability of using FFNS is considered cost-effective in 87.50% of cases from zero value followed by MFNS (0.80%), TANS (5.40%), and BANS (6.30%). With a threshold greater than THB20,000, FFNS is considered a cost-effective strategy. CONCLUSIONS: FFNS is a cost-effective option compared to alternative INCSs in Thailand for treating AR with ocular symptoms.

Genome-wide identification and annotation of SNPs and their mapping in candidate genes related to milk production and fertility traits in Badri cattle.

This study was conducted in Badri cattle using a double digest restriction-site associated DNA sequencing approach. The study aimed to identify and annotate high confidence single nucleotide polymorphisms (SNPs) and their mapping in candidate genes related to production and fertility in dairy cattle. A total of 7,168,552 genome-wide SNPs were initially identified in Badri cattle by alignment with the Bos indicus reference genome. After filtration of SNPs, 65,483 high confidence SNPs were retained and further used for downstream analysis. Annotation of high confidence SNPs revealed 99.197% SNPs had modifier impact, 0.326% SNPs were low impact, 0.036% were high impact, and 0.441% were moderate impact SNPs. Most SNPs in Badri cattle were found in intergenic, transcript and intronic regions. The candidate genes for milk production PRKCE, ABCG2, GHR, EPS8, CAST and NRXN1 were found to harbour maximum high confidence variants. Among candidate genes for fertility in cattle, ATP2B1, SOX5, WDR27, ARHGAP12, CACNA1D, ANKRD6, GRIA3, ZNF521 and CAST822 have maximum high confidence variants mapped in them. The SNPs found mapped in the candidate genes will be important genetic tools in the search for phenotype-modifying nucleotide changes and will aid in formulating relevant genetic improvement programmes for dairy cattle.

Chronic treatment with the complex I inhibitor MPP+ depletes endogenous PTEN-induced kinase 1 (PINK1) via up-regulation of Bcl-2-associated athanogene 6 (BAG6).

Mitochondrial dysfunction is implicated in sporadic and familial Parkinson's disease (PD). However, the mechanisms that impair homeostatic responses to mitochondrial dysfunction remain unclear. Previously, we found that chronic, low-dose administration of the mitochondrial complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+) dysregulates mitochondrial fission-fusion, mitophagy, and mitochondrial biogenesis. Given that PTEN-induced kinase 1 (PINK1) regulates mitochondrial function, dynamics, and turnover, we hypothesized that alterations in endogenous PINK1 levels contribute to depletion of mitochondria during chronic complex I injury. Here we found that chronic MPP+ treatment of differentiated SH-SY5Y neuronal cells significantly decreases PINK1 expression prior to reductions in other mitochondrial components. Furthermore, Bcl2-associated athanogene 6 (BAG6, BAT3, or Scythe), a protein involved in protein quality control and degradation, was highly up-regulated during the chronic MPP+ treatment. BAG6 interacted with PINK1, and BAG6 overexpression decreased the half-life of PINK1. Conversely, siRNA-mediated BAG6 knockdown prevented chronic MPP+ stress-induced loss of PINK1, reversed MPP+-provoked mitochondrial changes, increased cell viability, and prevented MPP+-induced dendrite shrinkage in primary neurons. These results indicate that BAG6 up-regulation during chronic complex I inhibition contributes to mitochondrial pathology by decreasing the levels of endogenous PINK1. Given that recessive mutations in PINK1 cause familial PD, the finding of accelerated PINK1 degradation in the chronic MPP+ model suggests that PINK1 loss of function represents a point of convergence between the neurotoxic and genetic causes of PD.

Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants.

Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs before the well-characterized phenotype of dendritic shortening. As mitochondria play a major role in the rapid buffering of cytosolic calcium, we hypothesized that altered mitochondrial calcium handling contributes to dendritic retraction elicited by the LRRK2-G2019S and -R1441C mutations. In primary mouse cortical neurons, we observed increased depolarization-induced mitochondrial calcium uptake. We found that expression of mutant LRRK2 elicited transcriptional upregulation of the mitochondrial calcium uniporter (MCU) and the mitochondrial calcium uptake 1 protein (MICU1) with no change in levels of the mitochondrial calcium antiporter NCLX. Elevated MCU and MICU1 were also observed in LRRK2-mutated patient fibroblasts, along with increased mitochondrial calcium uptake, and in postmortem brains of sporadic PD/PDD patients of both sexes. Transcriptional upregulation of MCU and MICU1 was caused by activation of the ERK1/2 (MAPK3/1) pathway. Inhibiting ERK1/2 conferred protection against mutant LRRK2-induced neurite shortening. Pharmacological inhibitors or RNAi knockdown of MCU attenuated mitochondrial calcium uptake and dendritic/neuritic shortening elicited by mutant LRRK2, whereas expression of a constitutively active mutant of NCLX that enhances calcium export from mitochondria was neuroprotective. These data suggest that an increased susceptibility to mitochondrial calcium dysregulation contributes to dendritic injury in mutant LRRK2 pathogenesis.SIGNIFICANCE STATEMENT Cognitive dysfunction and dementia are common features of Parkinson's disease (PD), causing significant disability. Mutations in LRRK2 represent the most common known genetic cause of PD. We found that PD-linked LRRK2 mutations increased dendritic and mitochondrial calcium uptake in cortical neurons and familial PD patient fibroblasts, accompanied by increased expression of the mitochondrial calcium transporter MCU. Blocking the ERK1/2-dependent upregulation of MCU conferred protection against mutant LRRK2-elicited dendrite shortening, as did inhibiting MCU-mediated calcium import. Conversely, stimulating the export of calcium from mitochondria was also neuroprotective. These results implicate increased susceptibility to mitochondrial calcium overload in LRRK2-driven neurodegeneration, and suggest possible interventions that may slow the progression of cognitive dysfunction in PD.

ERKed by LRRK2: a cell biological perspective on hereditary and sporadic Parkinson's disease.

The leucine rich repeat kinase 2 (LRRK2/dardarin) is implicated in autosomal dominant familial and sporadic Parkinson's disease (PD); mutations in LRRK2 account for up to 40% of PD cases in some populations. LRRK2 is a large protein with a kinase domain, a GTPase domain, and multiple potential protein interaction domains. As such, delineating the functional pathways for LRRK2 and mechanisms by which PD-linked variants contribute to age-related neurodegeneration could result in pharmaceutically tractable therapies. A growing number of recent studies implicate dysregulation of mitogen activated protein kinases 3 and 1 (also known as ERK1/2) as possible downstream mediators of mutant LRRK2 effects. As these master regulators of growth, differentiation, neuronal plasticity and cell survival have also been implicated in other PD models, a set of common cell biological pathways may contribute to neuronal susceptibility in PD. Here, we review the literature on several major cellular pathways impacted by LRRK2 mutations--autophagy, microtubule/cytoskeletal dynamics, and protein synthesis--in context of potential signaling crosstalk involving the ERK1/2 and Wnt signaling pathways. Emerging implications for calcium homeostasis, mitochondrial biology and synaptic dysregulation are discussed in relation to LRRK2 interactions with other PD gene products. It has been shown that substantia nigra neurons in human PD and Lewy body dementia patients exhibit cytoplasmic accumulations of ERK1/2 in mitochondria, autophagosomes and bundles of intracellular fibrils. Both experimental and human tissue data implicate pathogenic changes in ERK1/2 signaling in sporadic, toxin-based and mutant LRRK2 settings, suggesting engagement of common cell biological pathways by divergent PD etiologies.

Sirtuin-3 modulates Bak- and Bax-dependent apoptosis.

Sirtuin-3 exhibits properties of a tumor suppressor partly emanating from its ability to control the state of mitochondrial metabolism, with depletion of sirt-3 increasing tumor cell survival. In the present study we demonstrate that depletion of sirtuin-3 brings about an anti-apoptotic phenotype via stimulating cyclophilin-D activity, which promotes the binding of hexokinase II to the mitochondria, thereby preventing Bak/Bax dependent mitochondrial injury and cell death. By contrast, increased expression of sirtuin-3 decreases cyclophilin-D activity, resulting in detachment of hexokinase II from the mitochondria and potentiation of Bak- and Bax-induced mitochondrial injury and loss of cell viability.

Sirtuin-4 modulates sensitivity to induction of the mitochondrial permeability transition pore.

The sustained opening of the mitochondrial permeability transition pore (PTP) is a decisive event in the onset of irreversible cell injury. The PTP is modulated by numerous exogenous and endogenous effectors, including mitochondrial membrane potential, ions and metabolites. Mitochondrial sirtuins have recently emerged as pivotal mediators of mitochondrial metabolism. In the present study, we demonstrate that sirt-4 modulates sensitivity to PTP onset induced by calcium and the oxidative cross linking reagent phenylarsine oxide, and PTP dependent cytotoxicity brought about by TNF or doxorubicin. Moreover, the ability of sirt-4 to modulate onset of the PTP is dependent on the expression of glutamate dehydrogenase-1.

Transport Mode Selection for Toxic Gases: Rail or Road?

A significant majority of hazardous materials (hazmat) shipments are moved via the highway and railroad networks, wherein the latter mode is generally preferred for long distances. Although the characteristics of highway transportation make trucks the most dominant surface transportation mode, should it be preferred for hazmat whose accidental release can cause catastrophic consequences? We answer this question by first developing a novel and comprehensive assessment methodology-which incorporates the sequence of events leading to hazmat release from the derailed railcars and the resulting consequence-to measure rail transport risk, and second making use of the proposed assessment methodology to analyze hazmat transport risk resulting from meeting the demand for chlorine and ammonia in six distinct corridors in North America. We demonstrate that rail transport will reduce risk, irrespective of the risk measure and the transport corridor, and that every attempt must be made to use railroads to transport these shipments.

Adiponectin and HbA1c levels among Indian patients with diabetes mellitus.

Adiponectin is closely related to glucose metabolism and newly diagnosed type 2 diabetes mellitus (T2DM), and other kinds of diabetes linked to the risk of T2DM. Therefore, it is of interest to report the correlation between adiponectin levels and glycosylated hemoglobin (HbA1c) as a diagnostic marker of T2DM and healthy control. Total 210 participants were included of IPD & OPD healthy controls with glycosylated hemoglobin levels under 6% were included. Blood samples, collected using sterile clot activator or plain vials, were stored at -20°C. The biomarker score that comprised significant differences in age, gender distribution, and metabolic indicators are seen between the diabetes (n=105) and control (n=105) groups. Increase in both Adiponectin and HbA1c% Mean±SD (6.86±0.23, p<0.0001; 22.71±2.01; p<0.0001) is indicative of deteriorating glycaemic control and an accompanying rise in inflammatory response. Positively correlate adiponectin levels with HbA1c levels (r2=0.398; p<0.0001), suggesting a link between inflammatory response and glucose control. Lower adiponectin levels are statistically associated with diabetes. Diabetes and adiponectin were negatively correlated and positive linear relationship between HbA1c and adiponectin levels. Adiponectin may be a significant factor useful in understanding the pathophysiology; they are likely to be straight forward instruments for predicting future risk of diabetes.

Screening type 2 Diabetes mellitus among Indians using inflammatory biomarkers.

Diabetes is a metabolic disorder associated with chronic inflammation; pre-diabetes phase promotes to inflammatory mechanism then finally progress to diabetes and its associated complications. Therefore, it is of interest to investigate the changes in inflammatory biomarkers Evidence that inflammatory markers play a role in the development as well as severity of Type 2 diabetes mellitus (T2DM). This study has been designed to decipher the involvement of Tumor Necrosis Factor (TNFα), Interleukin-6 (IL-6), Nesfatin-1 and Blood sugar in the etiopathogenesis of T2DM. This retrospective observational study analyzed patient records from our hospital, focusing on those with diabetes or pre-diabetes. Glycosylated hemoglobin, inflammatory biomarkers, Fasting Blood Glucose, and Post-Prandial Blood Glucose were assessed. SPSS 28 facilitated statistical analysis; utilizing Bivariate Correlation assessed the relationship between inflammatory biomarkers and diabetes status (glycosylated hemoglobin). In the pre-diabetic vs. diabetic groups, significant differences exist in IL-6 (p=0.0344), TNF-α (p=0.041), Nesfatin-1 (p=0.0485), fasting blood glucose (p=0.036), and 2h post-prandial blood glucose (p=0.048). IL6 (AUC=0.729, p<0.001), TNF (AUC=0.761, p<0.001), and Nesfatin1 (AUC=0.892, p<0.001) show moderate discriminative power. PP (AUC=0.992, p<0.001) and hbA1c (AUC=0.993, p<0.001) exhibit excellent discriminatory ability. Correlations: IL6 with TNF (r=0.672, p<0.001) and Nesfatin1 (r=0.542, p<0.001); TNF with Nesfatin1 (r=0.591, p<0.001), hbA1c (r=0.683, p<0.001), and PP (r=0.367, p<0.001); Nesfatin1 with PP (r=0.594, p<0.001) and hbA1c (r=0.800, p<0.001). Age has a negative correlation with hbA1c (r=-0.119, p=0.086). Thus, data shows a significant association between inflammatory markers, blood glucose levels, and the progression from pre-diabetes to diabetes.

General practitioner and patient perspectives on intranasal corticosteroids for allergic rhinitis: Treatment duration and obstacles to adherence, findings from a recent survey.

Background and objective: Currently, there are no guideline recommendations for the duration of intranasal corticosteroid (INCS) treatment for allergic rhinitis (AR). We aimed to catalogue real-world AR-INCS prescription patterns. Materials and methods: This multicenter, non-interventional, cross-sectional study used online general practitioner (GP) and patient surveys from 4 countries. Eligible GPs had 3-35 years of practical experience, regularly prescribed INCSs for AR treatment, and had managed ≥5 patients with AR per month according to Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in the previous year. Eligible patients with AR were non-pregnant females or males, aged 18-65 years, previous AR-INCS users (≥12 months), and receiving GP-prescribed AR therapy. Survey participants were from countries with 15-50% AR prevalence and mostly prescription-only INCS use of ≥100 million units annually (Brazil, Mexico, Spain, Thailand). GP surveys and GP-completed patient record forms (PRFs) gathered AR-care and INCS-use data over 10 months; each GP completed patient record forms (PRFs) for 3 patients with AR under their care. The patient survey reflected actual AR-INCS experience, treatment duration, and adherence factors from patient perspectives. The target sample size was 75 GPs, 75 patients, and ≥30 respondents per country. Results: From 900 GP-PRFs, the mean GP-recommended AR-INCS durations reported were 8.4 (Brazil), 8.3 (Mexico), 5.4 (Spain), and 6.4 (Thailand) weeks. From 300 patient surveys, mean reported INCS recommended durations were 6.4 (Brazil), 5.1 (Mexico), 4.0 (Spain), and 4.9 (Thailand) weeks; reported actual use durations were 6.2, 4.8, 3.6, and 6.4 weeks, respectively. The most frequent GP-PRF-reported factors influencing AR-INCS treatment duration were symptom severity (76-85%), symptom recurrence (49-73%), and existing comorbidities (33-57%). The most frequent GP-PRF-reported obstacles to adherence included forgetting to take medication regularly (54-100%), subsiding symptoms (42-91%), and being unable to continue activities (33-51%). Subsiding symptoms (36-53%) and reaching the prescription duration end (20-51%) were most frequent obstacles reported by the patient survey. Patients from all surveyed countries indicated that they visited the GP, a different physician, or a pharmacy for assistance with symptom recurrence; some patients also self-medicated. Conclusions: Real-world AR-INCS prescription durations vary between countries and actual use tends to be shorter than prescribed. Understanding underlying factors may support appropriate AR-INCS use. The study was not powered to statistically compare intercountry differences; hence, comparisons have not been drawn, and the small sample may not reflect a complete picture of clinical practice and patients with AR in each country.

Systematic literature review of traits and outcomes reported in randomised controlled trials of asthma with regular dosing of inhaled corticosteroids with short-acting ß2-agonist reliever, as-needed ICS/formoterol, or ICS/formoterol maintenance and reliever therapy.

INTRODUCTION: Asthma treatments based solely on diagnostic label do not benefit patients equally. To identify patient traits that may be associated with improved treatment response to regular inhaled corticosteroid (ICSs) dosing with short-acting ß2-agonist reliever or ICS/formoterol-containing therapy, a systematic literature review (SLR) was conducted. METHODS: Searches of databases including MEDLINE and Embase identified randomised controlled trials (RCTs) of patients with asthma, aged ≥12 years, published 1998-2022, containing ≥1 regular ICS dosing or ICS/formoterol-containing treatment arm, and reporting patient traits and outcomes of interest. Relevant data was extracted and underwent a feasibility assessment to determine suitability for meta-analysis. RESULTS: The SLR identified 39 RCTs of 72,740 patients and 90 treatment arms, reporting 11 traits and 11 outcomes. Five patient traits (age, body mass index, FEV1, smoking history, asthma control) and five outcomes (exacerbation rate, lung function, asthma control, adherence, time to first exacerbation) were deemed feasible for inclusion in meta-analyses due to sufficient comparable reporting. Subgroups of clinical outcomes stratified by levels of patient traits were reported in 16 RCTs. CONCLUSION: A systematic review of studies of regular ICS dosing with SABA or ICS/formoterol-containing treatment strategies in asthma identified consistent reporting of five traits and outcomes, allowing exploration of associations with treatment response. Conversely, many other traits and outcomes, although being potentially relevant, were inconsistently reported and limited subgroup reporting meant analyses of treatment response for subgroups of traits was not possible. We recommend more consistent measurement and reporting of clinically relevant patient traits and outcomes in respiratory RCTs.

A network meta-analysis of the association between patient traits and response to regular dosing with ICS plus short-acting ß2-agonist reliever or ICS/formoterol reliever only in mild asthma.

INTRODUCTION/BACKGROUND: Mild asthma treatment recommendations include intermittent inhaled corticosteroid (ICS)/formoterol dosing or regular ICS dosing with short-acting ß2-agonist reliever. Due to the heterogeneity of asthma, identification of traits associated with improved outcomes to specific treatments would be clinically beneficial. AIMS/OBJECTIVES: To assess the impact of patient traits on treatment outcomes of regular ICS dosing compared with intermittent ICS/formoterol dosing, a systematic literature review (SLR) and network meta-analysis (NMA) was conducted. Searches identified randomised controlled trials (RCTs) of patients with asthma aged ≥12 years, containing ≥1 regular ICS dosing or intermittent ICS/formoterol dosing treatment arm, reporting traits and outcomes of interest. RESULTS: The SLR identified 11 RCTs of mild asthma, of 14,516 patients. A total of 11 traits and 11 outcomes of interest were identified. Of these, a feasibility assessment indicated possible assessment of three traits (age, baseline lung function, smoking history) and two outcomes (exacerbation rate, change in lung function). The NMA found no significant association of any trait with any outcome with regular ICS dosing relative to intermittent ICS/formoterol dosing. Inconsistent reporting of traits and outcomes between RCTs limited analysis. CONCLUSIONS: This is the first systematic analysis of associations between patient traits and differential treatment outcomes in mild asthma. Although the traits analysed were not found to significantly interact with relative treatment response, inconsistent reporting from the RCTs prevented assessment of some of the most clinically relevant traits and outcomes, such as adherence. More consistent reporting of respiratory RCTs would provide more comparable data and aid future analyses.

Baseline Characteristics and Maintenance Therapy Choice on Symptom Control, Reliever Use, Exacerbation Risk in Moderate-Severe Asthma: A Clinical Modelling and Simulation Study.

INTRODUCTION: Although some factors associated with asthma symptom deterioration and risk of exacerbation have been identified, these are not yet fully characterised. We conducted a clinical modelling and simulation study to understand baseline factors affecting symptom control, reliever use and exacerbation risk in patients with moderate-severe asthma during follow-up on regularly dosed inhaled corticosteroid (ICS) monotherapy, or ICS/long-acting beta2-agonist (LABA) combination therapy. METHODS: Individual patient data from randomised clinical trials (undertaken between 2001 and 2019) were used to model the time course of symptoms (n = 7593), patterns of reliever medication use (n = 3768) and time-to-first exacerbation (n = 6763), considering patient-specific and extrinsic factors, including treatment. Model validation used standard graphical and statistical criteria. Change in symptom control scores (Asthma Control Questionnaire 5 [ACQ-5]), reduction in reliever use and annualised exacerbation rate were then simulated in patient cohorts with different baseline characteristics and treatment settings. RESULTS: Being a smoker, having higher baseline ACQ-5 and body mass index affected symptom control scores, reliever use and exacerbation risk (p < 0.01). In addition, low forced expiratory volume in 1 s percent predicted, female sex, season and previous exacerbations were found to contribute to a further increase in exacerbation risk (p < 0.01), whereas long asthma history was associated with more frequent reliever use (p < 0.01). These effects were independent from the underlying maintenance therapy. In different scenarios, fluticasone furoate (FF)/vilanterol was associated with greater reductions in reliever use and exacerbation rates compared with FF or fluticasone propionate (FP) alone or budesonide/formoterol, independently from other factors (p < 0.01). CONCLUSIONS: This study provided further insight into the effects of individual baseline characteristics on treatment response and highlighted significant differences in the performance of ICS/LABA combination therapy on symptom control, reliever use and exacerbation risk. These factors should be incorporated into clinical practice as the basis for tailored management of patients with moderate-severe asthma.

In this study we quantified how individual baseline patient characteristics at the start of treatment influence the response to regular maintenance medication. Specifically, using computer modelling and simulations based on data from individual patients enrolled into clinical trials in moderate­severe asthma, we predicted how much reliever inhaler they need, how well they rate their asthma control, and how likely an asthma attack (exacerbation) is to occur within the next 12 months. Simulation scenarios were then implemented to evaluate opportunities to improve and personalise real-life management of patients in clinical practice. Considering symptom control level, reliever use and other patient-specific factors at the start of treatment, we assessed how well maintenance therapy with inhaled corticosteroids/bronchodilators contributes to symptom improvement and/or reduction in the risk of asthma attacks. These scenarios show that current smokers, people with higher asthma symptom scores, who are obese, and have a longer history of asthma tend to use their reliever inhalers more often. Moreover, this was linked to a higher risk of having an asthma attack and worse symptom control. This pattern appears to compensate in most cases for the effect of the same baseline factors on symptom control. Switching patients who are not responding well to initial treatment with the inhaled corticosteroid, fluticasone propionate, to fluticasone furoate/vilanterol resulted in a significantly greater reduction in reliever inhaler use and risk of asthma attack, compared with those switched to budesonide/formoterol. These findings highlight the importance of tailored choices for optimal management of patients with moderate­severe asthma.

Linking IL-6 and hsCRP among Indian patients with myocardial infarction.

The association between serum interleukin-6 (IL-6) and highly sensitive C - reactive protein (hsCRP) as predictors of the risk factors for Myocardial Infarction. The study included a total of 50 patients with Myocardial Infarction, aged between 25 to 74 years. The levels of hsCRP were measured using the immunoturbidimetry method, while Interleukin 6 was estimated using the sandwich ELISA method. Statistical analysis was conducted using SPSS version 21.0, with p values calculated using Quartile ratio, ANOVA unpaired t-test, and Kaplan-Meier Curve Method. A p-value of less than 0.05 was considered statistically significant. All participants underwent a questionnaire, physical examination, medical history assessment, and laboratory tests. The results of the study showed that there was a significant correlation between IL-6 and hsCRP levels in the Quartile groups, as well as with lipid profiles. The Kaplan-Meier method also demonstrated a significant association between IL-6 and hsCRP levels in participants. The comparison of biomarkers further supported these findings. Thus, data shows that elevated levels of hsCRP and IL-6 could serve as valuable diagnostic markers for predicting Acute Myocardial Infarction. Our study strongly suggests that IL-6 could be a powerful marker in evaluating the Myocardial Infarction.