Search

Studies the effects of fungicides azoxystrobin and epoxiconazole on phyllosphere fungi, senescence and yield of winter wheat. Yield-improving effects of azoxystrobin treatment; Interactions between plants, saprophytes and fungicides.

Background: Based on the findings from large randomized studies, Trastuzumab (T) was registered in 2006 for the treatment of early stage, HER2+ breast cancer (BC), after surgery, (neo)adjuvant chemotherapy (CT) and/or radiotherapy. However, limited systematic evidence is available on preceding, concomitant or sequential endocrine treatment (ET) based on the hormone receptor (HR) status. This large prospective observation study, reflecting the unrestricted routine practice of HER2 antibody treatment in Germany, allows to examine this topic. Methods: At present, more than 4000 patients (pts) have been enrolled in this ongoing study; 3446 pts from more than 316 centres were already sufficiently documented to be analysed. Details on concomitant treatment was collected at baseline and for 12 months after start of T. Results: With respect to an overall HR positivity (HR+), i.e. estrogen and/or progesterone receptor (ER, PR) being positive, of 2181/3446 (63%), these HER2+ptsdo not differ from the general BC population. Both hormone receptor types are positive in 47%, while ER+ only or PR+ only was detected in 13% and 3%, respectively. Adjuvant ET of any type, starting before or during T treatment, was given in 87% of HR+ and in 3% of HR- pts. 6% of HR+ pts received T and ET without concomitant CT. Details on the adjuvant treatment options are provided in the table: After a median follow-up of 26.4 months and the observation of a total of 296 relapse events (9%; HR-: 12%; HR+: 7%) relapse-free survival (RFS) was significantly shorter in the HR- compared to the HR+ group (at 3 years: 86 vs 92%, hazard ratio = 0.56, p < 0.0001). Conclusion: The vast majority of HER2+ BC pts receives concomitant endocrine therapy in case of a positive HR status. Regardless of the regulatory status in Germany, a small proportion of patients with co-positive early BC received T and ET without concomitant CT. No differences between receptor subgroups could be detected with respect to type of CT and its onset relative to T. HR status remains a paramount prognostic factor in this HER2+ sub-population of BC pts, with risk of early relapse (after a median follow-up of 2 years) almost twice as high in HR- tumors. [ABSTRACT FROM AUTHOR]

In liquid cultures of Pyrenophora teres, three phytotoxins may be found: L, L - N -(2-amino-2-carboxyethyl) aspartic acid (toxin A), anhydroaspergillomarasmine A (toxin B) and aspergillomarasmine A (toxin C). In particular, toxins A and C cause chlorotic and necrotic symptoms in detached barley leaves, toxin C being the most damaging, whereas toxin B is only weakly phytotoxic. When P. teres is grown in liquid modified Fries medium, toxin B is the main toxin accumulated, possibly due to a ring closure of toxin C at the low pH value of the medium. The amount of toxin B produced by 11 isolates of P. teres was compared in modified Fries medium. Generally, the most virulent isolates of P. teres produced higher amounts of toxin B than the less virulent isolates. During growth, the pH of the media decreased from 6.7 to about 3.0–3.5, followed by a slight increase to about 3.5–4.0. All isolates, except one, produced toxin B, whereas only two isolates produced toxin C and toxin A. Maintaining the pH at about 6.5 by sterile titration with 1 M NaOH resulted in a shift in toxin accumulation from toxin B to toxin C. The addition of tris or phosphate buffer to the media resulted in higher pH during the growth period, an increase in the total amount of toxins produced, and a shift in toxin accumulation from toxin B to toxin C. The higher pH value probably prevented the conversion of toxin C into toxin B. No toxins were produced in two routinely used media, potato glucose broth and grass broth. Toxin B and toxin C were purified by ion exchange chromatography and precipitation with HCl. [Copyright &y& Elsevier]

Detached leaves of 25 barleys, ranging from highly susceptible to highly resistant to Pyrenophora teres f. teres and Pyrenophora teres f. maculata, were tested for their reaction to three phytotoxins isolated from cultures of the fungus: toxin A [ L, L - N -(2-amino-2-carboxyethyl)aspartic acid], toxin C (aspergillomarasmine A) and toxin B (anhydroaspergillomarasmine A). 0.75 m M toxin A caused mainly dark yellow chlorotic symptoms but little necrosis, whereas leaves treated with 0.25 m M toxin C developed distinct necrotic symptoms and zones of light yellow chlorosis. Toxin B is only weakly toxic, and toxin B and control solutions containing aspartic acid in the concentration of 0.75 m M did not cause any symptoms. The best differentiation between the barleys was obtained by scoring chlorosis after 120 h, and the optimal toxin concentrations for this differentiation were 0.75 m M toxin A and 0.25 m M toxin C, respectively. Results with different toxin concentrations inducing distinct variation in symptom expression indicate that the two toxins have different potencies as phytotoxins. The reaction of the barleys to toxins A and C correlated well with their reaction to infection by P. teres f. teres and P. teres f. maculata, suggesting that toxins A and C may be used to select resistant barley lines in the early stages of a breeding programme. [Copyright &y& Elsevier]

More than 3550 species of mosquitoes are known worldwide, and only a fraction is involved in the transmission of arboviruses. Mosquitoes in sylvatic and semi-sylvatic habitats may rapidly adapt to urban parks and metropolitan environments, increasing human contact. Many of these mosquitoes have been found naturally infected with arboviruses from the Alphaviridae , Flaviviridae , and Bunyaviridae families, with many being the cause of medically important diseases. However, there is a gap in knowledge about the vector status of newly invasive species and their potential threat to human and domestic animal populations. Due to their rapid distribution, adaptation to urban environments, and anthropophilic habits, some neglected mosquito species may deserve more attention regarding their role as secondary vectors. Taking these factors into account, we focus here on Aedes ( Ochlerotatus ) scapularis (Rondani), Aedes japonicus japonicus (Theobald), and Aedes ( Fredwardsius ) vittatus (Bigot) as species that have the potential to become important disease vectors. We further discuss the importance of these neglected mosquitoes and how factors such as urbanization, climate change, and globalization profoundly alter the dynamics of disease transmission and may increase the participation of neglected species in propagating diseases.

Introduction: Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of "trial-ineligible" and "potentially trial-eligible" patients., Methods: Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either "potentially trial-eligible" or "trial-ineligible" according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042)., Results: Of 746 patients included, 343 patients (46.0%) were classified as "trial-ineligible" and had significantly worse outcomes compared with "potentially trial-eligible" patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2-8.4) versus 10.3 (95% CI: 8.4-13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19-1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4-20.3) versus 25.3 (95% CI: 19.8-30.4) months, hazard ratio of 1.36 (95% CI: 1.10-1.67), p equals 0.004., Conclusions: Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses., Competing Interests: Dr. Griesinger has received support for the present manuscript (grants to the institution) from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. Furthermore, he has received grants (to the institution) from Amgen and Siemens; personal fees for consulting from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; and personal fees for participation on a data safety monitoring board or advisory board from Merck Sharp & Dohme. He declares an unpaid fiduciary role in the German Society of Hematology and Oncology (first author of Oncopedia recommendations) and in the German Cancer Society (S3 guidelines author). Dr. Sebastian has a consulting or advisory role and has received honoraria from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Eli Lilly, Merck Sharp & Dohme, Merck-Serono, Novartis, Pfizer, Roche, Takeda, and Tesaro; he has also received research funding from AstraZeneca. Dr. Brueckl has received personal fees and fees for lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche and fees for educational events from AstraZeneca, Boehringer, Eli Lilly, Pfizer, and Roche. Furthermore, he has received congress fees and personal fees from AstraZeneca, Boehringer, and Roche Pharma and has received personal fees and support for participation on advisory boards from AstraZeneca, Boehringer, Bristol-Myers Squibb, Eli Lilly Pharma, Novartis, Merck Sharp & Dohme and Roche. He declares a patent planned (EP21183549). Dr. Hummel has received personal fees as steering board member and fees for consulting from Amgen; has received personal fees for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Bristol-Myers Squibb, and Boehringer Ingelheim; payment for expert testimony from Amgen and Boehringer Ingelheim; support for attending meetings and/or travel from Amgen and Bristol-Myers Squibb; and personal fees for participation on a data safety monitoring board or advisory board from Amgen and Boehringer Ingelheim. Dr. Kern has received support for attending meetings and/or travel from AstraZeneca, Merck Sharp & Dohme, Pfizer, and Roche and for participation on advisory boards from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck/Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda. Dr. Wesseler has received honoraria for lectures and travel from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda. Dr. Hipper and Mrs. Groth have received research funding (to their employer AIO-Studien-gGmbH) from Amgen Ltd., AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, GlaxoSmithKline Research & Development Limited, Janssen-Cilag GmbH, Eli Lilly Deutschland GmbH, Merck Sharp & Dohme GmbH, Novartis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG, and Takeda Pharma Vertriebs GmbH & Co. KG. Dr. Weichert has received research support (to the institution) from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche; fees for consulting, travel support, fees for participation on advisory boards and lectures, and payment or honoraria for presentations, speakers bureaus, manuscript writing, or educational events from ADC, Agilent, Amgen, Astellas, AstraZeneca, Bayer, Boehringer, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Illumina, Janssen, Eli Lilly, Merck, Molecular Health, Merck Sharp & Dohme, Novartis, Pfizer, Siemens, Takeda, and Roche. Mr. Dörfel holds iOMEDICO shares. Dr. Schröder has received consulting fees from iOMEDICO, Celgene, Roche, Bristol-Myers Squibb, Clovis Oncology GmbH, GlaxoSmithKline, Boehringer Ingelheim, Amgen, Novartis, Merck Sharp & Dohme, AOP, Searchlight, Pharma Partner, Medixline GmbH, Eisai, HE Research GmbH, AbbVie, NIO, I+E Research, Octapharma and IPSEN. Further he declares honoraria from iOMEDICO, Celgene, Roche, Bristol-Myers Squibb, Clovis Oncology GmbH, GlaxoSmithKline, Boehringer Ingelheim, Amgen, Novartis, Merck Sharp & Dohme, AOP, Searchlight, Pharma Partner, Medixline GmbH, Eisai, HE Research GmbH, AbbVie, NIO, I+E Research, Octapharma, IPSEN, BeiGene, and Miltenyi. Dr. Eberhardt has received research funding (to the institution) from Eli Lilly, AstraZeneca, and Bristol-Myers Squibb; honoraria for advisory boards from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Janssen-Cilag, Merck/Merck Sharp & Dohme, Roche, Pfizer, Novartis, Takeda, Boehringer Ingelheim, and AbbVie; and honoraria for lectures from Amgen, Baumgart Consult, Bristol-Myers Squibb, Merck/Merck Sharp & Dohme, Roche, Pfizer, Novartis, Takeda, Boehringer Ingelheim, and AbbVie. Dr. Thomas has received research funding (to the institution) from AstraZeneca, Bristol-Myers Squibb, Merck, Roche, and Takeda; personal fees for speakers bureaus and advisory boards from Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda; and support for attending meetings and/or travel from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen Oncology, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Takeda. The remaining authors declare no conflict of interest., (© 2024 by the International Association for the Study of Lung Cancer.)

Objective: To assess inflammatory bowel disease (IBD) activity with Doppler ultrasound in pediatric patients, comparing the accuracy of the ultrasound findings with that of the concentrations of fecal calprotectin (FC)., Materials and Methods: In a consecutive series, we evaluated 53 examinations of 44 pediatric patients seen between 2014 and 2020: 28 with Crohn's disease, 15 with ulcerative colitis, and one with IBD unclassified. The diagnosis of IBD was made in accordance with the Porto criteria. The alteration studied in the greatest detail was bowel wall flow, which was classified by the lead investigator and two pediatric radiologists, all of whom were blinded to the FC concentrations and the other ultrasound findings. Bowel wall flow was categorized as low if there were up to 2 Doppler ultrasound signals/cm 2 , moderate if there were 3-5 signals/cm 2 , and high if there were more than 5 signals/cm 2 ., Results: The agreement among the radiologists was substantial (kappa = 0.73). In cases in which ultrasound showed low bowel wall flow, the median FC concentration was 92 µg/g (interquartile range, 33-661 µg/g), whereas it was 2,286 µg/g (interquartile range, 1,728-5,612 µg/g) in those in which ultrasound showed high bowel wall flow. In the sample as a whole, the sensitivity and specificity of ultrasound was 89.7% and 92.0%, respectively, for the detection of inflammatory activity; 95.5% and 90.9%, respectively, for the detection of Crohn's disease; and 81.3% and 100.0%, respectively, for the detection of ulcerative colitis., Conclusion: Ultrasound of the bowel wall showed a strong correlation with FC concentrations in the assessment of inflammatory activity in pediatric patients with IBD.

Dengue viruses (DENVs) are mosquito-borne flaviviruses causing millions of human infections each year and pose a challenge for public health systems worldwide. Aedes aegypti is the principal vector species transmitting DENVs to humans. Controlling Ae. aegypti is difficult due to the abundance of breeding sites and increasing insecticide resistance in the vector populations. Developing new vector control strategies is critical for decreasing the disease burden. One potential approach is genetically replacing Ae. aegypti populations with vector populations highly resistant to DENV transmission. Here, we focus on an alternative strategy for generating dengue 2 virus (DENV-2) resistance in genetically-modified Ae. aegypti in which the mosquitoes express an inactive form of Michelob&#95;x (Mx), an antagonist of the Inhibitor of Apoptosis (IAP), to induce apoptosis in those cells in which actively replicating DENV-2 is present. The inactive form of Mx was flanked by the RRRRSAG cleavage motif, which was recognized by the NS2B/NS3 protease of the infecting DENV-2 thereby releasing and activating Mx which then induced apoptosis. Our transgenic strain exhibited a significantly higher mortality rate than the non-transgenic control when infected with DENV-2. We also transfected a DNA construct containing inactive Mx fused to eGFP into C6/36 mosquito cells and indirectly observed Mx activation on days 3 and 6 post-DENV-2 infections. There were clear signs that the viral NS2B/NS3 protease cleaved the transgene, thereby releasing Mx protein into the cytoplasm, as was confirmed by the detection of eGFP expression in infected cells. The present study represents proof of the concept that virus infection can be used to induce apoptosis in infected mosquito cells., (© 2023. The Author(s).)

Introduction: Cognitive impairment is common in individuals presenting to alcohol and other drug (AOD) settings and the presence of biopsychosocial complexity and health inequities can complicate the experience of symptoms and access to treatment services. A challenge for neuropsychologists in these settings is to evaluate the likely individual contribution of these factors to cognition when providing an opinion regarding diagnoses such as acquired brain injury (ABI). This study therefore aimed to identify predictors of cognitive functioning in AOD clients attending for neuropsychological assessment., Methods: Clinical data from 200 clients with AOD histories who attended for assessment between 2014 and 2018 were analysed and a series of multiple regressions were conducted to explore predictors of cognitive impairment including demographic, diagnostic, substance use, medication, and mental health variables., Results: Regression modelling identified age, gender, years of education, age of first use, days of abstinence, sedative load, emotional distress and diagnoses of ABI and developmental disorders as contributing to aspects of neuropsychological functioning. Significant models were obtained for verbal intellectual functioning (Adj R 2 = 0.19), nonverbal intellectual functioning (Adj R 2 = 0.10), information processing speed (Adj R 2 = 0.20), working memory (Adj R 2 = 0.05), verbal recall (Adj R 2 = 0.08), visual recall (Adj R 2 = 0.22), divided attention (Adj R 2 = 0.14), and cognitive inhibition (Adj R 2 = 0.07)., Conclusions: These findings highlight the importance of careful provision of diagnoses in clients with AOD histories who have high levels of unmet clinical needs. They demonstrate the interaction of premorbid and potentially modifiable comorbid factors such as emotional distress and prescription medication on cognition. Ensuring that modifiable risk factors for cognitive impairment are managed may reduce experiences of cognitive impairment and improve diagnostic clarity.

Background: Rural populations are older, have higher diabetes prevalence, and have less improvement in diabetes-related mortality rates compared to urban counterparts. Rural communities have limited access to diabetes education and social support services., Objective: Determine if an innovative population health program that integrates medical and social care models improves clinical outcomes for patients with type 2 diabetes in a resource-constrained, frontier area., Design/participants: Quality improvement cohort study of 1764 patients with diabetes (September 2017-December 2021) at St. Mary's Health and Clearwater Valley Health (SMHCVH), an integrated health care delivery system in frontier Idaho. The United States Department of Agriculture's Office of Rural Health defines frontier as sparsely populated areas that are geographically isolated from population centers and services., Intervention: SMHCVH integrated medical and social care through a population health team (PHT), where staff assess medical, behavioral, and social needs with annual health risk assessments and provide core interventions including diabetes self-management education, chronic care management, integrated behavioral health, medical nutritional therapy, and community health worker navigation. We categorized patients with diabetes into three groups: patients with two or more PHT encounters during the study (PHT intervention), one PHT encounter (minimal PHT), and no PHT encounters (no PHT)., Main Measures: HbA1c, blood pressure, and LDL over time for each study group., Key Results: Of the 1764 patients with diabetes, mean age was 68.3 years, 57% were male, 98% were white, 33% had three or more chronic conditions, and 9% had at least one unmet social need. PHT intervention patients had more chronic conditions and higher medical complexity. Mean HbA1c of PHT intervention patients significantly decreased from baseline to 12 months (7.9 to 7.6%, p < 0.01) and sustained reductions at 18 months, 24 months, 30 months, and 36 months. Minimal PHT patients decreased HbA1c from baseline to 12 months (7.7 to 7.3%, p < 0.05)., Conclusion: The SMHCVH PHT model was associated with improved hemoglobin A1c among less well-controlled patients with diabetes., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Objective: In considering the cognitive harms of methamphetamine (MA) use, there is currently a limited appreciation of the profile of pre-existing, comorbid, or modifiable risk factors for cognitive impairment in individuals with MA-polydrug use who present to clinical services. This is in contrast to the well-recognized evidence in alcohol use groups. The aim of this study was to investigate the biopsychosocial and neuropsychological profiles of MA-polysubstance using individuals reporting cognitive impairment in comparison to an alcohol-using group., Methods: A retrospective file audit was undertaken of individuals who presented for assessment to a specialist addiction neuropsychology service and reported either more than 1 year of heavy MA use as part of a polydrug use history ( n = 40) or having only used alcohol ( n = 27). Clinical histories including demographic, medical, mental health, substance use, and neuropsychological assessment results were extracted from medical records. Between group comparisons were conducted to explore differences in the MA-polydrug vs. the alcohol group., Results: Individuals in the MA-polydrug group were significantly younger, commenced substance use at an earlier age, were more likely to have an offending history, and experienced an overdose than those in the alcohol group. No differences in comorbid neurodevelopmental, psychiatric or acquired brain injury diagnoses were observed between groups. For neuropsychological functioning, significant group differences were observed in overall IQ, semantic verbal fluency, and psychomotor tracking, where individuals in the alcohol group performed significantly worse., Conclusions: Neuropsychological profiles were largely equivalent between groups across cognitive domains, with minor differences in favor of the MA-polydrug group. Relative to the general population, cognitive functioning was reduced for both groups across a range of domains. High rates of comorbid mental health concerns were common across both groups, however, individuals in the MA-polydrug group presented with a higher risk of overall harm from substance use at a significantly younger age which is a unique concern for this group. These findings highlight the importance of considering the biopsychosocial factors, such as age of first use, emotional distress, indirect substance related harms including overdose and blood born virus infection that may be relevant to experiences of cognitive difficulty in MA-polydrug users., Competing Interests: DL has received travel support and speaker honoraria from Astra Zeneca, Bristol Myers Squibb, Camurus, Indivior, Janssen, Lundbeck, Servier, and Shire. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gooden, Petersen, Bolt, Curtis, Manning, Cox, Lubman and Arunogiri.)

Background: The effects of convalescent plasma (CP) therapy in hospitalised patients with coronavirus disease 2019 (COVID-19) remain uncertain. This study investigates the effect of CP on clinical improvement in these patients., Methods: This is an investigator-initiated, randomised, parallel arm, open-label, superiority clinical trial. Patients were randomly (1:1) assigned to two infusions of CP plus standard of care (SOC) or SOC alone. The primary outcome was the proportion of patients with clinical improvement 28 days after enrolment., Results: A total of 160 (80 in each arm) patients (66.3% critically ill, 33.7% severely ill) completed the trial. The median (interquartile range (IQR)) age was 60.5 (48-68) years; 58.1% were male and the median (IQR) time from symptom onset to randomisation was 10 (8-12) days. Neutralising antibody titres >1:80 were present in 133 (83.1%) patients at baseline. The proportion of patients with clinical improvement on day 28 was 61.3% in the CP+SOC group and 65.0% in the SOC group (difference -3.7%, 95% CI -18.8-11.3%). The results were similar in the severe and critically ill subgroups. There was no significant difference between CP+SOC and SOC groups in pre-specified secondary outcomes, including 28-day mortality, days alive and free of respiratory support and duration of invasive ventilatory support. Inflammatory and other laboratory marker values on days 3, 7 and 14 were similar between groups., Conclusions: CP+SOC did not result in a higher proportion of clinical improvement on day 28 in hospitalised patients with COVID-19 compared to SOC alone., Competing Interests: Conflict of interest: L. Sekine has nothing to disclose. Conflict of interest: B. Arns has nothing to disclose. Conflict of interest: B.R. Fabro has nothing to disclose. Conflict of interest: M.M. Cipolatt has nothing to disclose. Conflict of interest: R.R.G. Machado received support from “Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)” (2017/24769-2). Conflict of interest: E.L. Durigon has nothing to disclose. Conflict of interest: E. Parolo has nothing to disclose. Conflict of interest: J.A.S. Pellegrini has nothing to disclose. Conflict of interest: M.V. Viana has nothing to disclose. Conflict of interest: P. Schwarz has nothing to disclose. Conflict of interest: T.C. Lisboa has nothing to disclose. Conflict of interest: J.M.S. Dora has nothing to disclose. Conflict of interest: J.P. Portich has nothing to disclose. A.A. Paz has nothing to disclose. L. Silla has nothing to disclose. A.M. Balsan has nothing to disclose. Conflict of interest: F.d-S. Schirmer has nothing to disclose. Conflict of interest: J.P.M. Franz has nothing to disclose. Conflict of interest: L.M. da-Silveira has nothing to disclose. Conflict of interest: R.C. Breunig has nothing to disclose. Conflict of interest: V. Petersen has nothing to disclose. Conflict of interest: M. Sosnoski has nothing to disclose. Conflict of interest: N.F. Mesquita has nothing to disclose. Conflict of interest: F.C.Z. Volpato has nothing to disclose. Conflict of interest: D. Sganzerla has nothing to disclose. Conflict of interest: M. Falavigna has nothing to disclose. Conflict of interest: R.G. Rosa received research grants from Brazilian Ministry of Health. Conflict of interest: A.P. Zavascki is a research fellow of the National Council for Scientific and Technological Development (CNPq), Ministry of Science and Technology, Brazil (304226/2018-1), and receives a research grant not related to this work from Pfizer (WI242215 2018)., (Copyright ©The authors 2022.)

Background: Aedes scapularis is a neotropical mosquito that is competent to vector viruses and filariae. It is reputed to be highly morphologically and genetically polymorphic, facts that have raised questions about whether it is a single taxonomic entity. In the last five decades, authors have posed the hypothesis that it could actually be a species complex under incipient speciation. Due to its epidemiological importance, its taxonomic status should be determined with confidence., Aim and Method: Our objective was to investigate more deeply the polymorphism of Ae. scapularis to detect any evidence of incipient speciation of cryptic species. We then compared populational samples from the Southeastern, Northern and Northeastern regions of Brazil. The biological markers used in the comparison were: the complete mitochondrial DNA, the isolated mitochondrial gene cytochrome oxidase subunit I (COI) and wing geometry., Results and Discussion: As expected, high morphological/genetic polymorphism was observed in all Ae. scapularis populations, however it was not indicative of segregation or incipient speciation. There was no correlation between wing shape and the geographical origin of the populations analysed. A congruent observation resulted from the analysis of the COI gene, which revealed a high number of haplotypes (51) and no clusterization of populational samples according to the original biomes. In the phylogenetic analysis of the 13 mitochondrial protein-coding genes, the Ae. scapularis clade clustered with maximum support (100% bootstrap support and posterior probability of 1). No significant internal structure was observed in the Ae. scapularis clade, which was nearly a polytomy. Taken together, our results indicate that this species is not a species complex., Conclusion: We conclude that there was no indication, in the analysed regions, of the occurrence of more than one taxon in the species Ae. scapularis, despite it being highly polymorphic. By ruling out the former species complex hypothesis, our phylogenetic results reinforce that Ae. scapularis is a single taxonomic unit and should be monitored with standardized surveillance and control methods., (Copyright © 2021. Published by Elsevier B.V.)

Background and Objectives: Sleep problems are common among clients attending alcohol and drug services, yet the specific components of sleep disturbed by primary drug of concern (PDOC), and their relationships to affective disorder symptoms are unclear., Methods: We examined sleep problems in clients (n = 32) attending a specialist addiction clinic., Results: Global sleep quality was rated poor by >90% of participants (particularly disturbances, latency and efficiency components), with significant associations (p < .05) between poor sleep quality and depression (r = .517), anxiety (r = .571) and stress (r = .503). Sleep quality was significantly poorer among those with a nonalcohol PDOC compared with alcohol as PDOC, t(22) = 3.09, p = .005., Conclusion and Scientific Significance: Poor sleep is almost ubiquitous among clients attending alcohol and drug services. However, components of sleep quality disturbed differ in terms of PDOC, highlighting the need for individualised sleep interventions., (© 2021 American Academy of Addiction Psychiatry.)

Background: Intimate partner violence (IPV) commonly affects surgical patients, particularly trauma patients. However, baseline knowledge of IPV is poor among surgeons and screening is variable. We designed a project to educate surgical residents on IPV and standardize screening in all trauma patients., Materials and Methods: Quality improvement frameworks and the Modified Provider Survey were used to examine residents' attitudes and behaviors regarding IPV at a level one trauma center. An educational curriculum was designed with a trainee-led, multidisciplinary team to address knowledge gaps, barriers, and relevant reporting laws, and provide framing language that normalized screening., Results: Fifty-seven surgical residents (64% response rate) spanning post-graduate years 1-7 completed surveys. All respondents believed IPV was relevant to their patients, yet only 4% correctly identified the prevalence of IPV. Only 15% felt comfortable screening for IPV and 75% felt they had received inadequate training. The most common barriers to screening were insufficient knowledge of community resources and what to do if patients screened positive. Most residents grossly underestimated the incidence of IPV and 19% believe healthcare providers have a limited role in being able to help IPV victims. There were no significant differences in responses between male and female residents or among residents from different postgraduate levels., Conclusions: Surgical residents believe IPV is relevant, but few feel they have adequate training. Residents vastly underestimated the societal prevalence of IPV and the majority never screened patients for IPV. A residency-wide curriculum can address common misperceptions and perceived barriers., (Copyright © 2021. Published by Elsevier Inc.)

This study was undertaken to assess the capacity of the upflow anaerobic sludge blanket (UASB) reactor, one of the most commonly used systems in Brazilian sewage treatment plants, to remove municipal sewage toxicity using different Danio rerio life stages (embryo, embryo-larval, larval, adult), and estrogenicity using in vitro (yeast Saccharomyces cerevisiae) and in vivo (vitellogenin induction in D. rerio) assays. Sensitivity of chronic fish assays were compared to the chronic Ceriodaphnia dubia assay. UASB-treated sewage met Brazilian legal limits for BOD and COD removals, but did not remove toxicity, and treated sewage remained extremely toxic to D. rerio larvae and C. dubia, and highly toxic to D. rerio embryos. The 4-day embryo assay had the same sensitivity as the adult acute toxicity assay, and could safely replace it, avoiding the need to sacrifice adult fish. No significant differences were identified in vitellogenin induction among organisms exposed to sewage or control. However, the in vitro test showed that anaerobic treatment increased sample estrogenicity from 27 to 40 ng equivalents of 17-β estradiol per liter, a result corroborated by the greater induction of vitellogenin in male fish exposed to 5% (2.73 μg/g) and 20% (2.12 μg/g) treated sewage compared to the same concentrations of raw sewage (0.174 μg/g at 5% and 0.188 μg/g at 20%). Thus, UASB reactor should be followed by post-treatment to reduce risks of sewage discharge to receiving waters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction and Aims: Cognitive impairment is a common feature of individuals with substance-use disorders. However, research tends to exclude highly complex clinical cases, limiting the generalisability of findings for 'real-world' populations. The objective of this study was to examine the complexities associated with addiction, substance use and cognitive impairment through the characterisation of client presentations to a newly established specialised addiction neuropsychology service., Design and Methods: Retrospective case file audit. Neuropsychological assessment reports for consenting clients over a 4-year period were de-identified and reviewed. Cognitive domains assessed included attention, processing speed, working memory, intellectual functioning, memory and executive functioning., Results: Of the 200 case files examined, the majority were male clients, with 11 years or lower of education and a history of daily substance use, with 30% continuing to use daily. Seventy-one percent had a formal mental health diagnosis and 41% had reported a history of trauma. The most prevalent cognitive impairments were observed in complex attention (50%) and memory (40%). New diagnoses were conveyed in 25% of cases, comprising acquired brain injury (16%) and neurodevelopmental disabilities (9%)., Discussion and Conclusions: It is common for clients with substance use histories referred to an addiction neuropsychology service to present with complex histories including psychosocial difficulties, comorbid mental health and medical issues and cognitive impairment. As such, careful diagnostic formulations are required when multiple factors may contribute to cognitive deficits. This study highlights the importance of a state-wide specialist addiction neuropsychology service in supporting diagnostic clarification and informing relevant treatment approaches., (© 2020 Australasian Professional Society on Alcohol and other Drugs.)

Insect-specific viruses do not replicate in vertebrates. Here, we report the genome sequence of a novel strain of a Phasi Charoen-like virus (PCLV) that was isolated from a wild Aedes aegypti mosquito collected in Aracajú, Sergipe State, Brazil. The coding-complete genome of the PCLV is described in this report., (Copyright © 2020 Cunha et al.)

The aim of the Avera Twin Register (ATR) is to establish a prospective longitudinal repository of twins, multiples, siblings and family members' biological samples to study environmental and genetic influences on health and disease. Also, it is our intention to contribute to international genome-wide association study (GWAS) twin consortia when appropriate sample size is achieved within the ATR. The ATR is young compared with existing registers and continues to collect a longitudinal repository of biological specimens, survey data and health information. Data and biological specimens were originally collected via face-to-face appointments or the postal department and consisted of paper-informed consents and questionnaires. Enrollment of the ATR began on May 18, 2016 and is located in Sioux Falls, South Dakota, a rural and frontier area in the Central United States with a regional population of approximately 880,000. The original target area for the ATR was South Dakota and the four surrounding states: Minnesota, Iowa, North Dakota and Nebraska. The ATR has found a need to expand that area based on twin and multiple siblings who live in various areas surrounding these states. A description of the state of the ATR today and its transition to online data collection and informed consent will be presented. The ATR collects longitudinal data on lifestyle, including diet and activity levels, aging, plus complex traits and diseases. All twins and multiples participating in the ATR are genotyped on the Illumina Global Screening Array and receive zygosity results.

Background: The granulocyte-colony stimulating factor (G-CSF) biosimilar filgrastim (Nivestim™) reduces the duration and severity of neutropenia and the frequency of occurrence of febrile neutropenia (FN). Administration of this biosimilar filgrastim and the patient population receiving it at home have not been sufficiently documented in day-to-day medical practice. Insight into home administration may help optimize the management of FN in this setting, potentially at a reduced cost and patient burden vs hospital administration., Materials and Methods: This was a prospective, non-interventional, non-comparative, multisite study involving 171 patients across 29 sites treated with at least one dose of filgrastim. Mean age was 59.3 years, and most patients were female and G-CSF-naïve. The data collected originated from paper-based patient questionnaires and routine documentation by the treating physicians. The primary endpoint was the characterization of patients treated with filgrastim. Secondary endpoints were satisfaction with filgrastim, effectiveness, safety and tolerability, and compliance with prescription., Results: Most patients had solid tumors (95.9%), mainly located in the breast, while 4.7% had malignant hematological disease. Solid tumors were recorded as grade 1 (7.9%), grade 2 (28.0%), grade 3 (45.7%), and grade 4 (3.0%), and the majority of patients classified at TNM Stages I and II. Many patients (71.0%) could self-inject filgrastim and 72.2% found the handling instructions "extremely straightforward and easy to understand" at least once. Nearly all (99.4%) patients found the syringes "easy to use" at least once and 91.7% were willing to continue home administration. The mean patient satisfaction score for home administration was 1.9±0.9, ranging from 1 (very satisfied) to 6 (absolutely dissatisfied). No cases of neutropenia were observed and only one event of FN occurred., Conclusion: Home-based prophylaxis for FN with filgrastim was found to be effective, well tolerated, and well received by patients (ClinicalTrials.gov Identifier: NCT02956967)., Competing Interests: Disclosure B Otremba has nothing to disclose regarding financial relationships or other conflicts of interest; C Hielscher has received honoraria from Pfizer, Roche and Celgene; V Petersen has nothing to disclose regarding financial relationships or other conflicts of interest; C Petrik is an employee of Pfizer Inc and holds stock in Pfizer.

Morphology of male genitalia of culicids is generally species-specific and often used as a taxonomic marker. However, some characters of the male genitalia vary intraspecifically and are not taxonomically diagnostic. This might be the case of Aedes scapularis, a Neotropical culicid with vector competence for arboviruses and filarial worms. Males of this species may or not present a retrorse process (RP) in the genitalic claspette filaments, which led authors to suspect that this variance might be indicative of population divergence or incipient speciation process. This suspicion has not been investigated hitherto and it is not known if there are variable patterns of RPs. We hypothesized that the presence of the RP varies intraspecifically in Ae. scapularis and then we statistically evaluated the variability of this character in a single population. To this study the genitalia of 73 males of Ae. scapularis were prepared, and their RPs were meristically quantified and categorized according to the phenotypes observed. We noted that the presence or RPs is a polymorphic character because it varied inter and intra-individually. The presence of a single RP on each claspette filament was the predominant pattern (77%), but absent or multiple RPs in each filament were also found either in bilateral symmetry or asymmetry. Thus, we conclude that the presence of RPs owing to its high variability is not indicative of populational divergence or diagnostic of species complex within Ae. scapularis.

The Avera Twin Register (ATR) aims to study environmental and genetic influences on health and disease using a longitudinal repository of biological specimens, survey data, and health information provided by multiples and their family members. The ATR is located in Sioux Falls, South Dakota, which is a rural and frontier area in the Midwestern United States with a density of four people per square kilometer. The target area of the ATR is South Dakota and the four surrounding states: Minnesota, Iowa, North Dakota, and Nebraska. Enrollment of twins and higher-order multiples of all ages and their family members started on May 18, 2016. A description of the first 13 months of enrollment in this longitudinal register will be provided. The ATR will collect longitudinal data on lifestyle, including diet and activity levels, aging, complex traits, and diseases. Upon registration, all participants are genotyped on the Illumina Global Screening Array (GSA) and twins and higher order multiples receive information on their zygosity. The ATR aims to contribute to large international GWAS consortia and collaborates closely with the Netherlands Twin Register, allowing for the comparison of collected data and analyses of results. In addition, the ATR will address twin-specific questions.

The field of morphometrics is developing quickly. Recent advances have enabled geometric techniques to be applied to many zoological problems, particularly those involving epidemiologically-relevant mosquitoes. Herein, we briefly introduce geometric morphometric (GM) techniques and then review selected groups of mosquitoes (Culicidae) to which those techniques have been applied. In most of the reviewed cases, GM was capable of satisfactorily discriminating among the tested groups primarily when the studies considered differences within and among species, sexual dimorphism, treatments and the separation of laboratory strains. Although GM approaches have developed quite rapidly, some caution must be taken during data processing for a reliable biometrical approach, such as allometry and asymmetry analyses, scale removal and wing clarification staining for landmark digitization. We also critically forecast directions in this field and discuss how the creation of image databases should enhance species identification in culicids., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cohesion refers to the linguistic elements of discourse that contribute to its continuity and is an important element to consider as part of written language intervention, especially in children with language learning disabilities (LLD). There is substantial evidence that children with LLD perform more poorly than typically developing (TD) peers on measures of cohesion in spoken language and on written transcription measures; however, there is far less research comparing groups on cohesion as a measure of written language across genres., Aims: The current study addresses this gap through the following two aims. First, to describe and compare cohesion in narrative and expository writing samples of children with and without language learning disabilities. Second, to relate measures of cohesion to written transcription and translation measures, oral language, and writing quality., Methods & Procedures: Fifty intermediate-grade children produced one narrative and one expository writing sample from which measures of written cohesion were obtained. These included the frequency, adequacy and complexity of referential and conjunctive ties., Outcomes & Results: Expository samples resulted in more complex cohesive ties and children with TD used more complex ties than peers with LLD. Different relationships among cohesion measures and writing were observed for narrative verse expository samples., Conclusions & Implications: Findings from this study demonstrate cohesion as a discourse-level measure of written transcription and how the use of cohesion can vary by genre and group (LLD, TD). Clinical implications for assessment, intervention, and future research are provided., (© 2016 Royal College of Speech and Language Therapists.)

A high proportion of patients with breast cancer develop bone metastases, yet data on routine treatment with bone-targeted agents (BTA) are rare. We report real-life outcome data of patients with breast cancer metastasised to the bone treated by office-based oncologists in Germany. The ongoing, prospective, multicentre, population-based cohort study Tumour Registry Breast Cancer (TMK) was started in 2007 in 140 centres across Germany. This interim analysis of 1094 patients with bone metastases revealed differences among the tumour subtypes: at start of first-line therapy, 36% of the patients with hormone receptor (HR)-positive and only 20% of the patients with HR-negative tumours presented with bone-only metastasis. The majority of patients with bone metastases (89%, n = 976) received BTA therapy. In 2014-2015, 37% of the patients received the bisphosphonate zoledronic acid and 36% the antibody denosumab. Median duration of BTA therapy was 20 months (interquartile range 31.5 months), starting a median of 3 weeks after diagnosis of bone metastases, and ending a median of 7 weeks before death. The median overall survival (OS) also varied among the types of metastasis at start of first-line therapy ranging from 54 months (95% confidence interval [CI] 37.6-70.8), 38 months (95% CI 29.4-44.2) to 28 months (95% CI 24.2-31.0) for patients with bone-only metastases, non-visceral with or without bone metastases and visceral with or without bone metastases respectively. We show that choice and duration of BTA therapies are in conformity with guidelines applicable in Germany. To our knowledge, this is the first presentation of data on incidence, metastatic pattern, treatment and survival of patients with bone metastases in routine practice., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The worldwide expansion of new emergent arboviruses such as Chikungunya and Zika reinforces the importance in understanding the role of mosquito species in spreading these pathogens in affected regions. This knowledge is essential for developing effective programs based on species specificity to avoid the establishment of endemic transmission cycles sustained by the identified local vectors. Although the first autochthonous transmission of Chikungunya virus was described in 2014 in the north of Brazil, the main outbreaks were reported in 2015 and 2016 in the northeast of Brazil., Methodology/principal Findings: During 5 days of February 2016, we collected mosquitoes in homes of 6 neighborhoods of Aracaju city, the capital of Sergipe state. Four mosquito species were identified but Culex quinquefasciatus and Aedes aegypti were the most abundant. Field-caught mosquitoes were tested for Chikungunya (CHIKV), Zika (ZIKV) and Dengue viruses (DENV) by qRT-PCR and one CHIKV-infected Ae. aegypti female was detected. The complete sequence of CHIKV genome was obtained from this sample and phylogenetic analysis revealed that this isolate belongs to the East-Central-South-African (ECSA) genotype., Conclusions: Our study describes the first identification of a naturally CHIKV-infected Ae. aegypti in Brazil and the first report of a CHIKV from ECSA genotype identified in this species in the Americas. These findings support the notion of Ae. aegypti being a vector involved in CHIKV outbreaks in northeast of Brazil.

Background: In metastatic colorectal cancer, no upfront or on-treatment markers are available to determine the prognosis or efficacy for chemotherapy in combination with bevacizumab., Patients and Methods: The current analysis was performed to evaluate the prognostic value of disease and patient characteristics (age, number of metastatic sites, stage of primary tumor, performance status, carcinoembryonic antigen (CEA)) and on-treatment changes of CEA (response after 8-12 weeks of treatment and specific patterns of CEA kinetics) in patients from an observational cohort study of chemotherapy with bevacizumab., Results: Baseline factors were available from 1,438 patients. Patients with baseline CEA levels > 20 ng/ml, more than 1 metastatic site, and age > 75 years showed significantly lower progression-free (PFS) and overall survival in multivariate analysis. A CEA response of > 30% during treatment was associated with increased PFS. In addition, the pattern of CEA kinetics predicts survival and response to treatment., Conclusion: In summary, baseline CEA, number of metastatic sites, and age are strong independent prognostic factors for survival. By monitoring CEA, clear patterns with distinct prognostic value can be determined. CEA kinetics and/or response after 8-12 weeks might be a useful and simple tool to stratify the post-induction treatment approach based on individual prognosis in the future., (© 2017 S. Karger GmbH, Freiburg.)

Catecholaminergic polymorphic ventricular tachycardia is a rare familial arrhythmogenic disease. It usually occurs in juvenile patients with a structurally normal heart and causes exercise-emotion triggered syncope and sudden cardiac death. The main gene associated with catecholaminergic polymorphic ventricular tachycardia is RyR2, encoding the cardiac ryanodine receptor protein which is involved in calcium homeostasis. After the identification of a 16 year-old man presenting with exercise-induced sudden cardiac death, clinically diagnosed as catecholaminergic polymorphic ventricular tachycardia, we collected the family information and performed a comprehensive genetic analysis using Next Generation Sequencing technology. The initial electrocardiogram in the emergency department revealed ventricular fibrillation. On electrocardiogram monitoring, sinus tachycardia degenerated into bidirectional ventricular and into ventricular fibrillation. Catecholaminergic polymorphic ventricular tachycardia was clinically diagnosed in 5 of the 14 family members evaluated. There were no additional reports of seizures, pregnancy loss, neonatal death, or sudden cardiac death in family members. Genetic analysis of the index case identified only one rare novel variant p.Ile11Ser (c.32T>G) in the RyR2 gene. Subsequent familial analysis identified segregation of the genetic variant with the disease. All current evidence supports that novel p.Ile11Ser variant in the RyR2 gene is a potential disease-causing variant in catecholaminergic polymorphic ventricular tachycardia. To our knowledge, there has been no previous case report of catecholaminergic polymorphic ventricular tachycardia associated to this missense variant., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Mass production of mosquitoes under laboratory conditions allows implementing methods to control vector mosquitoes. Colony development depends on mosquito size and weight. Body size can be estimated from its correlation with wing size, whereas weight is more difficult to determine. Our goal was to test whether wing size can predict the weight., Methods: We compared dry weight and wing centroid size of Culex quinquefasciatus reared at different temperatures and four diets., Results: Weight and wing size were strongly correlated. The diets did not influence wing size., Conclusions: Wing centroid size is a good predictor of Cx. quinquefasciatus body weight.

Background: Ochlerotatus scapularis is a potential vector of filarias and arboviruses in the Neotropics. This species was once typically associated with sylvatic environments; however, cases of synanthropy and urbanization of this species have been increasingly reported in southeast Brazil. Despite the medical relevance of Oc. scapularis, its populational variability is not yet known. To our knowledge, this is the first report describing the morphological and genetic variabilities of this species., Methods: Population samples were characterized using the cytochrome oxidase subunit I (COI) mitochondrial gene and wing geometrics. Adult mosquitoes were collected from five sampling sites from remnants of the Atlantic forest embedded in the urban or rural areas of southeast Brazil., Results: In the 130 individuals analyzed, 46 COI haplotypes were detected. Haplotype diversity was high and ranged from 0.66 to 0.97. Six haplotypes were present in 61% of the individuals, whereas the remaining haplotypes were less frequent (39%). Wing shape was also highly polymorphic. Differentiation of populations across sampling sites according to genetic distances (Fst = -0.009 to 0.060) and morphological distances (Qst = 0.47) indicated that populations were not identical. No correlations were noted for phenetic and genetic diversities (p = 0.19) or for genetic or phenetic distances with geographical distances (p = 0.2 and p = 0.18, respectively)., Conclusions: Our study results suggest that Oc. scapularis has a rich genetic patrimony, even though its habitat is fragmented. Implications of such genetic richness with respect to vectorial competence, plasticity, and ability to exploit urbanized areas need to be further investigated.

Background: After approval of bevacizumab in Germany in 2005 for the treatment of unresectable advanced or refractory colorectal cancer (CRC), this observational cohort study was initiated to assess the efficacy and safety of bevacizumab with various chemotherapy regimen in patients with metastatic CRC (mCRC)., Material and Methods: To facilitate enrolment of a typical mCRC population, eligibility criteria were minimised. Choice of chemotherapy regimen was at the physicians' discretion, but influenced by current registration status. Predefined endpoints were treatment characteristics, response rate, progression-free survival (PFS), overall survival (OS) and adverse events assessed as potentially related to bevacizumab treatment. Patients were followed for up to four years., Results: In total 1777 eligible patients were enrolled at 261 sites from January 2005 to June 2008. Median age: 64 years (range 19-100); male 62%; ECOG performance status 0-1/≥ 2 89%/11%. Chemotherapy choice was fluoropyrimidine (FU) 12%, FU/oxaliplatin 18%, FU/irinotecan 64%, no chemotherapy concurrent to bevacizumab 2% and other 4%. Best investigator-assessed response rate was 60% (complete response 10%, partial response 51%). Median PFS was 10.2 months and median OS was 24.8 months., Conclusions: The efficacy and safety profile of bevacizumab in this population of mCRC patients with different chemotherapy regimens is consistent with that observed in other patient registries/non-randomised trials and also corresponds well with data from similar treatment arms of phase III trials.

Background: To evaluate the efficacy of first-line bevacizumab-based chemotherapy for untreated metastatic colorectal cancer (mCRC) based on age., Methods: Eligibility criteria focused on M1 disease without prior palliative chemotherapy. Choice of chemotherapy regimen was at the physician's discretion. Predefined efficacy endpoints were response rate, progression-free and overall survival (PFS, OS). Patients were analysed by age (<70 vs. ≥70 years, <75 vs. ≥75 years)., Results: Of 1777 patients, 27% and 12% were ≥70 and ≥75 years, respectively. PFS was shorter in elderly patients (<70 vs. ≥70 years: 10.5 vs. 9.5 months, p = 0.074; <75 vs. ≥75 years: 10.5 vs. 8.9 months, p = 0.00019), as was OS (<70 vs. ≥70 years: 25.8 vs. 22.7 months, p < 0.0008; <75 vs. ≥75 years: 25.8 vs. 20.8 months; p < 0.0001). In the groups <70 and <75 years, PFS was longer in those receiving oxaliplatin-/irinotecan-containing regimens vs. those receiving 5-FU/capecitabine (<70 years: 10.6 vs. 9.0 months; p = 0.0065; <75 years: 10.6 vs. 9.2 months; p = 0.028); no difference in PFS was observed between oxaliplatin-/irinotecan-containing regimens vs. 5-FU/capecitabine regimens in both elderly age-group comparisons (≥70 years: 9.7 vs. 9.2 months; ≥75 years: 8.3 and 9.0 months)., Conclusion: First-line bevacizumab-based chemotherapies were effective in German mCRC patients ≥75 years of age, but PFS and OS were significantly shorter in this age group vs. younger patients.

Radiotherapy to the affected breast or chest wall is well established as an integral part of postoperative management of breast cancer. However, it is known to be associated with increased cardiac and pulmonary morbidities and mortalities. Modern technologies, such as CT planning, have shown to improve treatment planning by accurately delivering optimal doses to the target volumes, while minimizing doses to sensitive structures, thus reducing potential treatment-related adverse effects. The purpose of this study is to report on our experiences with CT planning of adjuvant radiotherapy for breast cancer.

Purpose: To prospectively evaluate the use of positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) to predict response to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with stage IIIB or IV NSCLC scheduled to undergo platinum-based chemotherapy were eligible for this study. Patients were studied by FDG-PET before and after the first cycle of therapy. Based on previous studies, a reduction of tumor FDG uptake by more than 20% as assessed by standardized uptake values (SUV) was used as a criterion for a metabolic response. Furthermore, changes in tumor SUVs were compared with changes in FDG net-influx constants (Ki) and tumor/muscle ratios (t/m)., Results: Fifty-seven patients were included in the study. There was a close correlation between metabolic response and best response to therapy according to Response Evaluation Criteria in Solid Tumors (P <.0001; sensitivity and specificity for prediction of best response, 95% and 74%, respectively). Median time to progression and overall survival were significantly longer for metabolic responders than for metabolic nonresponders (163 v 54 days and 252 days v 151 days, respectively). Similar results were obtained when Ki was used to assess tumor glucose use, whereas changes in t/m showed considerable overlap between responding and nonresponding tumors., Conclusion: In NSCLC, reduction of metabolic activity after one cycle of chemotherapy is closely correlated with final outcome of therapy. Using metabolic response as an end point may shorten the duration of phase II studies evaluating new cytotoxic drugs and may decrease the morbidity and costs of therapy in nonresponding patients.

Background and Aims: There is a need for objective easily determined pathological prognostic parameters in Dukes' B colon carcinoma to allow selection of such patients for further treatment as the role of adjuvant chemotherapy for these patients remains unclear. This study was initiated to assess the influence of pathological factors on prognosis in an unselected prospective series of Dukes' B colonic cancer., Methods: The Gloucester Colorectal Cancer study, established in 1988, recruited more than 1000 cases. Meticulous pathological assessment of the 268 Dukes' B colonic cancer resections in this series included evaluation of all pathological factors that could influence staging and prognosis. All patients entered a comprehensive follow up system., Results: Four pathologically determined factors--peritoneal involvement, venous spread (both submucosal and extramural), spread to involve a surgical margin, and perforation through the tumour-were independent prognostic factors in multivariate analysis. Combining these four factors into a simple cumulative scoring system generated clinically useful prognostic groups., Conclusions: The cumulative prognostic index allows apportionment of patients with Dukes' B colon cancer into defined prognostic groups, which in turn could allow more objective selection of patients for adjuvant therapy, especially as part of clinical trials.

Aims: Three cases of endometrioid adenocarcinoma arising in colorectal endometriosis are described with discussion of their macroscopic and microscopic pathology and diagnosis, using immunohistochemistry., Methods and Results: Three middle-aged women presented with symptoms and signs of colorectal mass effect. Two had a preceding history of gynaecological endometriosis and all three had either been on hormone replacement therapy or had functioning ovaries prior to presentation with colorectal disease. Each underwent resection of tumours of the distal large intestine. The definitive diagnosis was dependent on histological examination and immunohistochemistry, which was used to demonstrate an origin in endometriotic tissue., Conclusions: Endometrioid adenocarcinoma is a rare complication of colorectal endometriosis, this report contributing to a total of 25 cases in the literature. Definitive diagnosis, aided by immunohistochemical studies, is important to enable the identification of the optimal management for this uncommon condition.

The effects of divorce on children and adolescents remain a major public health issue. Over the last three decades, there has been ongoing debate among researchers and mental health and legal professionals who counsel divorcing families as to whether the effects are acute but time-limited or more enduring. This chapter looks at the tasks of normal adolescent psychosocial development and how divorce complicates those tasks. It suggests ways that pediatricians and other health professionals can intervene effectively with divorcing families within the context of their role. Divorce-specific resources and services are explained.

Peutz-Jeghers syndrome is characterized by multiple polyps throughout the gastrointestinal tract in association with mucocutaneous pigmentation. Small bowel polyps in the syndrome may exhibit epithelial misplacement, into the submucosa, the muscularis propria, and even the subserosa. The authors demonstrate two patients in whom there is also misplacement of dysplastic epithelium into the submucosa and muscularis propria of the small bowel. Epithelial misplacement is recognized to mimic invasive malignancy. Such mimicry is heightened substantially when the misplaced epithelium is dysplastic. Correct interpretation of the histologic changes is aided by the use of special stains, which demonstrate the associated lamina propria and the lack of a desmoplastic response, and immunohistochemistry, which shows that the misplaced dysplastic epithelium is accompanied by non-neoplastic mucosa. There is an increased prevalence of gastrointestinal malignancy in Peutz-Jeghers syndrome. However, the presence of perplexing histologic features, caused by epithelial misplacement, especially when some of that epithelium is dysplastic, in small bowel polyps at least has the potential for the overdiagnosis of malignancy in the syndrome.

Seedborne infection of rice by Pyricularia oryzae and its transmission to seedlings were studied quantitatively with naturally infected seeds of three rice cultivars collected from three locations in Nepal. A linear relationship on a logistic scale was found between panicle symptoms and seed infection, i.e., the more symptoms the higher seed infection. However, healthy-looking panicles and branches of panicles could also yield infected seeds. Postharvest measures such as winnowing and sun-drying significantly reduced seed infection by P. oryzae and filled grains had a lower degree of infection than unfilled grains. Sporulation of P. oryzae was most often confined to the embryonal end of germinating seeds. In contrast, most of the nongerminating seeds had sporulation all over the seed surface. Transmission of P. oryzae from seeds to seedlings, studied under various seeding conditions, showed that the transmission rate was always low. Thus, a seed sample with 21% seed infection resulted in less than 4% seedlings with blast lesions. Seed transmission was found for light covering of the seeds with soil or for moist seeding without covering. Transmission was rarely found when seeds were completely covered, and never in seedlings raised under water seeding conditions. Lower infection frequency was observed in seedlings raised in unsterilized soil than in seedlings raised in sterilized soil. Also, percent recovery of P. oryzae from infected seeds was higher in sterilized soil than in unsterilized soil and declined with time. Seedlings grown under low temperature (15 to 20°C) conditions did not develop blast lesions but when the same plants were transferred to high temperature (25 to 30°C) conditions, blast lesions were detected. This confirmed the latent infection in seedlings by P. oryzae grown under low temperature conditions.

A panel of five mouse monoclonal antibodies (MAbs) to human recombinant steroid 21-hydroxylase (21-OH) were produced, characterized, and used to study the interaction of 21-OH autoantibodies (AAbs) with different epitopes on human 21-OH. AAbs in patients with isolated autoimmune Addison's disease, autoimmune polyglandular syndromes types I and II, and 21-OH antibody-positive patients without overt Addison's disease (25 patients in total) were studied. Four MAbs were IgG1 subclass, one was IgG2a, and all had kappa light chains. The affinities of four of the antibodies were in the range 2.0 x 10(8) M(-1) to 7.0 x 10(8) M(-1), and the affinity of the other was 2.3 x 10(7) M(-1) 21-OH MAbs did not cross-react with 17alpha-hydroxylase (17alpha-OH)) or P450 side chain cleavage enzyme. Studies using a series of 21-OH fragments allowed the identification of short stretches of amino acids (AA) that were involved in forming the MAb binding sites. AA 391-405, defined as epitope region (ER) 1, were found to be important for binding of M21-OH1 and M21-OH2, AA 406-411 (ER2) were important for M21-OH3 and M21-OH4 binding, and AA 335-339 (ER3) for M21-OH5 binding. In addition, MAb Fab or F(ab')2 fragments were used to study 21-OH AAb epitopes in competition experiments. These investigations demonstrated that 21-OH AAbs recognize similar epitopes to the MAbs, with ER2 and ER3 being part of two distinct major epitopes, and ER 1 being part of a minor epitope. Mixtures of M21-OH antibody Fab or F(ab')2 fragments caused almost complete inhibition (80%-95%) of AAb binding in 24 out of 25 sera, and in the case of the remaining serum, the effect was marked but incomplete (67% inhibition). There were no major differences between the binding characteristics of AAbs from patients with different forms of autoimmune adrenal disease. All five 21-OH MAbs reacted with human adrenal tissue in an immunofluorescence test, but only M21-OH1 and M21-OH2 reacted with bovine adrenal tissue in these experiments. None of the MAbs reacted with human ovarian tissue in an immunofluorescence test. Overall, these studies indicate that 21-OH AAbs bind to at least three different epitopes in the C-terminal part of 21-OH, and two of these epitopes appear to be human 21-OH specific.