Experimental capabilities for liquid jet samples at sub-MHz rates at the FXE Instrument at European XFEL.

The Femtosecond X-ray Experiments (FXE) instrument at the European X-ray Free-Electron Laser (EuXFEL) provides an optimized platform for investigations of ultrafast physical, chemical and biological processes. It operates in the energy range 4.7-20 keV accommodating flexible and versatile environments for a wide range of samples using diverse ultrafast X-ray spectroscopic, scattering and diffraction techniques. FXE is particularly suitable for experiments taking advantage of the sub-MHz repetition rates provided by the EuXFEL. In this paper a dedicated setup for studies on ultrafast biological and chemical dynamics in solution phase at sub-MHz rates at FXE is presented. Particular emphasis on the different liquid jet sample delivery options and their performance is given. Our portfolio of high-speed jets compatible with sub-MHz experiments includes cylindrical jets, gas dynamic virtual nozzles and flat jets. The capability to perform multi-color X-ray emission spectroscopy (XES) experiments is illustrated by a set of measurements using the dispersive X-ray spectrometer in von Hamos geometry. Static XES data collected using a multi-crystal scanning Johann-type spectrometer are also presented. A few examples of experimental results on ultrafast time-resolved X-ray emission spectroscopy and wide-angle X-ray scattering at sub-MHz pulse repetition rates are given.

A versatile chamber for x-ray scattering on liquid jets with sample recycling.

We introduce the setup of a versatile sample chamber for x-ray scattering experiments on liquids delivered by µ-jets. The simple implementation at x-ray light sources, adaptability to different nozzle types, and the availability of a microscope for observation of the jet flow allow for its broad application. In combination with an inbuilt recycling circle, a continuous flow operation is provided. Functionality of the system was demonstrated in a rheology study at PETRA III.

Drug Survival of IL-12/23, IL-17 and IL-23 Inhibitors for Psoriasis Treatment: A Retrospective Multi-Country, Multicentric Cohort Study.

BACKGROUND: Drug survival analysis of biologic agents in psoriasis is of extreme importance, as it allows not only the evaluation of objective clinical outcomes (such as effectiveness and safety) but also of factors that are associated with patients' adherence to treatment. The aim of this study was to evaluate and compare the drug survival of the most recent biologic agents approved for the treatment of moderate-to-severe psoriasis-ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and risankizumab-and to identify clinical predictors that can influence the drug survival of these drugs. METHODS: This retrospective multicentric cohort study from 16 dermatology centers in Portugal, Spain, Italy, Switzerland, Czech Republic, Canada, and the United States included patients that started IL-12/23, IL-17 (IL-17A and IL-17R) and IL-23 inhibitors for the treatment of psoriasis between January 1, 2012 and December 31, 2019. Survival analysis was performed using a Kaplan-Meier estimator, to obtain descriptive survival curves, and proportional hazard Cox regression models. RESULTS: A total of 3312 treatment courses (total patients: 3145) were included in the study; 1118 (33.8%) with an IL-12/23 inhibitor (ustekinumab), 1678 (50.7%) with an IL-17 inhibitor [911 (27.5%) on secukinumab, 651 (19.7%) on ixekizumab, 116 (3.5%) on brodalumab], and 516 (15.5%) with an IL-23 inhibitor [398 (12.0%) on guselkumab, 118 (3.5%) on risankizumab]. At 18 months, the cumulative probability of survival was 96.4% for risankizumab, 91.1% for guselkumab, 86.3% for brodalumab, 86.1% for ustekinumab, 82.0% for ixekizumab, and 79.9% for secukinumab. Using ustekinumab as reference, drug survival of guselkumab was higher (HR 0.609; 95% CI 0.418-0.887) and that of secukinumab was lower (HR 1.490; 95% CI 1.257-1.766). In the final multivariable model, secukinumab, female sex, higher BMI, and prior exposure to biologic agents significantly increased the risk of drug discontinuation, whereas risankizumab was protective. CONCLUSION: In this multinational cohort with 8439 patient-years of follow-up, the cumulative probability of drug survival for all drugs was >79% at 18 months. Prescribed biologic, female sex, higher BMI, and previous exposure to biologic agents were predictors of drug discontinuation. Drug survival of guselkumab and risankizumab was higher than that of ustekinumab, and secukinumab was lower.

Describing variability in pig genes involved in coronavirus infections for a One Health perspective in conservation of animal genetic resources.

Coronaviruses silently circulate in human and animal populations, causing mild to severe diseases. Therefore, livestock are important components of a "One Health" perspective aimed to control these viral infections. However, at present there is no example that considers pig genetic resources in this context. In this study, we investigated the variability of four genes (ACE2, ANPEP and DPP4 encoding for host receptors of the viral spike proteins and TMPRSS2 encoding for a host proteinase) in 23 European (19 autochthonous and three commercial breeds and one wild boar population) and two Asian Sus scrofa populations. A total of 2229 variants were identified in the four candidate genes: 26% of them were not previously described; 29 variants affected the protein sequence and might potentially interact with the infection mechanisms. The results coming from this work are a first step towards a "One Health" perspective that should consider conservation programs of pig genetic resources with twofold objectives: (i) genetic resources could be reservoirs of host gene variability useful to design selection programs to increase resistance to coronaviruses; (ii) the described variability in genes involved in coronavirus infections across many different pig populations might be part of a risk assessment including pig genetic resources.

Shear-induced ordering in liquid microjets seen by x-ray cross correlation analysis.

We applied shear to a silica nanoparticle dispersion in a microfluidic jet device and observed direction-dependent structure along and across the flow direction. The asymmetries of the diffraction patterns were evaluated by x-ray cross correlation analysis. For different Rayleigh nozzle sizes and shapes, we measured the decay of the shear-induced ordering after the cessation of the shear. At large tube sizes and small shear rates, the characteristic times of the decay become longer, but Péclet-weighted times do not scale linearly with Péclet numbers. By modeling particle distributions with the corresponding diffraction patterns and comparing measured shape asymmetry to simulations, we determined the variation of volume fraction over the azimuthal angle for the maximum ordered state in the jet.

Clinical Impact of Corrections to Infliximab and Adalimumab Monitoring Results with the Homogeneous Mobility Shift Assay.

An upward drift for both infliximab and adalimumab concentrations measured by the homogenous mobility shift assay (HMSA) was previously reported. We aimed to investigate the impact of this drift on clinical care of patients with inflammatory bowel disease. This was a retrospective, multicenter study. Providers reviewed the individual patient data and drug concentrations before and after the laboratory corrections and then documented whether a different clinical decision would have been made had the corrected drug concentration been originally reported. A multivariable Cox proportional hazards regression analysis was performed to investigate the association of a documented treatment change with treatment failure, defined as drug discontinuation for primary nonresponse, loss of response, or serious adverse event, adjusting for confounding factors. The study population consisted of 479 patients (infliximab, n = 219; adalimumab, n = 260). Upon review, 14.9% (71/479) patients would have had a different treatment decision made had the corrected drug concentration been initially reported. After a median follow-up of 10.6 months, 25.7% of patients (123/479) had treatment failure. A theoretical different clinical decision based on the corrected drug concentrations was not associated with treatment failure (adjusted hazard ratio (HR): 1.452; 95% confidence interval (CI): 0.805-2.618; p = 0.216), which was consistent for both infliximab (adjusted HR: 1.977; 95% CI: 0.695-5.627; p = 0.201) and adalimumab (adjusted HR: 1.484; 95% CI: 0.721-3.054; p = 0.284). The drift in infliximab and adalimumab concentrations in the HMSA assay affected treatment decisions in 15% of cases. However, this discrepancy was not associated with a higher cumulative probability for treatment failure.

Whole-genome sequencing of European autochthonous and commercial pig breeds allows the detection of signatures of selection for adaptation of genetic resources to different breeding and production systems.

BACKGROUND: Natural and artificial directional selection in cosmopolitan and autochthonous pig breeds and wild boars have shaped their genomes and resulted in a reservoir of animal genetic diversity. Signatures of selection are the result of these selection events that have contributed to the adaptation of breeds to different environments and production systems. In this study, we analysed the genome variability of 19 European autochthonous pig breeds (Alentejana, Bísara, Majorcan Black, Basque, Gascon, Apulo-Calabrese, Casertana, Cinta Senese, Mora Romagnola, Nero Siciliano, Sarda, Krskopolje pig, Black Slavonian, Turopolje, Moravka, Swallow-Bellied Mangalitsa, Schwäbisch-Hällisches Schwein, Lithuanian indigenous wattle and Lithuanian White old type) from nine countries, three European commercial breeds (Italian Large White, Italian Landrace and Italian Duroc), and European wild boars, by mining whole-genome sequencing data obtained by using a DNA-pool sequencing approach. Signatures of selection were identified by using a single-breed approach with two statistics [within-breed pooled heterozygosity (HP) and fixation index (FST)] and group-based FST approaches, which compare groups of breeds defined according to external traits and use/specialization/type. RESULTS: We detected more than 22 million single nucleotide polymorphisms (SNPs) across the 23 compared populations and identified 359 chromosome regions showing signatures of selection. These regions harbour genes that are already known or new genes that are under selection and relevant for the domestication process in this species, and that affect several morphological and physiological traits (e.g. coat colours and patterns, body size, number of vertebrae and teats, ear size and conformation, reproductive traits, growth and fat deposition traits). Wild boar related signatures of selection were detected across all the genome of several autochthonous breeds, which suggests that crossbreeding (accidental or deliberate) occurred with wild boars. CONCLUSIONS: Our findings provide a catalogue of genetic variants of many European pig populations and identify genome regions that can explain, at least in part, the phenotypic diversity of these genetic resources.

Hypokalemic Paralysis due to Primary Sjögren Syndrome: Case Report and Review of the Literature.

Tubulointerstitial nephritis (TIN) is the main renal involvement associated with primary Sjögren syndrome (pSS). TIN can manifest as distal renal tubular acidosis (RTA), nephrogenic diabetes insipidus, proximal tubular dysfunction, and others. We present a 31-year-old female with hypokalemic paralysis due to distal RTA (dRTA). She received symptomatic treatment and hydroxychloroquine with a good response. There is insufficient information on whether to perform a kidney biopsy in these patients or not. The evidence suggests that there is an inflammatory background and therefore a potential serious affection to these patients, such as hypokalemic paralysis. We found 52 cases of hypokalemic paralysis due to dRTA in pSS patients. The majority of those patients were treated only with symptomatic medication. Patients who received corticosteroids had stable evolution even though they did not have another symptomatology. With such heterogeneous information, prospective studies are needed to assess the value of adding corticosteroids as a standardized treatment of this manifestation.

A liquid jet setup for x-ray scattering experiments on complex liquids at free-electron laser sources.

In this paper we describe a setup for x-ray scattering experiments on complex fluids using a liquid jet. The setup supports Small and Wide Angle X-ray Scattering (SAXS/WAXS) geometries. The jet is formed by a gas-dynamic virtual nozzle (GDVN) allowing for diameters ranging between 1 µm and 20 µm at a jet length of several hundred µm. To control jet properties such as jet length, diameter, or flow rate, the instrument is equipped with several diagnostic tools. Three microscopes are installed to quantify jet dimensions and stability in situ. The setup has been used at several beamlines performing both SAXS and WAXS experiments. As a typical example we show an experiment on a colloidal dispersion in a liquid jet at the X-ray Correlation Spectroscopy instrument at the Linac Coherent Light Source free-electron laser.

Warm-Season (C4) Turfgrass Genotypes Resistant to Spittlebugs (Hemiptera: Cercopidae).

Screening for resistance to insect pests is one of the early stages of grass breeding programs. Pasture spittlebugs are sap-sucking insects that potentially cause severe damage to turfgrasses, including the loss of functional quality and perenniallity. The Brazilian flora has a large number of grass species with wide morphological variability and adaptability to different soil and climate conditions that can potentially be used as lawns. However, no study has screened turfgrass genotypes for resistance to spittlebug attack. In this study, we evaluated the intra- and interspecific variability of 35 turfgrass genotypes in the genera Paspalum, Axonopus, and Zoysia for resistance to the pasture spittlebugs, Deois flavopicta (Stal) and Notozulia entreriana (Berg) (Hemiptera: Cercopidae), as measured by damage scores, densities of nymphs and adults, and level of antibiosis resistance. Genotypes were grouped into three groups using cluster analysis and principal component analysis: GroupI had genotypes associated with low damage scores and high density of adult spittlebugs; GroupII had genotypes with intermediate damage scores and low density of nymphs and adults; and GroupIII was formed by genotypes with high damage scores and high nymph density. Intra- and interspecific genotypic variability was related to antibiosis resistance and morphological variation among genotypes with some indicating nonpreference resistance and others indicating tolerance resistance. Our results indicate that besides antibiosis resistance studies, it is essential to evaluate the morphological variability of grass genotypes when screening for resistance to insects. Further studies are needed to elucidate the intraspecific variability of Paspalum notatum Flüggé genotypes for resistance to spittlebug attack.

Melanoma subungueal de la mano: reporte de un caso / Hand’s subungueal melanoma: A case report

El melanoma es considerado una neoplasia melanocítica maligna; la localización subungueal corresponde al 0.7-3.5% de todos los melanomas. Clínicamente se presenta como una melanoniquia en general asintomática. Comunicamos un paciente masculino de 67 años, que consulta por presentar melanoniquia estriada en el cuarto dedo de la mano izquierda. El estudio histopatológico de biopsia informa un melanoma acral, por lo que se procede a realizar resección completa de la lesión con amputación de la falange distal; el paciente evolucionó satisfactoriamente. Este melanoma se origina de la matriz ungular, aunque se ha propuesto la asociación con traumas, su etiología no está clara. Histológicamente, se caracteriza por una proliferación de melanocitos atípicos o fusiformes, con grados variables de invasión; algunas lesiones son pigmentadas y otras amelanóticas. Se debe establecer el diagnóstico diferencial con: hematomas, osteomielitis, onicomicosis, granuloma piógeno, paroniquia, enfermedad de Kaposi, carcinoma espinocelular, entre otras. Algunos factores pronósticos incluyen profundidad de invasión, índice mitótico, ulceración, índice de proliferación con Ki 67 para nombrar solo algunos factores del denominado “histopronóstico”. El retraso en el diagnóstico del melanoma subungueal condiciona un mal pronóstico. El tratamiento apunta hacia la intervención quirúrgica en estadios tempranos, con evaluación del ganglio centinela (esto varía según la escuela académica). Sin embargo, actualmente se hace referencia a nuevos fármacos, que modifican la respuesta inmune o que intervienen en el metabolismo celular, con lo que se dan los primeros pasos para modificar la historia natural de esta enfermedad.

Introduction: melanoma is considered a biologically aggressive neoplasm. It’s more common in the 6th decade. Subungual melanoma corresponding to 0.7-3.5% of all melanomas. The most common locations are hallux, thumb, index and ring. Clinically, it presents as an asymptomatic melanonychia. Case Report: male aged 67 who consulted for striated melanonychia fourth finger left hand. Biopsy histopathological study reports malignant melanoma. Complete resection of the lesion was performed with amputation of distal phalanx. Patient evolves satisfactorily. Discussion: this melanoma originates from the nail matrix. Although it has been proposed partnership with traumas, its etiology is unclear. Hasn’t been able to establish an association with race, skin type and sun exposure, as in other melanoma’s types. Histologically it is characterized by a proliferation of atypical melanocytes or fusiform with varying degrees of invasion. Some injuries are pigmented and others may be amelanotic. Should be established the differential diagnosis with hematomas, osteomyelitis, onychomycosis, pyogenic granuloma, paronychia, among other injuries. Some prognostic factors include depth of invasion, mitotic rat, ulceration, proliferation index among others. The delay in diagnosis of subungual melanoma determines a poor prognosis. The treatment aims to surgery in early stages, with evaluation of sentinel node. But now referred to new drugs that modify the immune response or that involve its cellular metabolism thus taking the first steps to modify the natural history of this disease.

Increased detection of latent tuberculosis by tuberculin skin test and booster phenomenon in early rheumatoid arthritis patients.

The incidence of tuberculosis (TB) in rheumatoid arthritis (RA) patients is up to four times higher when compared to the general population, but their risk increases with the use of TNF-a drugs. Appropriate screening of latent tuberculosis infection (LTBI) and proper management of such cases substantially reduce the incidence of active TB. Tuberculin skin test (TST) is a widely used method for the detection of LTBI. The time of diagnosis of RA as well as the age of the patient might modify the TST performance. We did an observational, comparative study of RA patients with early and established disease, with the objective to know the prevalence of LTBI using the TST and booster test; an induration ≥5 mm was considered reactive. We evaluated 143 patients (83 [58 %] early RA patients). We found 31.3 and 21.7 % TST positivity in early and established RA patients, respectively. With the use of booster test, the positivity increased to 46.5 and 28.8 %, respectively (p = 0.048, OR 1.33, 95 % CI 1.01-1.75). In conclusion, we found that TST and booster test increased LTBI detection in early RA patients, which may suggest that time of RA diagnosis might affect cellular immunity and therefore the TST response.

The first assess of the haplotypes from COI gene sequences in species of spittlebugs (Cicadomorpha: Hemiptera) and aquatic true bugs (Gerromorpha and Nepomorpha: Hemiptera) in Brazil.

We made the first analysis of the COI gene sequences of 22 species of spittlebugs and aquatic true bugs sampled in São Paulo State (Brazil) and used this information to determine the variability within these groups. Considering each codon position, we observed that the third base was the most variable, and the first base was the most conserved. Among species, Mahanarva fimbriolata and Deois flavopicta had the greatest genetic distance (0.181), and Notozulia entreriana and Mahanarva sp had the smallest distance (0.055), with an average variation of 0.119. In Gerromorpha, the greatest distance occurred between Halobatopsis platensis and Rhagovelia zela (0.401), while between Cylindrostethus palmaris and Brachymetra albinervis albinervis, the distance was only 0.187; the average value observed for the Gerromorpha was 0.265. In the Nepomorpha, the species Buenoa antigone antigone and Belostoma micantulum had the greatest genetic distance (0.337), while Martarega brasiliensis and B. a. antigone had the smallest (0.154). The average value observed for Nepomorpha was 0.203. In Cicadomorpha (Auchenorrhyncha) and Nepomorpha (Heteroptera), the COI gene has been conserved; however, it is still useful for characterization of the different taxa. COI analysis was unable to resolve some of the Gerromorpha groups.

Ethical implications of neuroimaging in sports concussion.

The Centers for Disease Control and Prevention estimates that 1.6 to 3.8 million traumatic brain injuries that occur each year are related to sports injuries. New research has broadened the understanding of the acute and chronic pathophysiology of concussion associated with brain injury, and recent advances in diagnostic capabilities with neuroimaging are leading to new ethical questions around sport and care of the head-injured athlete. In this review, we synthesize the current literature on neuroimaging for assessing concussed athletes and explore ethical issues in the context of return to play, short- and long-term neurologic health effects following concussion and resource allocation that are emerging with new implications as neurotechnology becomes an increasingly powerful tool on the playing field of health.

Ameloblastic fibro-odontosarcoma: a case report.

This paper reports one case, of an ameloblastic fibro-odontosarcoma (AFOS) affecting the mandible, in a 12-year-old girl. This neoplasm is a rare odontogenic neoplasm. To the authors' knowledge this is the fifteenth case of AFOS reported in English. The patient's chief complaint was a swelling in the face for 6 months. An incisional biopsy was performed diagnosing the case as an ameloblastic fibroma. After radiography ameloblastic fibro-odontoma was diagnosed. Computed tomography was performed and a stereolithography model made to plan the surgical procedures. A hemimandibulectomy followed by a vascularized fibular flap was then proposed. The surgery was uneventful. Microscopic features diagnosed an AFOS. After 23 months of close follow-up there is no sign of recurrence or metastasis. Dental implants were recently placed in the fibular flap.

Treatment of locally aggressive well-differentiated thyroid cancer.

The object of this study, conducted at Unicamp between 1988 and 1998, was to evaluate retrospectively the outcome of patients treated for locally aggressive well-differentiated thyroid carcinomas (LATC). Nineteen (42%) of 45 patients with thyroid carcinomas were considered to have LATC. The preoperative diagnosis of carcinoma was made either by fine needle aspiration biopsy (15 patients) or during surgery (4 patients). The usual prognostic factors were analyzed and classified according to risk groups. Survival was evaluated using the Kaplan-Meier method. Most of the patients were female (73%), with a mean age of 48 years. Eighteen (95%) had papillary carcinomas. Four patients were classified as high risk (21%) and the remaining 15 (79%) as intermediate risk. All patients underwent total thyroidectomy and different types of neck dissections. The structures invaded by tumors were strap muscles and trachea (four cases); recurrent nerve and larynx (three cases); manubrium, esophagus, and jugular vein (two cases); and hyoid bone and pharynx (one case). Complete tumor resection was carried out according to the extent of local invasion; no postoperative deaths resulted. Details of the procedures are provided in Table 4 and in the Discussion. Postoperative radioactive iodine treatment was used in 15 patients (79%). A mean follow-up (+/-7 years) revealed 13 (68%) patients without disease, 4 patients (21%) alive with controlled systemic disease, and 2 (11%) deaths from distant metastasis. The Kaplan-Meir survival curve was comparable with other studies in the literature. This study found that the frequency of LATC (42%) was higher than in most studies. Aggressive surgical therapy to treat these tumors is compatible with a low recurrence rate and long-term survival in a significant proportion of patients.

Diagnosis of superficial esophageal cancer and dysplasia using endoscopic screening with a 2% lugol dye solution in patients with head and neck cancer.

BACKGROUND: Head and neck cancer (HNC) has a high incidence in Brazil, with cancer of the oral cavity being one of the five most common cancers among Brazilians. Alcohol and tobacco consumption may contribute to synchronous or metachronous HNC and esophageal cancer. The early detection of superficial esophageal cancer and dysplasia in asymptomatic patients with HNC, after successfully treating the primary cancer, may provide an effective cure. METHODS: A prospective study involving 60 patients with HNC was carried out at the State University of Campinas (UNICAMP) to screen for superficial esophageal cancer and dysplasia using endoscopy and a 2% lugol dye solution followed by biopsy of the suspicious areas. RESULTS: Five patients (8.3%) had superficial esophageal cancer, which was diagnosed as intraepithelial carcinoma in three of them (5.0%). In four patients, the superficial esophageal cancer was synchronous, and in one it was metachronous to HNC. Five patients (8.3%) had dysplasias in the esophageal epithelium (three were classified as mild and two as moderate). CONCLUSION: These results demonstrate the value of endoscopic screening of the esophagus using lugol dye in patients with HNC, particularly because superficial esophageal cancer is extremely difficult to detect by conventional methods in asymptomatic patients.

Parapharyngeal space tumors: considerations in 26 cases.

CONTEXT: Parapharyngeal space tumors comprise less than 0.5% of all head and neck neoplasms. The majority of these tumors are benign, but surgery is usually required to establish the diagnosis and treat the patients. We present 26 patients treated surgically for tumors arising in the parapharyngeal space (PPS) at the State University of Campinas Hospital--UNICAMP. CASES SERIES: Of these, 17 (65.5%) had benign and 9 (34.6%) malignant neoplasms. The surgical and pathological data relevant to these cases are highlighted, observing any local recurrence, surgical complications and the five-year survival. Neurogenic tumors and soft tissue sarcomas were, respectively, the most frequent benign (35.3%) and malignant neoplasms (44.5%). Benign tumors accounted for the majority of the cases and involved minimal surgical morbidity with no recurrence during a median follow-up of five years. Malignant tumors had a high rate of recurrence and mortality. Surgery is the treatment of choice for PPS tumors. A knowledge of the anatomy of this site is essential for the safe performance of surgical procedures. Malignant neoplasms have a poor prognosis. Fine needle aspiration was helpful in diagnosis of all tumors.