Origin matters: Using a local reference genome improves measures in population genomics.

Genome sequencing enables answering fundamental questions about the genetic basis of adaptation, population structure and epigenetic mechanisms. Yet, we usually need a suitable reference genome for mapping population-level resequencing data. In some model systems, multiple reference genomes are available, giving the challenging task of determining which reference genome best suits the data. Here, we compared the use of two different reference genomes for the three-spined stickleback (Gasterosteus aculeatus), one novel genome derived from a European gynogenetic individual and the published reference genome of a North American individual. Specifically, we investigated the impact of using a local reference versus one generated from a distinct lineage on several common population genomics analyses. Through mapping genome resequencing data of 60 sticklebacks from across Europe and North America, we demonstrate that genetic distance among samples and the reference genomes impacts downstream analyses. Using a local reference genome increased mapping efficiency and genotyping accuracy, effectively retaining more and better data. Despite comparable distributions of the metrics generated across the genome using SNP data (i.e. π, Tajima's D and FST ), window-based statistics using different references resulted in different outlier genes and enriched gene functions. A marker-based analysis of DNA methylation distributions had a comparably high overlap in outlier genes and functions, yet with distinct differences depending on the reference genome. Overall, our results highlight how using a local reference genome decreases reference bias to increase confidence in downstream analyses of the data. Such results have significant implications in all reference-genome-based population genomic analyses.

Multiple myeloma with t(11;14): impact of novel agents on outcome.

Multiple myeloma (MM) patients with t(11;14) present unique biological features and their prognosis is not well established. We report a retrospective study of 591 MM patients, 17.3% of whom had t(11;14). It was designed to determine the prognostic impact of this abnormality and the effect of novel agents on the response and outcomes. Three groups were established based on their cytogenetics: (1) t(11;14); (2) high-risk chromosomal abnormalities; and (3) standard risk (SR). After 80.1 months (1.2-273.8 months) of follow-up, no differences were observed in overall survival (OS) between the t(11;14) and SR groups (75.8 vs. 87.2 months; P = 0.438). Treatment of MM t(11;14) with novel agents did not improve their overall response rate (ORR) or complete response (CR) compared with those who received conventional therapy (ORR: 87.2 vs. 79.5%, P = 0.336; CR: 23.4 vs. 12.8%, P = 0.215). This effect translated into a similar PFS (39.6 vs. 30.0 months; P = 0.450) and OS (107.6 vs. 75.7 months; P = 0.175). In summary, MM t(11;14) patients did not benefit from the introduction of novel agents as much as SR patients did, indicating that other therapies are needed to improve their outcomes.

Relevance of infections on the outcomes of patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia treated with hypomethylating agents: a cohort study from the GESMD.

Background: The consequences of infectious toxicity of hypomethylating agents (HMAs) on overall survival (OS) of patients diagnosed with high-risk myeloid neoplasms have not been thoroughly investigated. Objectives: We aimed to evaluate whether infectious events (IEs) negatively influenced the results of HMA treatment in a real-world setting. Design: Observational study. Methods: We obtained data from 412 non-selected consecutive patients from 23 Spanish hospitals who were diagnosed with high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia and were treated with HMA. HMAs received after chemotherapy or stem cell transplant were excluded. All IEs were recorded. Outcomes included OS, modifications to the pre-planned treatment, incidence and characteristics of IEs, hospitalization, red blood cell transfusions, and factors associated with infection. Results: The rate of infection was 1.2 per patient/year. Next-cycle delay (p = 0.001) and hospitalizations (p = 0.001) were significantly influenced by IEs. Transfusion requirements during each cycle were significantly higher after infection compared with cycles without infection (coefficient = 1.55 [95% confidence interval (CI) = 1.26-1.84], p < 0.001). The median number of cycles was lower in patients experiencing any infection during the first four cycles (5 [3-8] versu 8 [5-16], p < 0.001). In the multivariable analysis, factors associated with lower OS were having any infection during the first four cycles (hazard ratio (HR) = 1.43 [95% CI = 1.09-1.88], p = 0.01), bone marrow blasts ⩾30% (HR = 2.13 [95% CI = 1.14-3.96], p = 0.01), adverse cytogenetics (HR = 1.70 [95% CI = 1.30-2.24], p < 0.001), and platelet count <50 × 109/l (HR = 1.69 [95% CI = 1.3-2.2], p < 0.001). BM blasts >20% (HR = 1.57 [95% CI = 1.19-2.01], p < 0.001) and adverse cytogenetics (HR = 1.7 [95% CI = 1.35-2.14], p < 0.001) were associated with infection, whereas hemoglobin >9 g/dl (HR = 0.65 [95% CI = 0.51-0.82], p < 0.001) and higher platelet count (HR = 0.997 [95% CI = 0.996-0.998], p = 0.016) protected from it. Conclusion: HMA infectious toxicity worsens OS, hinders the adherence to antineoplastic treatment and results in significant morbidity. Preventive strategies are fundamental in vulnerable patients.

Actividad física, condición física y calidad de vida en los adultos mayores. Revisión sistemática / Physical activity, physical condition and quality of life in older adults. Systematic review

Introducción: El envejecimiento de la población junto al sedentarismo, puede ocasionar un deterioro funcional que conduciría a la disminución de la condición física y de la calidad de vida. La promoción del envejecimiento activo puede mejorar la calidad de vida y la condición física de nuestros mayores. Objetivo: Evaluar la evidencia científica disponible sobre el efecto de la actividad física en los mayores, en términos de calidad de vida, condición física y mantenimiento de la independencia funcional. Material y método: Revisión sistemática en las bases de datos WOS, SCOPUS y PubMed. Selección de artículos: Se incluyeron estudios de intervención que evaluaban la calidad de vida y capacidad funcional de los adultos mayores. Los estudios fueron evaluados según la calidad metodológica con la escala PEDro. Resultados: Se encontraron 1331 artículos, de los que se incluyeron 17. Las intervenciones incluyeron ejercicios de resistencia, fuerza, equilibrio, coordinación y velocidad de la marcha. Los hallazgos principales indicaron que un mayor índice de actividad física se relacionó con un menor deterioro de las funciones físicas y cognitivas de los mayores y, por lo tanto, con una mejor calidad de vida. Conclusiones: Un estilo de vida activo se asocia a una mejor calidad de vida, mejor condición física y mantenimiento de la independencia funcional. Serían convenientes otros estudios, con una mayor homogeneidad en los instrumentos de recogida de datos, con mayor frecuencia de intervenciones, para definir los programas de ejercicios más adecuados y para incrementar la evidencia científica.(AU)

Background: The aging of the population together with sedentary lifestyle, can cause a functional deterioration that leads to the decrease of physical condition and quality of life. Promoting active aging can improve the quality of life and physical condition of our elders. Objective: This work aims to investigate the available scientific evidence on the effect of physical activity in older adults, in terms of quality of life, physical condition, and maintenance of functional independence. Material and method: A systematic review was performed in the WOS, SCOPUS and PubMed databases. Selection of articles: Intervention studies evaluating the quality of life and functional capacity of older adults were included. The studies were evaluated according to methodological quality with the PEDro scale. Results: 1331 articles were found, of which 17 were included. Interventions included resistance, strength, balance, coordination, and gait speed exercises. The main findings indicated that a higher rate of physical activity was associated with less impairment of physical and cognitive functions in older adults and, therefore, with a better quality of life. Conclusions: an active lifestyle is associated with a better quality of life, better physical condition and maintenance of functional independence. Other studies, with greater homogeneity in the data collection instruments, with greater frequency of interventions, would be convenient to define the most appropriate exercise programs and to increase the scientific evidence.(AU)

Accuracy of Virtually Planned Maxillary Distraction in Cleft Patients - An Evaluative Study.

INTRODUCTION: Maxillary distraction may be used to treat severe maxillary hypoplasia in cleft lip and palate (CLP) patients. Three-dimensional (3D) planning has been shown to increase the accuracy of distraction and reduce operative time and complications. The aim of the study was to measure the accuracy of internal maxillary distraction after 3D planning in CLP patients, to add evidence to validate the virtual osteotomy and distraction procedure. MATERIALS AND METHODS: Eleven CLP patients with severe maxillary hypoplasia underwent maxillary distraction using internal distractors. Virtual planning was used to design the osteotomies, the distractor position, and the distraction vector. Cutting and positioning guides transferred this information to the surgical procedure. Four to six month postoperative computed tomography-scan was done before distractor removal; anatomical reference points were compared to the virtual planning to determine accuracy. RESULTS: A high accuracy (point dislocation <1.5 mm) was found in 90% of the points of the surface of the maxilla; the majority of the zygomatic screws were placed within a distance of 0.8-1 mm from their planned position. DISCUSSION: The high accuracy achieved through virtual planning promotes optimal distractor placement; a customized distraction vector has a direct effect on the final position of the maxilla.

Patient General Condition at Diagnosis: A Systematic Evaluation for Adults Diagnosed with Hematologic Malignancies.

Several societies have published recommendations for evaluating older adults with cancer in standard conditions. It is vital to assure a proper systematic patient condition evaluation, not only in the oldest (geriatric assessment) but in all adult patients. We have investigated the feasibility of a systematic evaluation of the general condition of all patients diagnosed with hematologic malignancies, and the degree of acceptance by the clinical team, in a prospective cohort of 182 consecutive adults, by using the ECOG performance status scale (ECOG, age 18 and over, 18+), Lee Index for Older Adults (LEE, 50+), Geriatric Assessment in Hematology (GAH, 65+), and the Comprehensive Geriatric Assessment (CGA, 75+). Clinical team acceptance was analyzed with a visual analogue scale, and the objective feasibility was calculated as the proportion of patients that could be finally evaluated with each tool. Acceptance was high, but the objective feasibility was progressively lower as the complexity of the different tools increased (ECOG 100%, LEE 99.4%, GAH 93.2%, and CGA 67.9%). LEE and GAH categories showed a weak concordance (Cohen's Kappa 0.24) that was slight between LEE and CGA (Kappa 0.18). Unexpectedly, we found no significant association between the GAH and CGA categories (p = 0.16). We confirm that a systematic evaluation of all adult patients diagnosed with hematologic malignancies is feasible in daily practice by using an age-adapted approach. Direct comparisons among the different predictive tools in regard to patients' tolerance to treatments of different intensities must be a priority research subject in the coming years.

Reflexión sobre el screening de neoplasias en glomerulonefritis / Review on the screnning of cancer in glomerulonephritis

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¿Está indicada la prescripción de antibióticos en la extracción del tercer molar retenido?: estudio comparativo entre patrones de prescripción / Is it necessary to prescribe antibiotics in impacted third molar surgical removal?: comparative study between prescribing patterns

Objetivo. Valorar si existe una diferencia significativa en tasa de infección tras cirugía de extracción dentaria en dos hospitales de Noruega y España, donde se aplican protocolos de profilaxis quirúrgica diferentes. Material y Métodos. Se realizó un estudio observacional analítico, tipo cohortes retrospectivo, analizando pacientes sanos, sin factores de riesgo, operados de tercer molar incluido en los servicios de maxilofacial de dos hospitales diferentes: St. Olav de Trondheim (Noruega) y Clínico San Carlos de Madrid (España). Se recogieron las variables: edad, número de piezas extraídas, tipo de anestesia, y observaciones recogidas en la historia clínica sobre el curso de la operación. Para valorar el desarrollo infección postoperatoria se recogieron los datos de los pacientes que escogieron el hospital como lugar de retirada de los puntos en el Hospital St. Olav, y en el Hospital Clínico San Carlos se llevó a cabo una encuesta telefónica para conocer el curso de la operación meses después. Resultados. El 11,1% de los pacientes operados en el Hospital St. Olav recibió pauta antibiótica durante una semana tras la operación, mientras que en el Hospital Clínico San Carlos fue del 100%. La tasa de infección tras ésta fue del 15% en el Hospital de St. Olav y del 7,5% en el Hospital Clínico siendo estas diferencias no estadísticamente significativas. Conclusiones. La administración sistemática de antibiótico a pacientes sanos sin factores de riesgo sometidos a extracción quirúrgica del tercer molar retenido es una práctica rutinaria en clínica que no parece estar justificada (AU)

Objective. To assess whether there is a significant difference in infection rate after surgery tooth extraction in two different hospitals from Norway and Spain where different surgical antimicrobial prophylaxis protocols are applied. Methods. An analytical observational study was conducted, retrospective cohorts type, analyzing healthy patients with no risk factors, who were third molar tooth operated in maxillofacial services of two different hospitals: St. Olav in Trondheim (Norway) and Clínico San Carlos in Madrid (Spain). The collected variables were: age, number of tooth removed, anesthesia type, and observations about the course of the operation registered in the clinical history. To assess the development of postoperative infection, patient’s data of those who chose the hospital as the place to remove the suture thread were collected in Norway, whereas in Spain a telephone survey was conducted to determine the course of the operation months later. Results. In St. Olav Hospital 11.1% of patients operated received antibiotic regimen after surgery, while in Hospital San Carlos were 100%. The infection rate was 15% in St.Olav Hospital and 7.5% in Hospital San Carlos. These differences were no statistically significant. Conclusions. The routine administration of antibiotics to healthy patients with no risk factors undergoing impacted third molar surgical removal is a common clinical practice which it does not seem to be justified (AU)

Clinical, pathological, and immunohistochemical findings in bald eagles (Haliaeetus leucocephalus) and golden eagles (Aquila chrysaetos) naturally infected with West Nile virus.

Fifteen bald eagles (Haliaeetus leucocephalus) and 3 golden eagles (Aquila chrysaetos) were diagnosed with West Nile disease based on 1) presence of lesions in brain, eyes, and heart, 2) viral antigen detection in brain, eyes, heart, kidney, and/or liver by immunohistochemical staining, 3) detection of viral RNA in tissue samples and/or cerebrospinal fluid (CSF) by polymerase chain reaction, and/or 4) detection of West Nile virus (WNV)-specific antibodies in CSF by serum neutralization assay. West Nile virus-associated gross lesions included cerebral pan-necrosis with hydrocephalus ex vacuo (7/15 bald eagles), fibrin exudation into the fundus in 1 golden eagle, retinal scarring in 1 bald eagle, and myocardial pallor and rounded heart apex in 4 bald eagles. Histologic lesions included lymphoplasmacytic encephalitis, most prominently in the cerebrum (17 eagles), lymphoplasmacytic pectenitis and choroiditis (15 and 8 eagles, respectively), and myocarditis (12 eagles). West Nile virus antigen was detected in the majority of the eagles in neurons of the brain (cerebrum and cerebellum), and less commonly present in neurons of the retina, tubular epithelial cells of the kidney, and cardiomyocytes. West Nile disease was diagnosed in 2 bald eagles based on the presence of cerebral pan-necrosis and WNV-specific antibodies in the CSF despite lacking viral antigen and RNA. In conclusion, WNV infection causes a fatal disease in bald and golden eagles. A variety of gross and histologic lesions are highly suggestive of WN disease in most eagles. A combination of detection of viral antigen and/or RNA or virus-specific antibodies proved useful in confirming the diagnosis.

In vitro leukocyte response of three-spined sticklebacks (Gasterosteus aculeatus) to helminth parasite antigens.

Helminth parasites of teleost fish have evolved strategies to evade and manipulate the immune responses of their hosts. Responsiveness of fish host immunity to helminth antigens may therefore vary depending on the degree of host-parasite counter-adaptation. Generalist parasites, infective for a number of host species, might be unable to adapt optimally to the immune system of a certain host species, while specialist parasites might display high levels of adaptation to a particular host species. The degree of adaptations may further differ between sympatric and allopatric host-parasite combinations. Here, we test these hypotheses by in vitro exposure of head kidney leukocytes from three-spined sticklebacks (Gasterosteus aculeatus) to antigens from parasites with a broad fish host range (Diplostomum pseudospathaceum, Triaenophorus nodulosus), a specific fish parasite of cyprinids (Ligula intestinalis) and parasites highly specific only to a single fish species as second intermediate host (Schistocephalus pungitii, which does not infect G. aculeatus, and Schistocephalus solidus, infecting G. aculeatus). In vitro responses of stickleback leukocytes to S. solidus antigens from six European populations, with S. solidus prevalence from <1% to 66% were tested in a fully crossed experimental design. Leukocyte cultures were analysed by means of flow cytometry and a chemiluminescence assay to quantify respiratory burst activity. We detected decreasing magnitudes of in vitro responses to antigens from generalist to specialist parasites and among specialists, from parasites that do not infect G. aculeatus to a G. aculeatus-infecting species. Generalist parasites seem to maintain their ability to infect different host species at the costs of relatively higher immunogenicity compared to specialist parasites. In a comparison of sympatric and allopatric combinations of stickleback leukocytes and antigens from S. solidus, magnitudes of in vitro responses were dependent on the prevalence of the parasite in the population of origin, rather than on sympatry. Antigens from Norwegian (prevalence 30-50%) and Spanish (40-66%) S. solidus induced generally higher in vitro responses compared to S. solidus from two German (<1%) populations. Likewise, leukocytes from stickleback populations with a high S. solidus prevalence showed higher in vitro responses to S. solidus antigens compared to populations with low S. solidus prevalence. This suggests a rather low degree of local adaptation in S. solidus populations, which might be due to high gene flow among populations because of their extremely mobile final hosts, fish-eating birds.

Disseminated mite infection with ocular involvement in a juvenile bald eagle (Haliaeetus leucocephalus).

A bald eagle (Haliaeetus leucocephalus) was found unable to fly and was admitted to The Raptor Center (TRC). Major clinical signs were thin body condition and a cardiac arrhythmia. Ten days after admission to TRC, ophthalmic examination revealed multiple, distinct serpiginous lesions of chorioretinal atrophy in the ocular fundus of the right eye (OD). The bird was euthanized because of clinical deterioration and poor prognosis. Mites of an undetermined species were found histologically in the retina, episcleral tissues, lungs, and liver at the postmortem examination. Disseminated mite infection should be considered in the differential diagnosis of serpiginous chorioretinal lesions in bald eagles (H. leucocephalus).

Induction of diploid gynogenesis in an evolutionary model organism, the three-spined stickleback (Gasterosteus aculeatus).

BACKGROUND: Rapid advances in genomics have provided nearly complete genome sequences for many different species. However, no matter how the sequencing technology has improved, natural genetic polymorphism complicates the production of high quality reference genomes. To address this problem, researchers have tried using artificial modes of genome manipulation such as gynogenesis for fast production of inbred lines. RESULTS: Here, we present the first successful induction of diploid gynogenesis in an evolutionary model system, the three-spined sticklebacks (Gasterosteus aculeatus), using a combination of UV-irradiation of the sperm and heat shock (HS) of the resulting embryo to inhibit the second meiotic division. Optimal UV irradiation of the sperm was established by exposing stickleback sperm to a UV- light source at various times. Heat shock parameters like temperature, duration, and time of initiation were tested by subjecting eggs fertilized with UV inactivated sperm 5, 10, 15, 20, 25, or 30 minutes post fertilization (mpf) to 30°C, 34°C, or 38°C for 2, 4, 6 or 8 minutes. Gynogen yield was highest when stickleback eggs were activated with 2 minutes UV-irradiated sperm and received HS 5 mpf at 34°C for 4 minutes. CONCLUSIONS: Diploid gynogenesis has been successfully performed in three-spined stickleback. This has been confirmed by microsatellite DNA analysis which revealed exclusively maternal inheritance in all gynogenetic fry tested. Ploidy verification by flow cytometry showed that gynogenetic embryos/larvae exhibiting abnormalities were haploids and those that developed normally were diploids, i.e., double haploids that can be raised until adult size.

Mercury exposure and neurochemical impacts in bald eagles across several Great Lakes states.

In this study, we assessed mercury (Hg) exposure in several tissues (brain, liver, and breast and primary feathers) in bald eagles (Haliaeetus leucocephalus) collected from across five Great Lakes states (Iowa, Michigan, Minnesota, Ohio, and Wisconsin) between 2002-2010, and assessed relationships between brain Hg and neurochemical receptors (NMDA and GABA(A)) and enzymes (glutamine synthetase (GS) and glutamic acid decarboxylase (GAD)). Brain total Hg (THg) levels (dry weight basis) averaged 2.80 µg/g (range: 0.2-34.01), and levels were highest in Michigan birds. THg levels in liver (r(p) = 0.805) and breast feathers (r(p) = 0.611) significantly correlated with those in brain. Brain Hg was not associated with binding to the GABA(A) receptor. Brain THg and inorganic Hg (IHg) were significantly positively correlated with GS activity (THg r(p) = 0.190; IHg r(p) = 0.188) and negatively correlated with NMDA receptor levels (THg r(p) = -0245; IHg r(p) = -0.282), and IHg was negatively correlated with GAD activity (r(s) = -0.196). We also report upon Hg demethylation and relationships between Hg and Se in brain and liver. These results suggest that bald eagles in the Great Lakes region are exposed to Hg at levels capable of causing subclinical neurological damage, and that when tissue burdens are related to proposed avian thresholds approximately 14-27% of eagles studied here may be at risk.

Management of select bacterial and parasitic conditions of raptors.

Raptors are susceptible to a broad array of established and emerging bacterial and parasitic diseases, including babesiosis, chlamydiosis, clostridiosis, coccidiosis, cryptosporidiosis, malaria, mycobacteriosis, pasteurellosis, salmonellosis, trichomoniasis, and pododermatitis. Many of these conditions are opportunistic and can be easily managed or averted with proper preventive measures related to captive management, husbandry and diet, and veterinary care. Once infected, treatment must be prompt, appropriate, and judicious. This article examines the significance, diagnosis, management, and prevention of select bacterial and parasitic pathogens of raptors.