Comparison of Classifiers Applied to Confocal Scanning Laser Ophthalmoscopy Data

Objectives: Comparison of classification methods using data of one clinical study. The tuning of hyperparameters is assessed as part of the methods by nested-loop cross-validation. Methods: We assess the ability of 18 statistical and machine learning classifiers to detect glaucoma. The training data set is one case-control study consisting of confocal scanning laser ophthalmoscopy measurement values from 98 glaucoma patients and 98 healthy controls. We compare bootstrap estimates of the classification error by the Wilcoxon signed rank test and box-plots of a bootstrap distribution of the estimate. Results: The comparison of out-of-bag bootstrap estimators of classification errors is assessed by Spearman?s rank correlation, Wilcoxon signed rank tests and box-plots of a bootstrap distribution of the estimate. The classification methods random forests 15.4%, support vector machines 15.9%, bundling 16.3% to 17.8%, and penalized discriminant analysis 16.8% show the best results. Conclusions: Using nested-loop cross-validation we account for the tuning of hyperparameters and demonstrate the assessment of different classifiers. We recommend a block design of the bootstrap simulation to allow a statistical assessment of the bootstrap estimates of the misclassification error. The results depend on the data of the clinical study and the given size of the bootstrap sample

A recipe for irreproducible results

Recent studies have shown that many results published in peer-reviewed scientific journals are not reproducible. This raises the following question: why is it so easy to fool myself into believing that a result is reliable when in fact it is not? Using Brownian motion as a toy model, we show how this can happen if ergodicity is assumed where it is unwarranted. A measured value can appear stable when judged over time, although it is not stable across the ensemble: a different result will be obtained each time the experiment is run.Comment: 11 pages, 4 figure

Acetabular retroversion: Diagnosis and treatment

Acetabular retroversion (AR) consists of a malorientation of the acetabulum in the sagittal plane. AR is associated with changes in load transmission across the hip, being a risk factor for early osteoarthrosis. The pathophysiological basis of AR is an anterior acetabular hyper-coverage and an overall pelvic rotation.The delay or the non-diagnosis of AR could have an impact in the overall management of femoroacetabular impingement (FAI). AR is a subtype of (focal) pincer deformity.The objective of this review was to clarify the pathophysiological, diagnosis and treatment fundaments inherent to AR, using a current literature review.Radiographic evaluation is paramount in AR: the cross-over, the posterior wall and ischial spine signs are classic radiographic signs of AR. However, computed tomography (CT) evaluation permits a three-dimensional characterization of the deformity, being more reliable in its recognition.Acetabular rim trimming (ART) and periacetabular osteotomy (PAO) are the best described surgical options for the treatment of AR.The clinical outcomes of both techniques are dependent on the correct characterization of existing lesions and adequate selection of patients. Cite this article: EFORT Open Rev 2018;3:595-603. DOI: 10.1302/2058-5241.3.180015

The effect of retirement on biomedical and behavioral risk factors for cardiovascular and metabolic disease

Retirement is a major life event potentially associated with changes in relevant risk factors for cardiovascular and metabolic conditions. This study analyzes the effect of retirement on behavioral and biomedical risk factors for chronic disease, together with subjective health parameters using Southern German epidemiological data. We used panel data from the KORA cohort study, consisting of 11,168 observations for individuals 45–80 years old. Outcomes included health behavior (alcohol, smoking, physical activity), biomedical risk factors (BMI, waist-to-hip ratio (WHR), glycosylated hemoglobin (HbA1c), total cholesterol/HDL quotient, systolic/diastolic blood pressure), and subjective health (SF12 mental and physical, self-rated health). We applied a parametric regression discontinuity design based on age thresholds for pension eligibility. Robust results after p-value corrections for multiple testing showed an increase in BMI in early retirees (at the age of 60) [β = 1.11, corrected p-val. < 0.05] and an increase in CHO/HDL in regular retirees (age 65) [β = 0.47, corrected p-val. < 0.05]. Stratified analyses indicate that the increase in BMI might be driven by women and low-educated individuals retiring early, despite increases in the level of physical activity. The increase in CHO/HDL might be driven by men retiring regularly, alongside an increase in subjective physical health. Blood pressure also increased, but the effect differs by retirement timing and sex and is not always robust to sensitivity analysis checks. Our study indicates that retirement has an impact on different risk factors for chronic disease, depending on timing, gender and education. Regular male, early female, and low-educated retirees should be further investigated as potential high-risk groups for worsening risk factors after retirement. Future research should investigate if and how these results are linked: in fact, especially in the last two groups, the increases in leisure time physical activity might not be enough to compensate for the loss of work related physical activity, leading thus to an increase in BMI

Prospective Sustainability Screening of Sodium-Ion Battery Cathode Materials

Sodium-ion batteries (SIB) are considered as a promising alternative to overcome existing sustainability challenges related to Lithium-ion batteries (LIB), such as the use of critical and expensive materials with high environmental impacts. In contrast to established LIBs, SIBs are an emerging technology in an early stage of development where a challenge is to identify the most promising and sustainable cathode active materials (CAM) for further research and potential commercialization. Thus, a comprehensive and flexible CAM screening method is developed, providing a fast and comprehensive overview of potential sustainability hotspots for supporting cathode material selection. 42 different SIB cathodes are screened and benchmarked against eight state-of-the-art LIB-cathodes. Potential impacts are quantified for the following categories: i) Cost as ten-year average; ii) Criticality, based on existing raw material criticality indicators, and iii) the life cycle carbon footprint. The results reveal that energy density is one of the most important factors in all three categories, determining the overall material demand. Most SIB CAM shows a very promising performance, obtaining better results than the LIB benchmark. Especially the Prussian Blue derivatives and the manganese-based layered oxides seem to be interesting candidates under the given prospective screening framework

Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8 x 10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8 x 10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation

Prospective Sustainability Screening of Sodium-Ion Battery Cathode Materials

Sodium-ion batteries (SIB) are considered as a promising alternative to overcome existing sustainability challenges related to Lithium-ion batteries (LIB), such as the use of critical and expensive materials with high environmental impacts. In contrast to established LIBs, SIBs are an emerging technology in an early stage of development where a challenge is to identify the most promising and sustainable cathode active materials (CAM) for further research and potential commercialization. Thus, a comprehensive and flexible CAM screening method is developed, providing a fast and comprehensive overview of potential sustainability hotspots for supporting cathode material selection. 42 different SIB cathodes are screened and benchmarked against eight state-of-the-art LIB-cathodes. Potential impacts are quantified for the following categories: i) Cost as ten-year average; ii) Criticality, based on existing raw material criticality indicators, and iii) the life cycle carbon footprint. The results reveal that energy density is one of the most important factors in all three categories, determining the overall material demand. Most SIB CAM shows a very promising performance, obtaining better results than the LIB benchmark. Especially the Prussian Blue derivatives and the manganese-based layered oxides seem to be interesting candidates under the given prospective screening framework

Some Comments on Models of Hadronic Interactions at Air Shower Energies

Several models of minimum-bias hadronic interactions at ultra-high energy that have been used for calculations of air showers share essential common features. In this talk I review these common elements and discuss some consequences. I concentrate on properties of hadron-nucleus interactions, and I use mean depth of shower maximum as a function of primary energy to illustrate my main points. I will contrast these models with models that use a more naive treatment of hadronic interactions in nuclei but which have been successfully used to interpret measurements of depth of shower maximum.Comment: 9 pages, LaTeX; 2 postscript figures, in Proc. 9th Int. Symposium on Very High Energy Cosmic Ray Interactions, Karlsruhe, 19-23 August, 199

GABAA receptors in GtoPdb v.2023.1

The GABAA receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT3 and strychnine-sensitive glycine receptors. GABAA receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed 'GABAA, slow' [45]. GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six &#945;, three &#946;, three &#947;, one &#948;, three &#961;, one &#949;, one &#960; and one &#952; GABAA receptor subunits have been reported in mammals [281, 237, 238, 288]. The &#960;-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g. &#945;4- and &#945;6- (both not functional) &#945;5-, &#946;2-, &#946;3- and &#947;2), along with RNA editing of the &#945;3 subunit [71]. The three &#961;-subunits, (&#961;1-3) function as either homo- or hetero-oligomeric assemblies [365, 50]. Receptors formed from &#961;-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors [365], but they are classified as GABAA receptors by NC-IUPHAR on the basis of structural and functional criteria [16, 237, 238].Many GABAA receptor subtypes contain &#945;-, &#946;- and &#947;-subunits with the likely stoichiometry 2&#945;.2&#946;.1&#947; [170, 237]. It is thought that the majority of GABAA receptors harbour a single type of &#945;- and &#946; -subunit variant. The &#945;1&#946;2&#947;2 hetero-oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the &#945;2&#946;3&#947;2 and &#945;3&#946;3&#947;2 isoforms. Receptors that incorporate the &#945;4- &#945;5-or &#945;6-subunit, or the &#946;1-, &#947;1-, &#947;3-, &#948;-, &#949;- and &#952;-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain &#945;6- and &#948;-subunits in cerebellar granule cells, or an &#945;4- and &#948;-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA [211, 275, 84, 19, 293]. GABA binding occurs at the &#946;+/&#945;- subunit interface and the homologous &#947;+/&#945;- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the &#945;+/&#946;- interface ([257]; reviewed by [287]). The particular &#945;-and &#947;-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either &#945;4- or &#945;6-subunits are not recognised by &#8216;classical&#8217; benzodiazepines, such as flunitrazepam (but see [362]). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews [52, 141, 190, 322] but one point worthy of note is that receptors incorporating the &#947;2 subunit (except when associated with &#945;5) cluster at the postsynaptic membrane (but may distribute dynamically between synaptic and extrasynaptic locations), whereas those incorporating the &#948; subunit appear to be exclusively extrasynaptic. NC-IUPHAR [16, 237, 3, 2] class the GABAA receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABAA receptors are classed as conclusively identified (i.e., &#945;1&#946;2&#947;2, &#945;2&#946;&#947;2, &#945;3&#946;&#947;2, &#945;4&#946;&#947;2, &#945;4&#946;2&#948;, &#945;4&#946;3&#948;, &#945;5&#946;&#947;2, &#945;6&#946;&#947;2, &#945;6&#946;2&#948;, &#945;6&#946;3&#948; and &#961;) with further receptor isoforms occurring with high probability, or only tentatively [237, 238]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABAA receptor isoforms in detail; such information can be gleaned in the reviews [16, 96, 170, 175, 144, 281, 218, 237, 238, 284, 9, 10]. Agents that discriminate between &#945;-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via &#946;-subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of &#961; receptors is summarised in the table and additional aspects are reviewed in [365, 50, 146, 225].Several high-resolution cryo-electron microscopy structures have been described in which the full-length human &#945;1&#946;3&#947;2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (&#947;-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [200]

GABAA receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The GABAA receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT3 and strychnine-sensitive glycine receptors. GABAA receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed &#8216;GABAA, slow&#8217; [41]. GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six &#945;, three &#946;, three &#947;, one &#948;, three &#961;, one &#949;, one &#960; and one &#952; GABAA receptor subunits have been reported in mammals [273, 232, 231, 278]. The &#960;-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g. &#945;4- and &#945;6- (both not functional) &#945;5-, &#946;2-, &#946;3- and &#947;2), along with RNA editing of the &#945;3 subunit [67]. The three &#961;-subunits, (&#961;1-3) function as either homo- or hetero-oligomeric assemblies [354, 46]. Receptors formed from &#961;-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors [354], but they are classified as GABAA receptors by NC-IUPHAR on the basis of structural and functional criteria [14, 232, 231].Many GABAA receptor subtypes contain &#945;-, &#946;- and &#947;-subunits with the likely stoichiometry 2&#945;.2&#946;.1&#947; [164, 232]. It is thought that the majority of GABAA receptors harbour a single type of &#945;- and &#946; -subunit variant. The &#945;1&#946;2&#947;2 hetero-oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the &#945;2&#946;3&#947;2 and &#945;3&#946;3&#947;2 isoforms. Receptors that incorporate the &#945;4- &#945;5-or &#945;6-subunit, or the &#946;1-, &#947;1-, &#947;3-, &#948;-, &#949;- and &#952;-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain &#945;6- and &#948;-subunits in cerebellar granule cells, or an &#945;4- and &#948;-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA [205, 268, 79, 17, 283]. GABA binding occurs at the &#946;+/&#945;- subunit interface and the homologous &#947;+/&#945;- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the &#945;+/&#946;- interface ([250]; reviewed by [277]). The particular &#945;-and &#947;-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either &#945;4- or &#945;6-subunits are not recognised by &#8216;classical&#8217; benzodiazepines, such as flunitrazepam (but see [351]). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews [48, 136, 184, 311] but one point worthy of note is that receptors incorporating the &#947;2 subunit (except when associated with &#945;5) cluster at the postsynaptic membrane (but may distribute dynamically between synaptic and extrasynaptic locations), whereas as those incorporating the d subunit appear to be exclusively extrasynaptic. NC-IUPHAR [14, 232] class the GABAA receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABAA receptors are classed as conclusively identified (i.e., &#945;1&#946;2&#947;2, &#945;1&#946;&#947;2, &#945;3&#946;&#947;2, &#945;4&#946;&#947;2, &#945;4&#946;2&#948;, &#945;4&#946;3&#948;, &#945;5&#946;&#947;2, &#945;6&#946;&#947;2, &#945;6&#946;2&#948;, &#945;6&#946;3&#948; and &#961;) with further receptor isoforms occurring with high probability, or only tentatively [232, 231]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABAA receptor isoforms in detail; such information can be gleaned in the reviews [14, 91, 164, 169, 140, 273, 212, 232, 231] and [8, 7]. Agents that discriminate between &#945;-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via &#946;-subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of &#961; receptors is summarised in the table and additional aspects are reviewed in [354, 46, 141, 219].Several high-resolution cryo-electron microscopy structures have been described in which the full-length human &#945;1&#946;3&#947;2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (&#947;-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [194]