Optimizing Glioblastoma, IDH-wildtype Treatment Outcomes : A Radiomics and Support Vector Machine -Based Approach to Overall Survival Estimation.

Objective: Glioblastoma multiforme (GBM), particularly the IDH-wildtype type, represents a significant clinical challenge due to its aggressive nature and poor prognosis. Despite advancements in medical imaging and its modalities, survival rates have not improved significantly, demanding innovative treatment planning and outcome prediction approaches. Methods: This study utilizes a Support Vector Machine (SVM) classifier using radiomics features to predict the overall survival (OS) of GBM, IDH-wildtype patients to short (< 12 Months) and long (>=12 Months) survivors. A dataset comprising multi-parametric MRI (mpMRI) scans from 574 patients was analyzed. Radiomic features were extracted from T1, T2, FLAIR, and T1-Gd sequences. Low variance features were removed, and Recursive Feature Elimination (RFE) was used to select the most informative features. The SVM model was trained using a k-fold cross-validation approach. Furthermore, clinical parameters such as age, gender, and MGMT promoter methylation status were integrated to enhance prediction accuracy. Results: The model showed reasonable results in terms of cross-validated AUC of 0.84 (95% CI: 0.80-0.90) with (p-value < 0.001) effectively categorizing patients into short and long survivors. Log-rank test (Chi-square statistics) analysis for the developed model was 0.00029 along with the 1.20 Cohen's d effect size. Most importantly, clinical data integration further refined the survival estimates, providing a more fitted prediction that considers individual patient characteristics by Kaplan-Meier curve with p-value<0.0001. Conclusion: The proposed method significantly enhances the predictive accuracy of OS outcomes in GBM, IDH-wildtype patients. By integrating detailed imaging features with key clinical indicators, this model offers a robust tool for personalized treatment planning, potentially improving OS.

Serine hydroxymethyltransferase6 is involved in growth and resistance against pathogens via ethylene and lignin production in Arabidopsis.

Photorespiratory serine hydroxymethyltransferases (SHMTs) are important enzymes of cellular one-carbon metabolism. In this study, we investigated the potential role of SHMT6 in Arabidopsis thaliana. We found that SHMT6 is localized in the nucleus and expressed in different tissues during development. Interestingly SHMT6 is inducible in response to avirulent, virulent Pseudomonas syringae and to Fusarium oxysporum infection. Overexpression of SHMT6 leads to larger flowers, siliques, seeds, roots, and consequently an enhanced overall biomass. This enhanced growth was accompanied by increased stomatal conductance and photosynthetic capacity as well as ATP, protein, and chlorophyll levels. By contrast, a shmt6 knockout mutant displayed reduced growth. When challenged with Pseudomonas syringae pv tomato (Pst) DC3000 expressing AvrRpm1, SHMT6 overexpression lines displayed a clear hypersensitive response which was characterized by enhanced electrolyte leakage and reduced bacterial growth. In response to virulent Pst DC3000, the shmt6 mutant developed severe disease symptoms and becomes very susceptible, whereas SHMT6 overexpression lines showed enhanced resistance with increased expression of defense pathway associated genes. In response to Fusarium oxysporum, overexpression lines showed a reduction in symptoms. Moreover, SHMT6 overexpression lead to enhanced production of ethylene and lignin, which are important components of the defense response. Collectively, our data revealed that SHMT6 plays an important role in development and defense against pathogens.

Variants in exon 2 of MED12 gene causes uterine leiomyoma's through over-expression of MMP-9 of ECM pathway.

AIMS: To study the impact of Mediator complex subunit 12 (MED12) gene variants on the encoded protein's function and pathogenic relevance for genesis of uterine leiomyoma's (ULs). METHODS: Mutational analysis in exon-2 of MED12 gene was performed by PCR amplification and DNA sequencing in 89 clinically diagnosed ULs tissues. Pathogenicity prediction of variation was performed by computational analysis. The functional effects of missense variation were done by quantity RT-PCR and western blot analysis. RESULT(S): Out of 89 samples, 40 (44.94%) had missense variation in 14 different CDS position of exon-2 of MED12 gene. Out of 40 missense variation, codon 44 had 25 (62.5%) looking as a hotspot region for mutation for ULs, because CDS position c130 and c131present at codon 44 that have necleotide change G>A, T, C at c130 and c131 have necleotide change G>A and C. We also find somenovel somatic mutations oncodon 36 (T > C), 38 (G>T) of exon-2 and 88 (G>C) of intron-2. No mutations were detected in uterine myometrium samples. Our computational analysis suggests that change in Med12c .131 G>A leads to single substitution of amino acid [Glycine (G) to Aspartate (D)] which has a pathogenic and lethal impact and may cause instability of MED12 protein. Further, analysis of extracellular matrix (ECM) component (MMP-2 & 9, COL4A2 and α-SMA) mRNA and protein expression levels in the set of ULs having MED12 mutation showed significantly higher expression of MMP-9 and α-SMA. CONCLUSION(S): The findings of present study suggest that missense variation in codon 44 of MED12 gene lead to the genesis of leiomyoma's through over-expression of MMP-9 of ECM pathway which could be therapeutically targeted for non-surgical management of ULs.

Bioconjugate-loaded solid lipid nanoparticles for enhanced anticancer drug delivery to brain cancer cells: An in vitro evaluation.

Background & objectives: The treatment of brain cancer is still challenging for an oncologist due to the presence of the blood-brain barrier (BBB) which inhibits the entry of more than 98 per cent of drugs used during the treatment of brain disease. The cytotoxic drugs used in chemotherapy for brain cancer treatment also affect the normal cells due to lack of targeting. Therefore, the objective of the study was to develop tween 80-coated solid lipid nanoparticles (SLNs) loaded with folic acid-doxorubicin (FAD) conjugate for site-specific drug delivery to brain cancer cells. Methods: The FAD conjugate was synthesized by the conjugation of folic acid with doxorubicin and characterized by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. SLNs loaded with FAD were prepared by the solvent injection method. The SLNs were characterized by the particle size, zeta potential, surface morphology, entrapment efficiency, etc. Results: The average particle size of FAD conjugate-loaded SLNs (SLN-C) was found to be 220.4±2.2 nm, with 36.2±0.6 per cent entrapment efficiency. The cytotoxicity and cellular uptake were determined on U87 MG cell lines. Half maximal inhibitory concentration value of the SLN-C was found to be 2.5 µg/ml, which confirmed the high antitumour activity against brain cancer cells. Interpretation & conclusions: The cell line studies confirmed the cytotoxicity and internalization of SLN-C in U87 MG brain cancer cells. The results confirmed that tween 80-coated SLNs have the potential to deliver the doxorubicin selectively in the brain cancer cells.

Identification and analysis of miRNAs-lncRNAs-mRNAs modules involved in stem-elongation of deepwater rice (Oryza sativa L.).

Deepwater is an abiotic stress that limits rice cultivation worldwide due to recurrent floods. The miRNAs and lncRNAs are two non-coding RNAs emerging as major regulators of gene expressions under different abiotic stresses. However, the regulation of these two non-coding RNAs under deepwater stress in rice is still unexplored. In this study, small RNA-seq and RNA-seq from internode and node tissues were analyzed to predict deepwater stress responsive miRNAs and lncRNAs, respectively. Additionally, a competitive endogenous RNA (ceRNA) study revealed about 69 and 25 lncRNAs acting as endogenous target mimics (eTM) with the internode and node miRNAs, respectively. In ceRNA analyses, some of the key miRNAs such as miR1850.1, miR1848, and IN-nov-miR145 were upregulated while miR159e was downregulated, and their respective eTM lncRNAs and targets were found to have opposite expressions. Moreover, we have transiently expressed one module (IN-nov-miR145-Cc-TCONS_00011544-Os11g36430.3) in tobacco leaves. The integrated analysis has identified differentially expressed (DE) miRNAs, lncRNAs and their target genes, and the complex regulatory network, which might lead to stem elongation under deepwater stress. In this novel attempt to identify and characterize miRNAs and lncRNAs under deepwater stress in rice, we have provided, probably for the first time, a reference platform to study the interactions of these two non-coding RNAs with respective target genes through transient expression analyses.

Machine learning approaches and their applications in drug discovery and design.

This review is focused on several machine learning approaches used in chemoinformatics. Machine learning approaches provide tools and algorithms to improve drug discovery. Many physicochemical properties of drugs like toxicity, absorption, drug-drug interaction, carcinogenesis, and distribution have been effectively modeled by QSAR techniques. Machine learning is a subset of artificial intelligence, and this technique has shown tremendous potential in the field of drug discovery. Techniques discussed in this review are capable of modeling non-linear datasets, as well as big data of increasing depth and complexity. Various machine learning-based approaches are being used for drug target prediction, modeling the structure of drug target, binding site prediction, ligand-based similarity searching, de novo designing of ligands with desired properties, developing scoring functions for molecular docking, building QSAR model for biological activity prediction, and prediction of pharmacokinetic and pharmacodynamic properties of ligands. In recent years, these predictive tools and models have achieved good accuracy. By the use of more related input data, relevant parameters, and appropriate algorithms, the accuracy of these predictions can be further improved.

Relationships, body image, and intimacy: A pilot to increase sexual health conversations between radiation therapists and cancer patients in Ontario.

BACKGROUND: In 2016, a sexual health guideline recommended that the first step to addressing sexual health and dysfunction resulting from cancer and its treatment is for healthcare providers to initiate sexual health conversations with patients. To action this, a sexual health knowledge translation (KT) pilot was developed. METHODS: The Relationships, Body image, and Intimacy (RBI) pilot was implemented at four regional cancer centres (RCCs) from January 2018 to February 2020 which focused on medical radiation therapists (MRT(T)s) initiating conversations with radiation therapy patients. MRT(T)s were recruited to be RBI champion role models and were trained on RBI topics, trained fellow MRT(T)s, and modelled best practice for sexual health conversations with cancer patients. Pilot interventions were developed to address barriers to RBI conversations. Both qualitative and quantitative data collection activities were implemented to evaluate pilot interventions. RESULTS: Before the RBI pilot, over 80% of MRT(T)s reported they did not initiate RBI conversations with patients. By the end of the pilot, over 52% of MRT(T)s reported initiating RBI conversations with all or almost all patients. Feedback from patients was positive. Barriers to comfort level with RBI topic were successfully addressed with continued education and training throughout the pilot. DISCUSSION: Results show increased RBI conversations during the pilot, and MRT(T)s reported increased comfort speaking with patients about RBI with continued practice. The RBI champions played a pivotal role in the pilot's success and increased MRT(T) comfort with RBI. Initial barriers to RBI conversations were less reported as the pilot progressed and RBI conversations were normalized for patients. CONCLUSIONS: The RBI pilot was a novel KT initiative focused on supporting MRT(T)s to ensure patients were aware of sexual health resources available to them during their radiation therapy. Knowledge gained from this pilot can easily be adapted to assist other health care providers and additional RCCs to confidently initiate RBI conversations with their patients.

The Cost of Patient Education Materials Development: Opportunities to Identify Value and Priorities.

The study aim was to evaluate the costs associated with developing and reviewing patient education materials (pamphlets) across Ontario cancer centers. While patient education often produces a positive return on investment, limited efforts have been dedicated to optimizing the personnel, time, and capital dedicated to this feat across healthcare systems. Patient education leaders at 14 cancer centers completed a survey measure, estimating the number of hours spent developing and reviewing pamphlets and identifying the personnel involved in each procedural step. The time expended per center in each step was then combined with average salary data for the identified personnel to derive total cost estimates. Cancer centers spend on average $5672 (SD = $3180) developing (M = $4560, SD = $2620) and reviewing (M = $1112, SD = $654) one pamphlet. This cumulates to an average per annum spending of $65,401 (SD = $75,494) for pamphlet development and $19,819 (SD = $28,524) for annual pamphlet review at each cancer center. The cost and number of hours spent developing and reviewing pamphlets varied substantially between cancer centers. While the security of budgets for patient education varies across cancer centers, opportunities to optimize human capital and monetary resources should be considered. Results of the study can be used to advocate for sustainable investment into cancer education programs, improve the coordination of educational materials production and review, and ensure that resource quality and access are consistent across the province.

Midazolam versus dexamethasone-ondansetron in preventing post-operative nausea-vomiting in patients undergoing laparoscopic surgeries.

BACKGROUND: Midazolam reduces post-operative nausea and vomiting (PONV) when compared to a placebo or when used as an adjuvant to other antiemetics. The present study was designed to compare midazolam with a combination of dexamethasone-ondansetron in preventing PONV. METHODS: One hundred and twenty patients undergoing laparoscopic surgeries having 2 or more risk factors for PONV (simplified Apfel score) were randomised into 2 groups of 60 each. Patients in group D received 8-mg dexamethasone and 4-mg ondansetron for PONV prophylaxis while those in group M received 2-mg midazolam towards the end of surgery. The proportion of patients (frequency) who had PONV, post-operative nausea (PON) and post-operative vomiting (POV) was noted over 24 hours over the following intervals: 0-2 hours, 2-24 hours and 0-24 hours. RESULTS: The frequency of PONV at 24 hours in group D and group M was 30% and 33.3% respectively and was not significantly different (P = .70). There was no difference in the time to achieve post-anaesthesia discharge score of ≥9 between the two groups {5 minutes (5, 5) in group D; 5 minutes (1.25, 5) in group M, P = .48}. Ten patients in group D and 11 in group M required a rescue antiemetic over 24 hours (P = .81). The frequency of PON, POV and PONV as well as the median PONV score was similar at all time periods. CONCLUSION: Midazolam does not result in significantly different frequency of PONV than a combination of dexamethasone-ondansetron.

Differentiating Biliary Atresia From Idiopathic Neonatal Hepatitis: A Novel Keratin 7 Based Mathematical Approach on Liver Biopsies.

BACKGROUND AND AIMS: Differentiating biliary atresia (BA) from idiopathic neonatal hepatitis (INH) is vital in routine pediatric practice. However, on liver biopsy, few cases offer a diagnostic challenge to discriminate these entities with certainty. Bile ductular reaction (DR), intermediate hepatobiliary cells (IHBC) and extra-portal ductules (EPD) indicate progenitor cell activation, as a response to various hepatic insults. The present study aims to quantify DR, IHBC and EPD by Keratin 7 (CK7) immunohistochemistry (IHC) in BA and INH and to devise a mathematical approach to better differentiate the two, especially in histologically equivocal cases. METHODS: A total of 98 cases were categorized on biopsy as BA, INH or equivocal histology, favoring BA or INH. CK7 DR mean, IHBC mean and EPD mean values were compared between BA and INH. A formula was derived to help distinguish these two entities, the cut-off value, sensitivity and specificity of which were determined by receiver operating characteristic (ROC) curve. This formula was applied and validated on histologically equivocal cases. RESULTS: Univariate logistic regression revealed significant difference between BA and INH with respect to CK7 DR and CK7 EPD mean (p < 0.001 in both); however, CK7 IHBC mean was not significant (p = 0.08). On multivariate logistic regression, only CK7 DR had significant impact on diagnosis (p < 0.001). A formula: (CK7 DR)2 + (CK7 EPD)/(CK7 IHBC) was derived to help distinguish BA from INH. Cut off value of 10.5 and above, determined by ROC curve, favored a diagnosis of BA (sensitivity= 93.4%, specificity= 94.6%). Histologically equivocal and discrepant cases could be correctly categorized using this formula. CONCLUSIONS: Formula using CK7 IHC parameters may aid pathologists better distinguish BA from INH, especially in histologically equivocal cases.

Alcohol associated liver cirrhotics have higher mortality after index hospitalization: Long-term data of 5,138 patients.

BACKGROUND/AIMS: Liver cirrhosis is an important cause of morbidity and mortality globally. Every episode of decompensation and hospitalization reduces survival. We studied the clinical profile and long-term outcomes comparing alcohol-related cirrhosis (ALC) and non-ALC. METHODS: Cirrhosis patients at index hospitalisation (from January 2010 to June 2017), with ≥1 year follow-up were included. RESULTS: Five thousand and one hundred thirty-eight cirrhosis patients (age, 49.8±14.6 years; male, 79.5%; alcohol, 39.5%; Child-A:B:C, 11.7%:41.6%:46.8%) from their index hospitalization were analysed. The median time from diagnosis of cirrhosis to index hospitalization was 2 years (0.2-10). One thousand and seven hundred seven patients (33.2%) died within a year; 1,248 (24.3%) during index hospitalization. 59.5% (2,316/3,890) of the survivors, required at least one readmission, with additional mortality of 19.8% (459/2,316). ALC compared to non-ALC were more often (P<0.001) male (97.7% vs. 67.7%), younger (40-50 group, 36.2% vs. 20.2%; P<0.001) with higher liver related complications at baseline, (P<0.001 for each), sepsis: 20.3% vs. 14.9%; ascites: 82.2% vs. 65.9%; spontaneous bacterial peritonitis: 21.8% vs. 15.7%; hepatic encephalopathy: 41.0% vs. 25.0%; acute variceal bleeding: 32.0% vs. 23.7%; and acute kidney injury 30.5% vs. 19.6%. ALC patients had higher Child-Pugh (10.6±2.0 vs. 9.0±2.3), model for end-stage liver-disease scores (21.49±8.47 vs. 16.85±7.79), and higher mortality (42.3% vs. 27.3%, P<0.001) compared to non-ALC. CONCLUSION: One-third of cirrhosis patients die in index hospitalization. 60% of the survivors require at least one rehospitalization within a year. ALC patients present with higher morbidity and mortality and at a younger age.

Reinventing the wheel: The incidence and cost implication of duplication of effort in patient education materials development.

OBJECTIVE: The development of patient education (PE) materials is costly and resource-intensive, and no mechanisms exist for sharing materials across cancer centers/hospitals to limit duplicated effort. The aim of this study was to explore the incidence and cost implication of duplicated PE efforts. METHODS: PE leaders from all (14) cancer centers in Ontario, Canada, submitted their collections of systemic therapy PE materials. Materials were categorized by topic and were coded as duplicate (more than one other material exists on the same topic and there was significant content and/or textual overlap), adapted (material was adapted from an existing material) or unique (no other material addresses the topic). RESULTS: 304 materials were included and <50 % of materials had duplicate content (n = 166, 55 %), a small proportion were adapted (n = 27, 9%), and less than half were unique (n = 111, 37 %). The majority of materials were considered amenable to adaptation meaning that the content was not dependent on a specific institutional context (n = 283, 93 %). The opportunity for cost savings if duplication of effort could be avoided is approximately $800 K for systemic therapy materials produced in cancer centers. CONCLUSION: There is need to refine the process for developing PE materials. Creating mechanisms of sharing can help facilitate equal access to materials and can result in significant cost savings. PRACTICE IMPLICATIONS: Efforts are needed to better coordinate the development of PE materials among patient educators. Better coordination would allow patient education programs to focus on other important challenges.

Designing next generation recombinant protein expression platforms by modulating the cellular stress response in Escherichia coli.

BACKGROUND: A cellular stress response (CSR) is triggered upon recombinant protein synthesis which acts as a global feedback regulator of protein expression. To remove this key regulatory bottleneck, we had previously proposed that genes that are up-regulated post induction could be part of the signaling pathways which activate the CSR. Knocking out some of these genes which were non-essential and belonged to the bottom of the E. coli regulatory network had provided higher expression of GFP and L-asparaginase. RESULTS: We chose the best performing double knockout E. coli BW25113ΔelaAΔcysW and demonstrated its ability to enhance the expression of the toxic Rubella E1 glycoprotein by 2.5-fold by tagging it with sfGFP at the C-terminal end to better quantify expression levels. Transcriptomic analysis of this hyper-expressing mutant showed that a significantly lower proportion of genes got down-regulated post induction, which included genes for transcription, translation, protein folding and sorting, ribosome biogenesis, carbon metabolism, amino acid and ATP synthesis. This down-regulation which is a typical feature of the CSR was clearly blocked in the double knockout strain leading to its enhanced expression capability. Finally, we supplemented the expression of substrate uptake genes glpK and glpD whose down-regulation was not prevented in the double knockout, thus ameliorating almost all the negative effects of the CSR and obtained a further doubling in recombinant protein yields. CONCLUSION: The study validated the hypothesis that these up-regulated genes act as signaling messengers which activate the CSR and thus, despite having no casual connection with recombinant protein synthesis, can improve cellular health and protein expression capabilities. Combining gene knockouts with supplementing the expression of key down-regulated genes can counter the harmful effects of CSR and help in the design of a truly superior host platform for recombinant protein expression.

RUNX Binding Sites Are Enriched in Herpesvirus Genomes, and RUNX1 Overexpression Leads to Herpes Simplex Virus 1 Suppression.

Herpes simplex virus 1 (HSV-1) and HSV-2 can efficiently establish lifelong, transcriptionally silent latency states in sensory neurons to escape host detection. While host factors have previously been associated with long-range insulators in the viral genome, it is still unknown whether host transcription factors can repress viral genes more proximately to promote latency in dorsal root ganglion (DRG) neurons. Here, we assessed whether RUNX (runt-related transcription factor) transcription factors, which are critical in the development of sensory neurons, could be binding HSV-1 genome directly to suppress viral gene expression and lytic infection. Using previously published transcriptome sequencing data, we confirmed that mouse DRG neurons highly express Runx1 mRNA. Through computational analysis of HSV-1 and HSV-2 genomes, we observed that putative RUNX consensus binding sites (CBSs) were more enriched and more closely located to viral gene transcription start sites than would be expected by chance. We further found that RUNX CBSs were significantly more enriched among genomes of herpesviruses compared to those of nonherpesviruses. Utilizing an in vitro model of HSV-1 infection, we found that overexpressed RUNX1 could bind putative binding sites in the HSV-1 genome, repress numerous viral genes spanning all three kinetic classes, and suppress productive infection. In contrast, knockdown of RUNX1 in neuroblastoma cells induced viral gene expression and increased HSV-1 infection in vitro In sum, these data support a novel role for RUNX1 in directly binding herpesvirus genome, silencing the transcription of numerous viral genes, and ultimately limiting overall infection.IMPORTANCE Infecting 90% of the global population, HSV-1 and HSV-2 represent some of the most prevalent viruses in the world. Much of their success can be attributed to their ability to establish lifelong latent infections in the dorsal root ganglia (DRG). It is still largely unknown, however, how host transcription factors are involved in establishing this latency. Here, we report that RUNX1, expressed highly in DRG, binds HSV-1 genome, represses transcription of numerous viral genes, and suppresses productive in vitro infection. Our computational work further suggests this strategy may be used by other herpesviruses to reinforce latency in a cell-specific manner.

Vitamin B12 and folic acid alleviate symptoms of nutritional deficiency by antagonizing aryl hydrocarbon receptor.

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.

Hypothetical Lifestyle Strategies in Middle-Aged Women and the Long-Term Risk of Stroke.

Background and Purpose- Long-term effect of lifestyle changes on stroke incidence has not been estimated in randomized trials. We used observational data to estimate the incidence of stroke under hypothetical lifestyle strategies in the NHS (Nurses' Health Study). Methods- We considered 3 nondietary strategies (smoking cessation, exercising ≥30 min/d, gradual body mass index reduction if overweight/obese) and several dietary strategies (eating ≥3 servings/wk of fish, ≤3 servings/wk of unprocessed red meat, no processed red meat, ≥1 servings/d of nuts, etc). We used the parametric g-formula to estimate the 26-year risk of stroke under these strategies. Results- In 59 727 women, mean age 52 years at baseline in 1986, the estimated 26-year risks under no lifestyle interventions were 4.7% for total stroke, 2.4% for ischemic stroke, and 0.7% for hemorrhagic stroke. Under the combined nondietary interventions, the estimated 26-year risk of total stroke was 3.5% (95% CI, 2.6%-4.3%) and ischemic stroke was 1.6% (95% CI, 1.1%-2.1%). Smaller reductions in total stroke risk were estimated under isolated dietary strategies of increased intake of fish and nuts and reduced intake of unprocessed red meat. Ischemic stroke risk was lower under reduced intake of unprocessed and processed red meat, and hemorrhagic stroke risk was lower under a strategy of increased fish consumption. Conclusions- In this population of middle-aged women, sustained, lifestyle modifications were estimated to reduce the 26-year risk of total stroke by 25% and ischemic stroke by 36%. Sustained dietary modifications were estimated to reduce the 26-year risk of total stroke by 23%.

Incidence, Risk Factors, and Outcomes of Transition of Acute Kidney Injury to Chronic Kidney Disease in Cirrhosis: A Prospective Cohort Study.

Transition to chronic kidney disease (CKD) after an episode of acute kidney injury (AKI) is known in patients without cirrhosis. We studied the incidence and risk factors for development of CKD in patients with cirrhosis. Competing risk analysis was performed to identify risk factors for CKD development. Of 818 patients with cirrhosis (age, 50.4 ± 11.8 years; 84% males; Model for End-Stage Liver Disease [MELD], 19.9 ± 9.9), 36% had AKI at enrollment, 27% had previous AKI, and 61% developed new episodes of AKI during the follow-up period. CKD developed in 269 (33%) patients. Serum cystatin C (CysC; subdistribution hazard ratio [SHR], 1.58; 1.07-2.33), episodes of previous AKI (SHR, 1.26; 1.02-1.56), and AKI stage at enrollment (no AKI [SHR, 1] vs. stage 1 [SHR, 3.28; 1.30-8.25] vs. stage 2 [SHR, 4.33; 1.76-10.66] vs. stage 3 [SHR, 4.5; 1.59-12.73]) were identified as baseline risk factors for CKD development. On time-varying competing risk analysis, MELD (SHR, 1.01; 1.00-1.03), number of AKI episodes (SHR, 1.25; 1.15-1.37), and CysC (SHR, 1.38; 1.01-1.89) predicted CKD development. Development of CKD was associated with higher risk of death. Reduction in glomerular filtration rate (GFR) not meeting CKD criteria was observed in 66% of patients with cirrhosis, more so in those with previous AKI episodes and a high CysC level and MELD score. Renal histology, available in 55 patients, showed tubulointerstitial injury in 86%, cholemic nephrosis in 29%, and glomerular changes in 38%. Conclusion: Almost two-thirds of patients with cirrhosis develop episodes of AKI and reduction in GFR; one-third progress to CKD, resulting in adverse outcomes. Higher MELD and CysC levels and number of AKI episodes predict development of CKD in patients with cirrhosis.

Weight Gain After Smoking Cessation and Lifestyle Strategies to Reduce it.

BACKGROUND: Weight gain following smoking cessation reduces the incentive to quit, especially among women. Exercise and diet interventions may reduce postcessation weight gain, but their long-term effect has not been estimated in randomized trials. METHODS: We estimated the long-term reduction in postcessation weight gain among women under smoking cessation alone or combined with (1) moderate-to-vigorous exercise (15, 30, 45, 60 minutes/day), and (2) exercise and diet modification (≤2 servings/week of unprocessed red meat; ≥5 servings/day of fruits and vegetables; minimal sugar-sweetened beverages, sweets and desserts, potato chips or fried potatoes, and processed red meat). RESULTS: Among 10,087 eligible smokers in the Nurses' Health Study and 9,271 in the Nurses' Health Study II, the estimated 10-year mean weights under smoking cessation were 75.0 (95% CI = 74.7, 75.5) kg and 79.0 (78.2, 79.6) kg, respectively. Pooling both cohorts, the estimated postcessation mean weight gain was 4.9 (7.3, 2.6) kg lower under a hypothetical strategy of exercising at least 30 minutes/day and diet modification, and 5.9 (8.0, 3.8) kg lower under exercising at least 60 minutes/day and diet modification, compared with smoking cessation without exercising. CONCLUSIONS: In this study, substantial weight gain occurred in women after smoking cessation, but we estimate that exercise and dietary modifications could have averted most of it.

Clinical evaluation of Ambu® Aura-i™ - A new intubating laryngeal mask airway as an independent ventilatory device and a conduit for tracheal intubation in pediatric patients.

BACKGROUND: Ambu® Aura-i™, a recently introduced second generation supraglottic airway device has been designed to function as an independent ventilatory device as well as a conduit for passage of conventional cuffed tracheal tubes through it. There is dearth of literature on experience of tracheal intubation through intubating laryngeal mask airway (ILMA) in paediatric age group. This study was conducted to study the ventilatory effectiveness and the intubating characteristics of Ambu® Aura-i™ in paediatric patients. AIM: To study the effectiveness of Ambu ® Aura-i ™ as a supraglottic device for its ventilatory effectiveness and intubation characteristics in paediatric patients. OBJECTIVES: To study the Ventilatory effectiveness of Ambu ® Aura-i ™ in terms of: 1) Time taken in insertion of Ambu ® Aura-i ™. 2) No of attempts made for successful insertion of Ambu ® Aura-i™. 3) Tidal volume attained on positive pressure ventilation. 4) Etco2, Spo2 and Leak pressure achieved. To study the Intubating characterstics of Ambu ® Aura-i ™ in terms of :- 1) Grade of alignment of the ventilating orifice achieved in relation to the larynx in the fibre optic view. 2) Time taken in intubation through Ambu ® Aura-i ™. 3) Number of attempts made in intubation. 4) Time taken for removal of the Ambu ® Aura-i ™ after intubation through it has been accomplished. METHOD: Sixty three children undergoing elective surgery under general anaesthesia requiring intubation of trachea, weighing between 5-30 kg were stratified into 3 groups (n= 21) each. Ambu® Aura-i™ size 1.5 , 2.0 ,2.5 were used based on their body weight for airway management. Ventilatory effectiveness was studied in terms of success rate, number of attempts made at insertion, time taken in insertion, tidal volume delivered and leak pressure achieved. Intubating characterstics studied during fibreoptic guided tracheal intubation included grade of alignment of the ventilating orifice achieved in relation to the larynx in fibre optic view, time taken in fibreoptic guided tracheal intubation, success rate and number of attempts made at intubation. Time taken in removal of the device and complications observed were also recorded. RESULTS: Ambu® Aura-i™ insertion, fibreoptic guided tracheal intubation and device removal were successful in all the patients in first attempt. The mean time taken in successful device insertion was 10.83±2.04 sec. The mean tidal volume delivered was 7.88±1.33 ml/kg body weight and mean leak pressure achieved was 16.27±5.2 cm H2O. The fibreoptic guided intubation was possible in first attempt in 100% of the patients (n=63). The Fibre optic view was grade 1 in 82.55% patients (n=52 /63) and grade 2 in 17.46% (n=11/ 63) patients. The mean time taken in fibre optic guided intubation was 12.68 ±2.82 sec. The mean time taken in removal of the device over the tracheal tube was 12.27 sec. There was no significant incidence of trauma to soft tissues, sore throat, laryngospasm or hoarseness of voice. CONCLUSION: On the basis of observations of this study, we conclude that Ambu ® Aura-i ™ is not only an effective ventilatoy device, but also an excellent conduit for fibre optic guided intubation using conventional uncuffed endotracheal tube in paediatric patients. Ambu ® Aura-i ™ , is also valuable for establishing rapid airway access in emergent difficult paediatric airway.