Do baseline participant characteristics impact the effectiveness of a mobile health intervention for depressive symptoms? A post-hoc subgroup analysis of the CONEMO trials.

OBJECTIVE: To ascertain whether sociodemographic and health-related characteristics known from previous research to have a substantive impact on recovery from depression modified the effect of a digital intervention designed to improve depressive symptoms (CONEMO). METHODS: The CONEMO study consisted of two randomized controlled trials, one conducted in Lima, Peru, and one in São Paulo, Brazil. As a secondary trial plan analysis, mixed logistic regression was used to explore interactions between the treatment arm and subgroups of interest defined by characteristics measured before randomization - suicidal ideation, race/color, age, gender, income, type of mobile phone, alcohol misuse, tobacco use, and diabetes/hypertension - in both trials. We estimated interaction effects between the treatment group and these subgroup factors for the secondary outcomes using linear mixed regression models. RESULTS: Increased effects of the CONEMO intervention on the primary outcome (reduction of at least 50% in depressive symptom scores at 3-month follow-up) were observed among older and wealthier participants in the Lima trial (p = 0.030 and p = 0.001, respectively). CONCLUSION: There was no evidence of such differential effects in São Paulo, and no evidence of impact of any other secondary outcomes in either trial. CLINICAL TRIAL REGISTRATION: NCT02846662 (São Paulo, Brazil - SP), NCT03026426 (Lima, Peru - LI).

Gender-Specific Fine Motor Skill Learning Is Impaired by Myelin-Targeted Neurofibromatosis Type 1 Gene Mutation.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. The clinical presentation of NF1 includes diverse neurological issues in pediatric and adult patients, ranging from learning disabilities, motor skill issues, and attention deficit disorder, to increased risk of depression and dementia. Preclinical research suggests that abnormal neuronal signaling mediates spatial learning and attention issues in NF1; however, drugs that improve phenotypes in models show inconclusive results in clinical trials, highlighting the need for a better understanding of NF1 pathophysiology and broader therapeutic options. Most NF1 patients show abnormalities in their brain white matter (WM) and myelin, and links with NF1 neuropathophysiology have been suggested; however, no current data can clearly support or refute this idea. We reported that myelin-targeted Nf1 mutation impacts oligodendrocyte signaling, myelin ultrastructure, WM connectivity, and sensory-motor behaviors in mice; however, any impact on learning and memory remains unknown. Here, we adapted a voluntary running test-the complex wheel (CW; a wheel with unevenly spaced rungs)-to delineate fine motor skill learning curves following induction of an Nf1 mutation in pre-existing myelinating cells (pNf1 mice). We found that pNf1 mutant females experience delayed or impaired learning in the CW, while proper learning in pNf1 males is predominantly disrupted; these phenotypes add complexity to the gender-dependent learning differences in the mouse strain used. No broad differences in memory of acquired CW skills were detected in any gender, but gene-dose effects were observed at the studied time points. Finally, nitric oxide signaling regulation differentially impacted learning in wild type (WT)/pNf1, male/female mice. Our results provide evidence for fine motor skill learning issues upon induction of an Nf1 mutation in mature myelinating cells. Together with previous connectivity, cellular, and molecular analyses, these results diversify the potential treatments for neurological issues in NF1.

Benefits of metabolic surgery on macrovascular outcomes in adult patients with type 2 diabetes: a systematic review and meta-analysis.

Type 2 diabetes (T2D) is a chronic metabolic disorder that affects millions of individuals associated with an increased risk of mortality and macrovascular complications. We aimed to synthesize the benefit of metabolic surgery (MS) on macrovascular outcomes in adult patients with T2D.We included both cohort studies and randomized controlled trials (RCTs) that evaluated MS added to medical therapy compared with medical therapy alone in the treatment of adult patients with T2D. Studies must have evaluated the incidence of any macrovascular complication of the disease for a period of at least 6 months. We performed our search using PubMed, Scopus, EMBASE, Web of Science, and COCHRANE Central database which was performed from inception date until March 2022. The trial protocol was previously registered at PROSPERO (CRD42021243739). A total of 6338 references were screened throughout the selection process from which 16 studies involving 179,246 participants fulfilled inclusion criteria. MS reduced the risk of any cardiovascular event by 44% (relative risk .56 [95% CI, .42-.75]; P = < .001), myocardial infarction by 54% (.46 [95% CI, .26-.83]; P = .009), coronary artery disease by 40% (.60 [95% CI, .42-.85]; P = .004) and heart failure by 71% (.29 [95% CI, .14-.61]; P = .001). It also provided a risk reduction of stroke by 29% (.71 [95% CI, .51-.99]; P = .04) and 38% (.62 [95% CI, .46-.85]; P = .001) for cerebrovascular events. On mortality, MS yields a risk reduction of 55% (.45 [95% CI, .36-.57]; P <.001) in overall mortality and 69% in cardiovascular mortality (relative risk .31 [95% CI, .22-.42]; P < .001). Peripheral vascular disease risk was also reduced. MS in adult patients with T2D can reduce the risk of mortality and of any macrovascular outcomes. However, there is a need for the planning of randomized clinical trials to further analyze and confirm the results.

Liraglutide modulates morpho-functional and inflammatory gastrointestinal responses in rats.

BACKGROUND: Obesity impairs homeostatic control of energy and is associated with chronic low-grade inflammation. Effects of glucagon-like peptide-1, the target in the gastrointestinal tract for anti-obesity drugs such as Liraglutide, were not properly associated with inflammation markers. This study investigated the effects of Liraglutide on metabolic and gastrointestinal parameters in a rat model of obesity. METHODS: Twenty-six Wistar rats with obesity were randomly distributed to receive saline (n = 10), 400 µg (n = 8), or 1200 µg of Liraglutide/kg/day (n = 8), subcutaneously for 30 consecutive days, once a day. Weight gain, feeding efficiency, caloric consumption, gastric motility, adiposity, histomorphometric, murinometric, biochemical parameters and cytokines TNF-α and TGF-ß1 in duodenal tissue were measured. Data were analysed by ANOVA, followed by Bonferroni post hoc or Kruskal-Wallis test, followed by Dunn's multiple comparison test. RESULTS: Liraglutide-treated animals had better feeding efficiency and higher caloric intake in a dose-dependent manner. Higher doses slowed gastric emptying and diminished the amplitude of gastric contractions. These effects were accompanied by decreases in intestinal muscle layer thickness and crypt depth. Liraglutide significantly reduced retroperitoneal and visceral white adipose tissue depots. High-dose treatment decreased levels of TNF-α and enhanced levels of TGF-ß1 in duodenal tissue. Liraglutide treatment provided significant reductions in total cholesterol, triglyceride and hepatic transaminases. CONCLUSIONS: Liraglutide reduced fat accumulation, improved metabolic parameters and downregulated levels of inflammatory signalling in duodenal tissue. Liraglutide at high doses controlled obesity-related outcomes, and such effects seemed to be driven by its action on glucagon-like peptide-1 receptors in the gastrointestinal tract slowing gastric motility.

Do baseline participant characteristics impact the effectiveness of a mobile health intervention for depressive symptoms? A post-hoc subgroup analysis of the CONEMO trials

Objective: To ascertain whether sociodemographic and health-related characteristics known from previous research to have a substantive impact on recovery from depression modified the effect of a digital intervention designed to improve depressive symptoms (CONEMO). Methods: The CONEMO study consisted of two randomized controlled trials, one conducted in Lima, Peru, and one in São Paulo, Brazil. As a secondary trial plan analysis, mixed logistic regression was used to explore interactions between the treatment arm and subgroups of interest defined by characteristics measured before randomization - suicidal ideation, race/color, age, gender, income, type of mobile phone, alcohol misuse, tobacco use, and diabetes/hypertension - in both trials. We estimated interaction effects between the treatment group and these subgroup factors for the secondary outcomes using linear mixed regression models. Results: Increased effects of the CONEMO intervention on the primary outcome (reduction of at least 50% in depressive symptom scores at 3-month follow-up) were observed among older and wealthier participants in the Lima trial (p = 0.030 and p = 0.001, respectively). Conclusion: There was no evidence of such differential effects in São Paulo, and no evidence of impact of any other secondary outcomes in either trial. Clinical trial registration: NCT02846662 (São Paulo, Brazil - SP), NCT03026426 (Lima, Peru - LI). Funded by the U.S. National Institute of Mental Health (grant U19MH098780).

The Role of Neurophysiology in Managing Patients with Chiari Malformations.

Chiari malformation type 1 (CM1) includes various congenital anomalies that share ectopia of the cerebellar tonsils lower than the foramen magnum, in some cases associated with syringomyelia or hydrocephalus. CM1 can cause dysfunction of the brainstem, spinal cord, and cranial nerves. This functional alteration of the nervous system can be detected by various modalities of neurophysiological tests, such as brainstem auditory evoked potentials, somatosensory evoked potentials, motor evoked potentials, electromyography and nerve conduction studies of the cranial nerves and spinal roots, as well as brainstem reflexes. The main goal of this study is to review the findings of multimodal neurophysiological examinations in published studies of patients with CM1 and their indication in the diagnosis, treatment, and follow-up of these patients, as well as their utility in intraoperative monitoring.

Intraoperative Neurophysiological Monitoring in Syringomyelia Surgery: A Multimodal Approach.

Syringomyelia can be associated with multiple etiologies. The treatment of the underlying causes is first-line therapy; however, a direct approach to the syrinx is accepted as rescue treatment. Any direct intervention on the syrinx requires a myelotomy, posing a significant risk of iatrogenic spinal cord (SC) injury. Intraoperative neurophysiological monitoring (IONM) is crucial to detect and prevent surgically induced damage in neural SC pathways. We retrospectively reviewed the perioperative and intraoperative neurophysiological data and perioperative neurological examinations in ten cases of syringomyelia surgery. All the monitored modalities remained stable throughout the surgery in six cases, correlating with no new postoperative neurological deficits. In two patients, significant transitory attenuation, or loss of motor evoked potentials (MEPs), were observed and recovered after a corrective surgical maneuver, with no new postoperative deficits. In two cases, a significant MEP decrement was noted, which lasted until the end of the surgery and was associated with postoperative weakness. A transitory train of neurotonic electromyography (EMG) discharges was reported in one case. The surgical plan was adjusted, and the patient showed no postoperative deficits. The dorsal nerve roots were stimulated and identified in the seven cases where the myelotomy was performed via the dorsal root entry zone. Dorsal column mapping guided the myelotomy entry zone in four of the cases. In conclusion, multimodal IONM is feasible and reliable and may help prevent iatrogenic SC injury during syringomyelia surgery.

Benefits of bariatric surgery on microvascular outcomes in adult patients with type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Microvascular diabetes complications impair patients' health-related quality of life. Bariatric surgery (BS) emerged as a compelling treatment that demonstrated to have beneficial effects on patients with diabetes and obesity. OBJECTIVE: We aimed to synthesize the benefit of bariatric surgery on microvascular outcomes in adult patients with type 2 diabetes. SETTING: 2011-2021. METHODS: We included both cohort studies and randomized trials that evaluated bariatric surgery added to medical therapy compared with medical therapy alone in the treatment of adult patients with type 2 diabetes. Studies must have evaluated the incidence of any microvascular complication of the disease for a period of at least 6 months. We performed our search using PubMed, Scopus, EMBASE, Web of Science, and COCHRANE Central database which was performed from inception date until March 2021. PROSPERO (CRD42021243739). RESULTS: A total of 25 studies (160,072 participants) were included. Pooled analysis revealed bariatric surgery to reduce the incidence of any stage of retinopathy by 71% (odds ratio [OR] .29; 95% confidence interval [CI] .10-.91), nephropathy incidence by 59% (OR .41; 95% CI 17-96), and hemodialysis/end-stage renal disease by 69% (OR .31 95% CI .20-.48). Neuropathy incidence revealed no difference between groups (OR .11; 95% CI .01-1.37). Bariatric surgery increased the odds of albuminuria regression by 15.15 (95% CI 5.96-38.52); higher odds of retinopathy regression were not observed (OR 3.73; 95% CI .29-47.71). There were no statistically significant differences between groups regarding the change in surrogate outcomes. CONCLUSIONS: Bariatric surgery in adult patients with diabetes reduced the odds of any stage of retinopathy, hemodialysis/end-stage renal disease, and nephropathy composite outcome. However, its effect on many individual outcomes, both surrogates, and clinically significant, remains uncertain.

RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit.

INTRODUCTION: Pathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system. METHODS: We recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed. RESULTS: Biallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients. CONCLUSION: Pathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.

Plasmonic Fluorescence Enhancement in Diagnostics for Clinical Tests at Point-of-Care: A Review of Recent Technologies.

Fluorescence-based biosensors have widely been used in the life-sciences and biomedical applications due to their low limit of detection and a diverse selection of fluorophores that enable simultaneous measurements of multiple biomarkers. Recent research effort has been made to implement fluorescent biosensors into the exploding field of point-of-care testing (POCT), which uses cost-effective strategies for rapid and affordable diagnostic testing. However, fluorescence-based assays often suffer from their feeble signal at low analyte concentrations, which often requires sophisticated, costly, and bulky instrumentation to maintain high detection sensitivity. Metal- and metal oxide-based nanostructures offer a simple solution to increase the output signal from fluorescent biosensors due to the generation of high field enhancements close to a metal or metal oxide surface, which has been shown to improve the excitation rate, quantum yield, photostability, and radiation pattern of fluorophores. This article provides an overview of existing biosensors that employ various strategies for fluorescence enhancement via nanostructures and have demonstrated the potential for use as POCT. Biosensors using nanostructures such as planar substrates, freestanding nanoparticles, and metal-dielectric-metal nanocavities are discussed with an emphasis placed on technologies that have shown promise towards POCT applications without the need for centralized laboratories.

Consumo colectivo de alcohol en jóvenes universitarios en Colombia: análisis desde una perspectiva etnográfica / Collective consumption of alcohol among young university students in Colombia: Analysis from an ethnographical perspective

Objetivo: reconocer los escenarios de consumo de alcohol como fenómeno colectivo, y las interrelaciones que se dan en estos espacios. Metodología: estudio cualitativo con enfoque etnográfico, realizado en dos etapas: cartografía y mapeo de lugares de consumo de alcohol y observación no participante, donde participaron jóvenes universitarios de ciencias de la salud. Se realizó análisis de contenido en ATLAS.Ti. Resultados: Emergieron 8 categorías: 1) Características del lugar de consumo 2) Motivaciones juveniles para beber, 3) Autonomía y autocontrol sobre el consumo, 4) Características del consumo, 5) Efectos del consumo de alcohol en el organismo, 6) Conocimiento de riesgo asociado al consumo, 7) Diferencias basadas en la división sexo-genérica,8) Rupturas por pandemia. Conclusión: Los sitios de consumo de alcohol usan la iluminación, muebles, pantallas, espectáculos, variedad de bebidas alcohólicas, diferentes formas de pago y estrategias de seguridad para atraer a los jóvenes. Las observadoras reportan que los jóvenes reconocen como motivos para consumir alcohol: las rupturas de pareja, desinhibirse, ser aceptados por el grupo, disfrutar con sus pares, eventos deportivos, celebraciones, liberar tensión provocada por responsabilidades académicas, laborales, familiares y sentimentales. Utilizan como mecanismos para enfrentar la presión social en los escenarios de consumo, el autocontrol y autoconocimiento, que les permiten establecer estrategias de cuidado antes, durante y después del consumo.(AU)

Objective: to recognize the scenarios of alcohol consumption as a collective phenomenon, and the interrelationships that occur in these spaces. Methodology: qualitative with an ethnographic approach, carried out in two stages: cartography and mapping of alcohol consumption study sites and non-participant observation, where young health sciences university students participated. A content analysis was performed in ATLAS.Ti. Results: Eight categories emerged: 1) Characteristics of the place of consumption, 2) Youth motivations to drink, 3) Autonomy and self-control over consumption, 4) Characteristics of consumption, 5) Effects of alcohol consumption on the body, 6) Knowledge of risk associated with consumption, 7) Differences based on the gender-sex division, 8) Pandemic ruptures. Conclusion: Consumption sites use lighting, furniture, screens, shows, a variety of alcoholic beverages, different forms of payment, and security strategies to attract young people. Observers report that young people recognize as reasons for consuming alcohol: breakups, loss of inhibition, being accepted by the group, enjoying with their peers, sporting events, celebrations, releasing tension caused by academic, work, family and sentimental responsibilities. They use self-control and self-knowledge as mechanisms to face social pressure in consumption scenarios, which allow them to establish care guidelines before, during and after consumption.(AU)

Genetic and environmental drivers of large-scale epigenetic variation in Thlaspi arvense.

Natural plant populations often harbour substantial heritable variation in DNA methylation. However, a thorough understanding of the genetic and environmental drivers of this epigenetic variation requires large-scale and high-resolution data, which currently exist only for a few model species. Here, we studied 207 lines of the annual weed Thlaspi arvense (field pennycress), collected across a large latitudinal gradient in Europe and propagated in a common environment. By screening for variation in DNA sequence and DNA methylation using whole-genome (bisulfite) sequencing, we found significant epigenetic population structure across Europe. Average levels of DNA methylation were strongly context-dependent, with highest DNA methylation in CG context, particularly in transposable elements and in intergenic regions. Residual DNA methylation variation within all contexts was associated with genetic variants, which often co-localized with annotated methylation machinery genes but also with new candidates. Variation in DNA methylation was also significantly associated with climate of origin, with methylation levels being lower in colder regions and in more variable climates. Finally, we used variance decomposition to assess genetic versus environmental associations with differentially methylated regions (DMRs). We found that while genetic variation was generally the strongest predictor of DMRs, the strength of environmental associations increased from CG to CHG and CHH, with climate-of-origin as the strongest predictor in about one third of the CHH DMRs. In summary, our data show that natural epigenetic variation in Thlaspi arvense is significantly associated with both DNA sequence and environment of origin, and that the relative importance of the two factors strongly depends on the sequence context of DNA methylation. T. arvense is an emerging biofuel and winter cover crop; our results may hence be relevant for breeding efforts and agricultural practices in the context of rapidly changing environmental conditions.

Reservoir-Style Polymeric Drug Delivery Systems: Empirical and Predictive Models for Implant Design.

Controlled drug delivery systems can provide sustained release profiles, favorable pharmacokinetics, and improved patient adherence. Here, a reservoir-style implant comprising a biodegradable polymer, poly(ε-caprolactone) (PCL), was developed to deliver drugs subcutaneously. This work addresses a key challenge when designing these implantable drug delivery systems, namely the accurate prediction of drug release profiles when using different formulations or form factors of the implant. The ability to model and predict the release behavior of drugs from an implant based on their physicochemical properties enables rational design and optimization without extensive and laborious in vitro testing. By leveraging experimental observations, we propose a mathematical model that predicts the empirical parameters describing the drug diffusion and partitioning processes based on the physicochemical properties of the drug. We demonstrate that the model enables an adequate fit predicting empirical parameters close to experimental values for various drugs. The model was further used to predict the release performance of new drug formulations from the implant, which aligned with experimental results for implants exhibiting zero-order release kinetics. Thus, the proposed empirical models provide useful tools to inform the implant design to achieve a target release profile.

Eosinophilic Ascites: An Infrequent Presentation of Eosinophilic Gastroenteritis.

Eosinophilic gastroenteritis (EGE) is an unusual and benign inflammatory disorder that mainly affects the digestive tract. Its main symptoms are cramp-like abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, and weight loss. Laboratory results show peripheral eosinophilia. This disease generally affects patients with a personal history of atopy and drug or food intolerance. The etiology remains unknown, the diagnosis is challenging, and the treatment depends on the severity of the disease and can range from supportive therapy to corticosteroid therapy. We report a case of a 24-year-old female known to have a history of iron deficiency anemia who was brought to the emergency department with an intense colicky abdominal pain, fatigue, diarrhea, and vomit right after a mild coronavirus disease 2019 (COVID-19) infection. The clinical investigation revealed moderate ascites identified in abdominal computed tomography (CT) scan, peripheral blood eosinophil count, and elevation of inflammatory parameters. An ultrasound-guided diagnostic paracentesis was performed, showing ascitic fluid with a clear predominance of eosinophils (57%). To confirm the diagnosis of EGE, an upper digestive endoscopy (UDE) was performed. The biopsies of the esophagus and gastric body revealed polymorphonuclear eosinophils and colonic mucosal biopsies revealed eosinophils (20 eosinophils per 10 fields). After reviewing the clinical history, we concluded that the patient was taking iron supplements due to her iron deficiency anemia, whose onset coincided with the symptoms presented. Exploring the clinical history a little more, the patient mentioned that in the past, she already had some intolerance to oral iron supplements, manifested by gastrointestinal symptoms, although milder. Approximately three weeks after suspending the supplements, we have seen an analytical improvement that was accompanied by clinical improvement. The patient was discharged with the resolution of abdominal pain.

Chromosome-level Thlaspi arvense genome provides new tools for translational research and for a newly domesticated cash cover crop of the cooler climates.

Thlaspi arvense (field pennycress) is being domesticated as a winter annual oilseed crop capable of improving ecosystems and intensifying agricultural productivity without increasing land use. It is a selfing diploid with a short life cycle and is amenable to genetic manipulations, making it an accessible field-based model species for genetics and epigenetics. The availability of a high-quality reference genome is vital for understanding pennycress physiology and for clarifying its evolutionary history within the Brassicaceae. Here, we present a chromosome-level genome assembly of var. MN106-Ref with improved gene annotation and use it to investigate gene structure differences between two accessions (MN108 and Spring32-10) that are highly amenable to genetic transformation. We describe non-coding RNAs, pseudogenes and transposable elements, and highlight tissue-specific expression and methylation patterns. Resequencing of forty wild accessions provided insights into genome-wide genetic variation, and QTL regions were identified for a seedling colour phenotype. Altogether, these data will serve as a tool for pennycress improvement in general and for translational research across the Brassicaceae.

Bone volume in the distal calcaneus correlates with body size but not leap frequency in galagids.

OBJECTIVES: Primate leap performance varies with body size, where performance will be optimized in lightweight individuals due to the inverse relationship between force generation and body mass. With all other factors equal, it is less energetically costly to swing a light hindlimb than a heavier hindlimb. Previous work on the calcaneus of galagids hypothesized that bone volume in leaping galagids may be minimized to decrease overall hindlimb mass. We predict that (1) lighter taxa will exhibit relatively less calcaneal bone volume than heavier taxa, and (2) taxa that are high-frequency leapers will exhibit relatively less bone volume than lower frequency leapers. MATERIALS AND METHODS: Relationships among bone volume, body size, and leap frequency (high vs. low) were examined in a sample of 51 individuals from four genera of galagids (Euoticus, Galago, Galagoides, and Otolemur) that differ in the percentage of time engaged in leaping locomotion. Using µCT scans of calcanei, we quantified relative bone volume (BV/TV) of the distal calcaneal segment and predicted that it would vary with body size and frequency of leaping locomotion. RESULTS: Phylogenetic generalized least squares (PGLS) regression models indicate that body size, but not leaping frequency, affects BV/TV in the distal calcaneus. Relative bone volume increases with body size, supporting our first hypothesis. DISCUSSION: These results support previous work demonstrating a positive correlation between BV/TV and body size. With some exceptions, small galagids tend to have less BV/TV than larger galagids. Leaping frequency does not relate to BV/TV in this sample; larger taxonomic and/or behavioral sampling may provide additional insights.

Cost-Utility Analysis of Eculizumab for the Treatment of Paroxysmal Nocturnal Hemoglobinuria From the Perspective of the Brazilian Public Health System.

OBJECTIVE: To perform a first cost-utility analysis of eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria from the perspective of the Brazilian Unified Health System. METHODS: A Markov decision model was developed for 35-year-old patients with symptomatic paroxysmal nocturnal hemoglobinuria. We used a cycle length of one month and a time horizon of 20 years. The effectiveness measure was the quality-adjusted life year (QALY). Data were extracted from clinical trials, historical cohorts, and Unified Health System databases. Resource use and costs were estimated from the perspective of the Unified Health System. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The estimated gain in effectiveness with the use of eculizumab was 1.08 QALY through the incremental cost of R$10,959,375.95. The incremental cost-effectiveness ratio was R$10,139,542.84 per QALY, being 331.92 times greater than the Brazilian gross domestic product per capita. In the deterministic sensitivity analysis, the parameters related to the utilities of health states were associated with greater impact in the model. The results of the probabilistic sensitivity analysis with 1000 simulations evidence that 100% of the simulations were not considered cost-effective with the arbitrated willingness to pay R$30,548.40 and R$91,645.20 per QALY. CONCLUSIONS: The gain in effectiveness with the use of eculizumab was modest, associated with an unjustifiable incremental cost. Therefore, eculizumab is not a cost-effective drug compared with the current standard of care in the treatment of paroxysmal nocturnal hemoglobinuria from the Brazilian Unified Health System perspective.

Epigenetics in plant organismic interactions.

Plants are hubs of organismic interactions. They constantly engage in beneficial or competitive interactions with fungi, oomycetes, bacteria, insects, nematodes, and other plants. To adjust the molecular processes necessary for the establishment and maintenance of beneficial interactions and for the defense against pathogens and herbivores, plants have evolved intricate regulatory mechanisms. Besides the canonical plant immune system that acts as the primary defense, epigenetic mechanisms have started to emerge as another regulatory entity and as a target of pathogens trying to overcome the plant's defenses. In this review, we highlight recent advances in understanding the contribution of various epigenetic components and of epigenetic diversity to plant-organismic interactions.