Obesity-Related Single-Nucleotide Polymorphisms and Weight Gain Following First-Line Antiretroviral Therapy.

BACKGROUND: We studied the association of obesity-related single-nucleotide polymorphisms (OR-SNPs) with weight gain after antiretroviral therapy (ART) in people with human immunodeficiency virus (HIV; PWH). METHODS: Participants were ART-naive PWH from the Spanish HIV Research Cohort who started ART from 2014 onward and had blood/DNA deposited in the cohort Biobank. The primary outcome was change in weight at 96 weeks after starting ART. We genotyped 14 OR-SNPs from a meta-analysis of genome-wide association studies of body mass index (BMI) loci. Changes over time in weight and BMI were studied using adjusted linear mixed models. RESULTS: A total of 1021 PWH were included. The mean weight gain over 96 weeks was 2.90 (95% confidence interval, 2.54-3.26) kg. Factors associated with higher weight gain were female sex, birth in sub-Saharan Africa, prior AIDS, CD4+ <200 cells/µL, HIV-RNA >100 000 copies/mL, negative hepatitis C virus serology, and use of tenofovir alafenamide. A significant association was found between ZC3H4 rs3810291 GG genotype and BCDIN3D/FAIM2 rs7138803 GG genotype polymorphisms and weight and BMI increase. The estimated adjusted mean (standard error [SE]) of weight gain was 4.26 (0.56) kg in ZC3H4 rs3810291 GG carriers and 2.66 (0.19) kg in AA/AG carriers (P = .007). Likewise the estimated weight gain at 96 weeks was 3.35 (0.29) kg in BCDIN3D/FAIM2 rs7138803 GG carriers and 2.51 (0.24) kg in AG/AA carriers (P = .020). CONCLUSIONS: Genetic factors may play a role in weight gain after ART initiation. Further work is needed to replicate our findings and understand how the identified SNPs lead to higher weight gain in this context.

"It wasn't me, check the cameras!" Suspects' apparent verifiable responses might not indicate innocence.

The verifiability of a suspect's alibi is often interpreted as a sign of innocence. Because the police resources are limited, verifiability could be used to dismiss suspects of minor offenses. We examined whether alibi verifiability actually indicates innocence for minor crimes. In Experiment 1, participants imagined they were guilty or innocent suspects of minor crimes and selected a response to convince the police of their innocence. Compared to innocent suspects, guilty suspects were more likely to select pseudo-verifiable responses (which seemed verifiable but were not) rather than non-verifiable responses. Experiment 2 revealed that pseudo-verifiable responses increased observers' perceptions of innocence (rather than guilt). Experiment 3 suggested that people infer the police will not verify alibis of minor crimes, which may lead people to invent pseudo-verifiable responses. These results indicate that apparent verifiability does not necessarily indicate innocence. The police should systematically test alternative hypotheses whenever they encounter apparent verifiable responses.

Estimation of gestational age in neonates using clavicular-pubis length on routine chest-abdomen radiographs.

BACKGROUND: Neonatal diseases differ depending on gestational age and weight. In the setting of an emergency in the neonatal intensive care unit (NICU), relevant clinical information is often not available when the first neonatal radiograph is obtained. When reading an initial chest-abdomen radiograph, the paediatric radiologist needs gestational age data for best radiologic practice. A transverse diameter of the chest has been previously described to estimate gestational age (GA). OBJECTIVES: To determine the strength of the correlation between GA/weight and clavicular-pubis length (CPL) on admission radiographs; to obtain a quadratic formula based on the correlation of CPL with GA and to demonstrate if a more simplified formula used by our group works as efficiently as the formula provided by the regression analysis. MATERIALS AND METHODS: A retrospective study was approved by the institutional review board and informed consent was waived. The length from the medial aspect of the clavicle to the pubic bone was measured on the initial portable chest-abdomen radiographs of 260 patients admitted to the NICU in 2016. Regression analysis was performed to investigate the association between CPL and GA/birth weight. RESULTS: One hundred eleven females and 149 males with GA between 23 and 42 weeks were evaluated. CPL was statistically associated with both GA (P<0,01) and birth weight. The estimation can be expressed with an equation of the model: GA (weeks) = (CPL in cm - 1.98)/0.42. A simplified formula: GA (weeks) = (CPL in cm) ×2+2, strongly correlates with the equation model. CONCLUSION: In patients in whom it is not known, GA can be estimated by measuring the length between medial clavicle and symphysis pubis using the formulae we propose.

Dealing with categorical data in a multidimensional context: The multidimensional balanced worth.

This paper presents an evaluation protocol that permits evaluating the relative performance of a set of populations in a multidimensional context when outcomes are measured in terms of categorical variables. This problem appears in many different fields, such as Medicine, Social Sciences, or Engineering. The key ingredient for this evaluation is comparing the likelihood of achieving higher performance levels in the different dimensions. This way of addressing this family of problems derives from extending the balanced worth (Herrero and Villar, 2018) to a multidimensional setting. This evaluation protocol is illustrated by means of two empirical applications regarding life satisfaction in Europe and multidimensional poverty measurement in Spain.

DALBACEN cohort: dalbavancin as consolidation therapy in patients with endocarditis and/or bloodstream infection produced by gram-positive cocci.

OBJECTIVES: To analyse the effectiveness of dalbavancin (DBV) in clinical practice as consolidation therapy in patients with bloodstream infection (BSI) and/or infective endocarditis (IE) produced by gram-positive cocci (GPC), as well as its safety and pharmacoeconomic impact. METHODS: A multicentre, observational and retrospective study was conducted of hospitalised patients with IE and/or BSI produced by GPC who received at least one dose of DBV. Clinical response was assessed during hospitalization, at 3 months and at 1 year. RESULTS: Eighty-three patients with median age of 73 years were enrolled; 73.5% were male; 59.04% had BSI and 49.04% IE (44.04% prosthetic valve IE, 32.4% native IE, 23.5% pacemaker lead). The most frequently isolated microorganism was Staphylococcus aureus in BSI (49%) and coagulase-negative staphylococci in IE (44.1%). All patients with IE were clinically cured in hospital; at 12 months, there was 2.9% loss to follow-up, 8.8% mortality unrelated to IE, and 2.9% therapeutic failure rate. The percentage effectiveness of DBV to treat IE was 96.7%. The clinical cure rate for BSI was 100% during hospital stay and at 3 months; there were no recurrences or deaths during the follow-up. No patient discontinued treatment for adverse events. The saving in hospital stay was 636 days for BSI (315,424.20€) and 557 days for IE (283,187.45€). CONCLUSIONS: DBV is an effective consolidation antibiotic therapy in clinically stabilized patients with IE and/or BSI. It proved to be a cost-effective treatment, reducing the hospital stay, thanks to the pharmacokinetic/pharmacodynamic profile of this drug.

Functional characterization of MODY2 mutations in the nuclear export signal of glucokinase.

Glucokinase (GCK) plays a key role in glucose homeostasis. Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Besides its particular kinetic characteristics, glucokinase is regulated by subcellular compartmentation in hepatocytes. Glucokinase regulatory protein (GKRP) binds to GCK, leading to enzyme inhibition and import into the nucleus at fasting. When glucose concentration increases, GCK-GKRP dissociates and GCK is exported to the cytosol due to a nuclear export signal (NES). With the aim to characterize the GCK-NES, we have functionally analysed nine MODY2 mutations located within the NES sequence. Recombinant GCK mutants showed reduced catalytic activity and, in most cases, protein instability. Most of the mutants interact normally with GKRP, although mutations L306R and L309P impair GCK nuclear import in cotransfected cells. We demonstrated that GCK-NES function depends on exportin 1. We further showed that none of the mutations fully inactivate the NES, with the exception of mutation L304P, which likely destabilizes its α-helicoidal structure. Finally, we found that residue Glu300 negatively modulates the NES activity, whereas other residues have the opposite effect, thus suggesting that some of the NES spacer residues contribute to the low affinity of the NES for exportin 1, which is required for its proper functioning. In conclusion, our results have provided functional and structural insights regarding the GCK-NES and contributed to a better knowledge of the molecular mechanisms involved in the nucleo-cytoplasmic shuttling of glucokinase. Impairment of this regulatory mechanism by some MODY2 mutations might contribute to the hyperglycaemia in the patients.

Experienced and novice officers' generalized communication suspicion and veracity judgments.

Deception detection research has shown that police officers are less truth-biased and make their veracity judgments with greater confidence than do nonofficers. Here we examined nonofficers, novice officers, and experienced officers' response bias, confidence, and generalized communicative suspicion. In Experiment 1, novice officers aligned with nonofficers in terms of both generalized communicative suspicion scores and confidence, with both these groups scoring lower than experienced officers. Generalized communicative suspicion scores and veracity judgments were not significantly related for either sample. However, novice officers aligned with experienced officers in terms of judgments: both police groups were lie-biased, whereas nonofficers were truth-biased. These findings suggest that unlike experienced officers, who have embraced the police culture to a greater degree, novice officers are not dispositionally suspicious (generalized communicative suspicion); however, they are able to mirror the prototypical police behavior (deception judgments) in police-related contexts. Experiment 2 supported these notions.

New trends in quantitative assessment of the corneal barrier function.

The cornea is a very particular tissue due to its transparency and its barrier function as it has to resist against the daily insults of the external environment. In addition, maintenance of this barrier function is of crucial importance to ensure a correct corneal homeostasis. Here, the corneal epithelial permeability has been assessed in vivo by means of non-invasive tetrapolar impedance measurements, taking advantage of the huge impact of the ion fluxes in the passive electrical properties of living tissues. This has been possible by using a flexible sensor based in SU-8 photoresist. In this work, a further analysis focused on the validation of the presented sensor is performed by monitoring the healing process of corneas that were previously wounded. The obtained impedance measurements have been compared with the damaged area observed in corneal fluorescein staining images. The successful results confirm the feasibility of this novel method, as it represents a more sensitive in vivo and non-invasive test to assess low alterations of the epithelial permeability. Then, it could be used as an excellent complement to the fluorescein staining image evaluation.

ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria.

Mutations in the uroporphyrinogen III synthase (UROS) gene cause congenital erythropoietic porphyria (CEP), an autosomal-recessive inborn error of erythroid heme biosynthesis. Clinical features of CEP include dermatologic and hematologic abnormalities of variable severity. The discovery of a new type of erythroid porphyria, X-linked dominant protoporphyria (XLDPP), which results from increased activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-controlling enzyme of erythroid heme synthesis, led us to hypothesize that the CEP phenotype may be modulated by sequence variations in the ALAS2 gene. We genotyped ALAS2 in 4 unrelated CEP patients exhibiting the same C73R/P248Q UROS genotype. The most severe of the CEP patients, a young girl, proved to be heterozygous for a novel ALAS2 mutation: c.1757 A > T in exon 11. This mutation is predicted to affect the highly conserved and penultimate C-terminal amino acid of ALAS2 (Y586). The rate of 5-aminolevulinate release from Y586F was significantly increased over that of wild-type ALAS2. The contribution of the ALAS2 gain-of-function mutation to the CEP phenotype underscores the importance of modifier genes underlying CEP. We propose that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders.

Uptake and delivery of antigens by mesenchymal stromal cells.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are multipotent stem cells with immunosuppressive properties. Nevertheless, it has been previously reported that MSCs might also trigger the immune response. We studied whether MSCs may act as carriers, capturing antigens that can be endocytosed by antigen-presenting cells later on. METHODS: We measured the cellular uptake of mannose receptor-mediated fluid phase macropinocytosis, assessed as cellular uptake of fluorescein isothiocyanate-dextran, and PKH-67-labeled cell lysates as a surrogate marker for antigen capture among dendritic cells (DCs, positive control), T lymphocytes (negative control) and MSCs. RESULTS: All experiments confirmed that MCSs displayed pinocytic and endocytic capacities, which were lower than those observed for DCs but significantly higher than those observed for T cells. We also demonstrated that MSCs release previously endocytosed antigens, which subsequently can be captured by DCs. CONCLUSIONS: MSCs have the ability to capture and release antigens.

Successful treatment of congenital erythropoietic porphyria using matched unrelated hematopoietic stem cell transplantation.

Congenital erythropoietic porphyria (CEP), or Günther's disease, is an inborn error of metabolism produced by a deficiency of uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthesis pathway. This enzymatic defect induces the accumulation of isomer I porphyrins in erythrocytes, skin, and tissues, producing various clinical manifestations. Severe cases are characterized by extreme photosensitivity, causing scarring and mutilations, and by hemolytic anemia, reducing life expectancy. CEP is caused by mutations in the UROS gene, and one of the most severe forms of the disease is associated with a cysteine to arginine substitution at residue 73 of the protein (C73R). CEP has been successfully treated only by the transplantation of hematopoietic precursors. We report the case of a male infant with severe postdelivery symptoms diagnosed with CEP and found to be homozygous for the C73R mutation. He underwent successful allogeneic bone marrow transplantation from a matched unrelated donor at 7 months of age. The hemolytic anemia was corrected and the porphyrin overproduction was significantly reduced. The patient remained asymptomatic after 1 year. This new case confirms that patients with severe CEP can benefit from early postnatal hematopoietic stem cell transplantation.

Diagnostic accuracy of imaging compared to histology in congenital lung malformations.

INTRODUCTION: The aim of this study was to evaluate the accuracy of imaging tests (prenatal ultrasound [US] and postnatal computed tomography [CT]) in comparison to histology for diagnosis of congenital lung malformations (CLMs). MATERIAL AND METHODS: Retrospective study of patients with a prenatal diagnosis of CLM whose postnatal follow-up included thoracic CT scan and histological examination of the lesion. We collected data on demographic variables, gestational age at diagnosis, US findings and the history of multiple gestation. We used the kappa coefficient to determine the level of agreement between the findings of prenatal US and postnatal tests (CT and histology).We analysed paired data on the size of the lesion, its location and the presence or absence of systemic arterial vascularization. RESULTS: The sample included 56 patients with 57 lesions. The mean gestational age at diagnosis was 22.42 weeks (SD, 3.94) and 57% were male. Malformations most frequently involved the left lung and the lower lobes. The agreement between CT and histology in the detection of cystic lesions was moderate (κ = 0.55) but stronger compared to the agreement between US and histology (κ = 0.10). The agreement between CT and histology was substantial (κ = 0.66) in the detection of systemic vascularization of the lesion and stronger compared to the agreement between US and histology. Both imaging methods were highly accurate in the identification of the location of the pulmonary lesions. CONCLUSIONS: postnatal CT offers a substantial concordance with histological findings, especially in the detection of systemic vascularization, and an accurate prediction of the anatomy of the lesion.

EN-DALBACEN 2.0 Cohort: real-life study of dalbavancin as sequential/consolidation therapy in patients with infective endocarditis due to Gram-positive cocci.

OBJECTIVES: Infective endocarditis (IE) has high mortality and morbidity and requires long hospital stays to deliver the antibiotic treatment recommended in clinical practice guidelines. We aimed to analyse the health outcomes of the use of dalbavancin (DBV) in the consolidation treatment of IEs caused by Gram-positive cocci and to perform a pharmacoeconomic study. MATERIALS AND METHODS: This observational, retrospective, Spanish multicentre study in patients with IE who received DBV as part of antibiotic treatment in consolidation phase were followed for at least 12 months. The study was approved by the Provincial Committee of the coordinating centre. RESULTS: The study included 124 subjects, 70.2% male, with a mean age of 67.4 years and median Charlson index of 4 (interquartile range: 2.5-6). Criteria for definite IE were met by 91.1%. Coagulase-negative staphylococci (38.8%), Staphylococcus aureus (22.6%), Enterococcus faecalis (19.4%), and Streptococcus Spp. (9.7%) were isolated more frequently, all susceptible to vancomycin. Before DVB administration, 91.2% had undergone surgery; 60.5% had received a second regimen for 24.5 d (16.6-56); and 20.2% had received a third regimen for 14.5 d (12-19.5). DBV was administered to facilitate discharge in 95.2% of cases. At 12 months, the effectiveness was of 95.9%, and there was 0.8% loss to follow-up, 0.8% IE-related death, and 3.2% relapse. Adverse events were recorded in 3.2%. The hospital stay was reduced by 14 d, and there was a mean savings of 5548.57 €/patient vs. conventional treatments. CONCLUSION: DBV is highly effective, safe, and cost-effective as consolidation therapy in patients with IE by Gram-positive cocci, with few adverse events.

Universal evaluation of MLC models in treatment planning systems based on a common set of dynamic tests.

PURPOSE: To demonstrate the feasibility of characterising MLCs and MLC models implemented in TPSs using a common set of dynamic beams. MATERIALS AND METHODS: A set of tests containing synchronous (SG) and asynchronous sweeping gaps (aSG) was distributed among twenty-five participating centres. Doses were measured with a Farmer-type ion chamber and computed in TPSs, which provided a dosimetric characterisation of the leaf tip, tongue-and-groove, and MLC transmission of each MLC, as well as an assessment of the MLC model in each TPS. Five MLC types and four TPSs were evaluated, covering the most frequent combinations used in radiotherapy departments. RESULTS: Measured differences within each MLC type were minimal, while large differences were found between MLC models implemented in clinical TPSs. This resulted in some concerning discrepancies, especially for the HD120 and Agility MLCs, for which differences between measured and calculated doses for some MLC-TPS combinations exceeded 10%. These large differences were particularly evident for small gap sizes (5 and 10 mm), as well as for larger gaps in the presence of tongue-and-groove effects. A much better agreement was found for the Millennium120 and Halcyon MLCs, differences being within ± 5% and ± 2.5%, respectively. CONCLUSIONS: The feasibility of using a common set of tests to assess MLC models in TPSs was demonstrated. Measurements within MLC types were very similar, but TPS dose calculations showed large variations. Standardisation of the MLC configuration in TPSs is necessary. The proposed procedure can be readily applied in radiotherapy departments and can be a valuable tool in IMRT and credentialing audits.

The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation.

BACKGROUND: We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reduce-graft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. DESIGN AND METHODS: We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. RESULTS: The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. CONCLUSIONS: The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.

Brainstem dysfunction in variegate porphyria.

INTRODUCTION: Variegate porphyria (VP) is a rare metabolic disorder that may present as an acute predominantly motor neuropathy. Cranial nerves and brainstem functions have been only scarcely studied. METHODS: Brainstem reflexes were examined in symptomatic and non-symptomatic VP mutation carriers of a single family. RESULTS: Similar results were found in the 2 patients with a history of porphyric crises. The blink reflex showed an absence of late responses (R2 and R2c) to stimulation of both sides. The masseter inhibitory reflex showed reduced inhibition of the second phase. The jaw jerk was normal. The asymptomatic carriers did not show any of the abnormalities just noted. CONCLUSIONS: Our results are compatible with a central lower pons-upper medulla disorder in the brainstem. We hypothesize that brainstem dysfunction in VP patients with a history of porphyric crises may be due to neurotoxic effects of porphyrin precursors as well as subclinical osmolarity changes due to hyponatremia.

Quality of life lost due to non-fatal road traffic injuries.

The objective of this paper is to evaluate the effect of a non-fatal road crash on the health-related quality of life of injured people. A new approach based on the cardinalization of categorical Self-Assessed Health valuations is suggested. Health losses have been estimated by using different Time Trade-off and Visual Analogue Scale tariffs, in order to assess the robustness of the results. The methodology is based on the existing literature about treatment effects. Our main contribution focuses on evaluating the loss of health up to 1 year after the non-fatal accident, for those who are non-institutionalized, which aids the appropriate estimation of the aggregated health losses in quality-of-life terms.

Deception detection from written accounts.

Most research into deception detection in written accounts has been conducted on transcripts instead of written messages, and has focused on identifying valid verbal deception correlates instead of also examining untrained readers' spontaneous lie-detection attempts (accuracy rates, the cues they use, and so on). Also, the question of whether good liars are also good detectors has not been examined using written accounts. In Study 1, 78 participants handwrote a story and then judged the veracity of another participant's story. Accuracy was at chance level. Good liars were not better detectors than poor liars, but participants who thought they were good liars also thought they were good detectors. The higher the participants' fluidity scores on a standardized test, the poorer liars they were and the better liars they thought they were. The cues participants said they used were related to their judgments but unrelated to actual veracity. In Study 2, some Linguistic Inquiry and Word Count (LIWC) categories (with the Spanish-language dictionary) permitted a 68% classification rate of the written accounts of Study 1.

Seven years of pig slurry fertilization: impacts on soil chemical properties and the element content of winter barley plants.

Intensive pig farming produces large amounts of slurry, which is applied to agricultural soils as fertilizer. A 7-year field study was performed to check the effect of pig slurry on soil properties and on the accumulation of some essential nutrients and heavy metals in a calcareous silty-loam soil (0-0.3 m) and in barley (Hordeum vulgare L.) plants in two cropping seasons with contrasting amounts of rainfall. Five fertilization treatments, control (no N applied), mineral fertilizer (90 kg N ha-1), and different N doses of pig slurry (146, 281, 534 kg N ha-1), were applied at sowing of a barley crop. Organic carbon, available P and K, and total P in soil increased with slurry dose. No differences were found in Co, Cr, Fe, Mn, Ni, and Pb soil concentrations. Slurries increased Cu, Mn, and Zn extractions and plant concentrations of P in straw and Zn in grain. However, the lowest slurry rate was able to maintain the highest grain yields while improving fertility. The results of this research study support the sustainability of pig slurry fertilization at appropriate rates in relation to soil chemical quality.