Analysis of costs for the use of pesticides in winter wheat and winter oil seed rape based on Network of Reference Farms Plant Protection 2007–2010

Seit dem Jahr 2007 wird das Netz Vergleichsbetriebe Pflanzenschutz betrieben. Dessen Ziel ist es, jedes Jahr Daten zur Intensität der Anwendung von Pflanzenschutzmitteln in Kulturen und Regionen zu gewinnen und durch Experten im Hinblick auf das notwendige Maß zu be­werten. Auf der Grundlage dieser Daten wurden ökonomische Analysen zur Anwendung von Pflanzenschutzmitteln in den Vergleichsbetrieben in Winterweizen und Winterraps durchgeführt. Insgesamt fanden 13 264 Einzelmaßnahmen auf 1457 untersuchten Schlägen in den Jahren 2007 bis 2010 Berücksichtigung. Die Daten wurden in einer Oracle-Datenbank verwaltet und nach Regionen und Pflanzenschutzmittelkategorien ausgewertet. Zusätzlich wurden für jede Pflanzenschutzmaßnahme die Mittelkosten und Überfahrtkosten ermittelt. Ausgehend von der Behandlungsintensität gemessen als Behandlungsindex, erfolgte die Bestimmung der durchschnittlichen Kosten für eine Pflanzenschutzmaßnahme, bezogen auf die einzelnen Pflanzenschutzmittelkatego­rien, und die Kosten für einen Behandlungsindex von 1,0. Außerdem wurden die Gesamtkosten für Pflanzenschutzmaßnahmen berechnet. Diese lagen im Durchschnitt der vier Jahre bei 214,40 € für Winterweizen und 247,00 € bei Winterraps pro ha und Anbaujahr. Schließlich wurden die Daten auf Korrelationen mit verschie­denen Einflussfaktoren geprüft. So zeigten sich im Winterweizen positive Korrelationen zwischen den Gesamtkosten und dem Ertrag sowie den Gesamtkosten und der Ackerzahl und eine negative Korrelation zwischen den Gesamtkosten und der Betriebsfläche. Im Winterraps konnten hingegen positive Korrelationen zwischen den Gesamtkosten und der Betriebsfläche sowie zwischen den Gesamtkosten und der Schlagfläche festgestellt werden. Insgesamt kann aus den Ergebnissen abgeleitet werden, dass die Kosten für Pflanzenschutzmaßnahmen im Winterraps deutlich über den Kosten im Winterweizen lagen. Das resultiert vor allem aus dem insgesamt höheren Behandlungsindex und den höheren Ausgaben für Herbizide und Insektizide in Winterraps.    Since 2007, the Network of Reference Farms Plant Protection has been in operation. Its aim is to gather information about the intensity of pesticide use in main crops and regions every year. Minimum need assessments are also carried out by experts from the plant protection services. Based on these findings, economic analyses regarding the pesticide use in the farms were conducted on winter wheat and winter oil seed rape. Altogether, 13 264 single measures on 1457 fields were considered during the period 2007–2010. The data were entered into an Oracle-database and evaluated according to regions and pesticide groups. Additionally, for every plant protection measure, both the product costs and operating costs were determined. Based on the intensity of the pesticide treatment measured as Treatment Frequency Index (TFI), the average costs of one plant protection measure and the costs of a TFI at 1.0 were determined. Furthermore, the total costs for plant protection measures were calculated. On average for four years, they amounted to 214.40 € for winter wheat and 247.00 € for winter oil seed rape per hectare per year. Finally, the data were evaluated in correlation with several influences. In winter wheat, there were positive correlations between total costs and yield as well as total costs and soil value and a negative correlation between total costs and farm area. In contrast, winter oil seed rape showed positive correlations between total costs and farm area as well as between total costs and field size. In conclusion, the results showed that the costs for plant protection measures in winter oil seed rape were clearly higher than the costs in winter wheat. This resulted mainly from the overall higher TFI and the higher expenditures for herbicides and insecticides in winter oil seed rape.   &nbsp

Multidrug-resistant Tuberculosis in Military Recruits

We conducted a tuberculosis contact investigation for a female military recruit with an unreported history of multidrug-resistant tuberculosis (MDRTB) and subsequent recurrence. Pertinent issues included identification of likely contacts from separate training phases, uncertainty on latent MDRTB infection treatment regimens and side effects, and subsequent dispersal of the contacts after exposure

Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe

Elevated Levels of Rad51 Recombination Protein in Tumor Cells

Rad51 is the key enzyme for homologous recombination, an evolutionarily conserved mechanism for the repair of DNA damage and the generation of genetic diversity. Given the observation that many tumors become resistant to radiation therapy and DNA-damaging chemotherapeutics and also that tumor cell populations can acquire a high number of genetic alterations and then expand clonally, dysfunction of the mammalian Rad51 recombinase could play a major role in the multistep process of tumorigenesis. The data we present provide further strong support for this hypothesis. Using anti-Rad51 immunofluorescence staining, widely different tumor cell lines displayed increased numbers of nuclei with focally concentrated Rad51 protein compared with nonmalignant control cell lines. These nuclear foci are thought to represent a repairosome-type assembly of Rad51 and other proteins required for recombinational DNA repair. By Western blot analyses, the net amount of Rad51 protein was increased 2–7-fold in all tested tumor cell lines. Inhibition of de novo protein synthesis by cycloheximide treatment showed a similar half-life of Rad51 protein in normal and tumor cells. Fluorescence in situ hybridization experiments did not detect Rad51 gene amplifications in tumors. Because Northern blot analysis demonstrated highly elevated Rad51 mRNA levels, we conclude that the increases in Rad51 protein and nuclear foci formation in tumor cells are the result of transcriptional up-regulation

A flagellum-specific chaperone facilitates assembly of the core type III export apparatus of the bacterial flagellum.

Many bacteria move using a complex, self-assembling nanomachine, the bacterial flagellum. Biosynthesis of the flagellum depends on a flagellar-specific type III secretion system (T3SS), a protein export machine homologous to the export machinery of the virulence-associated injectisome. Six cytoplasmic (FliH/I/J/G/M/N) and seven integral-membrane proteins (FlhA/B FliF/O/P/Q/R) form the flagellar basal body and are involved in the transport of flagellar building blocks across the inner membrane in a proton motive force-dependent manner. However, how the large, multi-component transmembrane export gate complex assembles in a coordinated manner remains enigmatic. Specific for most flagellar T3SSs is the presence of FliO, a small bitopic membrane protein with a large cytoplasmic domain. The function of FliO is unknown, but homologs of FliO are found in >80% of all flagellated bacteria. Here, we demonstrate that FliO protects FliP from proteolytic degradation and promotes the formation of a stable FliP-FliR complex required for the assembly of a functional core export apparatus. We further reveal the subcellular localization of FliO by super-resolution microscopy and show that FliO is not part of the assembled flagellar basal body. In summary, our results suggest that FliO functions as a novel, flagellar T3SS-specific chaperone, which facilitates quality control and productive assembly of the core T3SS export machinery

Subcellular localization of FliO revealed by structured illumination microscopy.

<p>The subcellular localization of FliO-HaloTag (A) or FliN-HaloTag (B) fusions expressed from their native chromosomal locus was analyzed in the wild-type (WT) and mutant backgrounds defective in MS-ring assembly (Δ<i>fliF</i>) or flagellar-specific type III secretion system (fT3SS) function (Δ<i>flhBAE</i>). WT FliO-HaloTag (EM1077), WT FliN-HaloTag (EM1081), Δ<i>fliF</i> FliO-HaloTag (EM6254), Δ<i>fliF</i> FliN-HaloTag (EM2640), Δ<i>flhBAE</i> FliO-HaloTag (EM6256), and Δ<i>flhBAE</i> FliN-HaloTag (EM6258). Strains were treated with 20 nM HaloTag ligands (HTL tetramethylrhodamine [TMR]) and observed using structured illumination microscopy (SIM). The autofluorescence of bacteria upon excitation with a 488 nm laser is shown in the middle panels. Scale bar 2 μm.</p

FliP protein is unstable in the absence of FliO.

<p>(A) FliP protein stability in the presence and absence of FliO. Protein levels of chromosomally expressed FliP-3×FLAG were monitored at 0, 60, 120, and 180 min after arrest of de novo protein synthesis. Wild-type (WT) (EM2225), Δ<i>fliO</i> (EM3201). FliP protein levels were normalized to DnaK, and relative FliP levels report the mean ± SD, <i>n</i> = 6. (B) Stability of episomally expressed FliP-3×HA protein in Δ<i>fliP</i> and Δ<i>fliOP</i> mutants after arrest of de novo protein synthesis. Δ<i>fliP</i> + p<i>fliP</i> (TH17448), Δ<i>fliOP</i> + p<i>fliP</i> (EM1610). Relative FliP levels report the mean ± SD, <i>n</i> = 3. (C) Protein stability of chromosomally expressed FliP-3×HA in presence or absence of FliO in the WT (TH17323), Δ<i>fliO</i> (EM1274), Δ<i>clpXP</i> (EM4018), Δ<i>clpXP</i> Δ<i>fliO</i> (EM4019), Δ<i>lon</i> (EM4478), and Δ<i>lon</i> Δ<i>fliO</i> (EM4479) mutants.</p

Single-particle tracking of FliO and colocalization with the flagellar basal body.

<p>(A) Strains expressing chromosomal FliN-HaloTag (EM1081) or FliO-HaloTag (EM1077) fusions were treated with 20 nM HaloTag ligands (HTL tetramethylrhodamine [TMR]) and analyzed by total internal reflection fluorescence (TIRF) microscopy. As described before, 500 frames were acquired with 5 mW laser power at the focal plane. The autofluorescence of bacteria upon excitation with a 488 nm laser is shown in the upper left corner. Scale bar 1 μm. (B) Single-molecule tracking (SMT) of TMR-labeled FliN and FliO. Selected frames from a series of 500 frames are shown, and frame numbers are indicated. (C) Mean square displacement (MSD) plots of pooled trajectories of at least 25 bacteria recorded under the same conditions. The diffusion coefficient <i>D</i> was calculated using the Jaqaman algorithm. (D) Dual-color direct stochastic optical reconstruction microscopy (dSTORM) of fixed bacteria expressing chromosomal FlgE-3×HA and FliO-HaloTag fusions (EM1214). Scale bar 1 μm.</p

Assembly of FliP subassemblies in core export apparatus mutants and model of the coordinated assembly of the flagellar-specific type III secretion system (fT3SS).

<p>Left: The assembly of stable FliP subassemblies is dependent on FliO and FliR but not on FliQ or FliF. Anti-FLAG Western blot of blue native PAGE (BN-PAGE) of crude membrane extracts prepared from the wild-type (WT) harboring untagged FliP (LT2, TH437) and mutant strains encoding for chromosomal FliP-3×FLAG: WT (EM6221), Δ<i>fliO</i> (EM6222), Δ<i>fliQ</i> (EM6223), Δ<i>fliR</i> (EM6224), Δ<i>fliF</i> (EM4859). Strains EM6221, EM6222, EM6223, and EM6224 additionally harbored a deletion of the proximal rod components <i>flgBC</i> in order to arrest flagellar synthesis after assembly of the core export apparatus. Right: Model of the coordinated assembly of the core flagellar export apparatus. Upon initiation of flagellum assembly, the flagellar type III secretion system (T3SS)-specific chaperone FliO facilitates formation of an oligomeric complex containing FliP and FliR. FliO then presumably dissociates from the stable FliP–FliR core complex. The FliP–FliR core complex forms the nucleus for the assembly of FliQ, FlhB, and FlhA [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2002267#pbio.2002267.ref011" target="_blank">11</a>], followed by MS-ring (FliF) polymerization and formation of the completed protein export-competent flagellar T3SS.</p