Counterfeit drugs in India: significance and impact on pharmacovigilance

Counterfeit drugs have emerged as a major global problem. This issue has been brought to the centre of the Indian media due to the death of 15 women attending a sterilization camp in Chhattisgarh. India’s pharmaceutical industry exports drugs worth 15 billion dollars, which means a high prevalence of counterfeiting in India’s drug industry has global repercussions. However, accurate figures on the extent of counterfeit drugs in India are not available. The scientific literature as well as media reports often quotes figures of 10-35%, though studies done by the Indian Government dispute this. Counterfeit drug numbers have been known to be under represented by Governments due to fear of undermining their economy and health systems. On the other hand, rival companies in other countries may have an incentive to over hype India’s counterfeit problem to dent India’s growing status as the leading global supplier of generic medicines. Lack of clear definitions and differences between laws of countries further complicate reporting. A high prevalence of counterfeit drugs has a large impact on both health and economic indicators. Additionally, counterfeit drugs provide significant challenges to Pharmacovigilance programmes. Hence, here we discuss the significance of use of counterfeit drugs in India and challenges faced by Pharmacovigilance due to the extensive use of counterfeit drugs

Comprehensive Brain MRI Segmentation in High Risk Preterm Newborns

Most extremely preterm newborns exhibit cerebral atrophy/growth disturbances and white matter signal abnormalities on MRI at term-equivalent age. MRI brain volumes could serve as biomarkers for evaluating the effects of neonatal intensive care and predicting neurodevelopmental outcomes. This requires detailed, accurate, and reliable brain MRI segmentation methods. We describe our efforts to develop such methods in high risk newborns using a combination of manual and automated segmentation tools. After intensive efforts to accurately define structural boundaries, two trained raters independently performed manual segmentation of nine subcortical structures using axial T2-weighted MRI scans from 20 randomly selected extremely preterm infants. All scans were re-segmented by both raters to assess reliability. High intra-rater reliability was achieved, as assessed by repeatability and intra-class correlation coefficients (ICC range: 0.97 to 0.99) for all manually segmented regions. Inter-rater reliability was slightly lower (ICC range: 0.93 to 0.99). A semi-automated segmentation approach was developed that combined the parametric strengths of the Hidden Markov Random Field Expectation Maximization algorithm with non-parametric Parzen window classifier resulting in accurate white matter, gray matter, and CSF segmentation. Final manual correction of misclassification errors improved accuracy (similarity index range: 0.87 to 0.89) and facilitated objective quantification of white matter signal abnormalities. The semi-automated and manual methods were seamlessly integrated to generate full brain segmentation within two hours. This comprehensive approach can facilitate the evaluation of large cohorts to rigorously evaluate the utility of regional brain volumes as biomarkers of neonatal care and surrogate endpoints for neurodevelopmental outcomes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Optimal control of HCV transmission under liquoring

© 2019 Chronic hepatitis C virus (HCV) and alcohol are common causes of chronic liver diseases and both are recognized as major causes of liver disease worldwide. Each poses a major public and economic burden to society, and when the two co-exist they appear to have a synergistic effect in the progression of chronic liver disease. In this research, we developed a SIRS model of transmission of the hepatitis C virus (HCV) under effect of liquoring in six compartments: Susceptible, Low liquoring, High liquoring, Acute, Chronic and Recovered Individuals. The system of non-linear ordinary differential equations is formulated. Basic reproduction number R0 is computed using the next generation matrix approach. The stability of the model is worked out at the equilibrium point. Model analysis shows that the disease-free equilibrium point is both locally and globally asymptotically stable. Sensitivity analysis with respect to key parameters of R0 indicates that control strategies should target reduction of the amount of alcohol use amongst people with HCV as it prevents or delays HCV disease progression. The control in our model is in terms of rehabilitation center which helps people to divert from high liquoring to low liquoring. Numerical simulation has been carried out to show the impact of control on different compartment. This research shows the positive impact of rehabilitation on liquoring habits and subsequently on HCV transmission

Clinico - diagnostic and therapeutic relevance of computed tomography scan of brain in children with partial seizures

Background: Therapeutic relevance of computed tomography (CT) in children with partial seizures is reported to be remarkably low (1-2%). However, in the developing countries where infections involving the nervous system are common, routine CT scan of brain may help in finding treatable causes of seizures. Objective: Aim of this study was to evaluate the significance of CT scan of brain in the management of children with partial seizures. Materials and Methods: Children with partial epilepsy, whose predominant seizure type was focal motor seizures, were included in the study. CT scan of brain was done in all children aged between 1 month and 12 years with partial seizures of unknown etiology prospectively. The clinical findings of these children were noted along with the CT findings. Results: Between August 2001 and July 2002, of the 200 children with seizure disorder 50 children who satisfied the inclusion criteria were included in the study. CT scan of brain was normal in 16 children (32%) and was abnormal in 34 children (68%). Twenty children (~60% of abnormal scan) had potentially correctable lesions: Tuberculoma ( n = 13), neurocysticercosis ( n = 3), and brain abscess ( n = 4). Five children had changes representing static pathology that did not influence patient management. The clinical features correlated with CT findings in 78% children. Conclusion: Children with partial motor seizures have high probability of having abnormal findings on CT scan of brain, especially, neuro-infections which are potentially treatable. Therefore, CT scan brain should be carried out in all children with partial motor seizures especially, in developing countries

Thermo-Switchable de Novo Ionic Liquid-Based Gelators with Dye-Absorbing and Drug-Encapsulating Characteristics

An ionic liquid-based surfactant with ester functionality self-aggregates in an aqueous medium and forms ionogels at 8.80% (w/v) concentration at physiological pH. The ionogel exhibited a remarkable change in its appearance with temperature from fibrillar opaque to transparent because of the dynamic changes within its supramolecular structure. This gel-to-gel phase transition occurs below the melting point of the solid ionic liquid. The ionogels were investigated using turbidity, differential scanning calorimetry, scanning electron microscopy (SEM), field emission SEM (FE-SEM), inverted microscopy, transmission electron microscopy imaging, Fourier transform infrared spectroscopy, and rheological measurements. The fibrillar opaque ionogel and transparent ionogel were studied for their ability to absorb dyes (methyl orange and crystal violet) and to encapsulate drugs (diclofenac sodium and imatinib mesylate)

Sesamin attenuates neurotoxicity in mouse model of ischemic brain stroke

© 2014 Elsevier Inc.. Stroke is a severe neurological disorder characterized by the abrupt loss of blood circulation into the brain resulting into wide ranging brain and behavior abnormalities. The present study was designed to evaluate molecular mechanism by which sesamin (SES) induces neuroprotection in mouse model of ischemic stroke. The results of this study demonstrate that SES treatment (30. mg/kg. bwt) significantly reduced infarction volume, lipid per-oxidation, cleaved-caspase-3 activation, and increased GSH activity following MCAO in adult male mouse. SES treatment also diminished iNOS and COX-2 protein expression, and significantly restored SOD activity and protein expression level in the ischemic cortex of the MCAO animals. Furthermore, SES treatment also significantly reduced inflammatory and oxidative stress markers including Iba1, Nox-2, Cox-2, peroxynitrite compared to placebo MCAO animals. Superoxide radical production, as studied by DHE staining method, was also significantly reduced in the ischemic cortex of SES treated compared to placebo MCAO animals. Likewise, downstream effects of superoxide free radicals i.e. MAPK/ERK and P38 activation was also significantly attenuated in SES treated compared to placebo MCAO animals. In conclusion, these results suggest that SES induces significant neuroprotection, by ameliorating many signaling pathways activated/deactivated following cerebral ischemia in adult mouse