bluuebunny/crossref_metadata_2025_split huggingface dataset:
Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management
Authors: Jensen Troels S , Karlsson Pall , Gylfadottir Sandra S , Andersen Signe T , Bennett David L , Tankisi Hatice , Finnerup Nanna B , Terkelsen Astrid J , Khan Karolina , Themistocleous Andreas C , Kristensen Alexander G , Itani Mustapha , Sindrup Søren H , Andersen Henning , Charles Morten , Feldman Eva L , Callaghan Brian C 
Published: March 2021

Abstract
Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30–40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes.
The need for a cardionephrology subspecialty
Authors: Díez Javier , Ortiz Alberto 
Published: March 2021

Abstract
Chronic kidney disease (CKD) has structural and functional repercussions for the cardiovascular system that facilitate the development of cardiovascular disease (CVD). In fact, cardiovascular complications are frequent in the CKD population and thus cause a great clinical, public health and economic burden. Despite this challenge, the prevention and management of cardiovascular complications is one among several aspects of CKD that meets the criteria of an unmet medical need. This probably has to do with the misperception by the nephrologist of the global relevance of CVD in the CKD patient which, in turn, may be due to insufficient cardiovascular training during nephrology specialization. Therefore a change in approach is necessary to understand CKD as a disease in which the manifestations and complications related to CVD become so frequent and important that they require dedicated multidisciplinary clinical management. From this perspective, it makes sense to consider training in the subspecialty of cardionephrology to provide adequate cardiovascular care for CKD patients by the nephrologist. In addition, the cardionephrology subspecialist would be better able to interact with other specialists in multidisciplinary care settings created to achieve a deeper understanding and more effective clinical handling of the interactions between CKD and CVD.
Whole-Transcriptome Analysis by RNA Sequencing for Genetic Diagnosis of Mendelian Skin Disorders in the Context of Consanguinity
Authors: Youssefian Leila , Saeidian Amir Hossein , Palizban Fahimeh , Bagherieh Atefeh , Abdollahimajd Fahimeh , Sotoudeh Soheila , Mozafari Nikoo , Farahani Rahele A , Mahmoudi Hamidreza , Babashah Sadegh , Zabihi Masoud , Zeinali Sirous , Fortina Paolo , Salas-Alanis Julio C , South Andrew P , Vahidnezhad Hassan , Uitto Jouni 
Published: March 2021

Abstract

Background
Among the approximately 8000 Mendelian disorders, &gt;1000 have cutaneous manifestations. In many of these conditions, the underlying mutated genes have been identified by DNA-based techniques which, however, can overlook certain types of mutations, such as exonic-synonymous and deep-intronic sequence variants. Whole-transcriptome sequencing by RNA sequencing (RNA-seq) can identify such mutations and provide information about their consequences.

Methods
We analyzed the whole transcriptome of 40 families with different types of Mendelian skin disorders with extensive genetic heterogeneity. The RNA-seq data were examined for variant detection and prioritization, pathogenicity confirmation, RNA expression profiling, and genome-wide homozygosity mapping in the case of consanguineous families. Among the families examined, RNA-seq was able to provide information complementary to DNA-based analyses for exonic and intronic sequence variants with aberrant splicing. In addition, we tested the possibility of using RNA-seq as the first-tier strategy for unbiased genome-wide mutation screening without information from DNA analysis.

Results
We found pathogenic mutations in 35 families (88%) with RNA-seq in combination with other next-generation sequencing methods, and we successfully prioritized variants and found the culprit genes. In addition, as a novel concept, we propose a pipeline that increases the yield of variant calling from RNA-seq by concurrent use of genome and transcriptome references in parallel.

Conclusions
Our results suggest that “clinical RNA-seq” could serve as a primary approach for mutation detection in inherited diseases, particularly in consanguineous families, provided that tissues and cells expressing the relevant genes are available for analysis.
Ketone therapy for heart failure: current evidence for clinical use
Authors: Takahara Shingo , Soni Shubham , Maayah Zaid H , Ferdaoussi Mourad , Dyck Jason R B 
Published: March 2021

Abstract
During conditions that result in depleted circulating glucose levels, ketone bodies synthesized in the liver are necessary fuel substrates for the brain. In other organs, such as the heart, the reliance on ketones for generating energy in the absence of glucose is less important as the heart can utilize alternative fuel sources, such as fatty acids. However, during pathophysiological conditions, such as heart failure, cardiac defects in metabolic processes that normally allow for sufficient energy production from fatty acids and carbohydrates contribute to a decline in contractile function. As such, it has been proposed that the failing heart relies more on ketone bodies as an energy source than previously appreciated. Furthermore, it has been shown that ketone bodies function as signaling molecules that can suppress systemic and cardiac inflammation. Thus, it is possible that intentionally elevating circulating ketones may be beneficial as an adjunct treatment for heart failure. Although many approaches can be used for ‘ketone therapy’, each of these has their own advantages and disadvantages in the treatment of heart failure. Thus, we summarize current preclinical and clinical studies involving various types of ketone therapy in cardiac disease and discuss the advantages and disadvantages of each modality as possible treatments for heart failure.
Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes
Authors: Ramachandra Chrishan J A , Kp Myu Mai Ja , Chua Jasper , Hernandez-Resendiz Sauri , Liehn Elisa A , Knöll Ralph , Gan Li-Ming , Michaëlsson Erik , Jonsson Malin K B , Ryden-Markinhuhta Katarina , Bhat Ratan V , Fritsche-Danielson Regina , Lin Ying-Hsi , Sadayappan Sakthivel , Tang Hak Chiaw , Wong Philip , Shim Winston , Hausenloy Derek J 
Published: March 2021

Abstract

Aims
Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM.

Methods and results
Human cardiomyocytes derived from control-induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy.

Conclusion
This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing.
Rosuvastatin for the prevention of venous thromboembolism: a pooled analysis of the HOPE-3 and JUPITER randomized controlled trials
Authors: Joseph Philip , Glynn Robert , Lonn Eva , Ramasundarahettige Chinthanie , Eikelboom John , MacFadyen Jean , Ridker Paul , Yusuf Salim 
Published: March 2021

AbstractAimsTo examine the association between rosuvastatin and VTE risk, and whether effects vary in different subpopulations stratified by key demographic, cardiovascular disease (CVD) risk factors, and other risk factors associated with VTE.Methods and resultsAn individual participant data meta-analysis was conducted across two randomized controlled trials in 30 507 participants over a mean follow-up of 3.62 years, individuals had no prior history of vascular disease but were at intermediate CV risk. In both trials, participants were randomized to receive rosuvastatin or matching placebo. The primary outcome was VTE during follow-up, defined as either deep vein thrombosis or pulmonary embolism. Associations between rosuvastatin and VTE were examined in the overall pooled cohort, and subpopulations stratified by demographic risk factors (i.e. age and sex), CVD risk factors (i.e. obesity, smoking, lipid levels, blood pressure levels, and C-reactive protein level), and a history of cancer. Mean age was 65.96 (SD 7.19) years of age, and 17 832 (58.45%) were male and 5434 (17.82%) were smokers, median BMI was 27.6 [interquartile range (IQR) 24.7–31.1] kg/m2, and median CRP level was 3.4 (IQR 2.1–6.0) mg/L. There were 139 VTE events. In the pooled cohort, rosuvastatin was associated with a large proportional reduction in the risk of VTE (hazard ratio 0.53, 95% CI 0.37–0.75). No significant interactions were observed between treatment with rosuvastatin and the risk of VTE across subpopulations stratified by demographic, CVD risk factors, or a history of cancer (P-values for interactions &gt;0.05 for all subgroups).ConclusionRosuvastatin is associated with a 47% proportional reduction in the risk of VTE, and its effect is consistent both in the presence or absence of VTE-related clinical risk factors.
Metabolic alterations in a rat model of takotsubo syndrome
Authors: Godsman Nadine , Kohlhaas Michael , Nickel Alexander , Cheyne Lesley , Mingarelli Marco , Schweiger Lutz , Hepburn Claire , Munts Chantal , Welch Andy , Delibegovic Mirela , Van Bilsen Marc , Maack Christoph , Dawson Dana K 
Published: March 2021

Abstract

Aims
Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies.

Methods and results
An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P &lt; 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P &gt; 0.0001). Both lactate and pyruvate were lower (P &lt; 0.05) despite increases in LDH-RNA and PDH (P &lt; 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P &lt; 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P = 0.01) with decreased fatty acids and acyl-carnitines levels (P = 0.0001–0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P &lt; 0.05) as was cellular ATP reporter dihydroorotate (P = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P &lt; 0.0001), inducing the oxidation of NAD(P)H and FAD (P = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated—increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P &lt; 0.05).

Conclusion
Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity.
Behavioral Responses of Asian Citrus Psyllid (Hemiptera: Liviidae) to Salinity-Stressed Citrus
Authors: dos Santos Maria Ângela Cruz Macêdo , Coelho Filho Mauricio Antônio , Modesto Francisco José Nunes , Patt Joseph M , Fancelli Marilene 
Published: March 2021

AbstractMost commercial citrus varieties are intolerant of salinity stress, but some rootstocks, such as Rangpur lime, tolerate moderately saline irrigation water. Development of salinity-tolerant citrus may allow for citriculture in semiarid and arid regions where salinity stress is problematic. Because salinity stress influences shoot growth in citrus, we compared the behavioral responses of Asian citrus psyllid, Diaphorina citri Kuwayama, to salinity-stressed versus nonstressed Rangpur lime seedlings. The effects of salinity stress on key physiological processes in the seedlings were also examined. Seedlings in the control group were fertilized with a solution having a salinity of 1.7 dS m−1 while seedlings in the salinity-stressed group were fertilized with a solution having a salinity of 10 dS m−1. The seedlings were exposed to salinity stress for increasing durations (15, 20, or 60 d). Seedlings presented differential physiological responses 15 d after the imposition of salinity stress, and differences in psyllid settling rate on control versus salinity-stressed seedlings were discernable within 1 h following the imposition of salinity stress. The levels of settling, oviposition, and egg survivorship were significantly lower on salinity-stressed versus control seedlings. Olfactometer tests showed that female psyllids preferred the odor from control seedlings, suggesting that the odors of control and salinity-stressed seedlings were different. The results showed that D. citri avoids salinity-stressed seedlings; this suggests the possibility of using moderate salinity stress as a management strategy to minimize psyllid settlement and reproduction and to reduce the spread of huanglongbing, especially in citrus grown in semiarid and arid areas.
Critical language pedagogy: an introduction to principles and values
Authors: Crookes Graham V 
Published: March 2021

AbstractCritical language pedagogy, teaching languages for social justice, is considered in terms of its history and principles. Several sets of principles, from different periods of the development of this literature, are juxtaposed. A connection is drawn from the possible values held by language teachers to the values espoused by critical language pedagogy. These are specified as democratic values, associated with equality, freedom, and solidarity. Values are identified as a means by which language teachers considering this perspective could approach it.
Cross-national time trends in adolescent alcohol use from 2002 to 2014
Authors: Leal-López Eva , Sánchez-Queija Inmaculada , Vieno Alessio , Currie Dorothy , Torsheim , Torbjorn , Pavlova Daria , Moreno-Maldonado Concepción , De Clercq , Bart , Kalman Michal , Inchley Joanna 
Published: March 2021

Abstract

Background
Adolescent alcohol consumption is a major public health concern that should be continuously monitored. This study aims (i) to analyze country-level trends in weekly alcohol consumption, drunkenness and early initiation in alcohol consumption and drunkenness among 15-year-old adolescents from 39 countries and regions across Europe and North America between 2002 and 2014 and (ii) to examine the geographical patterns in adolescent alcohol-related behaviours.

Methods
The sample was composed of 250 161 adolescents aged 15 from 39 countries and regions from Europe and North America. Survey years were 2002, 2006, 2010 and 2014. The alcohol consumption and drunkenness items of the HBSC questionnaire were employed. Prevalence ratios and 95% confidence intervals were estimated using Poisson regression models with robust variance.

Results
Data show a general decrease in all four alcohol variables between 2002 and 2014 except for some countries. However, there is variability both within a country (depending on the alcohol-related behaviour under study) and across countries (in the beginning and shape of trends). Some countries have not reduced or even increased their levels in some variables. Although some particularities have persisted over time, there are no robust patterns by regions.

Conclusions
Despite an overall decrease in adolescent alcohol consumption, special attention should be paid to those countries where declines are not present, or despite decreasing, rates are still high. Further research is needed to clarify factors associated with adolescent drinking, to better understand country specificities and to implement effective policies.
Evolution of inequalities in the coronavirus pandemics in Portugal: an ecological study
Authors: Alves Joana , Soares Patrícia , Rocha João Victor , Santana Rui , Nunes Carla 
Published: March 2021

Abstract

Background
Previous literature shows systematic differences in health according to socioeconomic status (SES). However, there is no clear evidence that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might be different across SES in Portugal. This work identifies the coronavirus disease 2019 (COVID-19) worst-affected municipalities at four different time points in Portugal measured by prevalence of cases, and seeks to determine if these worst-affected areas are associated with SES.

Methods
The worst-affected areas were defined using the spatial scan statistic for the cumulative number of cases per municipality. The likelihood of being in a worst-affected area was then modelled using logistic regressions, as a function of area-based SES and health services supply. The analyses were repeated at four different time points of the COVID-19 pandemic: 1 April, 1 May, 1 June, and 1 July, corresponding to two moments before and during the confinement period and two moments thereafter.

Results
Twenty municipalities were identified as worst-affected areas in all four time points, most in the coastal area in the Northern part of the country. The areas of lower unemployment were less likely to be a worst-affected area on the 1 April [adjusted odds ratio (AOR) = 0.36 (0.14–0.91)], 1 May [AOR = 0.03 (0.00–0.41)] and 1 July [AOR = 0.40 (0.16–1.05)].

Conclusion
This study shows a relationship between being in a worst-affected area and unemployment. Governments and public health authorities should formulate measures and be prepared to protect the most vulnerable groups.
Gill microbiome structure and function in the chemosymbiotic coastal lucinidStewartia floridana
Authors: Lim Shen Jean , Davis Brenton , Gill Danielle , Swetenburg John , Anderson Laurie C , Engel Annette Summers , Campbell Barbara J 
Published: March 2021

ABSTRACTLucinid bivalves harbor environmentally acquired, chemosynthetic, gammaproteobacterial gill endosymbionts. Lucinid gill microbiomes, which may contain other gammaproteobacterial and/or spirochete taxa, remain under-sampled. To understand inter-host variability of the lucinid gill microbiome, specifically in the bacterial communities, we analyzed the microbiome content of Stewartia floridana collected from Florida. Sampled gills contained a monospecific gammaproteobacterial endosymbiont expressing lithoautotrophic, mixotrophic, diazotrophic and C1 compound oxidation-related functions previously characterized in similar lucinid species. Another low-abundance Spirochaeta-like species in ∼72% of the sampled gills was most closely related to Spirochaeta-like species in another lucinid Phacoides pectinatus and formed a clade with known marine Spirochaeta symbionts. The spirochete expressed genes were involved in heterotrophy and the transport of sugars, amino acids, peptides and other substrates. Few muscular and neurofilament genes from the host and none from the gammaproteobacterial and spirochete symbionts were differentially expressed among quadrats predominantly covered with seagrass species or 80% bare sand. Our results suggest that spirochetes are facultatively associated with S. floridana, with potential scavenging and nutrient cycling roles. Expressed stress- and defense-related functions in the host and symbionts also suggest species–species communications, which highlight the need for further study of the interactions among lucinid hosts, their microbiomes and their environment.