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Within the framework of natural orbital functional theory, having a convenient representation of the occupation numbers and orbitals becomes critical for the computational performance of the calculations. Recognizing this, we propose an innovative parametrization of the occupation numbers that takes advantage of the electron-pairing approach used in Piris natural orbital functionals through the adoption of the softmax function, a pivotal component in modern deep-learning models. Our approach not only ensures adherence to the N-representability of the first-order reduced density matrix (1RDM) but also significantly enhances the computational efficiency of 1RDM functional theory calculations. The effectiveness of this alternative parameterization approach was assessed using the W4-17-MR molecular set, which demonstrated faster and more robust convergence compared to previous implementations., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

In this work, we explore the use of Piris natural orbital functionals (PNOFs) to calculate excited-state energies by coupling their reconstructed second-order reduced density matrix with the extended random-phase approximation (ERPA). We have named the general method PNOF-ERPA, and specific approaches are referred to as PNOF-ERPA0, PNOF-ERPA1, and PNOF-ERPA2, according to the way the excitation operator is built. The implementation has been tested in the first excited states of H 2 , HeH + , LiH, Li 2 , and N 2 showing good results compared to the configuration interaction (CI) method. As expected, an increase in accuracy is observed on going from ERPA0 to ERPA1 and ERPA2. We also studied the effect of electron correlation included by PNOF5, PNOF7, and the recently proposed global NOF (GNOF) on the predicted excited states. PNOF5 appears to be good and may even provide better results in very small systems, but including more electron correlation becomes important as the system size increases, where GNOF achieves better results. Overall, the extension of PNOF to excited states has been successful, making it a promising method for further applications.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Panis, Vos, Barić, Bosch, Brouwers, Burlina, Cassiman, Coman, Couce, Das, Demirbas, Empain, Gautschi, Grafakou, Grunewald, Kingma, Knerr, Leão-Teles, Möslinger, Murphy, Õunap, Pané, Paci, Parini, Rivera, Scholl-Bürgi, Schwartz, Sdogou, Shakerdi, Skouma, Stepien, Treacy, Waisbren, Berry and Rubio-Gozalbo.)

Introduction: Health care providers faced a challenge with the emergence of COVID-19 and its rapid spread. Early studies measuring the psychological impact of COVID-19 on the general population found high levels of anxiety and sleep disorders. The primary goal of this project was to assess the psychological impact of COVID-19 on physicians in Puerto Rico., Materials and Methods: A cross-sectional study of physicians in Puerto Rico was conducted anonymously and electronically from February 2021 through April 2021. The electronic survey included socio-demographic data and 4 self-administered assessment tools (Generalized Anxiety Disorder-7, Perceived Stress Scale-10, Pittsburgh Sleep Quality Index and COVID-19 Organizational Support) for anxiety, perceived stress, sleep disturbances, and organizational support during the COVID-19 pandemic., Results: A total of 145 physicians completed the survey, with a female predominance of 53.5% and a majority practicing in the San Juan metropolitan area (50.3%). Mild anxiety symptoms were reported in 26.9% of physicians, and 33.8% had moderate to severe anxiety symptoms. Moderate to high perceived stress was found in 69.9% of participants, and women reported statistically significantly higher levels of anxiety symptoms (8.84 ± 5.99; p  = 0.037) and stress (19.0 ± 6.94, p  = 0.001). The Pittsburgh Sleep Quality Index reported 67.9% of physicians with global scores associated with poor sleep quality. Assessment of perceived organizational support found a high perception of work support (65.7%) but low perception of personal support (43.4%) and risk support (30.3%). A correlation analysis found a negative correlation for work and personal support, but a positive correlation for risk support, all statistically significant., Conclusion: COVID-19 had a lasting psychological impact in health care providers in Puerto Rico a year after the beginning of the pandemic. Our data supports the importance of organizational support and its correlation with the development of anxiety. It is thus essential to develop strategies to identify individuals at risk of experiencing psychological disturbances and to provide effective support for medical professionals during medical emergencies for their well-being and optimal delivery of patient care., 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 © 2024 Sanchez-Plazas, García-De Jesus, Martinez-Gonzalez, Amaya-Ardila and Almodóvar-Rivera.)

It has been over 100 years since the discovery of one of the most fundamental statistical tests: the Student's t test. However, reliable conventional and objective Bayesian procedures are still essential for routine practice. In this work, we proposed an objective and robust Bayesian approach for hypothesis testing for one-sample and two-sample mean comparisons when the assumption of equal variances holds. The newly proposed Bayes factors are based on the intrinsic and Berger robust prior. Additionally, we introduced a corrected version of the Bayesian Information Criterion (BIC), denoted BIC-TESS, which is based on the effective sample size (TESS), for comparing two population means. We studied our developed Bayes factors in several simulation experiments for hypothesis testing. Our methodologies consistently provided strong evidence in favor of the null hypothesis in the case of equal means and variances. Finally, we applied the methodology to the original Gosset sleep data, concluding strong evidence favoring the hypothesis that the average sleep hours differed between the two treatments. These methodologies exhibit finite sample consistency and demonstrate consistent qualitative behavior, proving reasonably close to each other in practice, particularly for moderate to large sample sizes.

Fracture-related infection (FRI) is a common complication following open tibia fracture (OTF), especially in patients with high-energy trauma or comorbidities. The use of gentamicin-coated nail (GCN) has been proposed as a local adjuvant to prevent FRI in high-risk patients., Hypothesis: The incidence of FRI is expected to be lower in OTF treated with a GCN, alongside with no detrimental effects on fracture healing time., Objectives: This study aimed to evaluate the effectiveness of GCNs as a definitive fixation method and prophylaxis for FRI in OTFs. Secondary outcomes included non-union rates and time to healing., Methods: The study design was a mixed cohort, including a prospective group of patients treated with GCN (Expert Tibial Nail PROtect™, Depuy Synthes, Johnson&Johnson Company Inc, New Jersey, USA) and a retrospectively evaluated group treated with non-gentamicin-coated nail (NGCN). Patients with at least 12 months of follow-up were included. The treatment protocol consisted of timely administration of antibiotics, surgical debridement, and early soft-tissue coverage. Exclusion criteria included protocol infringement, traumatic amputation, and loss of follow-up. Statistical analysis was performed using Stata v14.0, with a significance level of p < 0.05., Results: The study included 243 patients, 104 in GCN group and 139 NGCN group. External Fixator use was higher in the NGCN group, but this did not significantly affect the FRI rate. GCN use was associated with a significantly lower incidence of FRI (2.88% GCN group vs. 15.83% NGCN group, OR 0.16, p < 0.01). Furthermore, GCN use was found to be a protective factor against tibial non-union (OR 0.41, p = 0.03). There were no adverse effects attributed to locally administered gentamycin. The NGCN cohort had a higher incidence of polytrauma, although the difference was not statistically significant. A longer time to heal as well as more FRI and Non-union according to the progression in Gustilo-Anderson classification was observed in the GCN group., Conclusion: Our findings suggest that GCN is an effective prophylactic method to reduce the risk of FRI in open tibial fractures at 12-month follow-up, as well as, probably derived from this protective effect, leading to lower fracture consolidation times when compared with cases treated without GCN., 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 © 2023. Published by Elsevier Ltd.)

Extreme temperature and precipitation events are the primary triggers of hazards, such as heat waves, droughts, floods, and landslides, with localized impacts. In this sense, the finer grids of Earth System models (ESMs) could play an essential role in better estimating extreme climate events. The performance of High Resolution Model Intercomparison Project (HighResMIP) models is evaluated using the Expert Team on Climate Change Detection and Indices (ETCCDI) over the 1981-2014 period and future changes (2021-2050) under Shared Socioeconomic Pathway SSP5-8.5, over ten regions in Latin America and the Caribbean. The impact of increasing the horizontal resolution in estimating extreme climate variability on a regional scale is first compared against reference gridded datasets, including reanalysis, satellite, and merging products. We used three different groups based on the resolution of the model's grid ( sg ): (i) low (0.8° ≤  sg  ≤ 1.87°), (ii) intermediate (0.5° ≤  sg  ≤ 0.7°), and (iii) high (0.23° ≥  sg  ≤ 0.35°). Our analysis indicates that there was no clear evidence to support the posit that increasing horizontal resolution improves model performance. The ECMWF-IFS family of models appears to be a plausible choice to represent climate extremes, followed by the ensemble mean of HighResMIP in their intermediate resolution. For future climate, the projections indicate a consensus of temperature and precipitation climate extremes increase across most of the ten regions. Despite the uncertainties presented in this study, climate models have been and will continue to be an important tool for assessing risk in the face of extreme events., Supplementary Information: The online version contains supplementary material available at 10.1007/s41748-022-00337-7., Competing Interests: Conflict of interestAll authors declare that there is no conflict of interest., (© The Author(s) 2022.)

Improving public health initiative requires an accurate anthropometric index that is better suited to a specific community. In this study, the anthropometric grouping index is proposed as a more efficient and discriminatory alternative to the popular BMI for the Eastern Caribbean population. A completely distribution-free cluster analysis was performed to obtain the 11 categories, leading to AGI-11. Further, we studied these groups using novel non-parametric clustering summaries. Finally, two generalized linear mixed models were fitted to assess the association between elevated blood sugar, AGI-11 and BMI. Our results showed that AGI-11 tends to be more sensitive in predicting levels of elevated blood sugar compared to BMI. For instance, individuals identified as obese III according to BMI are (POR: 2.57; 95% CI: (1.68, 3.74)) more likely to have elevated blood sugar levels, while, according to AGI, individuals with similar characteristics are (POR: 3.73; 95% CI: (2.02, 6.86)) more likely to have elevated blood sugar levels. In conclusion, the findings of the current study suggest that AGI-11 could be used as a predictor of high blood sugar levels in this population group. Overall, higher values of anthropometric measures correlated with a higher likelihood of high blood sugar levels after adjusting by sex, age, and family history of diabetes.

Objectives: To evaluate the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in patients with and without prior coronary artery bypass graft (CABG) surgery., Background: Data on the outcomes of CTO PCI in patients with versus without CABG remains limited and with scarce representation from developing regions like Latin America., Methods: We evaluated patients undergoing CTO PCI in 42 centers participating in the LATAM CTO registry between 2008 and 2020. Statistical analyses were stratified according to CABG status. The outcomes of interest were technical and procedural success and in-hospital major adverse cardiac and cerebrovascular events (MACCE)., Results: A total of 1662 patients were included (n = 1411 [84.9%] no-CABG and n = 251 [15.1%] prior-CABG). Compared with no-CABG, those with prior-CABG were older (67 ± 11 vs. 64 ± 11 years; p < 0.001), had more comorbidities and lower left ventricular ejection fraction (52.8 ± 12.8% vs. 54.4 ± 11.7%; p = 0.042). Anatomic complexity was higher in the prior-CABG group (J-CTO score 2.46 ± 1.19 vs. 2.10 ± 1.22; p < 0.001; PROGRESS CTO score 1.28 ± 0.89 vs. 0.91 ± 0.85; p < 0.001). Absence of CABG was associated with lower risk of technical and procedural failure (OR: 0.60, 95% CI: 0.43-0.85 and OR: 0.58, 95% CI: 0.40-0.83, respectively). No significant differences in the incidence of in-hospital MACCE (3.8% no-CABG vs. 4.4% prior-CABG; p = 0.766) were observed between groups., Conclusion: In a contemporary multicenter CTO-PCI registry from Latin America, prior-CABG patients had more comorbidities, higher anatomical complexity, lower success, and similar in-hospital adverse event rates compared with no-CABG patients., (© 2021 Wiley Periodicals LLC.)

In human metabolism, pyruvate dehydrogenase complex (PDC) is one of the most intricate and large multimeric protein systems representing a central hub for cellular homeostasis. The worldwide used antiepileptic drug valproic acid (VPA) may potentially induce teratogenicity or a mild to severe hepatic toxicity, where the underlying mechanisms are not completely understood. This work aims to clarify the mechanisms that intersect VPA-related iatrogenic effects to PDC-associated dihydrolipoamide dehydrogenase (DLD; E3) activity. DLD is also a key enzyme of α-ketoglutarate dehydrogenase, branched-chain α-keto acid dehydrogenase, α-ketoadipate dehydrogenase, and the glycine decarboxylase complexes. The molecular effects of VPA will be reviewed underlining the data that sustain a potential interaction with DLD. The drug-associated effects on lipoic acid-related complexes activity may induce alterations on the flux of metabolites through tricarboxylic acid cycle, branched-chain amino acid oxidation, glycine metabolism and other cellular acetyl-CoA-connected reactions. The biotransformation of VPA involves its complete β-oxidation in mitochondria causing an imbalance on energy homeostasis. The drug consequences as histone deacetylase inhibitor and thus gene expression modulator have also been recognized. The mitochondrial localization of PDC is unequivocal, but its presence and function in the nucleus were also demonstrated, generating acetyl-CoA, crucial for histone acetylation. Bridging metabolism and epigenetics, this review gathers the evidence of VPA-induced interference with DLD or PDC functions, mainly in animal and cellular models, and highlights the uncharted in human. The consequences of this interaction may have significant impact either in mitochondrial or in nuclear acetyl-CoA-dependent processes., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype., Methods: Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020., Results: Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17-5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM&#95;000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial., Conclusion: The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed.

Background: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients., Methods: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018., Results: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome., Conclusion: This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Introduction: Foreign body (FB) ingestion is a common home accident during childhood; a timely management by the specialists may help prevent complications in the short and long term., Objective: To describe the characteristics and complications of FB ingestion located in the gastrointestinal tract in the pediatric population., Material and Methods: Two phases, retrospective, and prospective study. Patients diagnosed with FB ingestion between January 1971 and December 2016 were included. The general characteristics of patients, FB type, removal method, and complications were registered. A descriptive analysis was performed., Results: Over 45 years, 2637 FBs were removed from the pharynx (n= 118), the esophagus (n= 2410), the stomach (n= 103), and the intestines (n= 6). Male patients predominated (50.9%); 74% were younger than 5 years. Besides, 57% arrived within the first 24 hours; ptyalism, dysphagia, and vomiting were the main symptoms; 16% of patients had no symptoms. It was possible to locate the FB using an X-ray in 93% of cases; the most common FBs were coins (78%); the most frequent location was the upper third of the esophagus (79%); 86% of FBs were removed using a rigid endoscope, and complications were observed in 7.8% of patients., Conclusions: FB ingestion predominated among children younger than 5 years; metal objects were the most common ones. A plain X-ray is the test of choice for diagnosis; removal is usually done with a rigid or flexible endoscope, depending on the endoscopist's experience., (Sociedad Argentina de Pediatría.)

The key regulatory point of L-methionine (Met) and L-homocysteine (Hcy) degradation is catalyzed by cystathionine beta-synthase (CBS). CBS deficiency is caused by mutations in CBS gene, often resulting in protein misfolding. The prevalence of CBS deficiency in Qatar is 1/1800, ∼200-fold higher than the worldwide prevalence of 1/344 000. Almost all patients bear the CBS p.R336C variant. More than 20 years ago, it was shown in vitro that two unrelated protein variants with a substitution of an arginine (Arg) residue by cysteine (Cys) could be rescued by cysteamine (mercaptoethylamine), likely via formation of a disulfide between Cys and cysteamine, functionally mimicking the wild-type (WT) Arg side-chain. Based on these findings, we aimed to study whether cysteamine was able to improve the function of p.R336C CBS variant. Additionally, we tested the effect of mercaptoethylguanidine (MEG), a compound with a guanidino and a thiol function that may resemble Arg structure better than cysteamine. Three purified recombinant CBS proteins (p.R336C, p.R336H and WT) were pre-incubated with cysteamine, MEG or Cys (as negative control), and CBS activity and stability were measured. Pre-incubation with cysteamine and MEG increased the enzymatic activity of the p.R336C protein, which was absent upon pre-incubation with Cys. The WT and the p.R336H variant enzyme activity presented no increase with any of the tested compounds. Our results show that cysteamine and MEG are able to specifically improve the function of the CBS p.R336C variant, suggesting that any Arg-to-Cys substitution accessible to these small molecules may be converted back to a moiety resembling Arg., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the commonest genetic defect of mitochondrial fatty acid β-oxidation. About 60% of MCADD patients are homozygous for the c.985A>G (p.Lys329Glu) mutation in the ACADM gene (G985 allele). Herein, we present the first report on the molecular and biochemical spectrum of Portuguese MCADD population. From the 109 patients studied, 83 were diagnosed after inclusion of MCADD in the national newborn screening, 8 following the onset of symptoms and 18 through segregation studies. Gypsy ancestry was identified in 85/109 patients. The G985 allele was found in homozygosity in 102/109 patients, in compound heterozygosity in 6/109 and was absent in one patient. Segregation studies in the Gypsy families showed that 93/123 relatives were carriers of the G985 allele, suggesting its high prevalence in this ethnic group. Additionally, three new substitutions-c.218A>G (p.Tyr73Cys), c.503A>T (p.Asp168Val) and c.1205G>T (p.Gly402Val)-were identified. Despite the particularity of the MCADD population investigated, the G985 allele was found in linkage disequilibrium with H1(112) haplotype. Furthermore, two novel haplotypes, H5(212) and H6(122) were revealed., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)