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Purpose – The authors estimate the multiplier effect of government public infrastructure investment in Spain. This paper aims to use annual data of the 17 Spanish autonomous communities for the 1980–2016 period. Design/methodology/approach – The authors use dynamic acyclic graphs and the heterogeneous panel structural vector autoregressive (P-SVAR) method of Pedroni (2013). This method is robust to cross-sectional heterogeneity and dependence, which are present in the data. Findings – The findings suggest that an increase in the level of government public infrastructure investment generates a positive and persistent effect on the level of output. Five years after the fiscal expansion, the multiplier effects of government public infrastructure investment reach values above one. This confirms that government public infrastructure investment expansions have Keynesian effects. The authors also find that the multiplier effects differ between autonomous communities with above-average and below-average GDP per capita. Originality/value – To the best of the authors’ knowledge, no research uses dynamic acyclic graphs and heterogeneous P-SVAR techniques to estimate fiscal multipliers of government public investment in Spain by using subnational data.

Abstract Background Methemoglobinemia can be an acquired or congenital condition. The acquired form occurs from exposure to oxidative agents. Congenital methemoglobinemia is a rare and potentially life-threatening cause of cyanosis in newborns that can be caused by either cytochrome B5 reductase or hemoglobin variants known as Hemoglobin M. Case presentation A term male infant developed cyanosis and hypoxia shortly after birth after an uncomplicated pregnancy, with oxygen saturations persistently 70–80% despite 1.0 FiO2 and respiratory support of CPAP+ 6 cm H2O. Pre- and post-ductal saturations were equal and remained below 85%. Initial radiographic and echography imaging was normal. Capillary blood gas values were reassuring with normal pH and an elevated pO2. Investigations to rule out hemolysis and end-organ dysfunction were within acceptable range. Given the absence of clear cardiac or pulmonary etiology of persistent cyanosis, hematologic causes such as methemoglobinemia were explored. No family history was available at the time of transfer to our institution. Unconjugated hyperbilirubinemia > 5 mg/dL (442 μmol/L) interfered with laboratory equipment measurement, making accurate methemoglobin levels unattainable despite multiple attempts. Initial treatment with methylene blue or ascorbic acid was considered. However, upon arrival of the presumed biological father, a thorough history revealed an extensive paternal family history of neonatal cyanosis due to a rare mutation resulting in a hemoglobin M variant. Given this new information, hematology recommended supportive care as well as further testing to confirm the diagnosis of congenital methemoglobinopathy. Whole genome sequencing revealed a likely pathogenic variation in hemoglobin. The neonate was discharged home at 2 weeks of age on full oral feeds with 0.25 L/min nasal cannula as respiratory support, with close outpatient follow-up. By 5 weeks of age, he was weaned off respiratory support. Conclusion Congenital methemoglobinemia should be considered in the differential diagnosis for newborns with persistent hypoxemia despite normal imaging and laboratory values. Accurate quantification of methemoglobin concentrations is challenging in neonates due to the presence of other substances that absorb light at similar wavelengths, including HbF, bilirubin, and lipids.

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80–90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis–relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies.

Abstract Background The bovine upper respiratory tract (URT) microbiome includes opportunistic pathogens that cause respiratory disease and stress associated with maternal separation and transportation contributes to the severity of this respiratory disease. Stress is known to alter the gut microbiome but little is known regarding the effect of stress on the URT microbiota. This study used six-month old suckling beef calves to investigate whether maternal separation (weaned), by itself or combined with transportation (weaned + transport), altered the URT microbiome and host immune responses to resident opportunistic pathogens. Results Taxonomic and functional composition of the URT microbiome in suckling and weaned beef calves did not change significantly when serially sampled over a one-month period. Subtle temporal changes in the URT microbiome composition were observed in weaned + transport calves. Total bacterial density was lower (p

Classic Hodgkin lymphoma (cHL) constitutes the most frequent lymphoma in young adults. Its histopathology is unique as a scattered tumor population, termed Hodgkin Reed-Sternberg (HRS) cells is diluted in a prominent tumor microenvironment (TME) composed of T lymphocytes, B lymphocytes, macrophages, neutrophils, eosinophils and histiocytes. Traditionally, the identification of prognostic biomarkers in the cHL TME has required visual inspection and manual counting by pathologists. The advent of whole-slide imaging (WSI) and digital image analysis methods could significantly contribute to improve this essential objective in cHL research, as a 10-20% of patients are still refractory or relapsed after conventional chemotherapy. In this work, we have digitized a total of 255 diagnostic cHL slides and quantified the proportion of HRS cells (CD30), B cells (CD20) and T cells (CD3) by digital image analysis. Data obtained where then correlated with the overall survival (OS) and progression free survival (PFS) of cHL patients. Quantification of HRS cells, B cells and T cells reflects the biological heterogeneity of the different cHL histological subtypes analyzed. A percentage of 2.00% of HRS cells statistically significantly discriminated between patients achieving a complete metabolic response (CMR) and refractory or relapsed (R/R) patients both for the OS (P=0.001) and PFS (P=0.005). Furthermore, patients with a percentage of T cells below the 26.70% in the TME showed a statistically significantly shorter OS (P=0.019) and PFS (P=0.041) in comparison with patients above this threshold. A subgroup of patients with a low content of T cells and high content of HRS cells exhibited a special aggressive clinical course. Currently, there is the need to implement quantitative and easy scalable methods to enhance clinical translation, as the cHL TME plays a central role in the clinical course of the disease. The results of this study could contribute to the identification of prognostic biomarkers specifically looking at the cHL TME and their inclusion in future clinical trials.

Background and purpose: Brachytherapy treatment outcomes depend on the accuracy of the delivered dose distribution, which is proportional to the reference air-kerma rate (RAKR). Current societal recommendations require the medical physicist to compare the measured RAKR values to the manufacturer source calibration certificate. The purpose of this work was to report agreement observed in current clinical practice in the European Union. Materials and methods: A European survey was performed for high- and pulsed-dose-rate (HDR and PDR) high-energy sources (192Ir and 60Co), to quantify observed RAKR differences. Medical physicists at eighteen hospitals from eight European countries were contacted, providing 1,032 data points from 2001 to 2020. Results: Over the survey period, 77% of the 192Ir measurements used a well chamber instead of the older Krieger phantom method. Mean differences with the manufacturer calibration certificate were 0.01% ± 1.15% for 192Ir and –0.1% ± 1.3% for 60Co. Over 95% of RAKR measurements in the clinic were within 3% of the manufacturer calibration certificate. Conclusions: This study showed that the agreement level was generally better than that reflected in prior societal recommendations positing 5%. Future recommendations on high-energy HDR and PDR source calibrations in the clinic may consider tightened agreements levels.

Abstract The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R 2 = 0.94, p =

Background CheckMate 9KD (NCT03338790) is a non-randomized, multicohort, phase 2 trial of nivolumab plus other anticancer treatments for metastatic castration-resistant prostate cancer (mCRPC). We report results from cohorts A1 and A2 of CheckMate 9KD, specifically evaluating nivolumab plus rucaparib.Methods CheckMate 9KD enrolled adult patients with histologically confirmed mCRPC, ongoing androgen deprivation therapy, and an Eastern Cooperative Oncology Group performance status of 0–1. Cohort A1 included patients with postchemotherapy mCRPC (1–2 prior taxane-based regimens) and ≤2 prior novel hormonal therapies (eg, abiraterone, enzalutamide, apalutamide); cohort A2 included patients with chemotherapy-naïve mCRPC and prior novel hormonal therapy. Patients received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg two times per day (nivolumab dosing ≤2 years). Coprimary endpoints were objective response rate (ORR) per Prostate Cancer Clinical Trials Working Group 3 and prostate-specific antigen response rate (PSA50-RR; ≥50% PSA reduction) in all-treated patients and patients with homologous recombination deficiency (HRD)-positive tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety.Results Outcomes (95% CI) among all-treated, HRD-positive, and BRCA1/2-positive populations for cohort A1 were confirmed ORR: 10.3% (3.9–21.2) (n=58), 17.2% (5.8–35.8) (n=29), and 33.3% (7.5–70.1) (n=9); confirmed PSA50-RR: 11.9% (5.9–20.8) (n=84), 18.2% (8.2–32.7) (n=44), and 41.7% (15.2–72.3) (n=12); median rPFS: 4.9 (3.7–5.7) (n=88), 5.8 (3.7–8.4) (n=45), and 5.6 (2.8–15.7) (n=12) months; and median OS: 13.9 (10.4–15.8) (n=88), 15.4 (11.4–18.2) (n=45), and 15.2 (3.0–not estimable) (n=12) months. For cohort A2 they were confirmed ORR: 15.4% (5.9–30.5) (n=39), 25.0% (8.7–49.1) (n=20), and 33.3% (7.5–70.1) (n=9); confirmed PSA50-RR: 27.3% (17.0–39.6) (n=66), 41.9 (24.5–60.9) (n=31), and 84.6% (54.6–98.1) (n=13); median rPFS: 8.1 (5.6–10.9) (n=71), 10.9 (6.7–12.0) (n=34), and 10.9 (5.6–12.0) (n=15) months; and median OS: 20.2 (14.1–22.8) (n=71), 22.7 (14.1–not estimable) (n=34), and 20.2 (11.1–not estimable) (n=15) months. In cohorts A1 and A2, respectively, the most common any-grade and grade 3–4 treatment-related adverse events (TRAEs) were nausea (40.9% and 40.8%) and anemia (20.5% and 14.1%). Discontinuation rates due to TRAEs were 27.3% and 23.9%, respectively.Conclusions Nivolumab plus rucaparib is active in patients with HRD-positive postchemotherapy or chemotherapy-naïve mCRPC, particularly those harboring BRCA1/2 mutations. Safety was as expected, with no new signals identified. Whether the addition of nivolumab incrementally improves outcomes versus rucaparib alone cannot be determined from this trial.Trial registration number NCT03338790.

Skin changes associated with alterations in the interstitial matrix and lymph system might provide significant and measurable effects due to the presence of breast cancer. This study aimed to determine if skin electrical resistance changes could serve as a diagnostic and therapeutic biomarker associated with physiological changes in patients with malignant versus benign breast cancer lesions. Forty-eight women (24 with malignant cancer, 23 with benign lesions) were enrolled in this study. Repeated skin resistance measurements were performed within the same session and 1 week after the first measurement in the breast lymphatic region and non-breast lymphathic regions. Intraclass correlation coefficients were calculated to determine the technique’s intrasession and intersession reproducibility. Data were then normalized as a mean of comparing cross-sectional differences between malignant and benign lesions of the breast. Six months longitudinal data from six patients that received therapy were analyzed to detect the effect of therapy. Standard descriptive statistics were used to compare ratiometric differences between groups. Skin resistance data were used to train a machine learning random forest classification algorithm to diagnose breast cancer lesions. Significant differences between malignant and benign breast lesions were obtained (p

Abstract Background Improved access to sexual and reproductive health (SRH) services and information is essential for supporting adolescents and youth in making informed decisions and optimizing each young person’s outcomes related to their SRH, health and well-being and countries’ current and future social and economic development. Mobile phones offer opportunities for young people to privately access SRH content and to be linked to SRH services. The objective of this study was to develop the content for an SMS (short message service or “text message”) platform jointly with adolescents and youth in three regions in Peru (Lima, Ayacucho and Loreto) as part of the ARMADILLO (Adolescent/Youth Reproductive Mobile Access and Delivery Initiative for Love and Life Outcomes) Study. Methods Content development was done in three stages. During Stage 1, we held community consultations with 13–17 year old adolescents, 18–24 year old youth and professionals who work with young people through the education and health sectors (“adult advisers”) to identify and rate SRH topics of interest through group free- and guided-brainstorming activities and an individual written sharing activity. During Stage 2, the team developed the preliminary domains, sub-domains and content for the SMS platform. During Stage 3, we held focus groups with adolescents to validate the SMS content, including both individual scoring of and group feedback for each SMS. Group feedback asked about their general impressions and understanding and their thoughts about the language and usefulness of the SMS. Results A total of 172 adolescents and youth ages 13–24 and 20 adult advisers participated. Adolescents and youth brainstormed and rated SRH topics and sub-topics that led to the initial structure for the SMS platform, with 9 domains, 25 sub-domains and 146 draft SMS. Adolescents provided high scores for the SMS, with all sub-domains receiving average scores of 3.0 or higher (out of 4.0) for the SMS included. Adolescents also provided suggestions to optimize content, including improvements to unclear messages, resulting in SMS with adolescent-friendly content in simple, straightforward language. This process also revealed that adolescents lacked knowledge and had misconceptions related to contraceptive methods. Conclusion This study details the systematic process used to develop relevant and accessible SRH information through a participatory approach. We document critical information about what young people know and how they think, enabling us to understand their perspective and literally speak their language. Results also provide future directions for programmatic, research and policy efforts with young people, in particular around gender norms, interpersonal violence, and access to SRH information and services, in similar settings.

Abstract Background Mycoplasma mycoides subsp. mycoides (Mmm) is the causative agent of contagious bovine pleuropneumonia in cattle. A prototype subunit vaccine is being developed, however, there is currently no diagnostic test that can differentiate between infected cattle and those vaccinated with the prototype subunit vaccine. This study characterized Mmm proteins to identify potential antigens for use in differentiating infected from vaccinated animals. Results Ten Mmm antigens expressed as recombinant proteins were tested in an indirect ELISA using experimental sera from control groups, infected, and vaccinated animals. Data were imported into R software for analysis and drawing of the box and scatter plots while Cohen’s Kappa assessed the level of agreement between the Mmm antigens. Two vaccine antigens (MSC_0499 and MSC_0776) were superior in detecting antibodies in sera of animals vaccinated with the subunit vaccines while two non-vaccine antigens (MSC_0636 and LppB) detected antibodies in sera of infected animals showing all clinical stages of the disease. Sensitivity and specificity of above 87.5% were achieved when the MSC_0499 and MSC_0636 antigens were tested on sera from vaccinated and infected animals. Conclusions The MSC_0499 and MSC_0776 antigens were the most promising for detecting vaccinated animals, while MSC_0636 and LppB were the best targets to identify infected animals. Further testing of sera from vaccinated and infected animals collected at different time intervals in the field should help establish how useful a diagnostic test based on a cocktail of these proteins would be.

Not all infants carry specialized gut microbes, meaning they cannot digest human milk oligosaccharides and therefore do not receive complete benefits from human milk. B. infantis EVC001 is equipped to convert the full array of complex oligosaccharides into compounds usable by the infant, making it an ideal candidate to stabilize gut function and improve nutrition in preterm infants. A prospective, open-label study design was used to evaluate the tolerability of B. infantis EVC001 and its effects on the fecal microbiota in preterm infants in a Neonatal Intensive Care Unit. Thirty preterm infants

Category: Ankle; Ankle Arthritis; Trauma Introduction/Purpose: Tibiotalocalcaneal (TTC) arthrodesis is a routinely utilized salvage procedure that treats patients with severe talar and subtalar joint disease. Unfortunately, nonunion is a relatively common complication postoperatively which can increase risks and costs for patients. The goal of this study is to review the literature to identify risk factors for nonunion post TTC arthrodesis and stratify them based on strength of evidence. A meta-analysis will be performed on risk factors when appropriate to establish values based on pre-existing studies. Methods: Five databases (CINAHL, Cochrane Library, EMBASE, MEDLINE, and Web of Science) were searched from inception to May 17th, 2020. Two independent reviewers screened abstracts and full-text articles for those that included risk factors predictive of nonunion for TTC arthrodesis. Any disagreements were discussed between the two reviewers and a third reviewer served as the ultimate decision maker if a consensus could not be reached. Relevant data regarding participants’ characteristics, study design, follow-up time, statistical tests and identified risk factors were extracted from the included studies. The two reviewers independently appraised the methodological quality of the studies using the Quality In Prognosis Studies tool. Those risk factors described in multiple studies were included in the meta-analysis. Random effects meta-analyses were summarized as forest plots of individual study and pooled random effect results. Results were reported as odds ratios (OR) with 95% confidence intervals (CI). Results: Database search identified 428 articles, of which 113 were screened for full text. Eight studies involving 607 patients were included and 33 potential risk factors for nonunion were identified. Risk factors were stratified into demographic, preoperative, intraoperative and postoperative. Results of the meta-analysis established two significant risk factors for nonunion following TTC arthrodesis. Strong evidence supports that prior neurological deficits, such as Charcot neuroarthropathy and diabetes neuropathy, are associated with nonunion following surgery (OR: 2.86, 95% CI: 1.56 - 5.23). There was moderate evidence to suggest that preoperative infection was predictive for nonunion (OR: 3.99, 95% CI: 1.26 - 12.68). Although our meta- analysis did not find smoking (OR: 1.75, 95% CI: 0.90 - 3.38) or diabetes (OR: 2.28, 95% CI: 0.98 - 5.34) to be significant risk factors, multiple high quality studies support these as comorbidities that increase the likelihood of nonunion. Conclusion: TTC arthrodesis can be an effective salvage procedure but is associated with high nonunion rates. The results of our meta-analysis suggest that prior neurological deficits, such as Charcot neuroarthropathy or diabetes neuropathy, have strong evidence for failure to achieve union. Although our meta-analysis did not find other statistically significant risk factors, the findings of individual studies in our review suggest that diabetes mellitus and smoking are both factors which can lead to failure of fusion. Surgeons should be cognizant of these risks when performing TTC arthrodesis and carefully monitor patients with the aforementioned comorbidities to achieve successful results.

Two different polyglycine-rich fragments were selected as representatives of major ampullate gland spidroins (MaSp) 1 and 2 types, and their behavior in a water-saturated environment was simulated within the framework of molecular dynamics (MD). The selected fragments are found in the sequences of the proteins MaSp1a and MaSp2.2a of Argiope aurantia with respective lengths of 36 amino acids (MaSp1a) and 50 amino acids (MaSp2.2s). The simulation took the fully extended β-pleated conformation as reference, and MD was used to determine the equilibrium configuration in the absence of external forces. Subsequently, MD were employed to calculate the variation in the distance between the ends of the fragments when subjected to an increasing force. Both fragments show an elastomeric behavior that can be modeled as a freely jointed chain with links of comparable length, and a larger number of links in the spidroin 2 fragment. It is found, however, that the maximum recovery force recorded from the spidroin 2 peptide (Fmax ≈ 400 pN) is found to be significantly larger than that of the spidroin 1 (Fmax ≈ 250 pN). The increase in the recovery force of the spidroin 2 polyglycine-rich fragment may be correlated with the larger values observed in the strain at breaking of major ampullate silk fibers spun by Araneoidea species, which contain spidroin 2 proteins, compared to the material produced by spider species that lack these spidroins (RTA-clade).

The purpose of this paper was to study the possible causes of Non-Specific Reactive Hepatitis (NSRH) in tissue samples of housed dogs that were collected from different cities of Andalucia (Spain). Histologically, this disease was characterized by the presence of lymphocytes and plasma cells spread throughout the liver parenchyma and in the portal stroma, with no evidence of hepatocyte necrosis. These animals showed non-specific chronic reactive hepatitis that varied from moderate to severe. In order of prevalence, the more common pathologies associated with NSRH were gastrointestinal and renal diseases, as well as pneumonia mainly of parasitic or infectious origin.

Presentamos un caso clínico-quirúrgico de una paciente de 68 años de edad que fue admitida en urgencias por presentar un infarto agudo del miocardio(IMA) sobre un bloqueo completo de rama izquierda(BCRI) antiguo. Durante su evolución se diagnosticó conjuntamente una apendicitis aguda que necesitó tratamiento quirúrgico inmediato. Para el diagnóstico del IMA se utilizaron criterios electrocardiográficos, no expuestos anteriormente en nuestro centro. Se discutió el caso entre un conjunto de especialistas constituido por internistas, intensivistas, cardiólogos y cirujanos. La evolución de la paciente, en sala de terapia intensiva y posteriormente en sala de cirugía, fue favorable por lo que se dio de alta con seguimiento en consulta externa de cardiología. Quedó demostrado que el IMA puede surgir durante el desarrollo de la apendicitis aguda.

Abstract Background Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are two forms of thrombotic microangiopathies. They are characterized by severe thrombocytopenia, microangiopathic hemolysis, and thrombosis, leading to a systemic inflammatory response and organ failure. Plasmapheresis is used to treat thrombotic microangiopathies. A different entity known as atypical hemolytic uremic syndrome has garnered more clinical recognition because reported cases have described that it does not respond to standard plasmapheresis. Diclofenac potassium is a non-steroidal anti-inflammatory drug that is used to treat pain. Case report A 35-year-old Hispanic man presented to our emergency department with complaints of generalized malaise, fever, and an evanescent skin rash. During admission, he reported the use of diclofenac potassium for back pain on a daily basis for 1 week. He was noted to have peripheral eosinophilia, so he was admitted for suspected drug reaction involving eosinophilia and systemic symptoms. His initial laboratory work-up showed microangiopathic hemolytic anemia and thrombocytopenia. He also experienced a seizure, encephalopathy, and had a PLASMIC score of 7, thus raising concerns for thrombotic thrombocytopenic purpura. He underwent emergent plasmapheresis, which improved his clinical condition. The diagnosis was confirmed by assessing the levels of disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, which was less than 3%. In addition, his skin biopsy was positive for patchy complement deposition, demonstrating complement dysregulation. Conclusion Thrombotic thrombocytopenic purpura is a rare condition that can be acquired. Our case is rare because it represents the first report of diclofenac potassium-induced thrombotic thrombocytopenic purpura with subjacent complement activation and dysregulation. Early recognition and aggressive management led to a favorable outcome.

Abstract Background The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2-positive early breast cancer. Methods Patients with stage II–IIIB HER2-positive breast cancer received neoadjuvant trastuzumab, pertuzumab, paclitaxel, and a non-pegylated liposomal doxorubicin every three weeks for six cycles. The primary endpoint was cardiac safety during neoadjuvant therapy. Type A (symptomatic congestive heart failure) and B (asymptomatic reduction of left ventricular ejection fraction) cardiac events were evaluated. Secondary endpoints included the evaluation of the pathological complete response (pCR) rate and overall response rate, among others. As an ad-hoc exploratory analysis, the expression of 55 breast cancer-related genes, including the PAM50 genes, was measured in 58 baseline tumor samples and 60 surgical specimens. Results Eighty-three patients were recruited. The incidence of cardiac events during neoadjuvant treatment was 2.4%. No type A cardiac event was observed. The overall pCR rate was 56.6% (95% confidence interval (CI) 45.3–67.5%). The HER2-enriched subtype, which represented 52.0% of all baseline samples, was associated with a higher pCR rate compared to non-HER2-enriched tumors (83.3% vs. 46.3%; odds ratio 5.76, 95% CI 1.71–19.42). The association of subtype with pCR was independent of known clinicopathological variables, including hormone receptor status. Compared to baseline samples, surgical specimens showed a significant downregulation of proliferation-related genes (MKI67 and CCNB1) and ERBB2 levels, and a significant upregulation of luminal-related (ESR1 and PGR) and immune (CD8A) genes. Conclusions The combination of dual HER2 blockade with trastuzumab and pertuzumab with paclitaxel and non-pegylated liposomal doxorubicin is associated with a low rate of cardiac events. The HER2-enriched subtype is associated with a high rate of pCR. Trial registration clinicaltrials.gov, NCT01669239, Registered 20 August 2012.

Background: This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients.Methods: A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated. Serum inflammatory profile, oxidative stress markers and NETosis-derived bioproducts were quantified and miRNomes were recognized by next-generation sequencing. Then, clinical and molecular changes induced by TNFi were delineated. Clinical and molecular signatures predictors of clinical response were assessed with supervised machine learning methods, using regularized logistic regressions.Results: Altered inflammatory, oxidative and NETosis-derived biomolecules were found in RA patients vs. HD, closely interconnected and associated with specific miRNA profiles. This altered molecular profile allowed the unsupervised division of three clusters of RA patients, showing distinctive clinical phenotypes, further linked to the TNFi effectiveness. Moreover, TNFi treatment reversed the molecular alterations in parallel to the clinical outcome. Machine-learning algorithms in the discovery cohort identified both, clinical and molecular signatures as potential predictors of response to TNFi treatment with high accuracy, which was further increased when both features were integrated in a mixed model (AUC: 0.91). These results were confirmed in the validation cohort.Conclusions: Our overall data suggest that: 1. RA patients undergoing anti-TNF-therapy conform distinctive clusters based on altered molecular profiles, which are directly linked to their clinical status at baseline. 2. Clinical effectiveness of anti-TNF therapy was divergent among these molecular clusters and associated with a specific modulation of the inflammatory response, the reestablishment of the altered oxidative status, the reduction of NETosis, and the reversion of related altered miRNAs. 3. The integrative analysis of the clinical and molecular profiles using machine learning allows the identification of novel signatures as potential predictors of therapeutic response to TNFi therapy.

OBJECTIVES/GOALS: MgSO4 is a frequently used to treat asthma exacerbations. Its role in the management of pediatric asthma remains controversial. Our objective is to demonstrate that the response of the small (peripheral) airways depends on airway de novo sphingolipid synthesis, clinically and experimentally. The small airways are the main site of asthma pathology. METHODS/STUDY POPULATION: We investigated airway reactivity in response to MgSO4 in murine small airways and children 1. Precision-cut lung slices (PCLS): Using heterozygous knockouts mice of one of the Sptlc2 subunit of the serine palmitoyl-CoA transferase (SPT) which results in reduced tissue sphingolipid levels compared to wild-type control littermates (Sptlc2+/+). We compared small airway dilation to MgSO4 in Sptlc2+/- and Sptlc2+/+ mice. This was assessed by directly visualization of small airway contractility in PCLS from Sptlc2+/- mice using video phase-contrast microscopy 2. Clinical response to MgSO4 in children by using a respiratory score before and after the treatment. The response to MgSO4 was the correlated to asthma-associated 17q21 specific single nucleotide polymorphisms (SNPs) from DNA isolated from buccal swabs RESULTS/ANTICIPATED RESULTS: Sphingolipid-mediated activity alters magnesium response in small airways. We assessed whether downregulation of SPT could lead to alterations in MgSO4-induced small airway dilation and in MgSO4 responsiveness in mouse tracheal rings and found that the magnesium-induced relaxation of airways pre-contracted with methacholine was impaired in Sptlc+/- mice compared to the control group (p=

Classic Hodgkin lymphoma (cHL) constitutes a B cell-derived neoplasm defined by a scarce tumoral population, termed Hodgkin and Reed–Sternberg (HRS) cells, submerged into a histologically heterogeneous microenvironment. The paucity of HRS cells has historically hampered genetic studies, rendering the identification of the recurrent genetic lesions and molecular pathways deregulated in this lymphoma difficult. The advent of high-throughput sequencing methods such as next-generation sequencing (NGS) could sensibly optimize the identification of the mutational landscape of cHL. However, there is no current consensus either in the design of panels for targeted NGS or in its most relevant clinical applications. In this work, we systematically review the current state of NGS studies of cHL, stressing the need for standardization both in the candidate genes to be analyzed and the bioinformatic pipelines. As different institutions have developed and implemented their own customized NGS-based protocols, to compare and systematically review the major findings of this ongoing research area could be of added value for centers that routinely perform diagnostic, monitoring and genotyping strategies in cHL samples. The results of this systematic review should contribute to the interdepartmental harmonization and achievement of a consensus in the current clinical applications of NGS studies of cHL.

Introduction The evidence currently available from enhanced recovery after surgery (ERAS) programmes concerns their benefits in the immediate postoperative period, but there is still very little evidence as to whether their correct implementation benefits patients in the long term. The working hypothesis here is that, due to the lower response to surgical aggression and lower rates of postoperative complications, ERAS protocols can reduce colorectal cancer-related mortality. The main objective of this study is to analyse the impact of an ERAS programme for colorectal cancer on 5-year survival. As secondary objectives, we propose to analyse the weight of each of the predefined items in the oncological results as well as the quality of life.Methods and analysis A multicentre prospective cohort study was conducted in patients older than 18 years of age who are scheduled to undergo surgery for colorectal cancer. The study involved 12 hospitals with an implemented enhanced recovery protocol according to the guidelines published by the Spanish National Health Service. The intervention group includes patients with a minimum implementation level of 70%, and the control group includes those who fail to reach this level. Compliance will be studied using 18 key performance indicators, and the results will be analysed using cancer survival indicators, including overall survival, cancer-specific survival and relapse-free survival. The time to recurrence, perioperative morbidity and mortality, hospital stay and quality of life will also be studied, the latter using the validated EuroQol Five questionnaire. The propensity index method will be used to create comparable treatment and control groups, and a multivariate regression will be used to study each variable. The Kaplan-Meier estimator will be used to estimate survival and the log-rank test to make comparisons. A p value of less than 0.05 (two-tailed) will be considered to be significant.Ethics and dissemination Ethical approval for this study was obtained from the Aragon Ethical Committee (C.P.-C.I. PI20/086) on 4 March 2020. The findings of this study will be submitted to peer-reviewed journals (BMJ Open, JAMA Surgery, Annals of Surgery, British Journal of Surgery). Abstracts will be submitted to relevant national and international meetings.Trial registration number NCT04305314.

The prognostic impact of the presence of Epstein–Barr virus (EBV) in classical Hodgkin lymphoma (cHL) is controversial. Previous studies reported heterogeneous results, rendering difficult the clinical validation of EBV as a prognostic biomarker in this lymphoma. The objective of this study was to evaluate the survival impact of the expression of EBV Latent-Membrane Protein 1 (EBV-LMP1) in tumoral Hodgkin–Reed–Sternberg (HRS) cells of primary diagnostic samples of cHL. Formalin-Fixed Paraffin-Embedded (FFPE) lymph node samples from 88 patients with cHL were analyzed. Patients were treated with the standard first-line chemotherapy (CT) with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) followed by radiotherapy. The Kaplan–Meier method and the Cox proportional hazards model were used for carrying out the survival analysis. In order to investigate whether the influence of EBV was age-dependent, analyses were performed both for patients of all ages and for age-stratified subgroups. In bivariate analysis, the expression of EBV was associated with older age (p = 0.011), mixed cellularity subtype cHL (p < 0.001) and high risk International Prognostic Score (IPS) (p = 0.023). Overall survival (OS) and progression-free survival (PFS) were associated with the presence of bulky disease (p = 0.009) and advanced disease at diagnosis (p = 0.016). EBV-positive cases did not present a significantly lower OS and PFS in comparison with EBV-negative cases, for all ages and when stratifying for age. When adjusted for covariates, absence of bulky disease at diagnosis (HR: 0.102, 95% CI: 0.02–0.48, p = 0.004) and limited disease stages (I–II) (HR: 0.074, 95% CI: 0.01–0.47, p = 0.006) were associated with a significant better OS. For PFS, limited-disease stages also retained prognostic impact in the multivariate Cox regression (HR: 0.145, 95% CI: 0.04–0.57, p = 0.006). These results are of importance as the early identification of prognostic biomarkers in cHL is critical for guiding and personalizing therapeutic decisions. The prognostic role of EBV in cHL could be modulated by the type of CT protocol employed and interact with the rest of presenting features.

Purpose : To present the implementation of a magnetic resonance imaging (MRI) pre-planning technique in multi-interstitial perineal and endocavitary gynecological brachytherapy. Material and methods : We used a new fully MRI-compatible applicator that is capable to engage titanium needles, and an intrauterine tandem, developed in our department for the treatment of gynecological cervical cancer patients. This applicator is an attempt to combine the technical advantages of the Martinez universal perineal interstitial template (MUPIT) with the improvement in dose distribution by adding an intrauterine probe with the imaging advantages of MRI-based brachytherapy, thus preserving the stability, geometry, and robustness of the implant, avoiding possible errors of free-hand needle placement. A pre-brachytherapy MRI T2 acquisition is carried out with the template in place 3-5 days before the implant. On this image set, clinical target volume (CTV) is drawn. The required needles and their depths are selected accordingly to encompass the CTV (as conformal as possible). To facilitate this task, a Java based application linked to the treatment planning system has been developed. From this procedure, each needle identification and its depth are obtained previously to the implantation. With this information, the radiation oncologist proceeds with implant and then, a post-implant MRI is carried out, in which the contouring, needles, tandem reconstruction, and optimization are established. Results : This pre-planning procedure has been successfully applied in 10 patients. An excellent reproduction of the virtual pre-planning has been achieved. Conclusions : We describe a virtual pre-planning technique using a multi-interstitial and endocavitary perineal template. It is based on a virtual work with MRI images. This procedure has shown to be feasible and efficient in clinical practice by facilitating the work of specialists, and reducing uncertainties of the application.

Abstract Immune signatures of sheep acutely-infected with Fasciola hepatica, an important pathogen of livestock and humans were analysed within the peritoneal compartment to investigate early infection. Within the peritoneum, F. hepatica antibodies coincided with an intense innate and adaptive cellular immune response, with infiltrating leukocytes and a marked eosinophilia (49%). However, while cytokine qPCR analysis revealed IL-10, IL-12, IL-13, IL-23 and TGFβ were elevated, these were not statistically different at 18 days post-infection compared to uninfected animals indicating that the immune response is muted and not yet skewed to a Th2 type response that is associated with chronic disease. Proteomic analysis of the peritoneal fluid identified infection-related proteins, including several structural proteins derived from the liver extracellular matrix, connective tissue and epithelium, and proteins related to the immune system. Periostin and vascular cell adhesion protein 1 (VCAM-1), molecules that mediate leukocyte infiltration and are associated with inflammatory disorders involving marked eosinophilia (e.g. asthma), were particularly elevated in the peritoneum. Immuno-histochemical studies indicated that the source of periostin and VCAM-1 was the inflamed sheep liver tissue. This study has revealed previously unknown aspects of the immunology and pathogenesis associated with acute fascioliasis in the peritoneum and liver.

Purpose: The use of radiation therapy (RT) for non-melanoma skin cancer (NMSC) has been changing throughout the last century. Over the last decades, the use of radiotherapy has surged with the development of new techniques, applicators, and devices. In recent years, electronic brachytherapy (eBT) devices that use small x-ray sources have been introduced as alternative to radionuclide dependence. Nowadays, several devices have been incorporated, with a few series reported, and with a short follow-up, due to the recent introduction of these systems. The purpose of this work is to describe the clinical results of our series after two years follow-up with a specific eBT system. Material and methods: This is a prospective single-center, non-randomized pilot study, to assess clinical results of electronic brachytherapy in basal cell carcinoma using the Esteya® system. In 2014, 40 patients with 60 lesions were treated. Patient follow-up on a regular basis was performed for a period of two years. Results: Twenty-six patients with 44 lesions achieved two years follow-up. A complete response was documented in 95.5% of cases. Toxicity was mild (G1 or G2) in all cases, caused by erythema, erosion, or alopecia. Cosmesis was excellent in 88.6% of cases, and good in the rest. Change in pigmentation was the most frequent cosmetic alteration. Conclusions : This work is special, since the equipment’s treatment voltage was 69.5 kV, and this is the first prospective study with long term follow-up with Esteya®. These preliminary report show excellent results with less toxicity and excellent cosmesis. While surgery has been the treatment of choice, certain patients might benefit from eBT treatment. These are elderly patients with comorbidities or undergoing anticoagulant treatment as well as those who simply refuse surgery or might have other contraindications.

Purpose: T2 magnetic resonance imaging (MRI) is recommended as the imaging modality for image-guided brachytherapy. In locally advanced cervical carcinoma, combined endocavitary and interstitial applicators are appropriate (Vienna or Utrecht). To cover extensive disease, Template Benidorm (TB) was developed. Treatment planning system applicator libraries are currently unavailable for the Utrecht applicator or the TB. The purpose of this work is to develop an applicator library for both applicators. Material and methods: The library developed in this work has been used in the Oncentra Brachytherapy TPS, version 4.3.0, which has a brachytherapy module that includes a library of rigid applicators. To add the needles of the Utrecht applicator and to model the TB, we used FreeCAD and MeshLab. The reconstruction process was based on the points that the rigid section and the interstitial part have in common. This, together with the free length, allowed us to ascertain the position of the tip. Results: In case of the Utrecht applicator, one of the sources of uncertainty in the reconstruction was determining the distance of the tip of needle from the ovoid. In case of the TB, the large number of needles involved made their identification time consuming. The developed library resolved both issues. Conclusions : The developed library for the Utrecht and TB is feasible and efficient improving accuracy. It allows all the required treatment planning to proceed using just a T2 MRI sequence. The additional use of specific free available software applications makes it possible to add this information to the already existing library of the Oncentra Brachytherapy TPS. Specific details not included on this manuscript will be available under request. This library is also currently being implemented also into the Sagiplan v 2.0 TPS.

Purpose: Esteya® (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden) is an electronic brachytherapy device used for skin cancer lesion treatment. In order to establish an adequate level of quality of treatment, a risk analysis of the Esteya treatment process has been done, following the methodology proposed by the TG-100 guidelines of the American Association of Physicists in Medicine (AAPM). Material and methods: A multidisciplinary team familiar with the treatment process was formed. This team developed a process map (PM) outlining the stages, through which a patient passed when subjected to the Esteya treatment. They identified potential failure modes (FM) and each individual FM was assessed for the severity (S), frequency of occurrence (O), and lack of detection (D). A list of existing quality management tools was developed and the FMs were consensually reevaluated. Finally, the FMs were ranked according to their risk priority number (RPN) and their S. Results : 146 FMs were identified, 106 of which had RPN ≥ 50 and 30 had S ≥ 7. After introducing the quality management tools, only 21 FMs had RPN ≥ 50. The importance of ensuring contact between the applicator and the surface of the patient’s skin was emphasized, so the setup was reviewed by a second individual before each treatment session with periodic quality control to ensure stability of the applicator pressure. Some of the essential quality management tools are already being implemented in the installation are the simple templates for reproducible positioning of skin applicators, that help marking the treatment area and positioning of X-ray tube. Conclusions : New quality management tools have been established as a result of the application of the failure modes and effects analysis (FMEA) treatment. However, periodic update of the FMEA process is necessary, since clinical experience has suggested occurring of further new possible potential failure modes.

Objective To evaluate changes in knee articular cartilage of novice half-marathon runners using magnetic resonance imaging T2 relaxation time mapping. Methods Healthy subjects were recruited from local running clubs who met the following inclusion criteria: (i) age 18–45 years; (ii) body mass index less than 30 kg/m 2 ; (iii) had participated in one half-marathon or less (none within the previous 6 months); (iv) run less than 20 km/week; (v) no previous knee injury or surgery; (vi) no knee pain. T2 signals were measured pre- and post-race to evaluate the biochemical changes in articular cartilage after the subjects run a half-marathon. Results A significant increase in the mean ± SD T2 relaxation time was seen in the outer region of the medial tibial plateau (50.1 ± 2.4 versus 54.7 ± 2.6) and there was a significant decrease in T2 relaxation time in the lateral femoral condyle central region (50.2 ± 4.5 versus 45.4 ± 2.9). There were no significant changes in the patella, medial femoral condyle and lateral tibia articular surfaces. Conclusion An increase in T2 relaxation time occurs in the medial tibial plateau of novice half-marathon runners. This limited region of increased T2 values, when compared with complete medial compartment involvement seen in studies of marathon runners, may represent an association between distance run and changes seen in articular cartilage T2 values.

Purpose : Esteya and Valencia surface applicators are designed to treat skin tumors using brachytherapy. In clinical practice, in order to avoid errors that may affect the treatment outcome, there are two issues that need to be carefully addressed. First, the selected applicator for the treatment should provide adequate margin for the target, and second, the applicator has to be precisely positioned before each treatment fraction. In this work, we describe the development and use of a new acrylic templates named Template La Fe-ITIC. They have been designed specifically to help the clinical user in the selection of the correct applicator, and to assist the medical staff in reproducing the positioning of the applicator. These templates are freely available upon request. Material and methods: Templates that were developed by University and Polytechnic Hospital La Fe (La Fe) and Hospital Clínica Benidorm (ITIC) in cooperation with Elekta, consist of a thin sheet made of transparent acrylic. For each applicator, a crosshair and two different circles are drawn on these templates: the inner one corresponds to the useful beam, while the outer one represents the external perimeter of the applicator. The outer circle contains slits that facilitate to draw a circle on the skin of the patient for exact positioning of the applicator. In addition, there are two perpendicular rulers to define the adequate margin. For each applicator size, a specific template was developed. Results: The templates have been used successfully in our institutions for more than 50 patients’ brachytherapy treatments. They are currently being used for Esteya and Valencia applicators. Conclusions : The template La Fe-ITIC is simple and practical. It improves both the set-up time and reproducibility. It helps to establish the adequate margins, an essential point in the clinical outcome.

Genomic analysis and digitalization of medical records have led to a big data scenario within hematopathology. Artificial intelligence and machine learning tools are increasingly used to integrate clinical, histopathological, and genomic data in lymphoid neoplasms. In this study, we identified global trends, cognitive, and social framework of this field from 1990 to 2020. Metadata were obtained from the Clarivate Analytics Web of Science database in January 2021. A total of 525 documents were assessed by document type, research areas, source titles, organizations, and countries. SciMAT and VOSviewer package were used to perform scientific mapping analysis. Geographical distribution showed the USA and People’s Republic of China as the most productive countries, reporting up to 190 (36.19%) of all documents. A third-degree polynomic equation predicts that future global production in this area will be three-fold the current number, near 2031. Thematically, current research is focused on the integration of digital image analysis and genomic sequencing in Non-Hodgkin lymphomas, prediction of chemotherapy response and validation of new prognostic models. These findings can serve pathology departments to depict future clinical and research avenues, but also, public institutions and administrations to promote synergies and optimize funding allocation.

The Valencia applicators (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden) are cup-shaped tungsten applicators with a flattening filter used to collimate the radiation produced by a high-dose-rate (HDR) 192 Ir source, and provide a homogeneous absorbed dose at a given depth. This beam quality provides a good option for the treatment of skin lesions at shallow depth (3-4 mm). The user must perform commissioning and periodic testing of these applicators to guarantee the proper and safe delivery of the intended absorbed dose, as recommended in the standards in radiation oncology. In this study, based on AAPM and GEC-ESTRO guidelines for brachytherapy units and our experience, a set of tests for the commissioning and periodic testing of the Valencia applicators is proposed. These include general considerations, verification of the manufacturer documentation and physical integrity, evaluation of the source-to-indexer distance and reproducibility, setting the library plan in the treatment planning system, evaluation of flatness and symmetry, absolute output and percentage depth dose verification, independent calculation of the treatment time, and visual inspection of the applicator before each treatment. For each test, the proposed methodology, equipment, frequency, expected results, and tolerance levels (when applicable) are provided.

Purpose : To study outcome and toxicity in 59 patients with locally advanced cervix carcinoma treated with computed tomography (CT)-based Martinez universal perineal interstitial template (MUPIT) and the new magnetic resonance imaging (MRI)-compatible template Benidorm (TB). Material and methods: From December 2005 to October 2015, we retrospectively analyzed 34 patients treated with MUPIT and 25 treated with the TB. Six 4 Gy fractions were prescribed to the clinical target volume (CTV) combined with external beam radiotherapy (EBRT). The organs at risk (OARs) and the CTV were delineated by CT scan in the MUPIT implants and by MRI in the TB implants. Dosimetry was CT-based for MUPIT and exclusively MRI-based for TB. Dose values were biologically normalized to equivalent doses in 2 Gy fractions (EQD2). Results : Median CTV volumes were 163.5 cm3 for CT-based MUPIT (range 81.8-329.4 cm3) and 91.9 cm3 for MRI-based TB (range 26.2-161 cm3). Median D90 CTV (EBRT + BT) was 75.8 Gy for CT-based MUPIT (range 69-82 Gy) and 78.6 Gy for MRI-based TB (range 62.5-84.2). Median D2cm3 for the rectum was 75.3 Gy for CT-based MUPIT (range 69.8-132.1 Gy) and 69.9 Gy for MRI-based TB (range 58.3-83.7 Gy). Median D2cm3 for the bladder was 79.8 Gy for CT-based MUPIT (range 71.2-121.1 Gy) and 77.1 Gy for MRI-based TB (range 60.5-90.8 Gy). Local control (LC) was 88%. Overall survival (OS), disease free survival (DFS), and LC were not statistically significant in either group. Patients treated with CT-based MUPIT had a significantly higher percentage of rectal bleeding G3 (p = 0.040) than those treated with MRI-based TB, 13% vs. 2%. Conclusions : Template Benidorm treatment using MRI-based dosimetry provides advantages of MRI volume definition, and allows definition of smaller volumes that result in statistically significant decreased rectal toxicity compared to that seen with CT-based MUPIT treatment.

Purpose : Groupe Européen de Curiethérapie (GEC) and European Society for Radiotherapy & Oncology (ESTRO) has proposed a rectal dose constraint of the most exposed 2-cc volume (D 2cc of ≤ 75 Gy EQD 2α/β = 3) during external- beam plus high-dose-rate brachytherapy (HDR-BT) in localized prostate cancer patients. This study aimed to evaluate D 2cc for rectal contouring via interobserver variability. Material and methods: Four blinded observers contoured rectums of 5 patients. Rectal contouring anatomical limits were determined through previous consensus. Dose-volume histogram (DVH) dosimetric parameters (D 0.1cc , D 1cc , and D 2cc ) were analyzed according to GEC/ESTRO recommendations and subjected to intra- and interobserver comparisons. Latter comparisons involved coefficients of variation. For each parameter, the mean, standard deviation (SD), and range were evaluated. The effect of interobserver variation on total dose was analyzed by estimating the biologically equivalent rectal dose (EQD 2α/β = 3). Results : Interobserver coefficients of variation for D 0.1cc , D 1cc , and D 2cc were 5.7%, 4.5%, and 4%, respectively. The high­est interobserver rectal delineation variation yielded a rectal dose difference up to 5.8 Gy EQD2. Estimated intraobserver variation for the reported D 2cc was 5.5% in the worst-case scenario (non-significant). Conclusions : We observed acceptable interobserver variability in EQD2 for D 2cc , with strong impacts on clinical threshold levels (D 2cc ≤ 75 Gy EQD2) in some cases. This small, single-center analysis will be extended in a multicenter study.

Pancreatogenic diabetes mellitus (T3cDM) is a highly frequent complication of pancreatic disease, especially chronic pancreatitis, and it is often misdiagnosed as type 2 diabetes mellitus (T2DM). A correct diagnosis allows the appropriate treatment of these patients, improving their quality of life, and various technologies have been employed over recent years to search for specific biomarkers of each disease. The main aim of this metabolomic project was to find differential metabolites between T3cDM and T2DM. Reverse-phase liquid chromatography coupled to high-resolution mass spectrometry was performed in serum samples from patients with T3cDM and T2DM. Multivariate Principal Component and Partial Least Squares-Discriminant analyses were employed to evaluate between-group variations. Univariate and multivariate analyses were used to identify potential candidates and the area under the receiver-operating characteristic (ROC) curve was calculated to evaluate their diagnostic value. A panel of five differential metabolites obtained an area under the ROC curve of 0.946. In this study, we demonstrate the usefulness of untargeted metabolomics for the differential diagnosis between T3cDM and T2DM and propose a panel of five metabolites that appear altered in the comparison between patients with these diseases.

Introduction. Pasteurella multocida is a gram-negative coccobacillus pathogenic to animals. It can cause infection in humans by a bite, scratch, or lick from a cat or dog. P. multocida can cause a variety of infections in humans, including cellulitis, osteomyelitis, endocarditis, peritonitis, and septic shock. Case Presentation. A 56-year-old male presented to our hospital with a 2-day history of fever, abdominal pain, nausea, and vomiting. He denied exposure to cats, dogs or other pets. He had severe respiratory distress requiring ventilator support, profound septic shock requiring multiple vasopressors, severe lactic acidosis, and renal failure requiring emergent hemodialysis. Blood cultures confirmed the presence of P. multocida. The patient subsequently died of cardiopulmonary arrest due to multiorgan failure with refractory shock. Conclusion. P. multocida septicemia can lead to septic shock. Early identification of this organism may decrease mortality. Although our patient had no known cat or dog exposure, physicians should enquire about a history of animal exposure when a patient presents with an infection with no obvious cause.

La infección causada por Salmonella spp. y por Campylobacter spp. son las enfermedades transmitidas por alimentos (ETA) reportadas más frecuentemente en el mundo, siendo la carne de pollo uno de los vehículos alimentarios más importantes para ambas. Se presenta los primeros resultados de la vigilancia antimicrobiana integrada de las ETA de Salmonella spp. y Campylobacter spp. en tres poblaciones. En este estudio descriptivo de corte transverso, de casos consecutivos, se recolectaron muestras de diversos orígenes de carne de pollo y distintas poblaciones para su aislamiento, caracterización y perfil de resistencia. Se observó una prevalencia de Campylobacter spp. del 13% en alimentos, 20% en muestras clínicas y 55% en heces cloacales de aves, con alta prevalencia de Campylobacter jejuni en las tres poblaciones; de Salmonella spp fue 6% en alimentos, 13% en muestras clínicas y 3% en heces cloacales de aves, con predominio del serotipo Salmonella ser. Enteritidis en las muestras clínicas y heces cloacales de aves. La resistencia a ciprofloxacina de Campylobacter spp., entre 59-81% se destacó en las tres poblaciones estudiadas. Para Salmonella spp. se observó una resistencia a nitrofurantoina del 73% en heces cloacales de aves, 55% en alimentos y 19,4% en humanos; a tetraciclina, 42% en alimentos, 5% en muestras clínicas y 9% en heces cloacales; para el ácido nalidíxico la resistencia fue del 72% en animales y 53% en muestras clínicas. Es importante fortalecer la vigilancia integrada de la resistencia antimicrobiana en estas tres poblaciones de manera a detectar en forma oportuna mecanismos de resistencia que pudieran afectar al ser humano a través de la cadena alimentaria.

Abstract Objective Describe potential consequences and remedy for not intermittently auscultating fetal heart tones during travel to the imaging department and misdiagnosing a ruptured uterus on ultrasound as a synechiae. Study Design Retrospective chart review of case. Results Spontaneous uterine rupture in pregnancy is a rare and catastrophic event. Fetal monitoring is an important component for diagnosis, but fetal heart auscultation is usually discontinued while the patient is receiving imaging. We present a ruptured uterus at 28 weeks with delayed diagnosis secondary to interrupted fetal heart tone auscultation and a misdiagnosis of a rupture as a synechiae resulting in a seriously compromised newborn at delivery. Conclusion Intermittent fetal heart tone auscultation is a possible method of monitoring when the patient is off continuous fetal monitoring.

Purpose: The common use of nomograms in Low Dose Rate (LDR) permanent prostate brachytherapy (BT) allowsto estimate the number of seeds required for an implant. Independent dosimetry verification is recommended for eachclinical dosimetry in BT. Also, nomograms can be useful for dose calculation quality assurance and they could be adaptedto High Dose Rate (HDR). This work sets nomograms for LDR and HDR prostate-BT implants, which are applied tothree different institutions that use different implant techniques. Material and methods: Patients treated throughout 2010 till April 2011 were considered for this study. This examplewas chosen to be the representative of the latest implant techniques and to ensure consistency in the planning. A sufficientnumber of cases for both BT modalities, prescription dose and different work methodology (depending on theinstitution) were taken into account. The specific nomograms were built using the correlation between the prostatevo lume and some characteristic parameters of each BT modality, such as the source Air Kerma Strength, numberof implanted seeds in LDR or total radiation time in HDR. Results: For each institution and BT modality, nomograms normalized to the prescribed dose were obtained andfitted to a linear function. The parameters of the adjustment show a good agreement between data and the fitting.It should be noted that for each institution these linear function parameters are different, indicating that each centreshould construct its own nomograms. Conclusions: Nomograms for LDR and HDR prostate brachytherapy are simple quality assurance tools, specific foreach institution. Nevertheless, their use should be complementary to the necessary independent verification.

Purpose: The Valencia HDR applicators are accessories of the microSelectron HDR afterloading system (Nucletron) shaped as truncated cones. The base of the cone is either 2 or 3 cm diameter. They are intended to treat skin lesions, being the typical prescription depth 3 mm. In patients with eyelid lesions, an internal shielding is very useful to reduce the dose to the ocular globe. The purpose of this work was to evaluate the dose enhancement from potential backscatter and electron contamination due to the shielding. Material and methods: Two methods were used: a) Monte Carlo simulation, performed with the GEANT4 code, 2 cm Valencia applicator was placed on the surface of a water phantom in which 2 mm lead slab was located at 3 mm depth; b) radiochromic EBT films, used to verify the Monte Carlo results, positioning the films at 1.5, 3, 5 and 7 mm depth, inside the phantom. Two irradiations, with and without the lead shielding slab, were carried out. Results: The Monte Carlo results showed that due to the backscatter component from the lead, the dose level raised to about 200% with a depth range of 0.5 mm. Under the lead the dose level was enhanced to about 130% with a depth range of 1 mm. Two millimeters of lead reduce the dose under the slab with about 60%. These results agree with film measurements within uncertainties. Conclusions: In conclusion, the use of 2 mm internal lead shielding in eyelid skin treatments with the Valencia applicators were evaluated using MC methods and EBT film dosimetry. The minimum bolus thickness that was needed above and below the shielding was 0.5 mm and 1 mm respectively, and the shielding reduced the absorbed dose delivered to the ocular globe by about 60%.

Purpose: In this work a spreadsheet based program is presented that to a large extent independently verifies the calculations of individual plans of brachytherapy treatment planning systems for low dose rate, high dose rate and pulsed dose rate techniques.Material and methods: The verification program has been developed based on workbooks/spreadsheets. The treatment planning system output text files are automatically loaded into the new program, allowing the use of the source coordinates, the desired calculation point coordinates, and the dwell times of a patient plan. The source strength and the reference dates are entered by the user and then dose points calculations are independently performed. The programshows its results in a comparison of its calculated point dose data with the corresponding TPS outcome.Results: Results of 250 clinical cases show agreement with the TPS outcome within a 2% level.Conclusions: The program allows the implementation of the recommendations to verify the clinical brachytherapy dosimetry in a simple and accurate way, in only few minutes and with a minimum of user interactions.

Purpose: The aim of this work was to determine dose distributions for high-energy brachytherapy sources at spatial locations not included in the radial dose function gL(r) and 2D anisotropy function F(r,θ) table entries for radial distancer and polar angle θ. The objectives of this study are as follows: 1) to evaluate interpolation methods in order to accurately derive gL(r) and F(r,θ) from the reported data; 2) to determine the minimum number of entries in gL(r) and F(r,θ) that allow reproduction of dose distributions with sufficient accuracy.Material and methods: Four high-energy photon-emitting brachytherapy sources were studied: 60Co model Co0.A86, 137Cs model CSM-3, 192Ir model Ir2.A85-2, and 169Yb hypothetical model. The mesh used for r was: 0.25, 0.5, 0.75, 1, 1.5, 2–8 (integer steps) and 10 cm. Four different angular steps were evaluated for F(r,θ): 1°, 2°, 5° and 10°. Linear-linear and logarithmic-linear interpolation was evaluated for gL(r). Linear-linear interpolation was used to obtain F(r,θ) with resolution of 0.05 cm and 1°. Results were compared with values obtained from the Monte Carlo (MC) calculations for thefour sources with the same grid.Results: Linear interpolation of gL(r) provided differences ≤ 0.5% compared to MC for all four sources. Bilinear interpolation of F(r,θ) using 1° and 2° angular steps resulted in agreement ≤ 0.5% with MC for 60Co, 192Ir, and 169Yb, while 137Cs agreement was ≤ 1.5% for θ < 15°.Conclusions: The radial mesh studied was adequate for interpolating gL(r) for high-energy brachytherapy sources, and was similar to commonly found examples in the published literature. For F(r,θ) close to the source longitudinalaxis, polar angle step sizes of 1°-2° were sufficient to provide 2% accuracy for all sources.

In this study, we tested whether over-expressing the GABAB receptor R1a subtype in transgenic mouse forebrain neurons would be sufficient to induce spontaneous absence seizures. As hypothesized, these transgenic mice develop spontaneous, recurrent, bilaterally synchronous, 3–6 Hz slow spike and wave discharges between 2 and 4 months of age. These discharges are blocked by ethosuximide and exacerbated by baclofen confirming their absence nature. The discharges occur coincident with absence-like behaviors such as staring, facial myoclonus, and whisker twitching. However, in contrast to typical absence epilepsy models, these mice move during the ictal event, display spike and wave discharges in both thalamocortical and limbic circuitry, exhibit impaired hippocampal synaptic plasticity, and display significantly impaired learning ability. Collectively, these features are more characteristic of the less common but more debilitating atypical form of absence epilepsy. Thus, these data support a role for the GABABR1a receptor subtype in the etiology of atypical absence epilepsy.