Functional dissection of complex and molecular trait variants at single nucleotide resolution.

Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics. The majority of these variants have individually weak effects and lie in non-coding gene-regulatory elements where we lack a complete understanding of how single nucleotide alterations modulate transcriptional processes to affect human phenotypes. To address this, we measured the activity of 221,412 trait-associated variants that had been statistically fine-mapped using a Massively Parallel Reporter Assay (MPRA) in 5 diverse cell-types. We show that MPRA is able to discriminate between likely causal variants and controls, identifying 12,025 regulatory variants with high precision. Although the effects of these variants largely agree with orthogonal measures of function, only 69% can plausibly be explained by the disruption of a known transcription factor (TF) binding motif. We dissect the mechanisms of 136 variants using saturation mutagenesis and assign impacted TFs for 91% of variants without a clear canonical mechanism. Finally, we provide evidence that epistasis is prevalent for variants in close proximity and identify multiple functional variants on the same haplotype at a small, but important, subset of trait-associated loci. Overall, our study provides a systematic functional characterization of likely causal common variants underlying complex and molecular human traits, enabling new insights into the regulatory grammar underlying disease risk.

Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome.

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than nondeployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the subjects in this cohort reported exposure to sulfur dioxide (SO2), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease. Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO2-exposed mice. SO2 exposure led to increased formation of isolevuglandins (isoLGs) adducts and superoxide dismutase 2 (SOD2) acetylation in endothelial cells, which were attenuated by treatment with the isoLG scavenger 2-hydroxybenzylamine acetate (2-HOBA). In addition, 2-HOBA treatment or Siruin-3 overexpression in a transgenic mouse model prevented vascular remodeling following SO2 exposure. In summary, our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress appears to mediate PV remodeling in this model. Together, these findings provide new insights regarding the critical mechanisms underlying PDRS.NEW & NOTEWORTHY We developed a mice model of "post-deployment respiratory syndrome" (PDRS), a condition in Veterans with unexplained exertional dyspnea. Our model successfully recapitulates many of the pathological and physiological features of the syndrome, revealing involvement of the ROS-isoLGs-Sirt3-SOD2 pathway in pulmonary vasculature pathology. Our study provides additional knowledge about effects and long-term consequences of sulfur dioxide exposure on the respiratory system, serving as a valuable tool for future PDRS research.

Gentamicincoated tibial nail is an effective prevention method for fracture-related infections in open tibial fractures.

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

Blocking of ebolavirus spread through intercellular connections by an MPER-specific antibody depends on BST2/tetherin.

Ebola virus (EBOV) and Bundibugyo virus (BDBV) belong to the family Filoviridae and cause a severe disease in humans. We previously isolated a large panel of monoclonal antibodies from B cells of human survivors from the 2007 Uganda BDBV outbreak, 16 survivors from the 2014 EBOV outbreak in the Democratic Republic of the Congo, and one survivor from the West African 2013-2016 EBOV epidemic. Here, we demonstrate that EBOV and BDBV are capable of spreading to neighboring cells through intercellular connections in a process that depends upon actin and T cell immunoglobulin and mucin 1 protein. We quantify spread through intercellular connections by immunofluorescence microscopy and flow cytometry. One of the antibodies, BDBV223, specific to the membrane-proximal external region, induces virus accumulation at the plasma membrane. The inhibiting activity of BDBV223 depends on BST2/tetherin.

Unraveling the Role of the Zinc-Dependent Metalloproteinase/HTH-Xre Toxin/Antitoxin (TA) System of Brucella abortus in the Oxidative Stress Response: Insights into the Stress Response and Virulence.

Toxin/antitoxin (TA) systems have been scarcely studied in Brucella abortus, the causative agent of brucellosis, which is one of the most prevalent zoonotic diseases worldwide. In this study, the roles of a putative type II TA system composed by a Zinc-dependent metalloproteinase (ZnMP) and a transcriptional regulator HTH-Xre were evaluated. The deletion of the open reading frame (ORF) BAB1_0270, coding for ZnMP, used to produce a mutant strain, allowed us to evaluate the survival and gene expression of B. abortus 2308 under oxidative conditions. Our results showed that the B. abortus mutant strain exhibited a significantly reduced capacity to survive under hydrogen peroxide-induced oxidative stress. Furthermore, this mutant strain showed a decreased expression of genes coding for catalase (katE), alkyl hydroperoxide reductase (ahpC) and transcriptional regulators (oxyR and oxyR-like), as well as genes involved in the general stress response, phyR and rpoE1, when compared to the wild-type strain. These findings suggest that this type II ZnMP/HTH-Xre TA system is required by B. abortus to resist oxidative stress. Additionally, previous evidence has demonstrated that this ZnMP also participates in the acidic stress resistance and virulence of B. abortus 2308. Therefore, we propose a hypothetical regulatory function for this ZnMP/HTH-Xre TA system, providing insight into the stress response and its potential roles in the pathogenesis of B. abortus.

Repetitive Sulfur Dioxide Exposure in Mice Models Post-Deployment Respiratory Syndrome.

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than non-deployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the deployers in this cohort reported exposure to sulfur dioxide (SO 2 ), we developed a model of repetitive exposure to SO 2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular disease (PVD). Although abnormalities in small airways were not sufficient to alter lung mechanics, PVD was associated with the development of pulmonary hypertension and reduced exercise tolerance in SO 2 exposed mice. Further, we used pharmacologic and genetic approaches to demonstrate a critical role for oxidative stress and isolevuglandins in mediating PVD in this model. In summary, our results indicate that repetitive SO 2 exposure recapitulates many aspects of PDRS and that oxidative stress may mediate PVD in this model, which may be helpful for future mechanistic studies examining the relationship between inhaled irritants, PVD, and PDRS.

Ebolavirus Species-Specific Interferon Antagonism Mediated by VP24.

Members of the Ebolavirus genus demonstrate a marked differences in pathogenicity in humans with Ebola (EBOV) being the most pathogenic, Bundibugyo (BDBV) less pathogenic, and Reston (RESTV) is not known to cause a disease in humans. The VP24 protein encoded by members of the Ebolavirus genus blocks type I interferon (IFN-I) signaling through interaction with host karyopherin alpha nuclear transporters, potentially contributing to virulence. Previously, we demonstrated that BDBV VP24 (bVP24) binds with lower affinities to karyopherin alpha proteins relative to EBOV VP24 (eVP24), and this correlated with a reduced inhibition in IFN-I signaling. We hypothesized that modification of eVP24-karyopherin alpha interface to make it similar to bVP24 would attenuate the ability to antagonize IFN-I response. We generated a panel of recombinant EBOVs containing single or combinations of point mutations in the eVP24-karyopherin alpha interface. Most of the viruses appeared to be attenuated in both IFN-I-competent 769-P and IFN-I-deficient Vero-E6 cells in the presence of IFNs. However, the R140A mutant grew at reduced levels even in the absence of IFNs in both cell lines, as well as in U3A STAT1 knockout cells. Both the R140A mutation and its combination with the N135A mutation greatly reduced the amounts of viral genomic RNA and mRNA suggesting that these mutations attenuate the virus in an IFN-I-independent attenuation. Additionally, we found that unlike eVP24, bVP24 does not inhibit interferon lambda 1 (IFN-λ1), interferon beta (IFN-ß), and ISG15, which potentially explains the lower pathogenicity of BDBV relative to EBOV. Thus, the VP24 residues binding karyopherin alpha attenuates the virus by IFN-I-dependent and independent mechanisms.

Symposium review: Fueling appetite: Nutrient metabolism and the control of feed intake.

Conceptual models developed over the past century describe 2 key constraints to feed intake (FI) of healthy animals: gut capacity and metabolic demand. Evidence that greater energy demands (e.g., greater milk production) drive a corresponding increase in caloric intake led to the dominant concept that animals "eat to energy requirements." Although this model provides reasonable initial estimates of FI, it lacks a proposed physiological basis for the control system, does not consider nutrient constraints beyond energy, and fails to explain differential energy intake responses to different fuels. To address these gaps, research has focused on mechanisms for sensing nutrient availability and providing feedback to hypothalamic centers that integrate signals to control feeding behavior. The elimination of FI response to certain nutrients by vagotomy suggests that peripheral tissues play a role in nutrient sensing. These findings and the central role of the liver in metabolic flux led to the development of the hepatic oxidation theory (HOT). According to the HOT, liver energy charge is the regulated variable that induces dietary intake changes and consequently affects whole-body energy balance. Evidence in support of HOT includes associations between hepatic energy charge and meal patterns, increased FI in response to phosphate trapping, and reduced FI in response to phosphate loading. In accordance with the HOT, infusion studies in dairy cattle have consistently demonstrated that providing fuels that either oxidize or stimulate oxidation in the liver decreases FI and energy intake to a greater extent than fuels that bypass the liver. Importantly, this holds true for glucose, which is readily oxidized by nerve cells, but is rarely taken up by the bovine liver. Although the brain integrates multiple signals including those related to gastric distention and illness, the HOT provides a physiological framework for understanding the dominant role the liver likely plays in sensing short-term energy status. Understanding this model provides insights into how to use or bypass the regulatory system to manage FI of animals.

SlS5H silencing reveals specific pathogen-triggered salicylic acid metabolism in tomato.

BACKGROUND: Salicylic acid (SA) is a major plant hormone that mediates the defence pathway against pathogens. SA accumulates in highly variable amounts depending on the plant-pathogen system, and several enzyme activities participate in the restoration of its levels. Gentisic acid (GA) is the product of the 5-hydroxylation of SA, which is catalysed by S5H, an enzyme activity regarded as a major player in SA homeostasis. GA accumulates at high levels in tomato plants infected by Citrus Exocortis Viroid (CEVd), and to a lesser extend upon Pseudomonas syringae DC3000 pv. tomato (Pst) infection. RESULTS: We have studied the induction of tomato SlS5H gene by different pathogens, and its expression correlates with the accumulation of GA. Transient over-expression of SlS5H in Nicotiana benthamiana confirmed that SA is processed by SlS5H in vivo. SlS5H-silenced tomato plants were generated, displaying a smaller size and early senescence, together with hypersusceptibility to the necrotrophic fungus Botrytis cinerea. In contrast, these transgenic lines exhibited an increased defence response and resistance to both CEVd and Pst infections. Alternative SA processing appears to occur for each specific pathogenic interaction to cope with SA levels. In SlS5H-silenced plants infected with CEVd, glycosylated SA was the most discriminant metabolite found. Instead, in Pst-infected transgenic plants, SA appeared to be rerouted to other phenolics such as feruloyldopamine, feruloylquinic acid, feruloylgalactarate and 2-hydroxyglutarate. CONCLUSION: Using SlS5H-silenced plants as a tool to unbalance SA levels, we have studied the re-routing of SA upon CEVd and Pst infections and found that, despite the common origin and role for SA in plant pathogenesis, there appear to be different pathogen-specific, alternate homeostasis pathways.

Assessing Remotely Piloted Aerial Systems in the characterization of rocky shores for oil spills environmental sensitivity mapping, northern São Paulo littoral, Brazil.

The Environmental Sensitivity Index (ESI) for oil spills was developed to assist coordinators to evaluate oil spill impact along shorelines and also to coordinate the allocation of resources during and after the incident, aiming to reduce environmental damage and consequences. Recently, Remotely Piloted Aerial Systems (RPAS) are being used in a wide range of areas, since they complement traditional remote sensing data (e.g., satellite images) and offer a rapidly, precise, detail and high-resolution images that fit well for environmental studies. Herein, the use of high-resolution RPAS images for ESI analysis of rocky shores in the Brazilian territory was performed. Using RPAS images, with their higher-resolution compared with ArcGIS Pro Basemap satellite images, increased the detailed of ESI analysis for oil spills, increasing the number of regions in the rocky shore that are more sensitive to oil spills. The RPAS images were able to decrease the number of areas that were less sensitive to oil spills, and increase areas that are more sensitive to oil spills. This increase is important, since they were not detected in the ESI analysis using conventional ArcGIS Pro Basemap satellite images. The RPAS images permit to delineate precisely rocky shores, improving ESI interpretation in rocky shores.

Seguimiento de graduados de la Carrera de Médico Especialista en cardiología de la Universidad de Buenos Aires. Experiencia del Hospital Cosme Argerich / Follow-up of Specialist in Cardiology Graduates at University of Buenos Aires. Cosme Argerich Hospital Experience

RESUMEN El seguimiento de los graduados en una carrera es un indicador de la calidad educativa de la misma. Su labor profesional y académica permite evaluar los resultados de los programas instituidos a largo plazo. Objetivo: Explorar la percepción de los egresados de la Carrera de Médico Especialista (CME) en cardiología de la Universidad de Buenos Aires (UBA) sede Hospital Argerich sobre la calidad de la formación recibida durante la carrera; conocer su inserción laboral en el mundo profesional, y la realización de subespecialidades. Material y métodos: Estudio descriptivo, de corte transversal, realizado del 1° al 31 de enero de 2020. Se diseñó una encuesta de opinión autoadministrada a través de surveymonkey.com. El universo encuestado fueron 28 egresados de 7 promociones consecutivas (año de admisión 2010-2016) de la Carrera de Médico Especialista (CME) en cardiología UBA-sede Argerich. Resultados: Del total de los egresados contestaron la encuesta 25 (89,2%). La edad promedio fue 34 años, sexo masculino 14 (56%). Se realizaron preguntas para la evaluación global, valoración de la actividad científica y académica en la Sede del Hospital, al igual que la valoración del Curso Bianual de Cardiología en la Sociedad Argentina de Cardiología. Las respuestas en su mayoría fueron favorables Los egresados continúan ejerciendo la profesión en un 100%, el 76% se perfeccionó en una subespecialidad. Conclusiones: Los egresados de la CME en cardiología sede Hospital Argerich perciben que su formación ha sido muy buena o excelente y ha contribuido a su desarrollo profesional de manera esencial. Toda la información recabada genera una fuente de información para retroalimentar y optimizar la enseñanza en la institución formadora.

ABSTRACT Background: Follow-up of graduates in a career is an indicator of educational quality, and their professional and academic work allows evaluating the results of long-term instituted programs Objective: The aim of this study was to explore the perception of graduates from the postgraduate specialist course (PSC) in cardiology at University of Buenos Aires (UBA) Hospital Argerich venue on the quality of training received, how they insert in the professional world, and their engagement in subspecialties. Methods: A descriptive, cross-sectional study was carried out from January 1 to 31, 2020. A self-administered opinion survey was designed using surveymonkey.com and submitted to 28 graduates of the PSC in cardiology UBA-Hospital Argerich, corresponding to 7 consecutive promotions (2010-2016 years of admission). Results: The survey was answered by 25 graduates (89.2%). Mean age was 34 years and 14 (56%) were men. The questions explored the global assessment, the evaluation of the scientific and academic activity at the hospital venue as well as that of the Argentine Society of Cardiology Biennial Course of Cardiology. Most of the answers were favorable. All the graduates continue practicing the profession and 76% have received advanced training in a subspecialty. Conclusions: Graduates from the PSC in cardiology at Hospital Argerich perceive that their training has been very good or excellent and has been essential for their professional development. All the data collected are a source of information to provide feedback and optimize teaching in the training institution.

Shoulder-specific rehabilitation combined with aerobic exercises versus solely shoulder-specific rehabilitation in patients with type 2 diabetes mellitus: study protocol for a randomized controlled superiority trial.

BACKGROUND: Musculoskeletal disorders are very common in patients with diabetes mellitus (DM). The upper limb is one of the regions that is most frequently affected generally presenting limited joint mobility, pain, and a decreased muscle strength. Most clinical trials with a focus on shoulder musculoskeletal rehabilitation are carried out in patients who do not present DM. Thus, the purpose of the present study is to compare the effects of two distinct treatment protocols (conventional shoulder musculoskeletal rehabilitation combined with aerobic exercises versus solely conventional shoulder musculoskeletal rehabilitation) on shoulder pain, function, strength, kinematics, and supraspinatus tendon thickness in patients with type 2 DM after 12 weeks of intervention and a subsequent follow-up at week 20. METHODS: A randomized controlled superiority trial will be conducted. Participants with a clinical diagnosis of type 2 DM of both sexes, age between 40 and 70 years, presenting shoulder pain will be randomly assigned to one of the following groups: (1) conventional shoulder musculoskeletal rehabilitation combined with aerobic exercises; (2) solely conventional shoulder musculoskeletal rehabilitation. All individuals will be evaluated before starting the treatment protocol (baseline) and at the end of treatment (post 12 weeks) and as a follow-up at 20 weeks. The shoulder function assessed by the SPADI (Shoulder Pain and Disability Index) questionnaire will be considered as primary outcome; the secondary outcome will be shoulder pain, measured with NPRS scales. Other outcomes will include range of motion, measured using a digital inclinometer; isometric shoulder muscle strength, measured using a manual muscle dynamometer; shoulder kinematics, measured using three-dimensional inertial units measurement; supraspinatus tendon thickness, measured using an ultrasound; AGE accumulation, using a skin autofluorescence measurement; and HbA1c (hemoglobin a1c), fasting glucose and lipid profile measured by a simple blood test. DISCUSSION: DM is a highly prevalent disease and a public health problem worldwide, and the upper extremity musculoskeletal disorders in DM are barely recognized and largely underestimated. In this way, it would be interesting to analyze if the combination of aerobic exercises with conventional musculoskeletal rehabilitation protocols could generate better results in the functionality, pain, mobility and an improvement in the biochemical aspects related to the hyperglycemia of these patients compared to solely the conventional musculoskeletal rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04817514. Registered on March 26, 2021.

Mucormicosis asociada a COVID-19: revisión de la literatura para odontólogos / COVID-19 associated mucormycosis: a literature review for dentists

La mucormicosis es una infección fúngica rara, con alta morbilidad y mortalidad. Se presenta principalmente en pa- cientes con diabetes mellitus no controlada, inmunocompro- metidos, con tratamiento crónicos con esteroides, entre otros. Actualmente, se cree que la pandemia de COVID-19 y los tratamientos con corticosteroides podrían estar implicados en el aumento de casos de esta micosis. Este hongo invade el sistema vascular, ocluyendo el flujo sanguíneo arterial y generando una rápida trombosis e isque- mia, lo que provoca la necrosis de los tejidos duros y blandos, con invasión rápida a los tejidos circundantes. Hay varias formas clínicas. En la cavidad bucal se presenta la variante rino-orbito-cerebral, que afecta el paladar en forma de lesión eritematosa o grisácea que puede progresar hacia la formación de una masa necrótica o ulceración con muy escaso sangrado de mucosa. Se manifiesta con síntomas típicos de una rinosinusitis con fiebre y dolor en las piezas dentarias superiores. El tratamiento consta de tres pilares fundamentales: el diagnóstico, un manejo adecuado de las comorbilidades y la combinación de las terapias antifúngica y quirúrgica. Desde el año 2020, la mucormicosis asociada a COVID-19 pasó a ser un evento de notificación obligatoria inmediata al Sistema Nacional de Vigilancia de la Salud (SNVS2.0) me- diante el Sistema Integrado de Información Sanitaria Argen- tina (SISA). Es importante destacar que se han reportado casos de mu- cormicosis luego de extracciones dentales; lo que impulsa a afianzar los conocimientos sobre esta enfermedad, extremar las medidas preventivas e incentivar el diagnóstico precoz en la atención odontológica, debido a la rapidez en la evolución de la patología (AU))

Mucormycosis is a rare fungal infection, with high mor- bidity and mortality. It occurs mainly in patients with uncon- trolled diabetes mellitus, immunocompromised, on chronic treatment with steroids, among others. Currently, it is believed that the COVID-19 pandemic and the corticosteroid treatments could be one of the causes of increased cases. This fungus invades the vascular system, occluding arteri- al blood flow and generating rapid thrombosis and ischemia, which causes necrosis of hard and soft tissues, with rapid in- vasion to the surrounding tissues. There are several clinical forms. In the oral cavity, the rhino-orbito-cerebral variant presents itself affecting the pal- ate in the form of an erythematous or grayish lesion that can progress towards the formation of a necrotic mass or ulcera- tion with very little mucosal bleeding. It manifests itself with typical symptoms of rhinosinusitis, with fever and pain in the upper teeth. The treatment consists of three fundamental pillars: diag- nosis, proper management of comorbidities and the combina- tion of antifungal and surgical therapies. Since 2020, COVID-19 associated mucormycosis became an event of mandatory immediate notification to the National Health Surveillance System (SNVS2.0,) through the Argentina Integrated Health Information System (SISA). It is important to emphasize that mucormycosis cases had been reported following tooth extractions, which drives to strengthen knowledge about this disease, extreme preventive measures and encourage early diagnosis in dental care, due to the speed of the evolution of the pathology (AU))

Essential oils loaded on polymeric nanoparticles: bioefficacy against economic and medical insect pests and risk evaluation on terrestrial and aquatic non-target organisms.

This paper introduces the lethal, sublethal, and ecotoxic effects of peppermint and palmarosa essential oils (EOs) and their polymeric nanoparticles (PNs). The physicochemical analyses indicated that peppermint PNs were polydisperse (PDI > 0.4) with sizes of 381 nm and loading efficiency (LE) of 70.3%, whereas palmarosa PNs were monodisperse (PDI < 0.25) with sizes of 191 nm and LE of 89.7%. EOs and their PNs were evaluated on the adults of rice weevil (Sitophilus oryzae L.) and cigarette beetle (Lasioderma serricorne F.) and the larvae of Culex pipiens pipiens Say. On S. oryzae and L. serricorne, PNs increased EOs' lethal activity, extended repellent effects for 84 h, and also modified behavioral variables during 24 h. Moreover, EOs and PNs generated toxic effects against C. pipiens pipiens. On the other hand, peppermint and palmarosa EOs and their PNs were not toxic to terrestrial non-target organisms, larvae of mealworm (Tenebrio molitor L.), and nymphs of orange-spotted cockroach (Blaptica dubia S.). In addition, PNs were slightly toxic to aquatic non-target organisms, such as brine shrimp (Artemia salina L.). Therefore, these results show that PNs are a novel and eco-friendly formulation to control insect pests.

Using self-etch adhesive agents with pit and fissure sealants. In vitro analysis of shear bond strength, adhesive remnant index and enamel etching patterns.

PURPOSE: The aim of this study was to evaluate in vitro, the shear bond strength (SBS) and adhesive remnant index (ARI) of pit and fissure sealants (PFS) after enamel conditioning with different new-generation self-etching (SE) agents; additionally, enamel etching patterns were assessed. METHODS: Healthy unerupted third molars surgically removed for therapeutic reasons (n = 25p/g), were randomly assigned to six groups. Conventional etching (CE) or SE was applied prior to pit and fissure sealants bonding. Enamel conditioned surfaces were evaluated by SEM at × 500, × 1000, and × 2000 magnification to determine etching patterns. Subsequently, 25 PFS blocks (3 × 2 × 1.5 mm) p/g were bonded to enamel surface. Samples were stored in water at 37 °C for 24 h, previous to SBS and ARI test. One-way ANOVA and Tamhane statistic tests were used for SBS; while Mann-Whitney U and Kruskal-Wallis were employed for ARI (p ≤ 0.05). RESULTS: For SBS test, CE_PFS_3M and SE1_PFS_Shofu groups showed the lowest values (8.74 ± 4.02 and 8.75 ± 3.90, respectively). The highest scores were observed in SE_PFS_Kuraray group (13.46 ± 5.83). Significant differences in SBS and ARI assessments were found. All experimental groups showed type 1 etching pattern. CONCLUSION: The etching pattern was less pronounced in self-etching groups, which showed an equal or superior in vitro performance compared to conventional etching agents. The clinical use of self-etching agents could be recommended before pit and fissure sealants application in new dental protocols. The best in vitro performance was observed when both applied materials, self-etching agent and pit and fissure sealant have 10-methacryloyloxydecyl dihydrogen phosphate in their chemical composition.

A new meta-module design for efficient reconfiguration of modular robots.

We propose a new meta-module design for two important classes of modular robots. The new meta-modules are three-dimensional, robust and compact, improving on the previously proposed ones. One of them applies to so-called edge-hinged modular robot units, such as M-TRAN, SuperBot, SMORES, UBot, PolyBot and CKBot, while the other one applies to so-called central-point-hinged modular robot units, which include Molecubes and Roombots. The new meta-modules use the rotational degrees of freedom of these two types of robot units in order to expand and contract, as to double or halve their length in each of the two directions of its three dimensions, therefore simulating the capabilities of Crystalline and Telecube robots. Furthermore, in the edge-hinged case we prove that the novel meta-module can also perform the scrunch, relax and transfer moves that are necessary in any tunneling-based reconfiguration algorithm for expanding/contracting modular robots such as Crystalline and Telecube. This implies that the use of meta-meta-modules is unnecessary, and that currently existing efficient reconfiguration algorithms can be applied to a much larger set of modular robots than initially intended. We also prove that the size of the new meta-modules is optimal and cannot be further reduced. SUPPLEMENTARY INFORMATION: The online version supplementary material available at 10.1007/s10514-021-09977-6.

Salivary gland extract from the deer tick, Ixodes scapularis, facilitates neuroinvasion by Powassan virus in BALB/c mice.

Powassan virus (POWV) is a neuroinvasive flavivirus transmitted to mammals by the bite of ixodid ticks. In this study, we sought to investigate the impact of tick salivary gland extract (SGE) on POWV neuroinvasion. BALB/c mice were footpad inoculated with either a high dose or a low dose of POWV, with and without Ixodes scapularis salivary gland extract. Brain and spinal cord were extracted daily, and immunohistochemical techniques were used for temporal tracking of POWV antigen. The temporal pattern of POWV staining showed a caudal to rostral spread of POWV in the brains of mice from both high dose infection groups. For the high dose infection groups, the presence of tick SGE did not influence the spread of POWV in the brain. Mice infected with the low dose of virus alone did not present POWV staining in the brain; however, in the presence of SGE, low dose infected mice presented scattered foci of POWV-infected cells throughout the brain. This study shows that tick SGE facilitates POWV neuroinvasion when mice are infected with the lower dose of POWV. We also found two patterns of central nervous system invasion that were directly influenced by the dose of POWV administered.

Rapidly progressive aortic stenosis treated with transcatheter aortic valve implantation in a patient with Fabry disease: a case report.

BACKGROUND: Fabry disease (FD) is a rare lysosomal storage disease, caused by mutations in the gene encoding the enzyme α-galactosidase A (α-Gal A). Cardiac involvement is one of the main causes of death and it is characterized by progressive concentric left ventricular hypertrophy (LVH), which in most cases is symmetric. Mild thickening of the left-sided valves is seen in as many as a quarter of patients. Severe aortic stenosis is an extremely rare disorder in FD. CASE SUMMARY: In this report, we describe the case of a 57-year-old male, who was diagnosed with a cardiac variant of FD 10 years ago. Since the patient had severe LVH, he was started on enzyme replacement therapy when he was 47 years old with an intravenous infusion of 0.2 mg/kg of agalsidase alpha every 14 days. The patient remained stable and asymptomatic for 9 years, until he presented with dyspnoea in New York Heart Association functional class II-III and severe aortic stenosis (aortic valve area: 0.97 cm2) together with severe systolic dysfunction [ejection fraction (EF): 29%]. Because of the patient's comorbidities and high surgical risk, he underwent successful transfemoral transcatheter aortic valve implantation (TAVI). At 2 months following TAVI, the patient was asymptomatic and, in spite of his Fabry cardiomyopathy, the EF had increased to 45%. DISCUSSION: To our knowledge, this is the first case in the literature to demonstrate a rapid progression of aortic stenosis with severe impairment of left ventricular function and worsening in functional class in a patient with FD, who following TAVI improved his EF, with disappearance of symptoms and ventricular arrhythmias.

5,926 hysterectomies: complications described by Clavien-Dindo classification.

Hysterectomy is the most common major gynaecological surgery. Due to its high volume, the analysis of its results is relevant. The objective of this study was to describe intraoperative complications and reoperations, for both benign and malignant causes, using the Clavien-Dindo classification (approved by local ethics committee, number 100220). Between 2000 and 2019, 5926 elective hysterectomies were performed, of which 90.2% were for benign aetiology and 9.8% for malignant causes. The abdominal route was 52.7%, vaginal 40.1% and laparoscopic 7.2%. Intraoperative complications and reoperations (grade III Clavien-Dindo) were 4% and 2.1%, respectively. Oncological surgery had significantly more intraoperative complications (10% vs. 3.4%) and reoperations (3.6% vs. 1.9%) than benign procedures. Noteworthy, intraoperative complications required a new operation in only 3.4% for malignant and 2.8% for benign surgery. Our data showed the relevance of detecting and rectifying intraoperative complications during surgery, which consequently leads to a lower reoperation rate, minimising postoperative morbidity and mortality for patients.Impact StatementWhat is already known on this subject? The surgical complications of hysterectomy, both intraoperative and postoperative, are extensively described. However, this information is not well systematised, in which elective and emergency surgery are mixed. In addition to the above, there are few documents comparing the results of hysterectomies due to benign versus malignant causes.What the results of this study add? Using the Clavien-Dindo classification, this study adds an organised description of intraoperative complications and reoperations of hysterectomy in the context of elective surgery. In addition, it provides information on the comparison between surgery for benign versus malignant causes, as well as information on intraoperative complications requiring a new operation.What the implications are of these findings for clinical practice and/or further research? These findings provide clear and orderly data about the risks of elective hysterectomy and showed the relevance of detecting and rectifying intraoperative complications during the procedure. This is useful for specialists to preoperatively identify the risks for each hysterectomy group and provide their patients with more detailed information during informed consent.

An Improved Approach to Automated Measurement of Body Condition Score in Dairy Cows Using a Three-Dimensional Camera System.

Body condition scoring is a valuable tool used to assess the changes in subcutaneous tissue reserves of dairy cows throughout the lactation resulting from changes to management or nutritional interventions. A subjective visual method is typically used to assign a body condition score (BCS) to a cow following a standardized scale, but this method is subject to operator bias and is labor intensive, limiting the number of animals that can be scored and frequency of measurement. An automated three-dimensional body condition scoring camera system is commercially available (DeLaval Body Condition Scoring, BCS DeLaval International AB, Tumba, Sweden), but the reliability of the BCS data for research applications is still unknown, as the system's sensitivity to change in BCS over time within cows has yet to be investigated. The objective of this study was to evaluate the suitability of an automated body condition scoring system for dairy cows for research applications as an alternative to visual body condition scoring. Thirty-two multiparous Holstein-Friesian cows (9 ± 6.8 days in milk) were body condition scored visually by three trained staff weekly and automatically twice each day by the camera for at least 7 consecutive weeks. Measurements were performed in early lactation, when the greatest differences in BCS of a cow over the lactation are normally present, and changes in BCS occur rapidly compared with later stages, allowing for detectable changes in a short timeframe by each method. Two data sets were obtained from the automatic body condition scoring camera: (1) raw daily BCS camera values and (2) a refined data set obtained from the raw daily BCS camera data by fitting a robust smooth loess function to identify and remove outliers. Agreement, precision, and sensitivity properties of the three data sets (visual, raw, and refined camera BCS) were compared in terms of the weekly average for each cow. Sensitivity was estimated as the ratio of response to precision, providing an objective performance criterion for independent comparison of methods. The camera body condition scoring method, using raw or refined camera data, performed better on this criterion compared with the visual method. Sensitivities of the raw BCS camera method, the refined BCS camera method, and the visual BCS method for changes in weekly mean score were 3.6, 6.2, and 1.7, respectively. To detect a change in BCS of an animal, assuming a decline of about 0.2 BCS (1-8 scale) per month, as was observed on average in this experiment, it would take around 44 days with the visual method, 21 days with the raw camera method, or 12 days with the refined camera method. This represents an increased capacity of both camera methods to detect changes in BCS over time compared with the visual method, which improved further when raw camera data were refined as per our proposed method. We recommend the use of the proposed refinement of the camera's daily BCS data for research applications.