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The main objectives of this analysis are to examine the benefits and costs of fuel-saving technologies for new heavy-duty vehicles (HDVs) in India over the next 10 years and, to explore how various scenarios for the deployment of vehicles with these technologies will impact petroleum consumption and carbon dioxide (CO2) emissions over the next three decades. The study team developed simulation models for three representative HDV types—a 40-tonne tractor-trailer, 25-tonne rigid truck, and 16-tonne transit bus—based on top-selling vehicle models in the Indian market. The baseline technology profiles for all three vehicles were developed using India-specific engine data and vehicle specification information from manufacturer literature and input from industry experts. For each of the three vehicles we developed a comprehensive set of seven efficiency technology packages drawing from five major areas: engine, transmission and driveline, tires, aerodynamics, and weight reduction. Our analysis finds that India has substantial opportunity to improve HDV fuel efficiency levels using cost-effective technologies. Results from our simulation modeling of three representative HDV types—a tractor-trailer, rigid truck, and transit bus—reveal that per-vehicle fuel consumption reductions between roughly 20% and 35% are possible with technologies that provide a return on the initial capital investment within 1 to 2 years. Though most of these technologies are currently unavailable in India, experiences in other more advanced markets such as the US and EU suggest that with sufficient incentives and robust regulatory design, significant progress can be made in developing and deploying efficiency technologies that can provide real-world fuel savings for new commercial vehicles in India over the next 10 years. Bringing HDVs in India up to world-class technology levels will yield substantial petroleum and GHG reductions. By 2030, the fuel and CO2 reductions of the scenarios range from 10% to 34%, and at the end of 2050, these reductions grow to 13% and 41%. If we constrain the analysis to select the most efficient technology package that provides the fleets with payback times of 3 years or less, there are annual fleet-wide savings of roughly 11 MTOE of diesel and 34 MMT of CO2 in 2030, and this grows to 31 MTOE and 97 MMT by 2050.

Ali Mobasheri,1– 4 Aliyyaa Spring-Charles,5 Francesco Carlo Gamaleri,6 Joyce McSwan,7 Manohar Garg,8 Vidhu Sood Sethi9 1Research Unit of Health Sciences and Technology, Physics and Technology, University of Oulu, Oulu, Finland; 2Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; 3Department of Joint Surgery, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4World Health Organization Collaborating Center for Public Health Aspects of Musculoskeletal Health and Aging, Université de Liège, Liège, Belgium; 5Hope Spring Clinic, London, UK; 6Pharmacy San Rocco, Cornaredo (Milan), Italy; 7PainWISE Pty Ltd, Gold Coast, Queensland, Australia; 8Nutraceuticals Research Program, University of Newcastle, Callaghan, Newcastle, NSW, Australia; 9Medical Affairs, Haleon (Formerly GlaxoSmithKline Consumer Healthcare) Pte. Ltd., SingaporeCorrespondence: Vidhu Sood Sethi, Haleon (Formerly GlaxoSmithKline Consumer Healthcare) Pte. Ltd., Singapore, Tel +65 96447203, Email vidhu.x.sethi@haleon.comBackground: Pharmacological approaches to acute and chronic pain management, including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, are respectively associated with adverse reactions (such as gastrointestinal, cardiovascular, and renal effects) that might limit their use in patients with comorbidities and controversy related to inappropriate use. Naturopathic remedies might offer patients alternative and integrative treatments with minimal side effects.Objective: To explore the regional variation in the acceptance and use of naturopathic remedies in pain management.Methods: Two expert panel discussions were held by GlaxoSmithKline Consumer Healthcare (now Haleon Pte. Ltd.) over 9 and 12 hours in 2020 and 2021, respectively, and attended by multidisciplinary experts in naturopathy, Ayurvedic medicine, community pharmacy, physiotherapy, clinical pharmacy, Western medicine, academics, and naturopathic pain relief. Experts shared and discussed their experiences of naturopathic treatments and relevant clinical evidence related to different types of pain (including joint and muscle pain, migraine, sleeplessness due to pain, and general pain) and examined barriers to providing support to patients.Results: Experts agreed on the potential for curcumin (2020, 71.4% [5/7]; 2021, 91.7% [11/12]) and fish oil (2020, 100% [7/7]) for management of osteoarthritic joint pain although these are not uniformly recommended in osteoarthritis treatment guidelines. In treatment of migraines, coenzyme Q10 and magnesium were favored by experts (2021, 90.9% [10/11] and 63.6% [7/11], respectively).Conclusion: The need was emphasized for more and higher quality clinical studies to support naturopathic remedies, which might not be reflected in the latest treatment guidelines. The expert panel also highlighted missed opportunities for physicians and pharmacists to recommend effective naturopathic treatments.Keywords: herbal remedies, naturopathy, osteoarthritis, migraine, expert panel discussion

Danuta Kielar,1 Andrew M Jones,2 Xia Wang,3 Heide Stirnadel-Farrant,1 Rohit K Katial,4 Abhinav Bansal,5 Manu Garg,5 Chandrakant Sharma,5 Shubhankar Thakar,5 Qin Ye5 1BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; 2Late-Stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 3Data Science & AI, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 4BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 5ZS, Philadelphia, PA, USACorrespondence: Danuta Kielar, AstraZeneca, Academy House, 136 Hills Road, Cambridge, CB2 8PA, UK, Tel +44 7384905053, Email danuta.kielar@astrazeneca.comBackground: Blood eosinophils can increase in response to infection, inflammation, and hypersensitivity reactions, yet their involvement in the progression of chronic kidney disease (CKD) is poorly understood. This study explores the relationship between blood eosinophils and CKD progression among patients in a real-world setting.Methods: This retrospective study analyzed data obtained from the Optum® de-identified electronic health records dataset in the United States. Patients diagnosed with CKD stage 3 or 4 (International Classification of Diseases diagnosis code or estimated glomerular filtration rate [eGFR] < 60 mL/min) between January 2011 and March 2018 were included and followed until progression to the next CKD stage, death, or dropout. The primary objective of this study was to assess the relationship between blood eosinophil counts (bEOS) and CKD progression, adjusting for clinical and demographic features as well as known risk factors for CKD stages 3– 4. The primary outcomes were CKD progression and all-cause mortality.Results: We found that high eosinophilic levels (bEOS ≥ 300 cells/μL) were associated with CKD progression from stage 3 to stages 4 or 5 (hazard ratio [HR] ranging from 1.30 to 1.50) and from stages 4 to 5 (HR ranging from 1.28 to 1.50). Among patients with CKD progression, those with blood eosinophils ≥ 300 cells/μL appeared to have a relatively lower eGFR, higher all-cause mortality, and reduced time to CKD progression and death than those with < 300 cells/μL. Factors including sex, race, hypertension, anemia, and treatments for cardiovascular and hematopoietic drugs were associated with CKD progression.Conclusion: Elevated eosinophils may increase the risk for CKD progression. Larger studies are needed to assess whether the risk of mortality is increased among patients with elevated eosinophils.Keywords: eosinophilic inflammation, renal insufficiency, glomerular filtration rate

The main objectives of this analysis are to examine the benefits and costs of fuel-saving technologies for new heavy-duty vehicles (HDVs) in India over the next 10 years and, to explore how various scenarios for the deployment of vehicles with these technologies will impact petroleum consumption and carbon dioxide (CO2) emissions over the next three decades. The study team developed simulation models for three representative HDV types—a 40-tonne tractor-trailer, 25-tonne rigid truck, and 16-tonne transit bus—based on top-selling vehicle models in the Indian market. The baseline technology profiles for all three vehicles were developed using India-specific engine data and vehicle specification information from manufacturer literature and input from industry experts. For each of the three vehicles we developed a comprehensive set of seven efficiency technology packages drawing from five major areas: engine, transmission and driveline, tires, aerodynamics, and weight reduction. Our analysis finds that India has substantial opportunity to improve HDV fuel efficiency levels using cost-effective technologies. Results from our simulation modeling of three representative HDV types—a tractor-trailer, rigid truck, and transit bus—reveal that per-vehicle fuel consumption reductions between roughly 20% and 35% are possible with technologies that provide a return on the initial capital investment within 1 to 2 years. Though most of these technologies are currently unavailable in India, experiences in other more advanced markets such as the US and EU suggest that with sufficient incentives and robust regulatory design, significant progress can be made in developing and deploying efficiency technologies that can provide real-world fuel savings for new commercial vehicles in India over the next 10 years. Bringing HDVs in India up to world-class technology levels will yield substantial petroleum and GHG reductions. By 2030, the fuel and CO2 reductions of the scenarios range from 10% to 34%, and at the end of 2050, these reductions grow to 13% and 41%. If we constrain the analysis to select the most efficient technology package that provides the fleets with payback times of 3 years or less, there are annual fleet-wide savings of roughly 11 MTOE of diesel and 34 MMT of CO2 in 2030, and this grows to 31 MTOE and 97 MMT by 2050.

Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.

Mandeep Garg,1 Muniraju Maralakunte,1 Suruchi Garg,2 Sahajal Dhooria,3 Inderpaul Sehgal,3 Ashu Seith Bhalla,4 Rajesh Vijayvergiya,5 Sandeep Grover,6 Vikas Bhatia,1 Priya Jagia,7 Ashish Bhalla,8 Vikas Suri,8 Manoj Goyal,9 Ritesh Agarwal,3 Goverdhan Dutt Puri,10 Manavjit Singh Sandhu1 1Department of Radiodiagnosis & Imaging, PGIMER, Chandigarh, India; 2Department of Dermatology, Aura Skin Institute, Chandigarh, India; 3Department of Pulmonary Medicine, PGIMER, Chandigarh, India; 4Department of Radiodiagnosis, AIIMS, New Delhi, India; 5Department of Cardiology, PGIMER, Chandigarh, India; 6Department of Psychiatry, PGIMER, Chandigarh, India; 7Department of Cardiovascular Imaging & Endovascular Interventions, AIIMS, New Delhi, India; 8Department of Internal Medicine, PGIMER, Chandigarh, India; 9Department of Neurology, PGIMER, Chandigarh, India; 10Department of Anaesthesia and Intensive Care, PGIMER, Chandigarh, IndiaCorrespondence: Mandeep GargDepartment of Radiodiagnosis and Imaging, PGIMER, Sector-12, Chandigarh, IndiaTel +91 9914209390Email gargmandeep@hotmail.comAbstract: COVID-19 is an ongoing pandemic with many challenges that are now extending to its intriguing long-term sequel. ‘Long-COVID-19ʹ is a term given to the lingering or protracted illness that patients of COVID-19 continue to experience even in their post-recovery phase. It is also being called ‘post-acute COVID-19ʹ, ‘ongoing symptomatic COVID-19ʹ, ‘chronic COVID-19ʹ, ‘post COVID-19 syndrome’, and ‘long-haul COVID-19ʹ. Fatigue, dyspnea, cough, headache, brain fog, anosmia, and dysgeusia are common symptoms seen in Long-COVID-19, but more varied and debilitating injuries involving pulmonary, cardiovascular, cutaneous, musculoskeletal and neuropsychiatric systems are also being reported. With the data on Long-COVID-19 still emerging, the present review aims to highlight its epidemiology, protean clinical manifestations, risk predictors, and management strategies. With the re-emergence of new waves of SARS-CoV-2 infection, Long-COVID-19 is expected to produce another public health crisis on the heels of current pandemic. Thus, it becomes imperative to emphasize this condition and disseminate its awareness to medical professionals, patients, the public, and policymakers alike to prepare and augment health care facilities for continued surveillance of these patients. Further research comprising cataloging of symptoms, longer-ranging observational studies, and clinical trials are necessary to evaluate long-term consequences of COVID-19, and it warrants setting-up of dedicated, post-COVID care, multi-disciplinary clinics, and rehabilitation centers.Keywords: ongoing symptomatic COVID-19, post-COVID-19 syndrome, chronic COVID, Long-COVID-19, post-COVID, Long-COVID

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant hematopoietic cells. In these cells, it downregulates activated tyrosine kinases at the cell surface resulting in an antiproliferative effect. To date, no studies have examined activities of LNK in solid tumors. In this study, we found by in silico analysis and staining tissue arrays that the levels of LNK expression were elevated in high-grade ovarian cancer. To test the functional importance of this observation, LNK was either overexpressed or silenced in several ovarian cancer cell lines. Remarkably, overexpression of LNK rendered the cells resistant to death induced by either serum starvation or nutrient deprivation, and generated larger tumors using a murine xenograft model. In contrast, silencing of LNK decreased ovarian cancer cell growth in vitro and in vivo. Western blot studies indicated that overexpression of LNK upregulated and extended the transduction of the mitogenic signal, whereas silencing of LNK produced the opposite effects. Furthermore, forced expression of LNK reduced cell size, inhibited cell migration and markedly enhanced cell adhesion. Liquid chromatography-mass spectroscopy identified 14-3-3 as one of the LNK-binding partners. Our results suggest that in contrast to the findings in hematologic malignancies, the adaptor protein LNK acts as a positive signal transduction modulator in ovarian cancers.

Background: Inactive glycogen synthase kinase-3β [phosphorylation at Serine 9 (pS9GSK-3β)] is known to regulate nuclear stabilization of β-catenin and activation of Epithelial-to-mesenchymal transition (EMT) inducing molecules. Present study is taken up to examine the prognostic impact of EMT markers in urothelial tumors with normal and immunoco-aberrantly expressed pS9GSK-3β and β-catenin. Material and methods: Expressions and subcellular localizations of pS9GSK-3β and β-catenin were checked immunohistochemically in 65 NMIBC and 55 MIBC patients. These tumors were later examined for transcriptomic and protein levels of EMT associated molecules followed by their statistical significance with patients' variables. Results: Number of clinicopathological variables exhibited statistical associations with altered EMT markers in non-muscle invasive and muscle invasive tumors with aberrantly immunoco-expressed pS9GSK-3β and β-catenin. Follow up data were collected in 53 NMIBC and 49 MIBC patients over the average timeline of 48 months. Of 25/53 NMIBC and 33/49 MIBC patients with aberrantly immunoco-expressed pS9GSK-3β and β-catenin, molecular anomaly in EMT markers (E−/M+/T+) was noted in 40% NMIBC and 27.3% MIBC patients. NMIBC patients (100%) exhibiting tumor recurrence had at least two molecular abnormalities, whereas 55.5% MIBC succumbed to death and 44.4% MIBC showed tumor progression suggesting that tumor aggressiveness could be linked to severity of abnormal phenotype. Conclusion: Survival analysis demonstrates altered expressions of pS9GSK-3β/β-catenin/EMT as prognostic markers for poor cancer specific survival (p ​= ​0.049) and short overall survival (p ​= ​0.03) probabilities of MIBC patients. Study establishes altered pS9GSK-3β/β-catenin/EMT profile as a sensitive and effective prognostic tool in a subset of bladder tumors.

Background/Objectives: Abnormalities in lipoprotein profiles (size, distribution and concentration) play an important role in the pathobiology of atherosclerosis and coronary artery disease. Dietary fat, among other factors, has been demonstrated to modulate lipoprotein profiles. We aimed to investigate if background dietary fat (saturated, SFA versus omega-6 polyunsaturated fatty acids, n-6PUFA) was a determinant of the effects of LCn-3PUFA supplementation on lipoprotein profiles. Subjects/Methods: A randomized controlled clinical intervention trial in a parallel design was conducted. Healthy subjects (n=26) were supplemented with 400 mg eicosapentaenoic acid plus 2000 mg docosahexaenoic acid daily and randomized to consume diets rich in either SFA or n-6PUFA for a period of 6 weeks. Blood samples, collected at baseline and after 6 weeks of intervention, were assessed for plasma lipoprotein profiles (lipoprotein size, concentration and distribution in subclasses) determined using nuclear magnetic resonance spectroscopy. Results: Study participants receiving the SFA or the n-6PUFA enriched diets consumed similar percentage energy from fat (41 and 42% respectively, P=0.681). However, subjects on the SFA diet consumed 50% more energy as saturated fat and 77% less as linoleic acid than those consuming the n-6PUFA diet (P Conclusions: LCn-3PUFA modulated lipoprotein profiles in a similar fashion when supplemented in diets rich in either SFA or n-6PUFA., Author(s): C B Dias [sup.1] , N Amigo [sup.2] [sup.3] [sup.4] , L G Wood [sup.5] , X Correig [sup.2] [sup.3] , M L Garg [sup.1] Author Affiliations: (1) Nutraceuticals [...]

Author(s): M. Garg [1]; M. Zhan [1]; T. T. Luu [1]; H. Lakhotia [1]; T. Klostermann [1]; A. Guggenmos [1]; E. Goulielmakis (corresponding author) [1] The frequency of electric currents [...]

The time it takes a bound electron to respond to the electromagnetic force of light sets a fundamental speed limit on the dynamic control of matter and electromagnetic signal processing. Time-integrated measurements of the nonlinear refractive index (1) of matter indicate that the nonlinear response of bound electrons to optical fields is not instantaneous; however, a complete spectral characterization of the nonlinear susceptibility tensors (2)--which is essential to deduce the temporal response of a medium to arbitrary driving forces using spectral measurements--has not yet been achieved. With the establishment of attosecond chronoscopy (3-5), the impulsive response of positive-energy electrons to electromagnetic fields has been explored through ionization of atoms (6) and solids (7) by an extreme-ultraviolet attosecond pulse (8) or by strong near-infrared fields (9-11). However, none of the attosecond studies carried out so far have provided direct access to the nonlinear response of bound electrons. Here we demonstrate that intense optical attosecond pulses synthesized in the visible and nearby spectral ranges allow subfemtosecond control and metrology of bound-electron dynamics. Vacuum ultraviolet spectra emanating from krypton atoms, exposed to intense waveform-controlled optical attosecond pulses, reveal a finite nonlinear response time of bound electrons of up to 115 attoseconds, which is sensitive to and controllable by the superoctave optical field. Our study could enable new spectroscopies of bound electrons in atomic, molecular or lattice potentials of solids (12), as well as light-based electronics operating on sub-femtosecond timescales and at petahertz rates (13-15)., Intramolecular atomic motion dynamically distorts the interatomic electron cloud and thereby gives rise to a transient electronic polarizability (16) and a finite nonlinear response of matter to light fields. Timeresolved [...]