RECENT ADVANCES IN NANOCARRIER BASED THERAPEUTIC AND DIAGNOSTIC TOOLS FOR COLORECTAL CANCER

Colorectal cancer (CRC) is among the frequently diagnosed cancers and one of the leading causes of deaths in the world. It has remarkably high rates of metastasis, which incidentally is one of the leading causes of CRC related deaths. Ineffective drug concentration at the desired site of action and toxicity due to peripheral targeting limits the efficacy of the conventional chemotherapeutic treatments. Currently used traditional diagnostic tools have various shortcomings such as poor intracellular contrast between malignant and benign cells and low detection sensitivity in biological environment. Smarter drug delivery systems based on nano carriers have been proven remarkably promising in enhancing drug distribution and bioavailability, increasing half-life and achieving targeted drug delivery, thus, minimizing toxicity. Diagnosis employing nanoparticles is more effective in terms of stability, duration and efficiency. CRC targeting, both for drug delivery as well as diagnosis, is improved manifold by incorporating ligands of tumor specific surface receptors on the nanoparticles. Recently documented data have furnished cogent evidence apropos, the potential of active-targeted nanotherapeutics, and diagnostics in CRC therapy involving myriad forms of nanoparticles. This review deliberates the current status of nanocarriers, and the significance of their use in colorectal cancer therapy

Living with arsenic in the environment: An examination of current awareness of farmers in the Bengal basin using hybrid feature selection and machine learning

High levels of arsenic in drinking water and food materials continue to pose a global health challenge. Over 127 million people alone in Bangladesh (BD) and West Bengal (WB) state of India are exposed to elevated levels of arsenic in drinking water. Despite decades of research and outreach, arsenic awareness in communities continue to be low. Specifically, very few studies reported arsenic awareness among low-income farming communities. A comprehensive approach to assess arsenic awareness is a key step in identifying research and development priorities so that appropriate stakeholder engagement may be designed to tackle arsenic menace. In this study, we developed a comprehensive arsenic awareness index (CAAI) and identified key awareness drivers (KADs) of arsenic to help evaluate farmers’ preferences in dealing with arsenic in the environment. The CAAI and KADs were developed using a questionnaire survey in conjunction with ten machine learning (ML) models coupled with a hybrid feature selection approach. Two questionnaire surveys comprising of 73 questions covering health, water and community, and food were conducted in arsenic affected areas of WB and BD. Comparison of CAAIs showed that the BD farmers were generally more arsenic-aware (CAAI = 7.7) than WB farmers (CAAI = 6.8). Interestingly, the reverse was true for the awareness linked to arsenic in the food chain. Application of hybrid feature selection identified 15 KADs, which included factors related to stakeholder interventions and cropping practices instead of commonly perceived factors such as age, gender and income. Among ML algorithms, classification and regression trees and single C5.0 tree could estimate CAAIs with an average accuracy of 84%. Both communities agreed on policy changes on water testing and clean water supply. The CAAI and KADs combination revealed a contrasting arsenic awareness between the two farming communities, albeit their cultural similarities. Specifically, our study shows the need for increasing awareness of risks through the food chain in BD, whereas awareness campaigns should be strengthened to raise overall awareness in WB possibly through media channels as deemed effective in BD

The Effectiveness of a Home Care Program for Supporting Caregivers of Persons with Dementia in Developing Countries: A Randomised Controlled Trial from Goa, India

OBJECTIVES: To develop and evaluate the effectiveness of a home based intervention in reducing caregiver burden, promoting caregiver mental health and reducing behavioural problems in elderly persons with dementia. METHODOLOGY AND PRINCIPAL FINDINGS: This was a randomised controlled trial in which the person with dementia-caregiver dyad was randomly allocated either to receive the intervention immediately or to a waiting list group which received the intervention after 6 months. It was carried out in communities based in two talukas (administrative blocks) in Goa, India. Mild to moderate cases with dementia (diagnosed using the DSM IV criteria and graded using the Clinical Dementia Rating scale) and their caregivers were included in the trial. Community based intervention provided by a team consisting of Home Care Advisors who were supervised by a counselor and a psychiatrist, focusing on supporting the caregiver through information on dementia, guidance on behaviour management, a single psychiatric assessment and psychotropic medication if needed. We measured caregiver mental health (General Health Questionnaire), caregiver burden (Zarit Burden Score), distress due to behavioural disturbances (NPI-D), behavioural problems in the subject (NPI-S) and activities of daily living in the elder with dementia (EASI). Outcome evaluations were masked to the allocation status. We analysed each outcome with a mixed effects model. 81 families enrolled in the trial; 41 were randomly allocated to the intervention. 59 completed the trial and 18 died during the trial. The intervention led to a significant reduction of GHQ (-1.12, 95% CI -2.07 to -0.17) and NPI-D scores (-1.96, 95%CI -3.51 to -0.41) and non-significant reductions in the ZBS, EASI and NPI-S scores. We also observed a non-significant reduction in the total number of deaths in people with dementia in the intervention arm (OR 0.34, 95% CI 0.01 to 1.03). CONCLUSION: Home based support for caregivers of persons with dementia, which emphasizes the use of locally available, low-cost human resources, is feasible, acceptable and leads to significant improvements in caregiver mental health and burden of caring. ClinicalTrials.gov NCT00479271

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation

BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial

Predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome

Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36months read in the core laboratory of 608 trial subjects, aged 6months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz)>3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year>90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R-2=0.01) or by change in AoR diameter (AoRd)/year>90th percentile with higher sinotubular junction z-score and non-white race (R-2=0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R-2=0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364

Fatal myocarditis in a child with systemic onset juvenile idiopathic arthritis during treatment with an interleukin 1 receptor antagonist

<p>Abstract</p> <p>Background</p> <p>The pathologic diagnosis of isolated myocarditis without pericardial involvement is uncommonly encountered in systemic onset Juvenile Idiopathic Arthritis (soJIA).</p> <p>Case</p> <p>An eleven year-old boy with soJIA died suddenly while being treated with the interleukin 1 (IL-1) receptor inhibitor, anakinra. His autopsy revealed an enlarged heart and microscopic findings were consistent with myocarditis, but not pericarditis. Viral PCR testing performed on his myocardial tissue was negative.</p> <p>Conclusion</p> <p>This case illustrates myocarditis as a fatal complication of soJIA, potentially enabled by anakinra.</p

Design and Rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short-term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double blind, placebo controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co., Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation

Delayed puberty and abnormal anthropometry and its associations with quality of life in young Fontan survivors: A multicenter crossâ sectional study

IntroductionWe sought to evaluate the prevalence of delayed puberty and abnormal anthropometry and its association with quality of life (QoL) in young Fontan survivors.MethodsThis was a crossâ sectional study at 11 Pediatric Heart Network centers. Demographic and clinical data, anthropomety, and Tanner stage were collected. Anthropometric measurements and pubertal stage were compared to US norms. QoL was assessed using Pediatric Quality of Life inventory (PedsQL). Mixed effects regression modeling adjusting for clustering by center was used to evaluate factors associated with abnormal anthropometry and delayed puberty and associations with QoL.ResultsOf the 299 subjects, 42% were female. The median enrollment age was 13.9 years, and the median age at Fontan was 3 years. Fontan survivors had a higher prevalence of short stature relative to normative data (20% vs 5%, P 2 surgeries before Fontan was associated with delayed puberty. Lower family income (<$25 000) and hypoplastic left heart syndrome were associated with lower QoL.ConclusionCompared to the normal population, Fontan survivors have high prevalence of short stature, abnormal BMI and delayed puberty. Abnormal anthropometry, but not delayed puberty, was associated with lower overall QoL and perceived physical appearance scores. Routine screening for abnormal anthropometry, especially in HLHS and in lower socioeconomic status families, should be considered to allow interventions, which might ameliorate the negative psychosocial impact.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144293/1/chd12597.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144293/2/chd12597_am.pd

Effect of ventricular size and function on exercise performance and the electrocardiogram in repaired tetralogy of Fallot with pure pulmonary regurgitation

Background: In repaired tetralogy of Fallot (TOF), exercise test parameters like peak oxygen uptake and ventilatory efficiency predict mortality. Studies have also suggested cardiac magnetic resonance (CMR)-derived right ventricular (RV) size threshold values for pulmonary valve replacement in repaired TOF. However, effects of proposed RV size on exercise capacity and morbidity are not known. Methods: The relationship between CMR-derived ventricular size, function, and pulmonary regurgitation (PR) and NYHA class, exercise performance, and electrocardiogram (ECG) was studied in patients of repaired TOF with pure PR in a retrospective review of records. Results: 46 patients (22 females), mean age 14 years (8−30.8), were studied. There was no relationship between CMR-derived ventricular size, function, or PR and exercise test parameters, or NYHA class. RV end systolic and end diastolic volume correlated positively with the degree of PR. QRS duration on ECG correlated positively with RV end-diastolic volume (P < 0.01, r2 = 0.34) and PR (P < 0.01, r2 = 0.52). Conclusions: In repaired TOF and pure PR, there is no correlation between ventricular size or function and exercise performance. RV size increases with increasing PR. Timing of pulmonary valve replacement in TOF with pure PR needs further prospective evaluation for its effect on morbidity and mortality