Lower Bounds on the Noiseless Worst-Case Complexity of Efficient Global Optimization.

Efficient global optimization is a widely used method for optimizing expensive black-box functions. In this paper, we study the worst-case oracle complexity of the efficient global optimization problem. In contrast to existing kernel-specific results, we derive a unified lower bound for the oracle complexity of efficient global optimization in terms of the metric entropy of a ball in its corresponding reproducing kernel Hilbert space. Moreover, we show that this lower bound nearly matches the upper bound attained by non-adaptive search algorithms, for the commonly used squared exponential kernel and the Matérn kernel with a large smoothness parameter ν. This matching is up to a replacement of d/2 by d and a logarithmic term logRϵ, where d is the dimension of input space, R is the upper bound for the norm of the unknown black-box function, and ϵ is the desired accuracy. That is to say, our lower bound is nearly optimal for these kernels.

Mapping the Insomnia Severity Index Instrument to EQ-5D Health State Utilities: A United Kingdom Perspective.

OBJECTIVE: This study aimed to map the Insomnia Severity Index (ISI) to the EQ-5D-3L utility values from a UK perspective. METHODS: Source data were derived from the 2020 National Health and Wellness Survey (NHWS) for France, Germany, Italy, Spain, the UK and the US. Ordinary least squares regression, generalised linear model (GLM), censored least absolute deviation, and adjusted limited dependent variable mixture model (ALDVMM) were employed to explore the relationship between ISI total summary score and EQ-5D utility while accounting for adjustment covariates derived from the NHWS. Fitting performance was assessed using standard metrics, including mean-squared error (MSE) and coefficient of determination (R2). RESULTS: A total of 17,955 respondent observations were included, with a mean ISI score of 12.12 ± 5.32 and a mean EQ-5D-3L utility (UK tariff) of 0.71 ± 0.23. GLM gamma-log and ALDVMM were the two best performing models. The ALDVMM had better fitting performance (R2 = 0.320, MSE 0.0347) than the GLM gamma-log (R2 = 0.303, MSE 0.0353); in train-test split-sample validation, ALDVMM also slightly outperformed the GLM gamma-log model, with an MSE of 0.0351 versus 0.0355. Based on fitting performance, ALDVMM and GLM gamma-log were the preferred models. CONCLUSIONS: In the absence of preference-based measures, this study provides an updated mapping algorithm for estimating EQ-5D-3L utilities from the ISI summary total score. This new mapping not only draws its strengths from the use of a large international dataset but also the incorporation of adjustment variables (including sociodemographic and general health characteristics) to reduce the effects of confounders.

Genetic epidemiology of familial ALS in Brazil.

Many genes associated with familial forms of the amyotrophic lateral sclerosis (fALS) have been identified in European and North American cohorts. However, little is known about the genetic bases of fALS in Latin America and Brazil, in particular. To address this question, we recruited 107 patients with fALS from 93 unrelated families from Southeastern, Southern, and Northeastern regions of the country. A 3-step diagnostic approach was used: 1) Triplet repeat primed polymerase chain reaction to search for C9orf72 expansions, then 2) fragment digestion to search for the c.166 C>T VAPB variant, and finally, 3) whole exome sequencing for those who tested negative. We identified the genetic cause for fALS in 70% of the families. VAPB and C9orf72 were the most frequent genes (30% and 22%, respectively), followed by SOD1, TARDBP, ANXA11, and FUS. Five novel variants in known ALS genes were found, including the SOD1 Val120Leu and ANXA11 Asp40Tyr, which were seen in 2 unrelated families each. In conclusion, VAPB and then C9orf72 are the genes most commonly related to fALS in Brazil.

Validity of bioelectrical impedance to estimate fat-free mass in boys with Duchenne muscular dystrophy.

The evaluation of fat-free mass (FFM) in patients with Duchenne muscular dystrophy (DMD) is useful to investigate disease progression and therapeutic efficacy. This study aimed to validate the Bioelectrical impedance (BIA) method compared with the dual-energy X-ray absorptiometry (DXA) for estimating the %FFM in boys with DMD. This is a cross-sectional study performed with children and adolescents diagnosed with DMD. Resistance and reactance were measured with a BIA analyzer, from which eight predictive equations estimated the %FFM. The %FFM was also determined by DXA and its used as a reference method. Pearson correlation test, coefficient of determination, the root-mean-square error, the interclass correlation coefficient, and linear regression analysis were performed between %FFM values obtained by BIA and DXA. The agreement between these values was verified with the Bland-Altman plot analysis. Forty-six boys aged from 5 to 20 years were enrolled in the study. All the equations showed a correlation between the %FFM estimated by BIA and determined by DXA (p < 0.05). The Bland-Altman method indicated that two equations have a significant bias (p < 0.05) and six equations showed no significant bias of %FFM (p > 0.05). However, one of them has high variation and wide limits of agreement. Five of eight %FFM predictive equations tested in DMD were accurate when compared with the DXA. It can be concluded that BIA is a validity method to evaluate patients with DMD.

Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion.

BACKGROUND: Brain circulation disorders such as chronic cerebral hypoperfusion have been associated with a decline in cognitive function during the development of dementia. Astrocytes together with microglia participate in the immune response in the CNS and make them potential sentinels in the brain parenchyma. In addition, astrocytes coverage integrity has been related to brain homeostasis. Currently, physical exercise has been proposed as an effective intervention to promote brain function improvement. However, the neuroprotective effects of early physical exercise on the astrocyte communication with the microcirculation and the microglial activation in a chronic cerebral hypoperfusion model are still unclear. The aim of this study was to investigate the impact of early intervention with physical exercise on cognition, brain microcirculatory, and inflammatory parameters in an experimental model of chronic cerebral hypoperfusion induced by permanent bilateral occlusion of the common carotid arteries (2VO). METHODS: Wistar rats aged 12 weeks were randomly divided into four groups: Sham-sedentary group (Sham-Sed), Sham-exercised group (Sham-Ex), 2VO-sedentary group (2VO-Sed), and 2VO-exercised group (2VO-Ex). The early intervention with physical exercise started 3 days after 2VO or Sham surgery during 12 weeks. Then, the brain functional capillary density and endothelial-leukocyte interactions were evaluated by intravital microscopy; cognitive function was evaluated by open-field test; hippocampus postsynaptic density protein 95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the capillaries, microglial activation, and structural capillary density were evaluated by immunohistochemistry. RESULTS: Early moderate physical exercise was able to normalize functional capillary density and reduce leukocyte rolling in the brain of animals with chronic cerebral hypoperfusion. These effects were accompanied by restore synaptic protein and the improvement of cognitive function. In addition, early moderate exercise improves astrocytes coverage in blood vessels of the cerebral cortex and hippocampus, decreases microglial activation in the hippocampus, and improves structural capillaries in the hippocampus. CONCLUSIONS: Microcirculatory and inflammatory changes in the brain appear to be involved in triggering a cognitive decline in animals with chronic cerebral ischemia. Therefore, early intervention with physical exercise may represent a preventive approach to neurodegeneration caused by chronic cerebral hypoperfusion.

Association of Copper Status with Lipid Profile and Functional Status in Patients with Amyotrophic Lateral Sclerosis.

Oxidative stress is one of the main mechanisms associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). Copper can affect cellular oxidation and lipid metabolism. The aim of this study was to evaluate the association of copper status with lipid profile and functional status in patients with ALS. A cross-sectional study was carried out including 27 patients with ALS (case group) and 26 healthy individuals (control group). Copper status was evaluated by habitual dietary copper intake, plasma copper, and serum ceruloplasmin concentrations. The lipid profile included analysis of serum total cholesterol (TC), LDL-cholesterol (LDL-c), HDL-cholesterol (HDL-c), and triglycerides (TGL). The functional status of patients with ALS was assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R). In the case group, plasma copper was lower compared with the control group (133.9 versus 164.1 µg/dL, p=0.0001) and was positively correlated with HDL-c (rs=0.398, p=0.044). In the control group, plasma copper was positively correlated with serum ceruloplasmin (rs=0.646, p < 0.001), TC (rs=0.446, p=0.025), LDL-c (rs=0.445, p=0.029), and HDL-c (rs=0.479, p=0.015), and serum ceruloplasmin was positively correlated only with LDL-c (rs=0.407, p=0.043). In the case group, dietary copper intake (B=-0.373, p < 0.001), plasma copper (B=-0.005, p=0.033), and TC (B=-0.312, p=0.001) were inversely associated with the functional status of patients with ALS. In contrast, serum ceruloplasmin (B=0.016, p=0.044), LDL-c (B=0.314, p=0.001), HDL-c (B=0.308, p=0.001), and TGL (B=0.062; p=0.001) were positively associated with their functional status. In conclusion, this study suggests a disturbance of copper status and its connection with the lipid profile in patients with ALS. Furthermore, copper status and lipid profile may influence the functional status of patients with ALS, standing out as potential biomarkers of disease severity.

Persistent effects of pre-Columbian plant domestication on Amazonian forest composition.

The extent to which pre-Columbian societies altered Amazonian landscapes is hotly debated. We performed a basin-wide analysis of pre-Columbian impacts on Amazonian forests by overlaying known archaeological sites in Amazonia with the distributions and abundances of 85 woody species domesticated by pre-Columbian peoples. Domesticated species are five times more likely than nondomesticated species to be hyperdominant. Across the basin, the relative abundance and richness of domesticated species increase in forests on and around archaeological sites. In southwestern and eastern Amazonia, distance to archaeological sites strongly influences the relative abundance and richness of domesticated species. Our analyses indicate that modern tree communities in Amazonia are structured to an important extent by a long history of plant domestication by Amazonian peoples.

American Confederation of Urology (CAU) experience in minimally invasive partial nephrectomy.

PURPOSE: To describe the perioperative and oncology outcomes in a series of laparoscopic or robotic partial nephrectomies (PN) for renal tumors treated in diverse institutions of Hispanic America from the beginning of their minimally invasive (MI) PN experience through December 2014. METHODS: Seventeen institutions participated in the CAU generated a MI PN database. We estimated proportions, medians, 95 % confidence intervals, Kaplan-Meier curves, multivariate logistic and Cox regression analyses. Clavien-Dindo classification was used. RESULTS: We evaluated 1501 laparoscopic (98 %) or robotic (2 %) PNs. Median age: 58 years. Median surgical time, warm ischemia and intraoperative bleeding were 150, 20 min and 200 cc. 81 % of the lesions were malignant, with clear cell histology being 65 % of the total. Median maximum tumor diameter is 2.7 cm, positive margin is 8.2 %, and median hospitalization is 3 days. One or more postoperative complication was recorded in 19.8 % of the patients: Clavien 1: 5.6 %; Clavien 2: 8.4 %; Clavien 3A: 1.5 %; Clavien 3B: 3.2 %; Clavien 4A: 1 %; Clavien 4B: 0.1 %; Clavien 5: 0 %. Bleeding was the main cause of a reoperation (5.5 %), conversion to radical nephrectomy (3 %) or open partial nephrectomy (6 %). Transfusion rate is 10 %. In multivariate analysis, RENAL nephrometry score was the only variable associated with complications (OR 1.1; 95 % CI 1.02-1.2; p = 0.02). Nineteen patients presented disease progression or died of disease in a median follow-up of 1.37 years. The 5-year progression or kidney cancer mortality-free rate was 94 % (95 % CI 90, 97). Positive margins (HR 4.98; 95 % CI 1.3-19; p = 0.02) and females (HR 5.6; 95 % CI 1.7-19; p = 0.005) were associated with disease progression or kidney cancer mortality after adjusting for maximum tumor diameter. CONCLUSION: Laparoscopic PN in these centers of Hispanic America seem to have acceptable perioperative complications and short-term oncologic outcomes.

Guidelines for the diagnosis, treatment and clinical monitoring of patients with juvenile and adult Pompe disease / Diretriz para o diagnóstico, tratamento e acompanhamento clínico de pacientes com doença de Pompe juvenil e do adulto

ABSTRACT Pompe disease (PD) is a potentially lethal illness involving irreversible muscle damage resulting from glycogen storage in muscle fiber and activation of autophagic pathways. A promising therapeutic perspective for PD is enzyme replacement therapy (ERT) with the human recombinant enzyme acid alpha-glucosidase (Myozyme®). The need to organize a diagnostic flowchart, systematize clinical follow-up, and establish new therapeutic recommendations has become vital, as ERT ensures greater patient longevity. A task force of experienced clinicians outlined a protocol for diagnosis, monitoring, treatment, genetic counseling, and rehabilitation for PD patients. The study was conducted under the coordination of REBREPOM, the Brazilian Network for Studies of PD. The meeting of these experts took place in October 2013, at L’Hotel Port Bay in São Paulo, Brazil. In August 2014, the text was reassessed and updated. Given the rarity of PD and limited high-impact publications, experts submitted their views.

RESUMO A doença de Pompe (DP) é uma doença grave, potencialmente letal, devida ao depósito de glicogênio na fibra muscular e ativação de vias autofágicas. Tratamento promissor para a DP é a reposição enzimática com a enzima recombinante humana alfa-glicosidase ácida (rhAGA -Myozyme®). A necessidade de organizar uma propedêutica diagnóstica, sistematizar o seguimento clínico e sedimentar as novas recomendações terapêuticas tornaram-se vitais à medida que o tratamento permite uma maior longevidade aos pacientes. Uma força-tarefa de clínicos experientes no manejo da DP foi constituída para elaborar um protocolo para o diagnóstico, acompanhamento clínico, tratamento, aconselhamento genético, entre outras considerações voltadas ao paciente adulto. O estudo foi realizado sob a coordenação da Rede Brasileira de Estudos da Doença de Pompe (REBREPOM). Diante da raridade da DP e escassez de trabalhos de alto impacto de evidência científica, os especialistas emitiram suas opiniões.

Guidelines for the diagnosis, treatment and clinical monitoring of patients with juvenile and adult Pompe disease.

Pompe disease (PD) is a potentially lethal illness involving irreversible muscle damage resulting from glycogen storage in muscle fiber and activation of autophagic pathways. A promising therapeutic perspective for PD is enzyme replacement therapy (ERT) with the human recombinant enzyme acid alpha-glucosidase (Myozyme®). The need to organize a diagnostic flowchart, systematize clinical follow-up, and establish new therapeutic recommendations has become vital, as ERT ensures greater patient longevity. A task force of experienced clinicians outlined a protocol for diagnosis, monitoring, treatment, genetic counseling, and rehabilitation for PD patients. The study was conducted under the coordination of REBREPOM, the Brazilian Network for Studies of PD. The meeting of these experts took place in October 2013, at L'Hotel Port Bay in São Paulo, Brazil. In August 2014, the text was reassessed and updated. Given the rarity of PD and limited high-impact publications, experts submitted their views.

Ferromagnetic resonance of intact cells and isolated crystals from cultured and uncultured magnetite-producing magnetotactic bacteria.

Most magnetotactic bacteria (MB) produce stable, single-domain magnetite nanocrystals with species-specific size, shape and chain arrangement. In addition, most crystals are elongated along the [111] direction, which is the easy axis of magnetization in magnetite, chemically pure and structurally perfect. These special characteristics allow magnetite crystal chains from MB to be recognized in environmental samples including old sedimentary rocks. Ferromagnetic resonance (FMR) has been proposed as a powerful and practical tool for screening large numbers of samples possibly containing magnetofossils. Indeed, several studies were recently published on FMR of cultured MB, mainly Magnetospirillum gryphiswaldense. In this work, we examined both uncultured magnetotactic cocci and the cultured MB M. gryphiswaldense using transmission electron microscopy (TEM) and FMR from 10 K to room temperature (RT). The TEM data supported the FMR spectral characteristics of our samples. The FMR spectra of both bacteria showed the intrinsic characteristics of magnetite produced by MB, such as extended absorption at the low field region of the spectra and a Verwey transition around 100 K. As previously observed, the spectra of M. gryphiswaldense isolated crystals were more symmetrical than the spectra obtained from whole cells, reflecting the loss of chain arrangement due to the small size and symmetrical shape of the crystals. However, the FMR spectra of magnetic crystals isolated from magnetotactic cocci were very similar to the FMR spectra of whole cells, because the chain arrangement was maintained due to the large size and prismatic shape of the crystals. Our data support the use of FMR spectra to detect magnetotactic bacteria and magnetofossils in samples of present and past environments. Furthermore, the spectra suggest the use of the temperature transition of spectral peak-to-peak intensity to obtain the Verwey temperature for these systems.