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Dietz, Mirco ; Lederer-Woods, Claudia ; Aberle, Oliver ; Andrzejewski, Józef ; Audouin, Laurent ; Bacak, Michael ; Balibrea Correa, Javier ; Barbagallo, Massimo ; Bečvář, František ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brown, Adam ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Cardella, Roberto ; Casanovas Hoste, Adrià ; Cerutti, Francesco ; Chen, Yonghao ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Dupont, Emmeric ; Durán, Ignacio ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Ferreira, Pedro G. ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; García Ríos, Aczel Regino ; Garg, Ruchi ; Gawlik, Aleksandra ; Gilardoni, Simone ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Harada, Hideo ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Kahl, David ; Kalamara, Antigoni ; Kavrigin, Pavel ; Kimura, Atsushi ; Kivel, Nikolay ; Kokkoris, Michael ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Leal Cidoncha, Esther ; Leeb, Helmut ; Lerendegui-Marco, Jorge ; Lo Meo, Sergio ; Lonsdale, Sarah Jane ; Macina, Daniela ; Marganiec, Justyna ; Martı́nez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Musumarra, Agatino ; Negret, Alexandru ; Nolte, Ralf ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Radeck, Désirée ; Rauscher, Thomas ; Reifarth, René ; Rubbia, Carlo ; Ryan, James A. ; Sabateé-Gilarte, Marta ; Saxena, Alok ; Schillebeeckx, Peter ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, Jose Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Warren, Stephen J. ; Weiß, Christina ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
The slow neutron capture process (s-process) is responsible for producing about half of the elemental abundances heavier than iron in the universe. Neutron capture cross sections on stable isotopes are a key nuclear physics input for s-process studies. The 72Ge(n, γ) cross section has an important influence on production of isotopes between Ge and Zr during s-process in massive stars and therefore experimental data are urgently required. 72Ge(n, γ) was measured at the neutron time-of-flight facility n_TOF (CERN) for the first time at stellar energies. The measurement was performed using an enriched 72GeO2 sample at a flight path of 185m with a set of liquid scintillation detectors (C6D6). The motivation, experiment and current status of the data analysis are reported.
Tony, Hans-Peter ; Burmester, Gerd-Rüdiger ; Schulze-Koops, Hendrik ; Grunke, Mathias ; Henes, Jörg Christoph ; Kötter, Ina ; Haas, Judith ; Unger, Leonore ; Lovric, Svjetlana ; Haubitz, Marion ; Fischer-Betz, Rebecca ; Chehab, Gamal ; Rubbert-Roth, Andrea ; Specker, Christof ; Weinerth, Jutta ; Holle, Julia Ulrike ; Müller-Ladner, Ulf ; König, Ramona ; Fiehn, Christoph ; Burgwinkel, Philip ; Budde, Klemens ; Sörensen, Helmut ; Meurer, Michael ; Aringer, Martin ; Kieseier, Bernd ; Erfurt-Berge, Cornelia ; Sticherling, Michael ; Veelken, Roland ; Ziemann, Ulf ; Strutz, Frank ; Wussow, Praxis von ; Meier, Florian Matthias Peter ; Hunzelmann, Nico ; Schmidt, Nico ; Bergner, Raoul ; Schwarting, Andreas ; Eming, Rüdiger ; Hertl, Michael ; Stadler, Rudolf ; Schwarz-Eywill, Michael ; Wassenberg, Siegfried ; Fleck, Martin ; Metzler, Claudia ; Zettl, Uwe Klaus ; Westphal, Jens ; Heitmann, Stefan ; Herzog, Anna Laura ; Wiendl, Heinz ; Jakob, Waltraud ; Schmidt, Enno ; Freivogel, Klaus ; Dörner, Thomas
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Vlijm, Rifka ; Li, Xue ; Panic, Marko ; Rüthnick, Diana ; Hata, Shoji ; Herrmannsdörfer, Frank ; Kuner, Thomas ; Heilemann, Mike ; Engelhardt, Johann ; Hell, Stefan ; Schiebel, Elmar
The centrosome linker proteins C-Nap1, rootletin, and CEP68 connect the two centrosomes of a cell during interphase into one microtubule-organizing center. This coupling is important for cell migration, cilia formation, and timing of mitotic spindle formation. Very little is known about the structure of the centrosome linker. Here, we used stimulated emission depletion (STED) microscopy to show that each C-Nap1 ring at the proximal end of the two centrioles organizes a rootletin ring and, in addition, multiple rootletin/CEP68 fibers. Rootletin/CEP68 fibers originating from the two centrosomes form a web-like, interdigitating network, explaining the flexible nature of the centrosome linker. The rootletin/CEP68 filaments are repetitive and highly ordered. Staggered rootletin molecules (N-to-N and C-to-C) within the filaments are 75 nm apart. Rootletin binds CEP68 via its C-terminal spectrin repeat-containing region in 75-nm intervals. The N-to-C distance of two rootletin molecules is ∼35 to 40 nm, leading to an estimated minimal rootletin length of ∼110 nm. CEP68 is important in forming rootletin filaments that branch off centrioles and to modulate the thickness of rootletin fibers. Thus, the centrosome linker consists of a vast network of repeating rootletin units with C-Nap1 as ring organizer and CEP68 as filament modulator.
Rieke, Johanna Magdalena ; Zhang, Rong ; Braun, Doreen ; Yilmaz, Öznur ; Japp, Anna S. ; Lopes, Filipa M. ; Pleschka, Michael ; Hilger, Alina Christine ; Schneider, Sophia ; Newman, William G. ; Schneider, Sophia ; Newman, William G. ; Beaman, Glenda M. ; Nordenskjöld, Agneta ; Ebert, Anne-Karoline ; Promm, Martin ; Rösch, Wolfgang H. ; Stein, Raimund ; Hirsch, Karin ; Schäfer, Frank-Mattias ; Schmiedeke, Eberhard ; Boemers, Thomas M. ; Lacher, Martin ; Kluth, Dietrich ; Gosemann, Jan-Hendrik ; Anderberg, Magnus ; Barker, Gillian ; Holmdahl, Gundela ; Läckgren, Göran ; Keene, David ; Cervellione, Raimondo M. ; Giorgio, Elisa ; Di Grazia, Massimo ; Feitz, Wouter F. J. ; Marcelis, Carlo L. M. ; Rooij, Iris Antonia Leonarda Martina van ; Bökenkamp, Arend ; Beckers, Goedele M. A. ; Keegan, Catherine E. ; Sharma, Amit ; Dakal, Tikam Chand ; Wittler, Lars ; Grote, Phillip ; Zwink, Nadine ; Jenetzky, Ekkehart ; Brusco, Alfredo ; Thiele, Holger ; Ludwig, Michael ; Schweizer, Ulrich ; Woolf, Adrian S. ; Odermatt, Benjamin ; Reutter, Heiko
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Schebelle, Laura ; Wolf, Claudia ; Stribl, Carola ; Javaheri, Tahereh ; Schnütgen, Frank ; Ettinger, Andreas ; Ivics, Zoltán ; Hansen, Jens ; Ruiz, Patricia ; Melchner, Harald von ; Wurst, Wolfgang ; Floss, Thomas
Recombinase-mediated cassette exchange (RMCE) exploits the possibility to unidirectionally exchange any genetic material flanked by heterotypic recombinase recognition sites (RRS) with target sites in the genome. Due to a limited number of available pre-fabricated target sites, RMCE in mouse embryonic stem (ES) cells has not been tapped to its full potential to date. Here, we introduce a universal system, which allows the targeted insertion of any given transcriptional unit into 85 742 previously annotated retroviral conditional gene trap insertions, representing 7013 independent genes in mouse ES cells, by RMCE. This system can be used to express any given cDNA under the control of endogenous trapped promoters in vivo, as well as for the generation of transposon ‘launch pads’ for chromosomal region-specific ‘Sleeping Beauty’ insertional mutagenesis. Moreover, transcription of the gene-of-interest is only activated upon Cre-recombinase activity, a feature that adds conditionality to this expression system, which is demonstrated in vivo. The use of the RMCE system presented in this work requires one single-cloning step followed by one overnight gateway clonase reaction and subsequent cassette exchange in ES cells with efficiencies of 40% in average.
Wilhelm, Alexander ; Schoth, Jens ; Meinert-Berning, Christina ; Bastian, Daniel ; Ciesek, Sandra ; Teichgräber, Burkhard ; Wintgens, Thomas ; Weber, Frank-Andreas ; Widera, Marek
Wastewater-based SARS-CoV-2 epidemiology (WBE) has been established as an important tool to support individual testing strategies. Omicron sub-variants BA.4/5 have spread globally displacing the predeceasing variants. Due to the severe transmissibility and immune escape potential of BA.4/5, early monitoring was required to asses and implement countermeasures in time.
In this study, we monitored the prevalence of SARS-CoV-2 BA.4/5 at six municipal wastewater treatment plants (WWTPs) in the Federal State of North-Rhine-Westphalia (NRW, Germany) in May and June 2022. Initially, L452R-specific primers/probes originally designed for SARS-CoV-2 Delta detection were validated using inactivated authentic viruses and evaluated for their suitability to detect BA.4/5. Subsequently, the assay was used for RT-qPCR analysis of RNA purified from wastewater obtained twice a week at six WWTPs. The occurrence of L452R carrying RNA was detected in early May 2022 and the presence of BA.4/5 was confirmed by variant-specific single nucleotide polymorphism PCR (SNP-PCR) targeting E484A/F486V. Finally, the mutant fractions were quantitatively monitored by digital PCR confirming BA.4/5 as the majority variant by 5th June 2022.
In conclusions, the successive workflow using RT-qPCR, variant-specific SNP-PCR, and RT-dPCR demonstrates the strength of WBE as a versatile tool to rapidly monitor variant spreading independent of individual test capacities.
Sens, Alena ; Rischke, Samuel ; Hahnefeld, Lisa Katharina ; Dorochow, Erika ; Schäfer, Stephan Martin Gastón Helmut Johannes ; Thomas, Dominique Jeanette ; Köhm, Michaela ; Geisslinger, Gerd ; Behrens, Frank ; Gurke, Robert
The emerging disciplines of lipidomics and metabolomics show great potential for the discovery of diagnostic biomarkers, but appropriate pre-analytical sample-handling procedures are critical because several analytes are prone to ex vivo distortions during sample collection. To test how the intermediate storage temperature and storage period of plasma samples from K3EDTA whole-blood collection tubes affect analyte concentrations, we assessed samples from non-fasting healthy volunteers (n = 9) for a broad spectrum of metabolites, including lipids and lipid mediators, using a well-established LC-MS-based platform. We used a fold change-based approach as a relative measure of analyte stability to evaluate 489 analytes, employing a combination of targeted LC-MS/MS and LC-HRMS screening. The concentrations of many analytes were found to be reliable, often justifying less strict sample handling; however, certain analytes were unstable, supporting the need for meticulous processing. We make four data-driven recommendations for sample-handling protocols with varying degrees of stringency, based on the maximum number of analytes and the feasibility of routine clinical implementation. These protocols also enable the simple evaluation of biomarker candidates based on their analyte-specific vulnerability to ex vivo distortions. In summary, pre-analytical sample handling has a major effect on the suitability of certain metabolites as biomarkers, including several lipids and lipid mediators. Our sample-handling recommendations will increase the reliability and quality of samples when such metabolites are necessary for routine clinical diagnosis.
Simon, Thorsten ; Hero, Barbara ; Faldum, Andreas ; Handgretinger, Rupert ; Schrappe, Martin ; Klingebiel, Thomas ; Berthold, Frank
Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.
Deuchler, Svenja ; Sebode, Christina ; Ackermann, Hanns ; Schmack, Ingo ; Singh, Pankaj ; Kohnen, Thomas ; Koch, Frank
Hintergrund: Die Ophthalmoskopie ist Bestandteil des medizinischen Curriculums, jedoch das Vermitteln der Inhalte oft unbefriedigend, da ein systematisches Lernen von Pathologien und deren Behandlungen dadurch erschwert ist, dass oftmals das passende Patientengut nicht zur Verfügung steht und dadurch gesunde Studenten einander untersuchen müssen. Aus diesem Grund haben wir eine Online-Plattform entwickelt, die in Kombination mit simulationsgestütztem Training sowohl das eigenständige als auch das angeleitete Lernen von Untersuchungsmethoden und Pathologien ermöglicht.
Ziel der Arbeit: Ziel der vorliegenden Arbeit war, ein Format für die Verbesserung der Lehre der direkten und indirekten Ophthalmoskopie im Studierendenunterricht zu evaluieren. Dabei wurden praktische Übungen an Virtual-Reality-basierten Simulatoren mit neu entwickelten und an den Lehrkatalog angepassten theoretischen Inhalten in der Online-Plattform EyesiNet verschränkt.
Material und Methoden: Die Studierenden bearbeiteten am ersten sowie am letzten Praktikumstag zufällig ausgewählte Fälle, die ihnen von den Eyesi Direct- und Eyesi Indirect-Simulatoren präsentiert wurden. Zwischen diesen beiden Einheiten konnten sie sich auf freiwilliger Basis mit den theoretischen Grundlagen typischer ophthalmologischer Krankheitsbilder im EyesiNet beschäftigen.
Ergebnisse: Eyesi Direct: Die Bewertung des Simulators ergab am ersten Praktikumstag für beide Gruppen keinen signifikant unterschiedlichen Wissensstand (p = 0,29). In der Gruppe OHNE Training (n = 54) ergab sich am letzten Praktikumstag mit p = 0,02 eine signifikante Verbesserung dieser Bewertung, jedoch mit einer geringen Effektgröße von 0,1. In der Gruppe MIT Training (n = 32) konnte mit p = 0,0004 eine hoch signifikante Verbesserung mit einer Effektgröße von 0,3 nach Rosenthal festgestellt werden. Eyesi Indirect: Die simulatorgestützte Bewertung ergab am ersten Praktikumstag keinen signifikanten Unterschied im Wissensstand der beiden Gruppen (p = 0,1). Nach dem Training schnitten zwar beide Gruppen etwas besser ab, jedoch ohne signifikanten Unterschied (OHNE Training p = 0,41/MIT Training p = 0,17).
Diskussion: Die Online-Plattform EyesiNet unterstützt beim Erlernen der wichtigsten Erkrankungsbilder. Lerninhalte werden reproduzierbar und auf für alle Lernenden standardisierte Weise zur Verfügung gestellt. Die Fertigkeiten der direkten Ophthalmoskopie sind hierbei deutlich schneller als die der indirekten Ophthalmoskopie zu erlernen.
Bauer, Michael ; Glenn, Tasha ; Achtyes, Eric D. ; Agaoglu, Esen ; Altınbaş, Kürşat ; Andreassen, Ole A. ; Angelopoulos, Elias ; Ardau, Raffaella ; Arrua Vares, Edgar ; Aydin, Memduha ; Ayhan, Yavuz ; Baethge, Christopher Jan ; Bauer, Rita ; Baune, Bernhard T. ; Balaban, Ceylan ; Becerra-Palars, Claudia ; Behere, Aniruddh P. ; Behere, Prakash B. ; Belete, Habte ; Belete, Tilahun ; Belizario, Gabriel Okawa ; Bellivier, Frank ; Belmaker, Robert H. ; Benedetti, Francesco ; Berk, Michael ; Bersudsky, Yuly ; Bicakci, Şule ; Birabwa-Oketcho, Harriet ; Bjella, Thomas D. ; Brady, Conan ; Cabrera, Jorge ; Cappucciati, Marco ; Castro, Angela Marianne Paredes ; Chen, Wei-Ling ; Cheung, Eric Y. Wo ; Chiesa, Silvia ; Crowe, Marie ; Cuomo, Alessandro ; Dallaspezia, Sara ; Del Zompo, Maria ; Desai, Pratikkumar ; Dodd, Seetal ; Donix, Markus ; Etain, Bruno ; Fagiolini, Andrea ; Fellendorf, Frederike Tabea ; Ferensztajn-Rochowiak, Ewa ; Fiedorowicz, Jess G. ; Fountoulakis, Kostas N. ; Frye, Mark A. ; Geoffroy, Pierre A. ; Gonzalez-Pinto, Ana ; Gottlieb, John F. ; Grof, Paul ; Haarman, Bartholomeus C. M. ; Harima, Hirohiko ; Hasse-Sousa, Mathias ; Henry, Chantal ; Høffding, Lone ; Houenou, Josselin ; Imbesi, Massimiliano ; Isometsä, Erkki T. ; Ivkovic, Maja ; Janno, Sven ; Johnsen, Simon ; Kapczinski, Flávio ; Karakatsoulis, Gregory N. ; Kardell, Mathias ; Kessing, Lars Vedel ; Kim, Seong Jae ; König, Barbara ; Kot, Timur L. ; Koval, Michael ; Kunz, Mauricio ; Lafer, Beny ; Landén, Mikael ; Larsen, Erik R. ; Lenger, Melanie ; Lewitzka, Ute ; Licht, Rasmus W. ; Lopez-Jaramillo, Carlos ; MacKenzie, Alan ; Madsen, Helle Østergaard ; Madsen, Simone Alberte Kongstad A. ; Mahadevan, Jayant ; Mahardika, Agustine ; Manchia, Mirko ; Marsh, Wendy ; Martinez-Cengotitabengoa, Monica ; Martiny, Klaus ; Mashima, Yuki ; McLoughlin, Declan M. ; Meesters, Ybe ; Melle, Ingrid ; Meza-Urzúa, Fátima ; Ming, Mok Yee ; Monteith, Scott ; Moorthy, Muthukumaran ; Morken, Gunnar ; Mosca, Enrica ; Mozzhegorov, Anton A. ; Munoz, Rodrigo ; Mythri, Starlin V. ; Nacef, Fethi ; Nadella, Ravi K. ; Nakanotani, Takako ; Nielsen, René Ernst ; O'Donovan, Claire ; Omrani, Adel ; Osher, Yamima ; Ouali, Uta ; Pantovic-Stefanovic, Maja ; Pariwatcharakul, Pornjira ; Petite, Joanne ; Pfennig, Andrea ; Pica Ruiz, Yolanda ; Pilhatsch, Maximilian ; Pinna, Marco ; Pompili, Maurizio ; Porter, Richard ; Quiroz, Danilo ; Rabelo-da-Ponte, Francisco Diego ; Ramesar, Raj ; Rasgon, Natalie ; Ratta-apha, Woraphat ; Ratzenhofer, Michaela ; Redahan, Maria ; Reddy, M. S. ; Reif, Andreas ; Reininghaus, Eva Z. ; Richards, Jenny Gringer ; Ritter, Philipp ; Rybakowski, Janusz K. ; Sathyaputri, Leela ; Scippa, Ângela M. ; Simhandl, Christian ; Severus, Emanuel ; Smith, Daniel ; Smith, José ; Stackhouse Jr., Paul W. ; Stein, Dan J. ; Stilwell, Kellen ; Strejilevich, Sergio ; Su, Kuan-Pin ; Subramaniam, Mythily ; Sulaiman, Ahmad Hatim ; Suominen, Kirsi ; Tanra, Andi J. ; Tatebayashi, Yoshitaka ; Teh, Wen Lin ; Tondo, Leonardo ; Torrent, Carla ; Tuinstra, Daniel ; Uchida, Takahito ; Vaaler, Arne E. ; Veeh, Julia ; Vieta, Eduard ; Viswanath, Biju ; Yoldi-Negrete, Maria ; Yalcinkaya, Oguz Kaan ; Young, Allan H. ; Zgueb, Yosra ; Whybrow, Peter C.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.