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The p.Arg301Gln variant in the α -galactosidase A gene ( GLA ) has been poorly described in the literature. The few reports show controversial information, with both classical and nonclassical Anderson-Fabry Disease (AFD) presentation patterns. The aim of this study was to analyze the penetrance, clinical phenotype, and biochemical profile of an international cohort of patients carrying the p.Arg301Gln genetic variant in the GLA gene. This was an observational, international, and retrospective cohort case series study of patients carrying the p.Arg301Gln variant in the GLA gene associated with AFD disease. Forty-nine p.Arg301Gln GLA carriers, 41% male, were analyzed. The penetrance was 63% in the entire cohort and 1.5 times higher in men. The mean age of symptoms onset was 41 years; compared to women, men presented symptoms earlier and with a shorter delay to diagnosis. The typical clinical triad-cornea verticillate, neuropathic pain, and angiokeratomas-affected only 20% of the cohort, with no differences between genders. During follow-up, almost 20% of the patients presented some type of nonfatal cardiovascular and renal event (stroke, need for dialysis, heart failure, and arrhythmias requiring intracardiac devices), predominantly affecting men. Residual levels were the most common finding of α-GAL A enzyme activity, only a few women had a normal level; a small proportion of men had undetectable levels. The incidence of combined outcomes including all causes of death was 33%, and the cumulative incidence of all-cause mortality was 9% at the follow-up. Patients carrying the p.Arg301Gln GLA variant have a high penetrance, with predominantly cardiorenal involvement and clinical onset of the disease in middle age. Only a small proportion showed the classic clinical presentation of AFD. As in other X-linked diseases, males were more affected by severe cardiovascular and renal events. This genotype-phenotype correlation could be useful from a practical clinical point of view and for future decision making.

Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13 C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Evidence supports associations of lifestyle (including diet and physical activity) and weight with cognitive functioning, but the pathways responsible for these associations have not been fully elucidated. Because healthier lifestyles have been associated with better left atrial structure and function, which in turn is associated with better cognitive functioning, we tested the hypothesis that left atrial structure and function is a potential mediator of the association between lifestyle and cognition. We included 476 participants classed as overweight or obese with metabolic syndrome from three centers in Spain. These participants underwent lifestyle assessments and transthoracic echocardiography at baseline and repeated measurements of the Trail Making A test, a measure of executive function, taken at baseline and at the two-year follow-up. We conducted mediation analyses to test if measures of left atrial structure and function mediated associations between adherence to the Mediterranean diet scores, physical activity, and weight at baseline, as well as a two-year change in Trail Making A scores. The analysis did not find an association between these factors and Trail Making A scores, and no indirect effects appeared to be mediated by echocardiographic measurements. The modest sample size in this analysis is a limitation, and larger studies should be conducted to determine potential cardiovascular factors mediating the association between lifestyle and cognition.

Thoracic aortic aneurysms (TAA) consist of abnormal dilation or the widening of a portion of the ascending aorta, due to weakness or destructuring of the walls of the vessel and are potentially lethal. The congenital bicuspid aortic valve (BAV) is considered a risk factor for the development of TAA because asymmetric blood flow through the bicuspid aortic valve detrimentally influences the wall of the ascending aorta. NOTCH1 mutations have been associated with non-syndromic TAAs as a consequence of BAV, but little is known regarding its haploinsufficiency and its relationship with connective tissue abnormalities. We report two cases in which there is clear evidence that alterations in the NOTCH1 gene are the cause of TAA in the absence of BAV. On the one hand, we describe a 117 Kb deletion that includes a large part of the NOTCH1 gene and no other coding genes, suggesting that haploinsufficiency can be considered a pathogenic mechanism for this gene associated with TAA. In addition, we describe two brothers who carry two variants, one in the NOTCH1 gene and another in the MIB1 gene, corroborating the involvement of different genes of the Notch pathway in aortic pathology.

Background: Fabry disease (FD) is an X-linked condition caused by variants in the GLA gene. Since females have two X chromosomes, they were historically thought to be carriers. Although increased knowledge has shown that females often develop the disease, data from Spain and other countries reported that females were undertreated. The aim of this study was to provide a wider and more recent description of the disease characteristics and associated management of females with a GLA variant in a Spanish cohort., Results: Ninety-seven females from 12 hospitals were included in this retrospective study. Mean age was 50.1 ± 17.2 years. Median follow-up time from GLA variant identification was 36.1 months, and most (70.1%) were identified through family screening. Variants associated with classic/non-classic phenotypes were similarly distributed (40.2%/53.6%). Missense variants were the most prevalent (n = 84, 86.6%). In the overall group, 70.4% had major organ involvement (i.e., cardiac, renal, cerebrovascular, peripheral nervous system or gastrointestinal), and 47.3% also had typical Fabry signs (angiokeratoma, cornea verticillata or increased plasma lyso-Gb3). Cardiac involvement was the most prevalent (49.5%) and the main reason for treatment initiation. A total of 33 (34%) patients received disease-specific therapy, 55% of whom were diagnosed by family screening. Females carrying variants associated with a classic phenotype had higher frequencies of clinical manifestations (92.3%) and were predominant in the treated subgroup (69.7%). Despite this, there were 34 untreated females (56.7% of total untreated), with both phenotypes represented, who had major organ involvement, with 27 of cardiac, renal or cerebrovascular nature. Age or comorbidities in this subgroup were comparable to the treated subgroup (P = 0.8 and P = 0.8, respectively)., Conclusions: Efforts have been made in recent years to diagnose and treat timely Fabry females in Spain. A high percentage of females with pathogenic variants, regardless of their associated phenotype, will likely develop disease. A proportion of females with severe disease in this cohort received specific treatment. Still a significant number of females, even with same profile as the treated ones, who may be eligible for treatment according to European recommendations, remained untreated. Reasons for this merit further investigation., (© 2023. The Author(s).)

Atrial fibrillation has been associated with cognitive impairment. Whether subclinical abnormalities in atrial function and substrate predisposing to atrial fibrillation impact cognitive function has received limited attention. We tested associations of echocardiographic markers of atrial structure and function with cognitive function and decrease in 510 participants with obesity and metabolic syndrome (mean age SD of 64.4 [5.2] years in men and 66.5 [3.9] years in women). Left atrial (LA) markers (volume index, emptying fraction, strain, function index, and stiffness index) were estimated based on transthoracic echocardiography. General cognitive functioning (Mini-mental state examination), verbal ability (verbal fluency test), memory and attention (Digit Span Tests), and processing speed and executive function (Trail-Making Tests A and B) were assessed at baseline and at 2-year follow-up. Multiple linear regression was used to test associations of atrial markers (modeled in SD units) with baseline and 2-year changes in cognitive scores adjusted for demographic and health covariates. LA structure and function were not associated with cognitive function at baseline. Larger LA volume index (standardized β [95% confidence interval] -0.13 [-0.22 to -0.03]), lower peak longitudinal strain (-0.11 [-0.20 to -0.01]), and higher stiffness index (-0.18 [-0.28 to -0.08]) were associated with 2-year worsening in Trail-Making Test A. Strain measurements were also associated with a 2-year change in the Controlled Oral Word Association Test. In conclusion, overall, adverse markers of LA structure and function were associated with 2-year detrimental executive function-related cognitive changes in a sample of participants at high risk for cardiovascular disease, highlighting LA substrate as a potential risk factor for cognitive decrease and dementia., Competing Interests: Disclosures Drs. Ines Gonzalez Casanova and Alvaro Alonso declare financial support from National Heart Lung and Blood Institute. The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The metabolic syndrome (MetS) is associated with increased cardiovascular morbidity and mortality. Characterization of cardiac structural and functional abnormalities due to the MetS can help recognize individuals who would benefit the most from preventive interventions. Transthoracic echocardiography (TTE) provides an opportunity to identify those abnormalities in a reproducible and cost-efficient manner. In research settings, implementation of protocols for the acquisition and analysis of TTE images are key to ensure validity and reproducibility, thus facilitating answering relevant questions about the association of the MetS with cardiac alterations., Methods and Results: The Palma Echo Platform (PEP) is a coordinated network that is built up to evaluate the underlying structural and functional cardiac substrate of participants with MetS. Repeated TTE will be used to evaluate 5-year changes in the cardiac structure and function in a group of 565 individuals participating in a randomized trial of a lifestyle intervention for the primary prevention of cardiovascular disease. The echocardiographic studies will be performed at three study sites, and will be centrally evaluated at the PEP core laboratory. Planned analyses will involve evaluating the effect of the lifestyle intervention on cardiac structure and function, and the association of the MetS and its components with changes in cardiac structure and function. Particular emphasis will be placed on evaluating parameters of left atrial structure and function, which have received more limited attention in past investigations. This PEP will be available for future studies addressing comparable questions., Conclusion: In this article we describe the protocol of a central echocardiography laboratory for the study of functional and structural alterations of the MetS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 López, Rossello, Romaguera, Alonso-Gómez, Toledo, Fortuny, Noris, Mas-Lladó, Fiol, Ramallal, Tojal-Sierra, Alonso and Fernandez-Palomeque.)

Introduction: Adult spinal deformity (ASD) results in significant patient morbidity and burden to quality of life. The degree to which systemic risk factors and comorbidities that contribute to ASD affect specific spinopelvic parameters is not well-documented. We determine the extent to which preoperative risk factors may contribute to spinopelvic parameters associated with ASD., Methods: Retrospective single-center study of 48 patients with ASD. Analysis of variance (ANOVA) linear regression analysis was performed to evaluate correlation between systemic comorbidities (obesity, arterial hypertension (HTN), hyperlipidemia (HLD), cardiomyopathy, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), and asthma) and the following radiographic parameters: pelvic incidence (PI), lumbar lordosis (LL), C7 sagittal vertical axis (C7SVA), and the T10-L2 sagittal cobb angle., Results: A total of 48 patients were included with mean C7SVA of 79.6 mm (SD: 63, range: 43-254), mean LL of 32.9° (SD: 15.9, range: -14 to 78), T10-L2 sagittal cobb angle of 3° (SD: 12.7, range: -24 to 30), and PI was 49° (SD: 10.7, range: 21 to 77). Only DM correlated with sagittal imbalance with high C7SVA and PI-LL mismatch. The beta coefficient for DM and preoperative C7SVA was 0.49, t=3.16, p=0.003, preoperative PI-LL mismatch standardized beta coefficient was -0.4, t=-2.38, p=0.022, and preoperative T10-L2 sagittal cobb standard beta coefficient was -0.07, t=-0.46, p=0.645. No significant correlations were found for asthma, COPD, HTN, HLD, or cardiomyopathy., Conclusions: Diagnosis of DM was found to correlate with pathologic C7SVA and significant PI-LL mismatch associated with ASD. HTN, HLD, cardiomyopathy, obesity, and pulmonary disease did not correlate with radiographic findings of sagittal imbalance., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Dietz et al.)

Dilated cardiomyopathy (DCM) has significant morbidity and mortality. Familial transmission is reported in 20-35% of cases, highlighting the role of genetics in this disorder. We present an interesting family in which the index case is a 64-year-old woman who survived a sudden cardiac arrest. She presented left ventricular dilatation and dysfunction, which indicated the presence of DCM, as well as a history of DCM and sudden arrest in her family (mother and sister). Genetic testing identified a heterozygous mutation c.74A > G missense change that causes an amino acid, p.Glu25Gly, change in the N-terminal domain of the SCN5A protein. After performing an exhaustive family medical history, we found that this previously not described mutation segregated within the family. All relatives with the DCM phenotype were carriers, whereas none of the noncarriers showed signs of heart disease, so this mutation is the most likely cause of the disease. This is the first time that a variant in the N-terminal domain of SCN5A has been associated with DCM.

Background: Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12 U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000 U, 3 × daily)., Objective: To assess the safety and efficacy of LDIVH in aSAH patients., Methods: We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW)., Results: The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9 vs 18%; P = .004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts., Conclusion: This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Introduction: Traumatic quadruple amputations limit daily living activities; however, the current literature regarding rehabilitation treatment for multi-limb amputations is scant. The patient showed adaptation to prosthetic fittings, acquiring a level of functional independence that enabled the patient to lead a nearly independent life., Methods: The patient's therapeutic intervention was divided into a pre-prosthetic phase, which consisted of functional physical adaptation to the amputation and preparation for the prostheses, and a prosthetic phase, in which different myoelectric and microprocessor limb prostheses were integrated to be used functionally. Its functional use was favored by the training with contact electromyography feedback carried out with the Biometrics E-Link System ® for the upper extremities that has made it possible to obtain many grip options in a natural way, for the lower extremities the use of the intelligent passive prostheses has overcome the functional capacity achieved in this type of patients referenced in the literature who had used prostheses of previous generations such as mechanical passive prostheses., Results: With rehabilitation, the patient showed improvements in the following scales and questionnaires (initial vs. final values): Disabilities of the Arm, Shoulder, and Hand Questionnaire; Functional Independence Measure; Berg Balance Scale; Locomotor Capabilities Index in Amputees (an assessment of overall motor capacity); and Special Interest Group in Amputee Medicine scale (an assessment of the degree of mobility)., Conclusions: The patient's age, psychological status, and family and personal support, in addition to technical and economic resources used for next-generation prostheses adapted to this clinical case, were crucial for his progress. IMPLICATIONS FOR REHABILITATION The use of next-generation myoelectric and microprocessor prostheses makes it possible to achieve greater end functionality in quadruple amputees. Proximal amputation levels present greater difficulty in achieving good functionality. Early and intensive rehabilitation could favour and contribute towards improving psychological states. Age, psychological status, and pain management are aspects to take into account during the rehabilitation process.

Background and Purpose- To identify the specific post-endovascular stroke therapy (EVT) peak systolic blood pressure (SBP) threshold that best discriminates good from bad functional outcomes (a priori hypothesized to be 160 mm Hg), we conducted a prospective, multicenter, cohort study with a prespecified analysis plan. Methods- Consecutive adult patients treated with EVT for an anterior ischemic stroke were enrolled from November 2017 to July 2018 at 12 comprehensive stroke centers accross the United States. All SBP values within 24 hours post-EVT were recorded. Using Youden index, the threshold of peak SBP that best discriminated primary outcome of dichotomized 90-day modified Rankin Scale score (0-2 versus 3-6) was identified. Association of this SBP threshold with the outcomes was quantified using multiple logistic regression. Results- Among 485 enrolled patients (median age, 69 [interquartile range, 57-79] years; 51% females), a peak SBP of 158 mm Hg was associated with the largest difference in the dichotomous modified Rankin Scale score (absolute risk reduction of 19%). Having a peak SBP >158 mm Hg resulted in an increased likelihood of modified Rankin Scale score 3 to 6 (odds ratio, 2.24 [1.52-3.29], P <0.01; adjusted odds ratio, 1.29 [0.81-2.06], P =0.28, after adjustment for prespecified variables). Conclusions- A peak post-EVT SBP of 158 mm Hg was prospectively identified to best discriminate good from bad functional outcome. Those with a peak SBP >158 had an increased likelihood of having a bad outcome in unadjusted, but not in adjusted analysis. The observed effect size was similar to prior studies. This finding should undergo further testing in a future randomized trial of goal-targeted post-EVT antihypertensive treatment.

Retinitis pigmentosa (RP) initiates with diminished rod photoreceptor function, causing peripheral and night-time vision loss. However, subsequent loss of cone function and high-resolution daylight and color vision is most debilitating. Visual pigment-rich photoreceptor outer segments (OS) undergo phagocytosis by the retinal pigment epithelium (RPE), and the RPE also acts as a blood-outer retinal barrier transporting nutrients, including glucose, to photoreceptors. We provide evidence that contact between externalized phosphatidylserine (PS) on OS tips and apical RPE receptors activates Akt, linking phagocytosis with glucose transport to photoreceptors for new OS synthesis. As abundant mutant rod OS tips shorten in RP, Akt activation is lost, and onset of glucose metabolism in the RPE and diminished glucose transport combine to cause photoreceptor starvation and accompanying retinal metabolome changes. Subretinal injection of OS tip mimetics displaying PS restores Akt activation, glucose transport, and cone function in end-stage RP after rods are lost., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this research is to study whether the presentation of the Voice Handicap Index-10 questionnaire administered at the beginning of the treatment impinged on the results of the responses from the end of the treatment., Methods: The questionnaire was administered at the beginning of the treatment to a total of 308 patients. After the treatment, a group of 235 patients answered the questionnaire again without any reference to their responses on the initial administration. The other group of participants, consisting of 73 subjects, completed the questionnaire with the answer sheet of their initial self-assessment in sight., Results: The data obtained show that patients who responded to the anchored answer test show less dispersion and a smaller coefficient of variation (0.90) than those who responded to the nonanchored answer test (coefficient of variation = 1.66)., Conclusions: The method of administration of the Voice Handicap Index-10 at the end of a treatment influences the dispersion of the results. We recommend that the patient be anchored to the initial answer sheet while responding to the final self-assessment., (Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Many of the state-of-the-art data mining techniques introduce nonlinearities in their models to cope with complex data relationships effectively. Although such techniques are consistently included among the top classification techniques in terms of predictive power, their lack of transparency renders them useless in any domain where comprehensibility is of importance. Rule-extraction algorithms remedy this by distilling comprehensible rule sets from complex models that explain how the classifications are made. This paper considers a new rule extraction technique, based on active learning. The technique generates artificial data points around training data with low confidence in the output score, after which these are labeled by the black-box model. The main novelty of the proposed method is that it uses a pedagogical approach without making any architectural assumptions of the underlying model. It can therefore be applied to any black-box technique. Furthermore, it can generate any rule format, depending on the chosen underlying rule induction technique. In a large-scale empirical study, we demonstrate the validity of our technique to extract trees and rules from artificial neural networks, support vector machines, and random forests, on 25 data sets of varying size and dimensionality. Our results show that not only do the generated rules explain the black-box models well (thereby facilitating the acceptance of such models), the proposed algorithm also performs significantly better than traditional rule induction techniques in terms of accuracy as well as fidelity.

Background: Chagas cardiomyopathy is a chronic sequela of infection by the parasite, Trypanosoma cruzi. Advanced cardiomyopathy is associated with a high mortality rate, and clinical characteristics have been used to predict mortality risk. Though multiple biomarkers have been associated with Chagas cardiomyopathy, it is unknown how these are related to survival., Objectives: This study aimed to identify biomarkers associated with mortality in individuals with severe Chagas cardiomyopathy in an urban Bolivian hospital., Methods: The population included individuals with and without T. cruzi infection recruited in an urban hospital in Santa Cruz, Bolivia. Baseline characteristics, electrocardiogram findings, medications, and serum cardiac biomarker levels (B-type natriuretic peptide [BNP], N-terminal pro-B-type natriuretic peptide [NT-proBNP], creatine kinase-myocardial band [CK-MB], troponin I, matrix metalloproteinase [MMP]-2, MMP-9, tissue inhibitor of metalloproteinases [TIMP] 1 and 2, transforming growth factor [TGF] beta 1 and 2) were ascertained. Echocardiograms were performed on those with cardiac symptoms or electrocardiogram abnormalities at baseline. Participants were contacted approximately 1 year after initial evaluation; deaths were reported by family members. Receiver-operating characteristic curves (ROC) were used to optimize cutoff values for each marker. For markers with area under the curve (AUC) >0.55, Cox proportional hazards models were performed to determine the hazards ratio (HR) and 95% confidence interval (CI) for the association of each marker with mortality., Results: The median follow-up time was 14.1 months (interquartile range 12.5, 16.7). Of 254 individuals with complete cardiac data, 220 (87%) had follow-up data. Of 50 patients with severe Chagas cardiomyopathy at baseline, 20 (40%) had died. Higher baseline levels of BNP (HR: 3.1, 95% CI: 1.2 to 8.4), NT-proBNP (HR: 4.4, 95% CI: 1.8 to 11.0), CK-MB (HR: 3.3, 95% CI: 1.3 to 8.0), and MMP-2 (HR: 4.2, 95% CI: 1.5 to 11.8) were significantly associated with subsequent mortality., Conclusions: Severe Chagas cardiomyopathy is associated with high short-term mortality. BNP, NT-proBNP, CK-MB, and MMP-2 have added predictive value for mortality, even in the presence of decreased ejection fraction and other clinical signs of congestive heart failure., (Copyright © 2015 World Heart Federation (Geneva). All rights reserved.)

With the increasingly widespread collection and processing of "big data," there is natural interest in using these data assets to improve decision making. One of the best understood ways to use data to improve decision making is via predictive analytics. An important, open question is: to what extent do larger data actually lead to better predictive models? In this article we empirically demonstrate that when predictive models are built from sparse, fine-grained data-such as data on low-level human behavior-we continue to see marginal increases in predictive performance even to very large scale. The empirical results are based on data drawn from nine different predictive modeling applications, from book reviews to banking transactions. This study provides a clear illustration that larger data indeed can be more valuable assets for predictive analytics. This implies that institutions with larger data assets-plus the skill to take advantage of them-potentially can obtain substantial competitive advantage over institutions without such access or skill. Moreover, the results suggest that it is worthwhile for companies with access to such fine-grained data, in the context of a key predictive task, to gather both more data instances and more possible data features. As an additional contribution, we introduce an implementation of the multivariate Bernoulli Naïve Bayes algorithm that can scale to massive, sparse data.