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Since carbon dots (CDs) exhibit excellent biocompatibility, low cytotoxicity, near-infrared (NIR) absorbance, and superior photostability, many types of CDs are considered as powerful candidates for photothermal therapy (PTT) applications. However, the development of a desirable CD is still difficult due to insufficient photothermal conversion, thus resulting in the use of high laser power densities at a high dose of CDs for the PTT effect. Herein, bioinspired sulfur-doped CDs (S-CDs) with strong NIR absorbance were prepared from Camellia japonica flowers via a facile hydrothermal method for enhancing the photothermal conversion efficiency. The as-prepared S-CDs exhibited various advantages including cost-effective preparation, good water-solubility, high biocompatibility, intense NIR absorption, and excellent photothermal effect with robust photostability. Most importantly, the optimal low dose of S-CDs (45 μg mL -1 ) successfully led to efficient PTT performance with a high photothermal conversion efficiency (55.4%) under moderate laser power (808 nm, 1.1 W cm -2 ) for safe and effective cancer therapy.

Objective: To compare the efficacy of insulin infusion of 0.05 Unit/kg/hour vs 0.1 Unit/kg/hour in the management of pediatric diabetic ketoacidosis (DKA)., Design: Randomized, double-blind controlled clinical trial., Subject: Pediatric critical care division of a tertiary care hospital from October, 2014 to July, 2018., Participants: Children aged 12 years or younger with a diagnosis of DKA. Children with septic shock and those who had received insulin before enrollment were excluded., Intervention: Low-dose (0.05 Unit/kg/hour) vs. Standard-dose (0.1 Unit/kg/hour) insulin infusion., Outcome Measures: The primary endpoint was time for resolution of DKA (pH ≥7.3, bicarbonate ≥15 mEq/L, beta-hydroxybutyrate <1 mmol/L). Secondary outcomes were the rate of fall in blood glucose until 250 mg/dL or less and the rate of complications (hypokalemia, hypoglycemia, and cerebral edema)., Results: Sixty patients were analyzed on an intention-to-treat basis (Low-dose group: n=30; Standard-dose group: n=30). Mean (SD) time taken for the resolution of ketoacidosis was similar in both groups [22 (12) vs 23 (18.5) hours; P=0.92]. The adjusted hazard ratio (95% CI) of the resolution of ketoacidosis was lower in the low-dose group [0.40 (0.19 to 0.85); P=0.017]. Mean (SD) rate of blood glucose decrease until 250 mg/dL or less reached [56 (41) vs 64 (65) mg/dL/hour; P=0.41] and time to achieve the target [4.2 (3.1) vs 4.8 (3.3) hours; P=0.44] were similar in both groups. Hypokalemia [30% vs 43.3%; P=0.28] and hypoglycemia [3.3% vs 13.3%; P=0.35] were lower in low-dose group. No child had cerebral edema, and no mortality occurred., Conclusions: Time for resolution of ketoacidosis was similar in the low-dose and standard-dose insulin with a lower rate of therapy-related complications in the low-dose group. Hence, low-dose insulin infusion can be a safer approach in the management of pediatric DKA.

Migration health is affected by decision making at levels ranging from global to local, both within and beyond the health sector. These decisions impact seeking, entitlements, service delivery, policy making and knowledge production on migration health. It is key that ethical challenges faced by decision makers are recognised and addressed in research and data, clinical practice and policy making on migration health. An ethical approach can provide methods to identify ethical issues, frameworks for systematising information and suggesting ethically acceptable solutions, and guidance on procedural concerns and legitimate decision making processes. By unpacking dilemmas, conflicts of interests and values at stake, an ethical approach is relevant for all who make decisions about migration health policy and practice. Adopting an ethical approach to migration health benefits governments, organisations, policy makers, health workers, data managers, researchers and migrants themselves. First, it highlights the inherent normative questions and trade-offs at stake in migration health. Second, it assists decision makers in deciding what is the ethically justifiable thing to do through an 'all things considered' approach. Third, ethical frameworks and technical guidance set normative and practical standards for decision makers facing ethical questions - from 'bedside rationing' to collection of big data or in policy making - that can ensure that migrants' interests are considered. Fourth, there is a need for greater transparency and accountability in decision making, as well as meaningful participation of migrant groups. An ethical approach connects to public health, economic and human rights arguments and highlights the urgent need to mainstream concerns for migrants in global and national health responses., Competing Interests: Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: KHO and IM have volunteered as medical doctors providing care by, or in association with, a healthcare centre for undocumented migrants in Bergen, Norway., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Systemic lupus erythematosus (SLE) is associated with an IL-2-deficient state, with regulatory T cells (Tregs) showing diminished immune regulatory capacity. A low dose of IL-2 has shown encouraging clinical benefits in SLE patients; however, its clinical utility is limited because of the requirement of daily injections and the observation of increase in proinflammatory cytokines and in non-Tregs. We recently showed that a fusion protein of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, was effective in treating diabetes in NOD mice by selectively inducing Treg expansion. In this report, we show that mouse IL-2 (mIL-2)/CD25 at doses up to 0.5 mg/kg twice a week induced a robust Treg expansion without showing signs of increase in the numbers of NK, CD4 + Foxp3 - , or CD8 + T cells or significant increase in proinflammatory cytokines. In both NZB × NZW and MRL/lpr mice, mIL-2/CD25 at 0.2-0.4 mg/kg twice a week demonstrated efficacy in inducing Treg expansion, CD25 upregulation, and inhibiting lupus nephritis based on the levels of proteinuria, autoantibody titers, and kidney histology scores. mIL-2/CD25 was effective even when treatment was initiated at the time when NZB × NZW mice already showed signs of advanced disease. Furthermore, we show coadministration of prednisolone, which SLE patients commonly take, did not interfere with the ability of mIL-2/CD25 to expand Tregs. The prednisolone and mIL-2/CD25 combination treatment results in improvements in most of the efficacy readouts relative to either monotherapy alone. Taken together, our results support further evaluation of IL-2/CD25 in the clinic for treating immune-mediated diseases such as SLE., (Copyright © 2021 by The American Association of Immunologists, Inc.)

The maintenance of intracellular NAD + /NADH homeostasis across multiple, subcellular compartments requires the presence of NADH-shuttling proteins, which circumvent the lack of permeability of organelle membranes to these cofactors. Very little is known regarding these proteins in the methylotrophic yeast, Pichia pastoris . During the study of the subcellular locations of these shuttling proteins, which often have dual subcellular locations, it became necessary to develop new ways to detect the weak peroxisomal locations of some of these proteins. We have developed a novel variation of the traditional Bimolecular Fluorescence Complementation (BiFC), called divergent BiFC, to detect intraorganellar colocalization of two noninteracting proteins based on their proximity-based protein crowding within a small subcellular compartment, rather than on the traditional protein-protein interactions expected for BiFC. This method is used to demonstrate the partially peroxisomal location of one such P. pastoris NADH-shuttling protein, malate dehydrogenase B, only when cells are grown in oleate, but not when grown in methanol or glucose. We discuss the mode of NADH shuttling in P. pastoris and the physiological basis of the medium-dependent compartmentalization of Pp MdhB.

Introduction: The post-2005 rise in clinical trials and clinical research conducted in India was accompanied by frequent reports of unethical practices, leading to a series of regulatory changes. We conducted a systematic scoping review to obtain an overview of empirical research pertaining to the ethics of clinical trials/research in India., Methods: Our search strategy combined terms related to ethics/bioethics, informed consent, clinical trials/research and India, across nine databases, up to November 2019. Peer-reviewed research exploring ethical aspects of clinical trials/research in India with any stakeholder groups was included. We developed an evidence map, undertook a narrative synthesis and identified research gaps. A consultation exercise with stakeholders in India helped contextualise the review and identify additional research priorities., Results: Titles/Abstracts of 9699 articles were screened, full text of 282 obtained and 80 were included. Research on the ethics of clinical trials/research covered a wide range of topics, often conducted with little to no funding. Studies predominantly examined what lay (patients/public) and professional participants (eg, healthcare staff/students/faculty) know about topics such as research ethics or understand from the information given to obtain their consent for research participation. Easily accessible groups, namely ethics committee members and healthcare students were frequently researched. Research gaps included developing a better understanding of the recruitment-informed consent process, including the doctor-patient interaction, in multiple contexts and exploring issues of equity and justice in clinical trials/research., Conclusion: The review demonstrates that while a wide range of topics have been studied in India, the focus is largely on assessing knowledge levels across different population groups. This is a useful starting point, but fundamental questions remain unanswered about informed consent processes and broader issues of inequity that pervade the clinical trials/research landscape. A priority-setting exercise and appropriate funding mechanisms to support researchers in India would help improve the clinical trials/research ecosystem., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objective: Despite the significant advancement in the understanding of the pathophysiology of systemic lupus erythematosus (SLE) variable clinical response to newer therapies remain a major concern, especially for patients with lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE). We performed this study with an objective to comprehensively characterize Indian SLE patients with renal and neuropsychiatric manifestation with respect to their gene signature, cytokine profile and immune cell phenotypes., Methods: We characterized 68 Indian SLE subjects with diverse clinical profiles and disease activity and tried to identify differentially expressed genes and enriched pathways. To understand the temporal profile, same patients were followed at 6 and 12-months intervals. Additionally, auto-antibody profile, levels of various chemokines, cytokines and the proportion of different immune cells and their activation status were captured in these subjects., Results: Multiple IFN-related pathways were enriched with significant increase in IFN-I gene signature in SLE patients as compared to normal healthy volunteers (NHV). We identified two transcriptionally distinct clusters within the same cohort of SLE patients with differential immune cell activation status, auto-antibody as well as plasma chemokines and cytokines profile., Conclusions: Identification of two distinct clusters of patients based on IFN-I signature provided new insights into the heterogeneity of underlying disease pathogenesis of Indian SLE cohort. Importantly, patient within those clusters retain their distinct expression dynamics of IFN-I signature over the time course of one year despite change in disease activity. This study will guide clinicians and researchers while designing future clinical trials on Indian SLE cohort.

THIS SPECIAL article is the 13th in an annual series for the Journal of Cardiothoracic and Vascular Anesthesia. The authors thank the editor-in-chief, Dr Kaplan, and the editorial board for the opportunity to continue this series; namely, the research highlights of the past year in the specialty of cardiothoracic and vascular anesthesiology. 1 The major themes selected for 2020 are outlined in this introduction, and each highlight is reviewed in detail in the main body of the article. The literature highlights in the specialty for 2020 begin with an update on valvular disease, with a focus on updates in management of aortic and mitral valve disorders. The second major theme is an update on coronary artery disease, with discussion of both medical and surgical management. The third major theme is focused on the perioperative management of patients with coronavirus disease 2019 (COVID-19), with the authors highlighting literature discussing medical, surgical, and anesthetic considerations for their cardiac care. The fourth major theme is an update in heart failure, with discussion of medical, psychosocial, and procedural aspects of this complicated disease process. The fifth and final theme focuses on the latest analyses regarding survival in heart transplantation. The themes selected for this 13th special article are only a few of the diverse advances in the specialty during 2020. These highlights will inform the reader of key updates on a variety of topics, leading to improvement of perioperative outcomes for patients with cardiothoracic and vascular disease., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite major advances in our understanding of players and mechanisms involved in peroxisome biogenesis and peroxisome degradation, very few studies have focused on unraveling the multi-layered connections between, and the coordination of, these two opposing processes that regulate peroxisome homeostasis. The intersection between these processes also provides exciting avenues for future research. This review highlights the links between peroxisome biogenesis and degradation, incorporating an integrative approach that is critical not only for a mechanistic understanding, but also for manipulating the balance between these processes in relevant disease models., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Unfolding and refolding of multidomain proteins under force have yet to be recognized as a major mechanism of function for proteins in vivo. In this review, we discuss the inherent properties of multidomain proteins under a force vector from a structural and functional perspective. We then characterize three main systems where multidomain proteins could play major roles through mechanical unfolding: muscular contraction, cellular mechanotransduction, and bacterial adhesion. We analyze how key multidomain proteins for each system can produce a gain-of-function from the perspective of a fine-tuned quantized response, a molecular battery, delivery of mechanical work through refolding, elasticity tuning, protection and exposure of cryptic sites, and binding-induced mechanical changes. Understanding how mechanical unfolding and refolding affect function will have important implications in designing mechano-active drugs against conditions such as muscular dystrophy, cancer, or novel antibiotics., (© 2020 Federation of European Biochemical Societies.)

Background: The mosquito Anopheles stephensi is a vector of urban malaria in Asia that recently invaded Africa. Studying the genetic basis of vectorial capacity and engineering genetic interventions are both impeded by limitations of a vector's genome assembly. The existing assemblies of An. stephensi are draft-quality and contain thousands of sequence gaps, potentially missing genetic elements important for its biology and evolution., Results: To access previously intractable genomic regions, we generated a reference-grade genome assembly and full transcript annotations that achieve a new standard for reference genomes of disease vectors. Here, we report novel species-specific transposable element (TE) families and insertions in functional genetic elements, demonstrating the widespread role of TEs in genome evolution and phenotypic variation. We discovered 29 previously hidden members of insecticide resistance genes, uncovering new candidate genetic elements for the widespread insecticide resistance observed in An. stephensi. We identified 2.4 Mb of the Y chromosome and seven new male-linked gene candidates, representing the most extensive coverage of the Y chromosome in any mosquito. By tracking full-length mRNA for > 15 days following blood feeding, we discover distinct roles of previously uncharacterized genes in blood metabolism and female reproduction. The Y-linked heterochromatin landscape reveals extensive accumulation of long-terminal repeat retrotransposons throughout the evolution and degeneration of this chromosome. Finally, we identify a novel Y-linked putative transcription factor that is expressed constitutively throughout male development and adulthood, suggesting an important role., Conclusion: Collectively, these results and resources underscore the significance of previously hidden genomic elements in the biology of malaria mosquitoes and will accelerate the development of genetic control strategies of malaria transmission.

Iatrogenic aortic dissection is a rare and serious complication of cardiac surgery with an incidence between 0.12' and 0.16'. Dissections involving an intimal flap can be detected using trans-esophageal echocardiography (TEE) with a sensitivity of 94'-100' and specificity of 77'-100'. Rarely, dissections can occur that are not detectable by TEE. There have been reports of iatrogenic dissection in the ascending aortic cannulation site; however, a dissection at the antegrade cardioplegia cannulation site is very rare. It also presents challenges associated with early diagnosis and appropriate intervention. We are describing a rare case of aortic dissection at the antegrade cardioplegia cannulation site in the proximal ascending aorta. The dissection was unable to be visualized with TEE initially, and required epi-aortic ultrasound to diagnose dissection in timely manner., Competing Interests: None

Closed traumatic dislocation of multiple metatarsophalangeal joints is a rare injury. Until now only one case of simultaneous dislocation of all five metatarsophalangeal joints has been reported in peer-reviewed studies. The complex anatomy of the metatarsophalangeal joints prevents the relocation of the joints in a closed manner in maximum cases. We are reporting a case of dorsal dislocation of the second to fifth metatarsophalangeal joints in the left foot after road traffic accident. Bony prominence over the plantar aspect and increased web space between toes on presentation, then incongruity of metatarsophalangeal joints has to be thoroughly checked on radiograph. Since closed reduction attempts failed open reduction was done through dorsal approach using two incisions. Button holing of the capsule with interposition of capsule and plantar plate was noted. Dorsal approach avoids damage to the plantar plate and surrounding soft tissues., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Raj et al.)

Malaria remains a major healthcare risk to growing economies like India, and a chromosome-level reference genome of Anopheles stephensi is critical for successful vector management and understanding of vector evolution using comparative genomics. We report chromosome-level assemblies of an Indian strain, STE2, and a Pakistani strain SDA-500 by combining draft genomes of the two strains using a homology-based iterative approach. The resulting assembly IndV3/PakV3 with L50 of 9/12 and N50 6.3/6.9 Mb had scaffolds long enough for building 90% of the euchromatic regions of the three chromosomes, IndV3s/PakV3s, using low-resolution physical markers and enabled the generation of the next version of genome assemblies, IndV4/PakV4, using HiC data. We have validated these assemblies using contact maps against publicly available HiC raw data from two strains including STE2 and another lab strain of An. stephensi from UCI and compare the quality of the assemblies with other assemblies made available as preprints since the submission of the manuscript. We show that the IndV3s and IndV4 assemblies are sensitive in identifying a homozygous 2Rb inversion in the UCI strain and a 2Rb polymorphism in the STE2 strain. Multiple tandem copies of CYP6a14, 4c1, and 4c21 genes, implicated in insecticide resistance, lie within this inversion locus. Comparison of assembled genomes suggests a variation of 1 in 81 positions between the UCI and STE2 lab strains, 1 in 82 between SDA-500 and UCI strain, and 1 in 113 between SDA-500 and STE2 strains of An. stephensi , which are closer than 1 in 68 variations among individuals from two other lab strains sequenced and reported here. Based on the developmental transcriptome and orthology of all the 54 olfactory receptors (ORs) to those of other Anopheles species, we identify an OR with the potential for host recognition in the genus Anopheles . A comparative analysis of An. stephensi genomes with the completed genomes of a few other Anopheles species suggests limited inter-chromosomal gene flow and loss of synteny within chromosomal arms even among the closely related species., (Copyright © 2020 Chida, Ravi, Jayaprasad, Paul, Saha, Suresh, Whadgar, Kumar, Rao K, Ghosh, Choudhary, Subramani and Srinivasan.)

The highlights in cardiothoracic transplantation focus on the recent research pertaining to heart and lung transplantation, including expansion of the donor pool, the optimization of donors and recipients, the use of mechanical support, the perioperative and long-term outcomes in these patient populations, and the use of transthoracic echocardiography to diagnose rejection., Competing Interests: Conflicts of Interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2020. Published by Elsevier Inc.)

This article illustrates the less-acknowledged social construction of the concept of 'incompetency' and draws attention to the moral concerns it raises in health care encounters in the south Indian city of Chennai. Based on data drawn from qualitative research, this study suggests that surgeons subjectively construct the idea of incompetency through their understanding of the perceived circumstantial characteristics of the patients and family members they serve. The findings indicate that surgeons often underestimate patients and family members' capacity based on constructed assessments, which leads to paternalistic practice. In this article, I illustrate how these assessments influence the surgeons' practices and provide the moral and practical justifications for their actions. The constructed knowledge becomes a source for drawing normative justification for surgeons' actions and, in conjunction with socially enforced power relationships, results in patients and family members to be on the receiving end of disrespectful attitudes. Based on the data analysis and by drawing on philosophical analysis, I emphasize the need to focus on 'respect for persons,' to rethink the framework of 'capacity,' and to practice respect in hospital settings.

Introduction: Morphometric evaluation of the pedicle and isthmus of second cervical vertebra (C2) (Axis) is extremely vital before contemplating any surgical stabilization involving the Craniovertebral region, in view of its proximity to the vertebral artery and the cervical nerve root. The dimensions of pedicles and isthmuses in C2 vary between individuals and there is paucity of data in the Indian population. This study strives to measure the average pedicle and isthmus dimensions in a sample of population, which would enable selection of screws with safest diameters to be used in C2; thereby avoiding injury to adjacent neurovascular structures., Materials and Methods: One Hundred patients in the age group between 18 and 70 years who underwent CT scan of head and neck region were included in the study. The aim of this study was to assess the anatomic suitability of transarticular and pedicle screw placement in Axis vertebrae of Indian population and determine the maximum safe diameter for screw placement. The following parameters were measured in millimeters: Pedicle width, Pedicle angle, Internal height and Isthmic height., Results: The Mean maximum diameter of potential pedicle screw was 4.99 ± 1.1 mm for the right side with the left side being slightly wider at 5.20 ± 1.16 mm. Twenty eight (28%; 56 out of 200 pedicles) had a measurement < 4.5 mm. The internal height in sagittal images representing the pedicle height was found to be 4.79 ± 0.96 mm on the right side and 4.75 ± 1.04 mm on the left side. Sixty five (65) out of 200 pedicles (32.5%) had measurements < 4.5 mm in sagittal plane. The Mean maximum diameter of potential Transarticular screw (outer diameter of isthmus) was 5.05 ± 0.78 mm for the right side and 5.18 ± 0.84 mm on the left side., Discussion: Isthmic height < 4.5 mm could potentially violate the vertebral foramen when a 3.5 mm screw is used. In our study 22.5% isthmuses were narrow (<4.5 mm). The mean maximum safe diameter for a potential transarticular screw in the present study was 5.11 mm. Though our patients had smaller isthmus dimensions compared with literature, 77.5% of C2 could take a 4 mm transarticular screw quite comfortably considering the 0.5 mm margin on either side. In the present study, 28% of pedicles were found to be inappropriately sized (<4.5 mm) to accommodate the standard 3.5 mm screw. The mean maximum diameter of a potential pedicle screw in our study was 5.09 mm; and in 72% of patients a 4 mm screw could be placed with confidence. Though our patients on an average can accommodate a 4 mm screw comfortably, we suggest a protocol of obtaining CT measurements of C2 prior to operative intervention for identifying those individuals at risk of neurovascular injury; 22.5% for transarticular screw and 28% for pedicle screw., Competing Interests: Nil., (© 2020 Delhi Orthopedic Association. All rights reserved.)

HEART FAILURE (HF) is one of the most common causes of hospitalization in the United States. Loop diuretics (LD) are the mainstay of treatment in the management of acute and chronic HF. Although they generally are effective in relieving symptoms and reducing congestion, LD have not been shown to significantly affect morbidity and mortality. The initial decongestion strategy for management of HF is likely to be an LD, with evidence suggesting that an initial "high-dose" strategy either by twice-daily bolus injection or by continuous infusion is likely to be more successful than an initial lower dose in respect to relief of symptoms but at the expense of increased worsening of renal function. This review focuses on the current state of evidence of different strategies related to the use of LD in the treatment of congestive symptoms in critically ill patients and presents a summary of the body of evidence regarding dosages, timing, and different diuretic agents., (Copyright © 2019. Published by Elsevier Inc.)

Background: Current protocols for the perioperative care of lung transplant (LTX) recipients lack rigorous evidence and are often empiric, based upon institutional preferences. We surveyed LTX anesthesiologists to determine the most common practices., Methods: We developed a survey of 40 questions regarding perioperative care of LTX recipients using Qualtrics software. The survey was sent out to members of the Society of Cardiovascular Anesthesiologists performing LTX at geographically diverse sites to facilitate data collection for as many practices as possible., Results: The responses were center-weighed (127 responses, 85% from academic settings). The clamshell approach was commonly used (70%). Cardiopulmonary bypass was preferred by 56%, ex vivo lung perfusion utilized by 43%, and 49.4% indicated they use lungs from donation after circulatory determination of death. Most (69%) used oximetric pulmonary artery catheters, 60% used tissue oximetry, and 89.3% utilized transesophageal echocardiography. Inhaled nitric oxide was preferred by 48%, restrictive fluid management by 48%, and systemic analgesia advocated by 49% of participants. Inspired oxygen concentration <30% was applied to the new lung on reperfusion by 28% of the respondents., Conclusion: Variations in healthcare delivery and utilization for LTX recipients indicate gaps in knowledge and potential opportunities to improve the quality of care., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21 , which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Over the last decade, transcatheter aortic valve replacement (TAVR) has emerged as the recommended approach for patients with high and intermediate risk for surgical aortic valve replacement. Even though initial trials demonstrated a higher incidence of conduction abnormalities (CAs), such as left bundle branch block, atrial fibrillation, and permanent pacemaker implantation with TAVR, the incidence of CAs has not decreased. With an increasing number of patients expected to undergo TAVR in the coming decades, even those at low risk for surgical aortic valve replacement, it is important to review the incidence, course, risk factors, mortality, and rehospitalization associated with CAs and permanent pacemaker implantation after TAVR. The newer-generation valves have demonstrated an improved safety profile, but have failed to demonstrate a clinically significant reduction in the incidence of CAs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Alpha adrenergic stimulation is known to produce vasoconstriction. We have earlier shown that, in spiral strips of small arteries Phenylephrine (PE) caused vasorelaxation under high nitric oxide (NO) environment. However, on further experimentation it was realized that the PE-induced vasorelaxant response occurred only with longitudinal strips of small arteries even under normal NO environment while circular strips showed contraction with PE even under high NO environment. Such PE-induced vasorelaxation of longitudinal strips was blocked by Phentolamine, an alpha-adrenergic receptor blocker. On delineation of specific receptor subtype, PE-induced relaxation was found to be mediated through alpha 1D receptor. However, this phenomenon is specific to small artery, as longitudinal smooth muscle of aorta showed only contractile response to adrenergic stimulation. There is no prior report of longitudinal smooth muscle in small artery up to our knowledge. The results of this study and histological examination of vessel sections suggest the presence of longitudinal smooth muscle in small artery and their relaxant response to alpha adrenergic stimulation is a novel phenomenon., Competing Interests: The authors have declared that no competing interests exist.

Heart transplant can be considered as the "gold standard" treatment for end-stage heart failure, with nearly 5.7 million adults in the United States carrying a diagnosis of heart failure. According to the International Society for Heart and Lung Transplantation registry, nearly 3300 orthotopic heart transplants were performed in 2016 in North America. In spite of significant improvements in overall perioperative care of heart transplant recipients for the past few decades, the risk of 30-day mortality remains 5% to 10%, primarily related to early failure of the allograft. Early graft dysfunction (EGD) occurs within 24 hours after transplant, manifesting as left ventricular dysfunction, right ventricular dysfunction, or biventricular dysfunction. EGD is further classified into primary and secondary graft dysfunction. This review focus on describing overall incidences of EGD, potential risk factors associated with EGD, perioperative preventive measures, and various management options.

Macroautophagy (referred to hereafter as autophagy) is an intracellular degradation pathway in which the formation of a double-membrane vesicle called the autophagosome is a key event in the transport of multiple cytoplasmic cargo (e.g., proteins, protein aggregates, lipid droplets or organelles) to the vacuole (lysosome in mammals) for degradation and recycling. During this process, autophagosomes are formed de novo by membrane fusion events leading to phagophore formation initiated at the phagophore assembly site. In yeast, Atg11 and Atg17 function as protein scaffolds, essential for selective and non-selective types of autophagy, respectively. While Atg17 functions in non-selective autophagy are well-defined in the literature, less attention is concentrated on recent findings regarding the roles of Atg11 in selective autophagy. Here, we summarize current knowledge about the Atg11 scaffold protein and review recent findings in the context of its role in selective autophagy initiation and autophagosome formation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Semecarpus anacardium is an important herbal drug that has been used against various ailments. To evaluate the cardioprotective effect of the drug against altered cardiac energy metabolism in type-2 diabetes rats, type-2 diabetes was induced in rats by feeding them with a high-fat diet for 2 weeks followed by intraperitoneal injection of streptozotocin (STZ) 35 mg/kg body weight twice 24 h apart and left for 12 weeks to develop cardiovascular complication. The effects of the nut milk extract on the glucose metabolizing enzymes and mitochondrial complex enzymes were studied using biochemical assays. The drug effectively ameliorated the alteration in cardiac energy metabolism in diabetic rats. The cardioprotective effect may be mediated through the ability of the drug to enhance glucose utilization and control the oxidative stress under diabetic conditions.

Damaged or redundant peroxisomes and their luminal cargoes are removed by pexophagy, a selective autophagy pathway. In yeasts, pexophagy depends mostly on the pexophagy receptors, such as Atg30 for Pichia pastoris and Atg36 for Saccharomyces cerevisia e, the autophagy scaffold proteins, Atg11 and Atg17, and the core autophagy machinery. In P. pastoris , the receptors for peroxisomal matrix proteins containing peroxisomal targeting signals (PTSs) include the PTS1 receptor, Pex5, and the PTS2 receptor and co-receptor, Pex7 and Pex20, respectively. These shuttling receptors are predominantly cytosolic and only partially peroxisomal. It remains unresolved as to whether, when and how the cytosolic pools of peroxisomal receptors, as well as the peroxisomal matrix proteins, are degraded under pexophagy conditions. These cytosolic pools exist both in normal and mutant cells impaired in peroxisome biogenesis. We report here that Pex5 and Pex7, but not Pex20, are degraded by an Atg30-independent, selective autophagy pathway. To enter this selective autophagy pathway, Pex7 required its major PTS2 cargo, Pot1. Similarly, the degradation of Pex5 was inhibited in cells missing abundant PTS1 cargoes, such as alcohol oxidases and Fox2 (hydratase-dehydrogenase-epimerase). Furthermore, in cells deficient in PTS receptors, the cytosolic pools of peroxisomal matrix proteins, such as Pot1 and Fox2, were also removed by Atg30-independent, selective autophagy, under pexophagy conditions. In summary, the cytosolic pools of PTS receptors and their cargoes are degraded via a pexophagy-independent, selective autophagy pathway under pexophagy conditions. These autophagy pathways likely protect cells from futile enzymatic reactions that could potentially cause the accumulation of toxic cytosolic products. Abbreviations: ATG: autophagy related; Cvt: cytoplasm to vacuole targeting; Fox2: hydratase-dehydrogenase-epimerase; PAGE: polyacrylamide gel electrophoresis; Pot1: thiolase; PMP: peroxisomal membrane protein; Pgk1: 3-phosphoglycerate kinase; PTS: peroxisomal targeting signal; RADAR: receptor accumulation and degradation in the absence of recycling; RING: really interesting new gene; SDS: sodium dodecyl sulphate; TCA, trichloroacetic acid; Ub: ubiquitin; UPS: ubiquitin-proteasome system Vid: vacuole import and degradation.

This highlights in our specialty for 2019 begin with the ongoing major developments in transcatheter valve interventions. Thereafter, the advances in left ventricular assist devices are reviewed. The recent focus on conduit selection and robotic options in coronary artery bypass surgery are then explored. Finally, this special articles closes with a discussion of pulmonary hypertension in noncardiac surgery, anesthetic technique in cardiac surgery, as well as postoperative pneumonia and its outcome consequences., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this paper, I examine the rhetoric employed by court judgements, with a particular emphasis on the narrative construct of the 'passive patient'. This construction advances and reinforces paternalistic values, which have scant regard for the patients' preferences, values, or choices within the legal context. Further, I critique the rhetoric employed and argue that the use of this rhetoric is the basis for a precedent that limits the understanding and respect of patients. Through this paper, I present the contemporary use of the 'passive patient' construct in the context of the Indian legal system and describe how such constructions have become a source of normative justification for legal reasoning that jeopardizes the patient's agency. I argue for the primacy of 'respect for persons' within Indian law and the need to treat each patient as a person who has agency, preferences, and values during clinical interactions. I conclude by suggesting that laws that adopt narratives that acknowledging the significance of patient engagement and the relevance of effective communication during clinical encounters would help cultivate a culture of patient-centred care, by moving beyond the rhetoric of 'passive patient' and the 'health/choice' dichotomy., (© National University of Singapore and Springer Nature Singapore Pte Ltd. 2019.)

Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular degeneration characterized by the formation of sub-retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L-ORD results from mutations in the C1q-tumor necrosis factor-5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L-ORD pathology, we used a human cDNA library yeast two-hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM-Ch) from wild-type (Wt), heterozygous S163R Ctrp5 mutation knock-in (Ctrp5 S163R/wt ), and homozygous knock-in (Ctrp5 S163R/S163R ) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C-terminal PDZ-binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R-CTRP5 protein also binds to HTRA1 but is resistant to HTRA1-mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM-Ch of Ctrp5 S163R/S163R and Ctrp5 S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L-ORD pathology., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background: The paper introduces a deep learning-based approach for real-time detection and insights generation about one of the most prevalent chronic conditions in Australia - Pollen allergy. The popular social media platform is used for data collection as cost-effective and unobtrusive alternative for public health monitoring to complement the traditional survey-based approaches., Methods: The data was extracted from Twitter based on pre-defined keywords (i.e. 'hayfever' OR 'hay fever') throughout the period of 6 months, covering the high pollen season in Australia. The following deep learning architectures were adopted in the experiments: CNN, RNN, LSTM and GRU. Both default (GloVe) and domain-specific (HF) word embeddings were used in training the classifiers. Standard evaluation metrics (i.e. Accuracy, Precision and Recall) were calculated for the results validation. Finally, visual correlation with weather variables was performed., Results: The neural networks-based approach was able to correctly identify the implicit mentions of the symptoms and treatments, even unseen previously (accuracy up to 87.9% for GRU with GloVe embeddings of 300 dimensions)., Conclusions: The system addresses the shortcomings of the conventional machine learning techniques with manual feature-engineering that prove limiting when exposed to a wide range of non-standard expressions relating to medical concepts. The case-study presented demonstrates an application of 'black-box' approach to the real-world problem, along with its internal workings demonstration towards more transparent, interpretable and reproducible decision-making in health informatics domain.

Bleeding after cardiac surgery is a common and serious complication leading to transfusion of multiple blood products and resulting in increased morbidity and mortality. Despite the publication of numerous guidelines and consensus statements for patient blood management in cardiac surgery, research has revealed that adherence to these guidelines is poor, and as a result, a significant variability in patient transfusion practices among practitioners still remains. In addition, although utilization of point-of-care (POC) coagulation monitors and the use of novel therapeutic strategies for perioperative hemostasis, such as the use of coagulation factor concentrates, have increased significantly over the last decade, they are still not widely available in every institution. Therefore, despite continuous efforts, blood transfusion in cardiac surgery has only modestly declined over the last decade, remaining at ≥50% in high-risk patients. Given these limitations, and in response to new regulatory and legislature requirements, the Society of Cardiovascular Anesthesiologists (SCA) has formed the Blood Conservation in Cardiac Surgery Working Group to organize, summarize, and disseminate the available best-practice knowledge in patient blood management in cardiac surgery. The current publication includes the summary statements and algorithms designed by the working group, after collection and review of the existing guidelines, consensus statements, and recommendations for patient blood management practices in cardiac surgery patients. The overall goal is creating a dynamic resource of easily accessible educational material that will help to increase and improve compliance with the existing evidence-based best practices of patient blood management by cardiac surgery care teams.

Ove the last decade, transcatheter aortic valve replacement (TAVR) has emerged as the recommended approach over surgical aortic valve replacement (SAVR) for many patients with aortic stenosis. While initial trials demonstrated a higher incidence of stroke with TAVR compared to SAVR, the incidence of stroke appears to have improved over time. With the increasing number of patients expected to undergo TAVR in the coming decades, it is important to review the incidence and etiology of stroke after SAVR and TAVR. Alterations in surgical technique for SAVR, and embolic protections devices for TAVR, have failed to demonstrate a clinically significant reduction in the incidence of post-procedural stroke. However, the definitions and assessment methods used for assessing stroke and neurological events varies among studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The paper aims to leverage the highly unstructured user-generated content in the context of pollen allergy surveillance using neural networks with character embeddings and the attention mechanism. Currently, there is no accurate representation of hay fever prevalence, particularly in real-time scenarios. Social media serves as an alternative to extract knowledge about the condition, which is valuable for allergy sufferers, general practitioners, and policy makers. Despite tremendous potential offered, conventional natural language processing methods prove limited when exposed to the challenging nature of user-generated content. As a result, the detection of actual hay fever instances among the number of false positives, as well as the correct identification of non-technical expressions as pollen allergy symptoms poses a major problem. We propose a deep architecture enhanced with character embeddings and neural attention to improve the performance of hay fever-related content classification from Twitter data. Improvement in prediction is achieved due to the character-level semantics introduced, which effectively addresses the out-of-vocabulary problem in our dataset where the rate is approximately 9%. Overall, the study is a step forward towards improved real-time pollen allergy surveillance from social media with state-of-art technology., (© The Author(s) 2019.)

Cleistanthus collinus is a poisonous shrub used for deliberate self-harm in rural areas of South India and intake of boiled decoction of leaves is a common method of self-harm. Distal renal tubular acidosis (dRTA) is an important clinical symptom observed in C. collinus poisoning, and renal V-ATPases may be potential targets of damage. However, a lack of understanding of molecular mediators involved hampers medical management, which is mainly supportive. We hypothesized that C. collinus poisoning induces renal oxidative stress; probably by inducing mitochondrial uncoupling, which compromises V-ATPase activity to ultimately produce dRTA. This was tested by exposing renal BBMV, kidney cells in culture, and Wistar rats to C. collinus poisoning. Exposure to C. collinus aqueous extract resulted in significant elevations in the lipid peroxidation marker, conjugated dienes, in cell culture and in vivo . A significant decrease in mitochondrial respiratory control ratio was observed in kidneys from C. collinus -treated animals suggesting that mitochondrial oxidative phosphorylation is uncoupled. This was accompanied by significant increase in ADP levels and a decrease in proton pump activity. Thus, these results demonstrate that C. collinus poisoning induces oxidative stress which influences proton pump activity, probably due to feedback inhibition by elevated ADP levels because of mitochondrial dysfunction in the rat kidney.

I use the case study presented by Bawaskar (1), which I refer to as the "The Case of the Uninformed Spouse", to illustrate an ethical conflict between medical confidentiality and the duty to protect and inform an involved third party, who in this case is the patient's spouse. The central question raised by Bawaskar based on this case is, 'Is it the physician's professional obligation to counsel the patient against marriage?' In this commentary, I will attempt to answer this question while also engaging with the ethical conflict in this case and what issues may arise if the physician had indeed considered revealing information to the patient's partner against the wishes of the patient. I engage on the concept of "harm" to discuss the moral scope of the duty to warn an involved third party and when it is justified to breach confidentiality of the patient. Based on the ethical analysis, I conclude that, in this case and in analogous cases, healthcare professionals should not breach the confidentiality of patients and should uphold it as the basis for trust within the doctor-patient relationship. Further, I state that it is part of their professional obligation to advise and provide psychosocial care through counselling to ensure comprehensive care.

Kinesin motors can induce a buckling instability in a microtubule with a fixed minus end. Here we show that by modifying the surface with a protein-repellent functionalization and using clusters of kinesin motors, the microtubule can exhibit persistent oscillatory motion resembling the beating of sperm flagella. The observed period is of the order of 1 min. From the experimental images we theoretically determine a distribution of motor forces that explains the observed shapes using a maximum likelihood approach. A good agreement is achieved with a small number of motor clusters acting simultaneously on a microtubule. The tangential forces exerted by a cluster are mostly in the range 0-8 pN toward the microtubule minus end, indicating the action of 1 or 2 kinesin motors. The lateral forces are distributed symmetrically and mainly below 10 pN, while the lateral velocity has a strong peak around zero. Unlike well-known models for flapping filaments, kinesins are found to have a strong "pinning" effect on the beating filaments. Our results suggest new strategies to utilize molecular motors in dynamic roles that depend sensitively on the stress built-up in the system.

The ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein quality control (PQC) pathways that are responsible for cellular proteostasis (homeostasis of the proteome) by ensuring the timely degradation of misfolded, damaged, and unwanted proteins. Ubiquitination serves as the degradation signal in both these systems, but substrates are precisely targeted to one or the other pathway. Determining how and when cells target specific proteins to these two alternative PQC pathways and control the crosstalk between them are topics of considerable interest. The ubiquitin (Ub) recognition code based on the type of Ub-linked chains on substrate proteins was believed to play a pivotal role in this process, but an increasing body of evidence indicates that the PQC pathway choice is also made based on other criteria. These include the oligomeric state of the Ub-binding protein shuttles, their conformation, protein modifications, and the presence of motifs that interact with ATG8/LC3/GABARAP (autophagy-related protein 8/microtubule-associated protein 1A/1B-light chain 3/GABA type A receptor-associated protein) protein family members. In this review, we summarize the current knowledge regarding the Ub recognition code that is bound by Ub-binding proteasomal and autophagic receptors. We also discuss how cells can modify substrate fate by modulating the structure, conformation, and physical properties of these receptors to affect their shuttling between both degradation pathways., Competing Interests: The authors declare no conflict of interest.

Background: A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression-like behavior., Aims: We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice., Methods and Results: MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies' titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT 2a R expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity., Conclusion: In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.

Purpose: Ensuring compliance to treatment protocol, especially regular visit to treating facility, is an important aspect of clubfoot management. However, the factors affecting compliance to follow-up schedule are myriad., Methods: A cross-sectional study was undertaken among caregivers of clubfoot patients from a tertiary referral clubfoot clinic in a developing country. Hospital records were reviewed to collect demographic data and subjects were classified as either "regular" or "irregular" if they missed ≤3 and >3 scheduled hospital visits, respectively. Various factors that could affect compliance such as family size, number of children, literacy of caregiver, occupation of breadwinner, and time taken to travel to hospital were studied. Caregivers were probed regarding the reason for their irregularity., Results: A total of 238 patients were included, of which 138 formed the "regular" group and the rest 100 formed the "irregular" group. Patients in the regular group were significantly younger (mean age 43.8 months) compared to the irregular group (59.8 months; p = 0.001). The mean follow-up period in the regular group was 28.1 months and in the irregular group was 33.8 months. On univariate analysis, age, duration of follow-up, and transport duration were found to be significant between the two groups. However, multivariate analysis revealed that female children with clubfoot are more likely to be irregular as compared to males ( p = 0.038)., Conclusion: In a developing country setting, higher age and being a female child are associated with irregularity to hospital visit protocol. At clubfoot clinics, identifying these children and counseling their caregivers might improve compliance.

Peroxisomes are conserved organelles of eukaryotic cells with important roles in cellular metabolism, human health, redox homeostasis, as well as intracellular metabolite transfer and signaling. We review here the current status of the different co-existing modes of biogenesis of peroxisomal membrane proteins demonstrating the fascinating adaptability in their targeting and sorting pathways. While earlier studies focused on peroxisomes as autonomous organelles, the necessity of the ER and potentially even mitochondria as sources of peroxisomal membrane proteins and lipids has come to light in recent years. Additionally, the intimate physical juxtaposition of peroxisomes with other organelles has transitioned from being viewed as random encounters to a growing appreciation of the expanding roles of such inter-organellar membrane contact sites in metabolic and regulatory functions. Peroxisomal quality control mechanisms have also come of age with a variety of mechanisms operating both during biogenesis and in the cellular response to environmental cues., (© 2018 The Authors.)

Introduction: This simulation on cardiac tamponade and complete heart block in the context of severe aortic stenosis presents the learner with a rare (cardiac tamponade) and a common (complete heart block) complication in the intraoperative setting of transfemoral aortic valve implantation in a high-fidelity, low-risk simulation environment. Based on an amalgam of index cases, the simulation was developed to address a recognized area of need for cardiothoracic anesthesia scenarios in the simulation curriculum of our home institution., Methods: The simulation case file covered the case narrative, learning objectives, a summary of critical actions performed, and supplemental figures needed to complete the educational activity. A high-fidelity patient simulator, an anesthesia machine, monitors, and a computer capable of displaying standard computer slide presentation software and movie files provided the optimal environment for simulation., Results: Fifteen anesthesia residents experienced the simulation over the 2016-2017 and 2017-2018 academic years. The trainees who experienced this simulation improved their understanding of tamponade hemodynamic pathophysiology and recognition of hemodynamically unstable bradycardia., Discussion: This case has been an effective addition to the repertoire of simulation scenarios at the University of Iowa and has been incorporated into the general curriculum of simulation cases for mid-training junior and senior anesthesia residents., Competing Interests: None to report.

Tuberculosis (TB) continues to be a major health burden globally more so in low/middle-income countries like India. There is an increase in the prevalence of extrapulmonary TB (EPTB) because of HIV epidemics and increased usage of immunomodulating drugs. EPTB constitutes 15%-20% of all patients with TB and >50% of HIV-TB coinfected patients. We present three such atypical presentations of EPTB in head and neck region. EPTB can mimic any disease, hence knowledge of the unusual presentations helps in making early diagnosis and thereby reduces the morbidity and mortality involved with the disease., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)