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Purpose: As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service., Methods: Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes ( DPYD , NUDT15 , TPMT , UGT1A1 ) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, DPYD variants were reported back to clinicians and outcomes were collected., Results: We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in DPYD and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported DPYD variants were deemed informative for clinical decision making in a majority of cases., Conclusion: Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.

This study evaluates the transformative impact of the Deen Dayal Upadhyaya Grameen Kaushalya Yojana (DDU-GKY) on rural youth in Gujarat, focusing on vocational skill enhancement and employability. Employing a robust mixed-methods approach grounded in the Kirkpatrick training evaluation model, this research dives deeper into the nuanced effects of gender, educational background, and Project Implementing Agencies (PIAs) on the effectiveness of skill development initiatives. Quantitative data from over 500 beneficiaries and qualitative insights through in-depth interviews reveal critical success factors and areas for improvement, underscoring the scheme's pivotal role in bridging the rural-urban skill gap. This comprehensive analysis not only affirms the positive outcomes of the DDU-GKY initiative but also identifies key leverage points for policymakers and practitioners to enhance vocational training programs in Gujarat and similar contexts., Competing Interests: Declaration of Competing Interest The author reports no conflict of interest., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Extracellular vesicles (EVs) are associated with intercellular communications, immune responses, viral pathogenicity, cardiovascular diseases, neurological disorders, and cancer progression. EVs deliver proteins, metabolites, and nucleic acids into recipient cells to effectively alter their physiological and biological response. During their transportation from the donor to the recipient cell EVs face differential ionic concentrations, which can be detrimental to their integrity and impact their cargo content. EVs are known to possess ion channels and transporters in their membrane but neither the function nor the role of these channels in EVs is known. In this study, we discover a functional calcium-activated large-conductance potassium channel (BK Ca ) in the membrane of EVs. Furthermore, we establish that BK Ca is essential for the structural and functional integrity of EVs. Together, these findings establish the critical role of ion channels such as BK Ca in functioning as gatekeepers and maintaining EV-mediated signaling., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Pseudomonas aeruginosa (P.a.) is a gram-negative, opportunistic bacterium abundantly present in the environment. Often P.a. infections cause severe pneumonia, if left untreated. Surprisingly, up to 30% of patients admitted to the hospital for community- acquired pneumonia develop adverse cardiovascular complications such as myocardial infarction, arrhythmia, left ventricular dysfunction, and heart failure. However, the underlying mechanism of infection-mediated cardiac dysfunction is not yet known. Recently, we demonstrated that P.a. infection of the lungs led to severe cardiac electrical abnormalities and left ventricular dysfunction with limited P.a. dissemination to the heart tissue. To understand the mechanism of cardiac dysfunction during P.a. infection, we utilized both in vitro and in vivo models. Our results revealed that inflammatory cytokines contribute but are not solely responsible for severe contractile dysfunction in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Instead, exposure of hiPSC-CMs with conditioned media from P.a. infected human monocyte-derived macrophages (hMDMs) was sufficient to cause severe contractile dysfunction and arrhythmia in hiPSC-CMs. Specifically, exosomes released from infected hMDMs and bacterial outer membrane vesicles (OMVs) are the major drivers of cardiomyocyte contractile dysfunction. By using LC-MS/MS, we identified bacterial proteins, including toxins that are packaged in the exosomes and OMVs, which are responsible for contractile dysfunction. Furthermore, we demonstrated that systemic delivery of bacterial OMVs to mice caused severe cardiac dysfunction, mimicking the natural bacterial infection. In summary, we conclude that OMVs released during infection enter circulation and drive cardiac dysfunction.

Introduction: Obesity is worldwide health concern, with its prevalence rising steeply specially in low and middle-income countries in the past decade. World Obesity Federation estimates that one in five women and one in seven men - will be obese by 2030.Obesity numbers are expected to double during same year in South and South Asian countries, with obesity in children over age of five estimated to be at forty-five million., Methods: Relevant articles, full text and abstract pertaining to childhood obesity, pediatric obesity, technology in childhood obesity and specifically articles on obesity in children in South Asian countries were obtained from search engines like PUBMED, Google Scholar and Cochrane data base. The full text relevant articles and abstracts and the cross references after verification suitable to the topic were used to draft this review., Results: The double burden of undernutrition and obesity poses a unique public health challenge in Southeast Asia. In recent decades, South and Southeast Asia have experienced a period of rapid nutrition and lifestyle transition, leading to a proportional rise in the burden of obesity and Type 2 diabetes. The traditional diets of whole grains and vegetables in this region are being replaced by highly processed fast food due to rapid urbanization and westernisation in this region.There is growing and unrelenting burden of health risks in adulthood like diabetes, heart disease, hypertension, dyslipidaemia and mental health issues due to childhood obesity. Therapy mainly focuses on lifestyle changes underpinned by underlying behaviour changes, addressing emotional stress and sleep issues, pharmacotherapy and metabolic surgery in certain situations. Personalisation of therapy remains corner stone of therapeutics in childhood obesity., Conclusion: This comprehensive review aims at addressing the risk factors, complications, treatment and highlights effective preventive strategies for childhood obesity in South Asia., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Myocardial infarction (MI) is a significant cause of death in diabetic patients. Growing evidence suggests that mitochondrial dysfunction contributes to heart failure in diabetes. However, the molecular mechanisms of mitochondrial dysfunction mediating heart failure in diabetes are still poorly understood., Methods: We examined MRPL12 levels in right atrial appendage tissues from diabetic patients undergoing coronary artery bypass graft (CABG) surgery. Using AC-16 cells overexpressing MRPL12 under normal and hyperglycemic conditions we performed mitochondrial functional assays OXPHOS, bioenergetics, mitochondrial membrane potential, ATP production and cell death., Results: We observed elevated MRPL12 levels in heart tissue samples from diabetic patients with ischemic heart disease compared to non-diabetic patients. Overexpression of MRPL12 under hyperglycemic conditions did not affect oxidative phosphorylation (OXPHOS) levels, cellular ATP levels, or cardiomyocyte cell death. However, notable impairment in mitochondrial membrane potential (MMP) was observed under hyperglycemic conditions, along with alterations in both basal respiration oxygen consumption rate (OCR) and maximal respiratory capacity OCR., Conclusions: Overall, our results suggest that MRPL12 may have a compensatory role in the diabetic myocardium with ischemic heart disease, suggesting that MRPL12 may implicate in the pathophysiology of MI in diabetes., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in differential regulation of cellular functions such as transcription and translation, post-translation modifications, cell cycle and proliferation, cell volume, and pH levels. In intracellular compartments, Cl- modulates the function of lysosomes, mitochondria, endosomes, phagosomes, the nucleus, and the endoplasmic reticulum. In extracellular fluid (ECF), Cl- is present in blood/plasma and interstitial fluid compartments. A reduction in Cl- levels in ECF can result in cell volume contraction. Cl- is the key physiological anion and is a principal compensatory ion for the movement of the major cations such as Na+, K+, and Ca2+. Over the past 25 years, we have increased our understanding of cellular signaling mediated by Cl-, which has helped in understanding the molecular and metabolic changes observed in pathologies with altered Cl- levels. Here, we review the concentration of Cl- in various organs and cellular compartments, ion channels responsible for its transportation, and recent information on its physiological roles., (© 2024 The Author(s).)

Objectives: Total Hip Arthroplasty (THA) may be a risky proposition in patients with comorbidities, and they may require systemic analgesics for chronic hip pain (CHP). Since traditional pain medications may not provide complete pain relief or carry prohibitive adverse effects, pulsed radiofrequency (PRF) treatment of the hip articular nerves (HAN) has been proposed for effective clinical outcomes. We determined the efficacy of PRF-HAN in improvement in CHP compared to baseline pain on conventional systemic analgesics., Methods: Between August 2015 and December 2021, 31 adult patients with severe comorbid conditions and excruciating chronic hip pain were subjected to a PRF-HAN procedure following a diagnostic block. All 31 patients received PRF of the articular branches of the femoral and obturator nerves. Demographic parameters, numerical rating scale (NRS), Harris Hip Score (HHS), WOMAC scores, the change of these scores from baseline, and any adverse effects were recorded before treatment and on day 1, 1st week, 6 weeks, and 6 months after treatment., Results: All the patients who underwent the PRF-HAN reported a significant improvement in NRS, HHS, and WOMAC scores compared to the baseline values on day 1, at the end of the 1st week, and the 6th week (p<0.001). No adverse events were documented in the study post-procedure until the end of 6 months., Conclusion: PRF-HAN is a strong alternative for chronic pain management and augments physical functioning and a return to daily activity in patients who would be deprived of arthroplasty considering associated comorbid conditions.

Background: This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT)., Methods: Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n = 36) or TACE (n = 40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2 Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost., Results: Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54-0.86, and 65%, 95% CI, 0.52-0.83 (p = .80), however, median PFS was improved for PBT versus TACE (not reached vs. 12 months, p = .002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78-17.9, p = .003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p < .001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT., Conclusions: PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Chloride intracellular channels (CLICs) are a family of proteins that exist in soluble and transmembrane forms. The newest discovered member of the family CLIC6 is implicated in breast, ovarian, lung gastric, and pancreatic cancers and is also known to interact with dopamine-(D(2)-like) receptors. The soluble structure of the channel has been resolved, but the exact physiological role of CLIC6, biophysical characterization, and the membrane structure remain unknown. Here, we aimed to characterize the biophysical properties of this channel using a patch-clamp approach. To determine the biophysical properties of CLIC6, we expressed CLIC6 in HEK-293 cells. On ectopic expression, CLIC6 localizes to the plasma membrane of HEK-293 cells. We established the biophysical properties of CLIC6 by using electrophysiological approaches. Using various anions and potassium (K + ) solutions, we determined that CLIC6 is more permeable to chloride-(Cl - ) as compared to bromide-(Br - ), fluoride-(F - ), and K + ions. In the whole-cell configuration, the CLIC6 currents were inhibited after the addition of 10 μM of IAA-94 (CLIC-specific blocker). CLIC6 was also found to be regulated by pH and redox potential. We demonstrate that the histidine residue at 648 (H648) in the C terminus and cysteine residue in the N terminus (C487) are directly involved in the pH-induced conformational change and redox regulation of CLIC6, respectively. Using qRT-PCR, we identified that CLIC6 is most abundant in the lung and brain, and we recorded the CLIC6 current in mouse lung epithelial cells. Overall, we have determined the biophysical properties of CLIC6 and established it as a Cl - channel., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. Health economies are actively considering how pharmacogenomic tests can be integrated into health care systems to improve use of medicines. However, one of the barriers to effective implementation is evaluation of the evidence including clinical usefulness, cost-effectiveness, and operational requirements. We sought to develop a framework that could aid the implementation of pharmacogenomic testing. We take the view from the National Health Service (NHS) in England., Methods: We used a literature review using EMBASE and Medline databases to identify prospective studies of pharmacogenomic testing, focusing on clinical outcomes and implementation of pharmacogenomics. Using this search, we identified key themes relating to the implementation of pharmacogenomic tests. We used a clinical advisory group with expertise in pharmacology, pharmacogenomics, formulary evaluation, and policy implementation to review data from our literature review and the interpretation of these data. With the clinical advisory group, we prioritized themes and developed a framework to evaluate proposals to implement pharmacogenomics tests., Results: Themes that emerged from review of the literature and subsequent discussion were distilled into a 10-point checklist that is proposed as a tool to aid evidence-based implementation of pharmacogenomic testing into routine clinical care within the NHS., Conclusion: Our 10-point checklist outlines a standardized approach that could be used to evaluate proposals to implement pharmacogenomic tests. We propose a national approach, taking the view of the NHS in England. Using this approach could centralize commissioning of appropriate pharmacogenomic tests, reduce inequity and duplication using regional approaches, and provide a robust and evidence-based framework for adoption. Such an approach could also be applied to other health systems., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. They account for 2% of all malignancies in the United States. A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. Over the last decade, pathologic categorization, diagnostic techniques and therapeutic choices for NENs-both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs)-have appreciably evolved. Diagnosis of NEN mostly follows a suspicion from clinical features or incidental imaging findings. Hormonal or non-hormonal biomarkers (like serum serotonin, urine 5-HIAA, gastrin and VIP) and histology of a suspected NEN is, therefore, critical for both confirmation of the diagnosis and classification as an NET or NEC. Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection. As the incidence of NENs is on the rise in the United States and several other countries, physicians are more likely to see these cases, and their better understanding may support earlier diagnosis and tailoring treatment to the patient. We have compiled clinically significant evidence for NENs, including relevant changes to clinical practice that have greatly updated our diagnostic and therapeutic approach for NEN patients.

Aims: To report on a retrospective study of individual funding request (IFR) submissions from a large tertiary hospital and describe gaps in current mechanisms for funding of high-cost medicines in England., Methods: Data on the number and outcome of IFR submissions submitted to commissioners between 2014/15 and 2018/19 was extracted from the electronic patient health record and a local high-cost drug database., Results: In total, 230 IFRs were submitted: 112 to NHS England and 118 to a Clinical Commissioning Group (CCG). The decline rate for IFRs was 71% for NHS England and 34% for CCGs. Lack of exceptionality was the primary reason cited for declining IFRs submitted between 2016-18 (n = 42/45; 93%). Half of the patients whose IFR was declined received treatment funded through other routes, the majority (13/23; 57%) from internal hospital budget. This was governed via a local high-cost drug panel. Positive clinical outcomes were observed in 50% (4/8) of patients who received NHS England IFR-funded treatment, 54% (19/35) who received CCG IFR-funded treatment and 91% (21/23) who were funded via other routes., Conclusion: The high rate of IFR decline signals inefficient use of resource expended in the IFR process. Gaps in access to high-cost medicines remain for patients with rare and refractory disease requiring urgent treatment, largely due to the demand for exceptionality from NHS commissioners. Local mechanisms address this unmet need but have limitations. An outcomes-based evaluation approach to commissioning and greater transparency of previous funding decisions by commissioners may improve efficiency and equity in the IFR system., (© 2020 The British Pharmacological Society.)

Pacemaker lead perforation is a rare complication of pacemaker device implantation. We report a case where a ventricular lead perforated through right ventricle, pericardium and went into left lung parenchyma without the development of pericardial effusion, cardiac tamponade, pleural effusion, pneumo or hemo thorax. Patient presented with complaints solely related to failure of pacing rather than disastrous or life threating complications. Echocardiography didn't reveal any evidence of perforation and it was detected on fluoroscopy and computed tomography helped in making the diagnosis. Patient was treated with second procedure where second device placed on other side without manipulating previous device or lead., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Indian Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.)

Anomalous aortic origin of a coronary artery is a rare congenital anomaly and potential aetiology for sudden cardiac death. However, the mere presence of this anomaly does not portend clinical significance, and there are many factors that contribute to limiting coronary blood flow in these patients. The standard of care for symptomatic individuals is surgical management with coronary unroofing although not all cases are amenable to surgery. We report the case of an anomalous right coronary artery with interarterial course managed by percutaneous coronary intervention due to surgical contraindication secondary to comorbidities. The proposed mechanism of action culminating in aborted sudden cardiac death is unique and involves aggravated pulmonary hypertension in an individual with severe comorbid pulmonary disease., Competing Interests: Disclosure: The authors have no conflicts of interest to declare. Informed Consent to Participate and Publish: All patients have given written informed consent., (Copyright © 2022, Radcliffe Cardiology.)

Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate the outcome of IR injury will hold a key to efficient therapeutics. Here, we found chloride intracellular channel protein (CLIC4) presence in MAMs of cardiomyocytes and demonstrate its role in modulating ER and mitochondrial calcium homeostasis under physiological and pathological conditions. In a murine model, loss of CLIC4 increased myocardial infarction and substantially reduced cardiac function after IR injury. CLIC4 null cardiomyocytes showed increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation injury in comparison to wild-type cardiomyocytes. Overall, our results indicate that MAM-CLIC4 is a key mediator of cellular response to IR injury and therefore may have a potential implication on other pathophysiological processes.

Background: Breast attenuation artifacts occurring with upright cadmium-zinc-telluride (CZT) cardiac imaging systems have not been well characterized., Methods: 216 consecutive patients with Single Photon Emission Computerized Tomography myocardial perfusion imaging and no angiographically significant obstructive coronary artery disease were identified. All upright and supine SPECT images as well as coronary angiograms were reviewed and analyzed in blinded fashion., Results: In women imaged upright, more visual false positive defects were noted in the inferior wall compared to the anterior wall (26 vs. 10 at rest, p = 0.006, and 33 vs. 13 at stress, p < 0.001). Visual inferior wall defects were more common in the upright than supine position at stress (33 vs. 23, p = 0.018) and rest (26 vs. 14, p = 0.011), and most apparent in non-obese women (13 vs. 8, at stress, p = 0.059 and 11 vs. 5, at rest, p = 0.014)., Conclusions: With upright CZT myocardial perfusion imaging, women often have visible inferior wall attenuation artifact defects, likely from pendant breast tissue. These inferior wall attenuation artifacts may be seen in non-obese female patients., (© 2021. American Society of Nuclear Cardiology.)

Aims: For diseases with a genetic cause, genomics can deliver improved diagnostics and facilitate access to targeted treatments. Drug pharmacodynamics and pharmacokinetics are often dependent on genetic variation underlying these processes. As pharmacogenomics comes of age, it may be the first way in which genomics is utilised at a population level. Still required is guidance and standards of how genomic information can be communicated within the health record, and how clinicians should be alerted to variation impacting the use of medicines., Methods: The Professional Record Standards Body commissioned by NHS England developed guidance on using pharmacogenomics information in clinical practice. We conducted research with those implementing pharmacogenomics in England and internationally to produce guidance and recommendations for a systems-based approach., Results: A consensus viewpoint is that systems need to be in place to ensure the safe provision of pharmacogenomics information that is curated, actionable and up-to-date. Standards should be established with respect to notification and information exchange, which could impact new or existing prescribing and these must be in keeping with routine practice. Alerting systems should contribute to safer practices., Conclusion: Ensuring pharmacogenetics information is available to make safer use of medicines will require a major effort, of which this guidance is a beginning. Standards are required to ensure useful genomic information within the health record can be communicated to clinicians in the right format and at the right times to be actioned successfully. A multidisciplinary group of stakeholders must be engaged in developing pharmacogenomic standards to support the most appropriate prescribing., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

BK Ca channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BK Ca channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, the BK Ca channel's activity has never been detected in the plasma membrane of adult ventricular cardiomyocytes. In this study, we report the presence of the BK Ca channel in the plasma membrane and mitochondria of neonatal murine and rodent cardiomyocytes, which protects the heart on inhibition but not activation. Furthermore, K + currents measured in neonatal cardiomyocyte (NCM) was sensitive to iberiotoxin (IbTx), suggesting the presence of BK Ca channels in the plasma membrane. Neonatal hearts subjected to IR when post-conditioned with NS1619 during reoxygenation increased the myocardial infarction whereas IbTx reduced the infarct size. In agreement, isolated NCM also presented increased apoptosis on treatment with NS1619 during hypoxia and reoxygenation, whereas IbTx reduced TUNEL-positive cells. In NCMs, activation of BK Ca channels increased the intracellular reactive oxygen species post HR injury. Electrophysiological characterization of NCMs indicated that NS1619 increased the beat period, field, and action potential duration, and decreased the conduction velocity and spike amplitude. In contrast, IbTx had no impact on the electrophysiological properties of NCMs. Taken together, our data established that inhibition of plasma membrane BK Ca channels in the NCM protects neonatal heart/cardiomyocytes from IR injury. Furthermore, the functional disparity observed towards the cardioprotective activity of BK Ca channels in adults compared to neonatal heart could be attributed to their differential localization., (© 2022. The Author(s).)