Geochemistry and geodynamic implications of magmatic rocks from the Trans-Himalayan arc

Present study aims at understanding the genetic and tectonic relationship between the enclaves and enclosing granitoids, acidic volcanics and mafic dykes of the Ladakh plutonic complex. Similar rocks from Lhasa Block (Tibet) are also studied and compared. In terms of SiO2 abundance, the enclaves vary in composition from basic to acidic but are predominantly andesitic-basalt. Mafic dykes intruding the Ladakh plutonic complex are of predominantly andesitic-basalt composition. Granitoids and acidic volcanics from Ladakh and Lhasa blocks are compositionally granodiorite, quartz monzonite and granite. They are predominantly meta-aluminous with slight peraluminous characters. The acidic volcanics, however, have K2O/Na2O > 1. All these rocks show calc-alkaline characteristics with high Al2O3 abundance, their rare earth elements (REE) and multi-element patterns depict enrichment of large ion lithophile elements (LILE)-light REE (LREE) and depletion of high field strength elements (HFSE) including Nb, P and Ti. It is suggested that the enclaves in Ladakh plutonic complex probably represent the initial pulses of magmatism, in response to intra-oceanic northward subduction of Neo-Tethyan ocean beneath an immature arc. Subsequently huge pulses of granitoids were intruded as the arc matured, sutured with southern continental margin of Eurasian plate and the lithosphere thickened. The granitoids in turn were cut by mafic dykes and acidic volcanics probably representing the last significant episode of subduction related magmatism in this region. It is suggested that the youngest, highly siliceous acidic volcanics may represent melts generated by partial melting and/or dehydration of upper part of subducted north Indian continental lithosphere and southern Eurasian active margin wedge, subsequent to the closing of Neo-Tethyan ocean and collision of Indian and Eurasian plates

Day case discharge of patients treated with drug coated balloon only angioplasty for de novo coronary artery disease:A single center experience

Objective: To report our initial experience with Drug Coated Balloon (DCB) only angioplasty and propose a protocol to achieve this safely. Background: There are no articles published in the literature currently regarding the safety of same day discharge in patients treated with DCB-only angioplasty. Methods: Retrospective review of all our patients treated with DCB-only angioplasty from Sept 2017 to April 2018 with identification of potential complications relating to same day discharge. Results: A total of 100 consecutive patients who underwent elective DCB-only angioplasty for de novo coronary artery disease and were discharged on the same day as the procedure were included. In 99% no cardiac symptoms relating to the procedure requiring urgent hospitalisation or urgent investigations were identified. One patient was readmitted the next day requiring stenting of the previously treated lesion. Our 30 day mortality was zero. Some 97 hospital bed days were saved with 100 patients treated. Conclusion: Elective day-case DCB-only angioplasty according to our local protocol is safe and cost-effective and should be considered for the majority of the patients

Pharmaceutical Digital Design: From Chemical Structure through Crystal Polymorph to Conceptual Crystallization Process

A workflow for the digital design of crystallization processes starting from the chemical structure of the active pharmaceutical ingredient (API) is a multistep, multidisciplinary process. A simple version would be to first predict the API crystal structure and, from it, the corresponding properties of solubility, morphology, and growth rates, assuming that the nucleation would be controlled by seeding, and then use these parameters to design the crystallization process. This is usually an oversimplification as most APIs are polymorphic, and the most stable crystal of the API alone may not have the required properties for development into a drug product. This perspective, from the experience of a Lilly Digital Design project, considers the fundamental theoretical basis of crystal structure prediction (CSP), free energy, solubility, morphology, and growth rate prediction, and the current state of nucleation simulation. This is illustrated by applying the modeling techniques to real examples, olanzapine and succinic acid. We demonstrate the promise of using ab initio computer modeling for solid form selection and process design in pharmaceutical development. We also identify open problems in the application of current computational modeling and achieving the accuracy required for immediate implementation that currently limit the applicability of the approach

Comparison of the antiplatelet and antithrombotic effects of bivalirudin versus unfractionated heparin: A platelet substudy of the HEAT PPCI trial

In randomised trials, bivalirudin has been associated with higher rates of acute stent thrombosis (AST) compared to unfractionated heparin (UFH), without mechanistic explanation. Furthermore, data are discrepant regards the antiplatelet effects of bivalirudin. This prespecified study, part of a larger HEAT-PPCI Platelet Substudy, aimed to compare the antiplatelet and antithrombotic effects of bivalirudin and UFH using short thrombelastography (s-TEG), an ex vivo whole blood platelet function assay. In HEAT-PPCI, patients were randomised to receive UFH or bivalirudin before angiography. Assay with s-TEG was performed in 184 patients (10.2%) at end of procedure (EOP) and repeated at 24 h. In addition to adenosine diphosphate- (ADP) and arachidonic acid- (AA) mediated platelet aggregation, thrombin-mediated clotting (TMC) was assessed using kaolin with and without heparinase. There were no significant differences between UFH and bivalirudin in ADP- and AA-mediated platelet aggregation at EOP or 24 h. Whilst UFH obliterated TMC at EOP, bivalirudin prolonged R time (19.7 min [15.9-25.4] vs. 8.4 min [7.5-10]; P &lt; 0.0001), K time (2.4 min [1.9-3.4] vs. 2.2 min [1.8-2.7]; P = 0.007) and significantly increased maximum clot strength (MA 62.7 mm [58.7-67.4] vs. 58.6 [55-63]; P = 0.0005), compared to control. In conclusion, there were no significant differences in the antiplatelet effects of UFH and bivalirudin. However, whilst UFH obliterated TMC, bivalirudin prolonged clot initiation but potentiated maximum clot strength. As AST is likely multifactorial in aetiology, in patients treated with bivalirudin, increased clot strength may contribute to this hazard in some individuals and this observation warrants further investigation.</p

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. METHODS: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. FINDINGS: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. INTERPRETATION: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Nations within a nation: variations in epidemiological transition across the states of India, 1990–2016 in the Global Burden of Disease Study

18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Digital Design of Crystals: Predicting Driving Forces For Crystallization Using Atomistic Simulations

One of the most awe-inspiring class of materials are crystals. These highly ordered groups of atoms/molecules propel our lives through myriad products we humans rely upon. Right from the salt and sugar we consume to elevate the taste of our foods, the silicon chips that form the brains of every computing device we use, to the life saving drugs that have prevented millions if not billions of deaths, all belong to the humble class of materials — the crystal. Therefore, the engineering of this material is crucial to — improve the manufacturing of products that touch our lives daily — ultimately improving the quality of every human life!The two physical attributes of a crystalline material that have a major impact on its processability and performance are its shape and size. For e.g., in a crystalline catalyst one wants to engineer the shape of the crystal to maximize the area of its reactive surfaces. In pharmaceutical applications, the crystal size distribution may determine the rate of plasma uptake of a drug when the process is dissolution rate limited. Therefore, engineering the shape and size of the crystals is of immense consequence.In silico tools that can predict the shape and size of a crystal based on inputs such as crystal structure, temperature, supersaturation, etc. are vital to efficiently navigate the process design space. Such tools help achieve the efficiency gains by being a guiding light to experimentalists, thus enabling cheaper and more effective screening. This dissertation lays out the digital design framework to make these predictions starting from a molecule. It focuses on the development of a computational toolkit to predict driving forces for crystallization — a key prediction to enable size predictions — of complex molecules harnessing atomistic simulations