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Bu çalışmada öğrencilerin öğrenmiş oldukları dilbilgisel yapıyı nasıl işlevsel hale getireceği, pasif halde bulunan dilbilgisel yapının nasıl aktif hale getirileceği teorik ve deneysel bağlamda incelenmiştir. Tek tip pasif alıştırmaların yerine aktif alıştırma tiplerinden seçenek sunularak öğrencilerin bu bilgiyi, dört beceriye aktarımı mümkün kılınmaya çalışılmıştır. Çalışmada dört beceri birbirinden soyutlanmış biçimde değil bütünleştirici şekilde ele alınmıştır.
Bu çalışmada deneysel yöntemin 'kontrol gruplu öntest ve sontest deney' deseni kullanılmıştır. Hem nitel hem de nicel boyutları içeren karma bir çalışmadır. Çalışmada eylemsel ve üretimsel yöntemlerin kullanıldığı deney grubundaki öntest ve sontest puanları arasındaki başarı farkının; geleneksel yöntemin uygulandığı kontrol grubundaki başarı farkından anlamlı derecede fazla olduğu görülmüştür (F(1,48)=366,149; p<0,001). Buradan hareketle deney grubundaki öğrencilerin daha fazla ilerleme gösterdiği ve başarılı oldukları sonucuna varılmıştır.
Dilbilgisi dersinin iletişimsel yetinin geliştirilmesi için bir araç olduğu görüşü deneysel ve uygulamalı olarak araştırılmıştır. Yaratıcı, eyleme ve öğrencilerin üretimine dayalı bir dilbilgisi dersi geliştirilerek geleneksel dilbilgisi dersine alternatif ders modelleri geliştirilmiştir.
Jedes literarische Werk wird durch seinen Titel identifiziert. Buchtitel sollen das Interesse des Lesers wecken und ihn zum Lesen des Werkes anregen. Sie sind wohl meist kurz, geben dennoch einen ersten Hinweis auf den Inhalt und wirken rezeptionssteuernd. Bekannt ist, dass literarische Werke in andere Sprachen nicht selten unter einem anderen Titel oder unter verschiedenen Titeln erscheinen. Ein Beispiel dafür ist Thomas Manns Erzählung Die Betrogene (1953). Sie ist zuerst von Kâmuran Şipal fast 'wortgetreu' unter dem Titel Aldatılmış Kadın [Die Betrogene] (1999) und sodann davon abweichend von Esen Tezel unter dem neuen Titel Aldanan Kadın [wörtlich: Die Sichtäuschende] (2012) ins Türkische übersetzt worden. Im Allgemeinen wird die nichtwortgetreue Übersetzung von Buchtiteln beanstandet und als ein Problem gesehen, was nach translationswissenschaftlich funktionalistischer Auffassung einer differenzierten Betrachtung bedarf. Vorliegende Fallstudie behandelt diverse translationswissenschaftliche Aspekte und Faktoren der unterschiedlichen Betitelungen von Kâmuran Şipal und Esen Tezel und leistet damit einen Beitrag zur Problematik des Übersetzens von literarischen Titeln.
Abnormitäten oder Analogien bei Übersetzungen deutscher und türkischer Nebensatzkonstruktionen
(2016)
Jede Sprache hat ihre eigene grammatikalische Struktur und dementsprechend unterscheidet sich auch der Aufbau der Sätze. Was in der Grammatik als ein Teilsatz bezeichnet wird, ist ein Nebensatz, welcher in jeder Sprache seine eigene Struktur besitzt. Diese strukturellen Merkmale, Unterschiede und Ähnlichkeiten im Deutschen und im Türkischen werden in dieser Arbeit dargestellt und miteinander verglichen. In dieser Arbeit werden die deutschen Nebensatzarten samt den dazugehörigen Beispielen dargestellt. Nach denselben Gesichtspunkten werden auch die jeweiligen türkischen Übersetzungen wiedergegeben. Diese Aufteilung soll als Mittel zum Zweck der übersichtlicheren Darlegung der Nebensätze und zur Erklärung der Übersetzungsmöglichkeiten dienen. Es ist klar, dass eine konkrete Übersetzung mehr oder weniger angleichend bzw. mehr oder weniger verfremdend erscheint, welche auf Varietät der Zielsprache zurückzuführen ist. Die Gegenüberstellung zwischen von Grund aus unterschiedlichen Sprachen scheint in erster Linie in Bezug auf den Wortschatz (z. B. kulturspezifische Begriffe) und Redeweisen getroffen worden zu sein. Sie ist jedoch auch für den grammatikalischen Bereich relevant. Nach diesem Exkurs werden einige deutsche Märchen mit ihren türkischen Übersetzungen verglichen und analysiert
Çeviri eyleminin yüzyıllarla ifade edilen ve Milattan önceki devirlere kadar uzanan tarihine karşın çeviri etkinliğinin öğretilebilir bir olgu olarak ele alınması, bilindiği üzere yeni bir konudur. Bu öğretme işinin eğitme biçimiyle ele alınıp üniversiter eğitim modelleri ile ele alınması ise, görece çok daha yeni bir görüngüdür. Türkiye'de de son birkaç on yıldır çeviri eğitimi veren akademik birimlerin varlığı ile konu tamamı ile akademik mecraya taşınmış ve tartışılmaya başlanmıştır. Bu tartışmalar ise, akademik çeviri eğitimi yoluyla oluşturulması ve/veya geliştirilmesi amaçlanan 'çeviri edinci' kavramı üzerinden yürütülmektedir. Çeviri edinci, akademik çeviri eğitimi açısından merkezi bir konu olarak değerlendirilebilir. Çünkü 'çeviri edinci'nin nasıl tanımlandığı, verilen eğitimin içeriğini ve usulünü belirleyebilecek denli temel bir sorgulamadır. Bu çalışmada 'çeviri edinci' kavramı tanımlanmaya çalışılacak, buradan hareketle akademik çeviri eğitiminin koşulları ve çevirmenin öznitelikleri içeriklendirilmeye çalışılacaktır.
Chronic kidney disease and diabetes mellitus are associated with extensive media calcification, which leads to increased cardiovascular morbidity and mortality. Here, we investigated the role of autophagy in the pathogenesis of uremic vascular media calcification. DBA/2 mice were fed with high-phosphate diet (HPD) in order to cause vascular calcification. DBA/2 mice on standard chow diet were used as control. In parallel, autophagy and its response to rapamycin, 3-methyladenine (3-MA), and bafilomycin were studied in an in vitro model using mouse vascular smooth muscle cells (MOVAS). DBA/2 mice on HPD developed severe vascular media calcification, which is mirrored in vitro by culturing MOVAS under calcifying conditions. Both, in vitro and in vivo, autophagy significantly increased in MOVAS under calcifying conditions and in aortas of HPD mice, respectively. Histologically, autophagy was located to the aortic Tunica media, but also vascular endothelial cells, and was found to continuously increase during HPD treatment. 3-MA as well as bafilomycin blocked autophagy in MOVAS and increased calcification. Vice versa, rapamycin treatment further increased autophagy and resulted in a significant decrease of vascular calcification in vitro and in vivo. Rapamycin reduced Runx2 transcription levels in aortas and MOVAS to control levels, whereas it increased α-smooth muscle actin and Sm22α transcription in MOVAS to control levels. Furthermore, rapamycin-treated HPD mice survived significantly longer compared to HPD controls. These findings indicate that autophagy is an endogenous response of vascular smooth muscle cells (VSMC) to protect from calcification in uremia. Induction of autophagy by rapamycin protects cells and mice from uremic media calcification possibly by inhibiting osteogenic transdifferentiation of VSMC.
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34+-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3+, CD3+CD4+, and CD3+CD8+ T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34+-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3+CD4+ helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34+-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
Background: Scientifically evaluated cognitive intervention programs are essential to meet the demands of our increasingly aging society. Currently, one of the “hottest” topics in the field is the improvement of working memory function and its potential impact on overall cognition. The present study evaluated the efficacy of WOME (WOrking MEmory), a theory-based working memory training program, in a double-blind, placebo-controlled, and randomized controlled trial (www.drks.de, DRKS00013162).
Methods: N = 60 healthy older adults were allocated to (1) the WOME intervention, (2) an active low-level intervention, or (3) a passive control group. Overall, the intervention groups practiced twelve sessions of 45 min within 4 weeks of their respective training. Transfer effects were measured via an extensive battery of neuropsychological tests and questionnaires both pre-/post-training and at a 3-month follow-up.
Results: WOME led to a significant improvement in working memory function, demonstrated on a non-trained near transfer task and on two different composite scores with moderate to large effect sizes. In addition, we found some indication of relevant impact on everyday life. The effects were short-term rather than stable, being substantially diminished at follow-up with only little evidence suggesting long-term maintenance. No transfer effects on other cognitive functions were observed.
Conclusion: WOME is an appropriate and efficient intervention specifically targeting the working memory system in healthy older adults.
Trial Registration: German Clinical Trials Register (DRKS), Identifier: DRKS00013162.
Im Rahmen dieser Studie wurden jeweils ein türkischer und deutscher Gebrauchs-und Informationstext und einige Sätze von literarischen Texten mit Hilfe der Online-Übersetzungsprogramme "google translate", "Babylon", "Almanca Sözlük" und "İngilizceturkce.gen" übersetzt und überprüft, ob, wenn man die Texte in der Zielsprache mit den Ausgangstexten vergleicht, syntaktische und semantische Fehler aufträten und welche der Online-Übersetzungsprogramme beim Übersetzen zuverlässig sind.
Die Daten haben dargelegt, das bei der Sprachkombination Deutsch-Türkisch/Türkisch-Deutsch Gebrauchstexte und Informationstexte, auch wenn sie einige syntaktische und semantische Fehler beinhalten, im Ganzen und Großen in die Zielsprache richtig transferiert werden, wobei literarische Texte einen höheren Anteil an Fehlern beinhalten. Laut der Untersuchungsergebnisse sollten die übersetzten Texte zur Sicherheit immer von jemand Fachkundigem gelesen werden, da beim Übersetzen von ganzen Sätzen bzw. Textpassagen aus der türkischen Sprache ins Deutsche und umgekehrt aus der deutschen Sprache ins Türkische der Sinn nicht immer erfasst wird.
Zur Kontrolle könnten außerdem noch übersetzte Passagen mit verschiedenen Programmen stückweise mehrmals oder in eine Drittsprache z. B. ins Englische übersetzt werden. Bei feststehenden Aussagen bzw. Ausdrücken hingegen ist ein hohes Maß an Aufmerksamkeit erforderlich.
Nucleation and growth of aerosol particles from atmospheric vapors constitutes a major source of global cloud condensation nuclei (CCN). The fraction of newly formed particles that reaches CCN sizes is highly sensitive to particle growth rates, especially for particle sizes <10 nm, where coagulation losses to larger aerosol particles are greatest. Recent results show that some oxidation products from biogenic volatile organic compounds are major contributors to particle formation and initial growth. However, whether oxidized organics contribute to particle growth over the broad span of tropospheric temperatures remains an open question, and quantitative mass balance for organic growth has yet to be demonstrated at any temperature. Here, in experiments performed under atmospheric conditions in the Cosmics Leaving Outdoor Droplets (CLOUD) chamber at the European Organization for Nuclear Research (CERN), we show that rapid growth of organic particles occurs over the range from −25 ∘C to 25 ∘C. The lower extent of autoxidation at reduced temperatures is compensated by the decreased volatility of all oxidized molecules. This is confirmed by particle-phase composition measurements, showing enhanced uptake of relatively less oxygenated products at cold temperatures. We can reproduce the measured growth rates using an aerosol growth model based entirely on the experimentally measured gas-phase spectra of oxidized organic molecules obtained from two complementary mass spectrometers. We show that the growth rates are sensitive to particle curvature, explaining widespread atmospheric observations that particle growth rates increase in the single-digit-nanometer size range. Our results demonstrate that organic vapors can contribute to particle growth over a wide range of tropospheric temperatures from molecular cluster sizes onward.
An aerosol foam formulation of a once-daily, fixed-dose combination of a synthetic vitamin D3 analog/synthetic corticosteroid (calcipotriol [Cal] 50 µg/g and betamethasone dipropionate [BD] 0.5 mg/g) has recently been introduced for the topical treatment of plaque psoriasis in adults. Data from several sources – randomized controlled trials, case reports (as highlighted in this review), and real-world evidence (RWE) – underscore the considerable and rapid clinical response, effectiveness, and favorable safety and tolerability of Cal/BD aerosol foam in mild-to-moderate psoriatic patients previously treated with class 3 or 4 topical corticosteroids, in patients unsatisfied with ongoing phototherapy in combination with topical therapy and in patients with moderate-to-severe psoriasis. In addition, our case series, considered together with other RWE, highlights that Cal/BD aerosol foam is more effective and with greater levels of patient preference and acceptability than comparator preparations. Thus, Cal/BD aerosol foam offers several treatment advantages, including relief of itch, and is an appropriate first-line topical therapy for consideration in patients with psoriasis of any severity.
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Georg Forster took part in Captain Cook's second journey of the world (1772) with his father at the age of 17. After his return, he published his impressions and observations in a comprehensive book. The book contains not only the observations on the nature of the places they visited, but also numerous philosophical notes on the culture of the people. A closer reading of these observations shows that Forster developed a method according to which he assessed the foreign cultures. The criteria of this method enables Forster even to understand and objectively assess cannibalism in New Zealand. Forster developed this method after questioning the conditions which can have a significant effect on the origin and the development of a particular culture in a particular space. His observations on the different cultures and the comparison of them with the Western culture which brought him to the conclusion that the geographical location, in which the human being lives, has a great effect on human existence. The aim of this paper is to show how Forster perceives the foreign culture and how he deals with it.
Background: The city of Wrocław in Poland represents one of Central Europeans oldest capitals of science with numerous Nobel laureates. Due to a long history of political suppressions with Nazi Germany and Communism from 1933 until 1989, its scientific community was suppressed for more than half a century.
Methods: The present study assessed scientific activities in the field of social and neighbouring sciences using density equalizing mapping. On the basis of the NewQIS (New Quality and Quantity Indices in Science) platform and the Social Sciences Citation Index (SSCI) of the Web of Science database, a total of 1787 articles originating from Wrocław were identified between 1966 and 2017.
Results: In total, 549 research collaborations of Wrocław with 96 different countries were present (30.7%). Among the 107 research areas the highest activity was found for the field of Business and Economics with n = 272 articles (average citation rate (AVR) of 12.54), followed by Psychology (n = 252 articles, AVR = 9.06), Psychiatry (n = 205 articles, AVR = 4.74) and Public, Environmental and Occupational Health (n = 145 articles, AVR = 7.96). The highest AVR was found for Operations Research (25.36 with n = 87 articles). Density equalizing mapping procedures revealed a global pattern of social sciences research collaborations with scientists from Germany, the UK and the US as the primary cooperating partner of Wrocław. The different countries had major differences in the area of research collaborations.
Conclusions: This is the first study that depicts the global network of Wrocław scientific activities in the field of social sciences. The exorbitant increase in research activity from 2006 onwards can lead to the assumption that Wrocław social sciences encounter a fruitful future.
Franz Kafka'nın Dava'sının Melih Cevdet Anday'ın İsa'nın Güncesi adlı romanına etkisi açık olmakla birlikte, incelenen romanlar arasındaki ilişki, basit bir esinlenmenin ötesinde, eserlerin kaleme alındığı dönemlerdeki toplumsal ve hukuki sorunların özüne ilişkin benzerlikle dikkat çekmektedir. Romanların karşılaştırmalı analizi, modernitenin, toplumsal farklılıklar ve iki roman arasındaki altmış yıla rağmen, değişik kültürlerde hukuk felsefesine ilişkin benzer sorunlara yol açtığını göstermektedir. Ulus devletlerinin kurulması ve demokrasinin gelişmesiyle ortaya çıkan kriz kalıcı olmuş, dünya savaşları ve askeri darbeler arasında olağan hâle gelen olağanüstü hâl modern dönemin hukuki durumu hâline gelmiştir.
Determining the cell fate and the distribution of mesenchymal stromal/stem cells (MSCs) after transplantation are essential parts of characterizing the mechanisms of action and biosafety profile of stem cell therapy. Many recent studies have shown that MSCs migrate into injured tissues, but are only detectable at extremely low frequencies. We investigated the cell fate of MSCs after transplantation in an acute kidney injury (AKI) mouse model using in vivo bioluminescence imaging (BLI) and subsequent verification of cell migration using quantitative real-time polymerase chain reaction (qRT-PCR). The AKI was induced by a single injection of cisplatin (8 or 12 mg/kg). One day later, adipose-derived mesenchymal stromal/stem cells isolated from luciferase transgenic mice (Luc+-mASCs, 5 × 105) were intravenously transplanted. Migration kinetics of the cells was monitored using BLI on day 1, 3, and 6, and finally via quantitative real-time PCR at the endpoint on day 6. Using BLI, infused Luc+-mASCs could only be detected in the lungs, but not in the kidneys. In contrast, PCR endpoint analysis revealed that Luc-specific mRNA could be detected in injured renal tissue; compared to the control group, the induction was 2.2-fold higher for the 8 mg/kg cisplatin group (p < 0.05), respectively 6.1-fold for the 12 mg/kg cisplatin group (p < 0.001). In conclusion, our study demonstrated that Luc-based real-time PCR rather than BLI is likely to be a better tool for cell tracking after transplantation in models such as cisplatin-induced AKI.
Subduction zone magmas are more oxidised on eruption than those at mid-ocean ridges. This is attributed either to oxidising components, derived from subducted lithosphere (slab) and added to the mantle wedge, or to oxidation processes occurring during magma ascent via differentiation. Here we provide direct evidence for contributions of oxidising slab agents to melts trapped in the sub-arc mantle. Measurements of sulfur (S) valence state in sub-arc mantle peridotites identify sulfate, both as crystalline anhydrite (CaSO4) and dissolved SO42− in spinel-hosted glass (formerly melt) inclusions. Copper-rich sulfide precipitates in the inclusions and increased Fe3+/∑Fe in spinel record a S6+–Fe2+ redox coupling during melt percolation through the sub-arc mantle. Sulfate-rich glass inclusions exhibit high U/Th, Pb/Ce, Sr/Nd and δ34S (+ 7 to + 11‰), indicating the involvement of dehydration products of serpentinised slab rocks in their parental melt sources. These observations provide a link between liberated slab components and oxidised arc magmas.
GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m2/d; d8–18) combined with s.c. IL-2 (6 × 106 IU/m2/d; d1–5, d8–12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction.
Introduction: Hip fracture surgery is associated with high in-hospital and 30-day mortality rates and serious adverse patient outcomes. Evidence from randomised controlled trials regarding effectiveness of spinal versus general anaesthesia on patient-centred outcomes after hip fracture surgery is sparse.
Methods and analysis: The iHOPE study is a pragmatic national, multicentre, randomised controlled, open-label clinical trial with a two-arm parallel group design. In total, 1032 patients with hip fracture (>65 years) will be randomised in an intended 1:1 allocation ratio to receive spinal anaesthesia (n=516) or general anaesthesia (n=516). Outcome assessment will occur in a blinded manner after hospital discharge and inhospital. The primary endpoint will be assessed by telephone interview and comprises the time to the first occurring event of the binary composite outcome of all-cause mortality or new-onset serious cardiac and pulmonary complications within 30 postoperative days. In-hospital secondary endpoints, assessed via in-person interviews and medical record review, include mortality, perioperative adverse events, delirium, satisfaction, walking independently, length of hospital stay and discharge destination. Telephone interviews will be performed for long-term endpoints (all-cause mortality, independence in walking, chronic pain, ability to return home cognitive function and overall health and disability) at postoperative day 30±3, 180±45 and 365±60.
Ethics and dissemination: iHOPE has been approved by the leading Ethics Committee of the Medical Faculty of the RWTH Aachen University on 14 March 2018 (EK 022/18). Approval from all other involved local Ethical Committees was subsequently requested and obtained. Study started in April 2018 with a total recruitment period of 24 months. iHOPE will be disseminated via presentations at national and international scientific meetings or conferences and publication in peer-reviewed international scientific journals.
Trial registration number: DRKS00013644; Pre-results
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects’ fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects’ fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.