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Publication Metadata only Machine-learning-based prediction of disability progression in multiple sclerosis: an observational, international, multi-center study(Public Library of Science, 2024) De Brouwer, Edward; Becker, Thijs; Werthen-Brabants, Lorin; Dewulf, Pieter; Iliadis, Dimitrios; Dekeyser, Cathérine; Laureys, Guy; Van Wijmeersch, Bart; Popescu, Veronica; Dhaene, Tom; Deschrijver, Dirk; Waegeman, Willem; De Baets, Bernard; Stock, Michiel; Horakova, Dana; Patti, Francesco; Izquierdo, Guillermo; Eichau, Sara; Girard, Marc; Prat, Alexandre; Lugaresi, Alessandra; Grammond, Pierre; Kalincik, Tomas; Alroughani, Raed; Grand’Maison, Francois; Skibina, Olga; Terzi, Murat; Lechner-Scott, Jeannette; Gerlach, Oliver; Khoury, Samia J.; Cartechini, Elisabetta; Van Pesch, Vincent; Sà, Maria José; Weinstock-Guttman, Bianca; Blanco, Yolanda; Ampapa, Radek; Spitaleri, Daniele; Solaro, Claudio; Maimone, Davide; Soysal, Aysun; Iuliano, Gerardo; Gouider, Riadh; Castillo-Triviño, Tamara; Sánchez-Menoyo, José Luis; Laureys, Guy; van der Walt, Anneke; Oh, Jiwon; Aguera-Morales, Eduardo; Al-Asmi, Abdullah; de Gans, Koen; Fragoso, Yara; Csepany, Tunde; Hodgkinson, Suzanne; Deri, Norma; Al-Harbi, Talal; Taylor, Bruce; Gray, Orla; Lalive, Patrice; Rozsa, Csilla; McGuigan, Chris; Kermode, Allan; Sempere, Angel Pérez; Mihaela, Simu; Simo, Magdolna; Hardy, Todd; Decoo, Danny; Hughes, Stella; Grigoriadis, Nikolaos; Sas, Attila; Vella, Norbert; Moreau, Yves; Peeters, Liesbet; Altıntaş, Ayşe; ; School of Medicine;Background Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking. Methods Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS. Findings Machine learning models achieved a ROC-AUC of 0.71 ± 0.01, an AUC-PR of 0.26 ± 0.02, a Brier score of 0.1 ± 0.01 and an expected calibration error of 0.07 ± 0.04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history. Conclusions Good discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study. Copyright: © 2024 De Brouwer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Publication Metadata only Successful outcome following a multimodal pelvic rehabilitation program in a woman with neurogenic bladder and bowel dysfunction: a case report(Taylor and Francis, 2024) ; Albayrak, Havvanur; Atlı, Ecenur; Aydın, Serdar; Taşkıran, Özden Özyemişçi; ; School of Medicine; Koç University HospitalBackground Neurogenic bladder and bowel dysfunctions lead to physical, social, and emotional disability and affects one's quality of life. Initial treatment is conservative including several rehabilitation techniques such as pelvic floor muscle training, biofeedback, electrical stimulation, and posterior tibial nerve stimulation. Objective In this case report, a 45-year-old woman with neurogenic bladder and bowel dysfunction was presented. Case Description Her urinary and fecal incontinence symptoms began twenty years before this episode of care, after an incomplete spinal cord injury secondary to spinal ependymoma and syringomyelia. She discontinued medical treatments due to side effects and ceased intermittent catheterization. A multimodal pelvic rehabilitation program was administered consisting of posterior tibial nerve stimulation, active pelvic floor muscle training accompanied by biofeedback, and electrical stimulation of pelvic floor muscles. Outcomes There were clinically important favorable differences in the scores of King's health questionnaire (reductions in symptom severity from 25 to 18 and in each of the impact of incontinence, physical and social limitations, personal relationships, sleep/energy, and severity measures from 100 to 67), pelvic floor distress inventory (decreased from 257 to 146) and female sexual function index (increased from 15.1 to 25.1) after 12 weeks of a multimodal pelvic rehabilitation program. Manual muscle tests demonstrated improvements in pelvic floor muscle strength and endurance. Conclusion A 12-week multimodal pelvic rehabilitation program reduced urinary and fecal incontinence symptoms, together with improvements in her sexual life and alleviation of neuropathic pain.Publication Metadata only Integration of virtual and traditional medical education: scholarship pivots from the Covid-19 pandemic(Lippincott Williams and Wilkins, 2024) Tang, Sherry Y. Q.; Kozlow, Jeffrey H.; Sandhu, Gurjit; Cederna, Paul S.; Berberoğlu, İpek; Sezgin, Billur; ; School of Medicine;Background: The coronavirus disease 2019 (COVID-19) pandemic required an unprecedented transformation of medical education, shifting from traditional, in-person learning to distanced, online learning. This study aimed to review changes to medical education and describe the advantages and disadvantages of virtual medical education experienced by medical students during the pandemic. Methods: An online survey study was conducted at two medical schools, University of Michigan Medical School in the United States and Koc University School of Medicine in Turkey. Medical students completed questionnaires regarding their educational experience before and during the pandemic. Survey instruments were designed to assess differences in the educational curriculum, study methods, clinical skills self-evaluations, perceptions of the quality of in-person and online learning, and overall satisfaction. Results: A total of 184 medical students completed the survey. There was an increase in the use of online study tools since the pandemic. There was no statistically significant difference in self-reported assessments of clinical preparedness and overall clinical competence during surgical clerkship. The percentage of students interested in pursuing a career in surgery has nearly doubled from 34% to 63%. A majority of students (83%) believed that the time available for self-study and research increased during the pandemic. Fifty-two percent of students believed that online education is less efficacious than in-person education, but 86% of students still preferred a blended approach. Conclusions: Medical schools have continued to update their curricula following the COVID-19 pandemic. This study illustrates the transformations in medical education to ensure that the most effective and suitable teaching is delivered.Publication Metadata only The forkhead transcription factor FOXJ1 controls vertebrate olfactory cilia biogenesis and sensory neuron differentiation(Public Library Science, 2024) Rayamajhi, Dheeraj; Ege, Mert; Ukhanov, Kirill; Ringers, Christa; Zhang, Yiliu; Jung, Inyoung; D'Gama, Percival P.; Li, Summer Shijia; Cosacak, Mehmet Ilyas; Kizil, Caghan; Park, Hae-Chul; Martens, Jeffrey R.; Brody, Steven L.; Jurisch-Yaksi, Nathalie; Roy, Sudipto; Yakşi, Emre; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine;In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation. In keeping with the immotile nature of olfactory cilia, we observed that ciliary motility genes are repressed in zebrafish, mouse, and human OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the differentiation of the OSNs themselves by regulating their cell type-specific gene expression, such as that of olfactory marker protein (omp) involved in odor-evoked signal transduction. In line with this, response to bile acids, odors detected by OMP-positive OSNs, was significantly diminished in foxj1 mutant zebrafish. Taken together, our findings establish how the canonical Foxj1-mediated motile ciliogenic transcriptional program has been repurposed for the biogenesis of immotile olfactory cilia, as well as for the development of the OSNs. Olfaction is mediated by ciliated sensory neurons, but how olfactory cilia and sensory neuron differentiation is regulated has remained obscure. This study of zebrafish and mice shows that the forkhead domain transcription factor Foxj1 is critical for olfactory cilia and sensory neuron differentiation.Publication Metadata only Liver transplantation for Nijmegen breakage syndrome with hepatic malignancy and hepatopulmonary syndrome after bone marrow transplantation: a case report(John Wiley and Sons Inc, 2024) Karasu, Gülsün; Şal, Oğuzhan; Erbey, Mehmet Fatih; Armutlu, Ayşe; Demir, Barış; Akbulut, Akın; Kanmaz, Turan; Alim, Altan; ; School of Medicine; Koç University HospitalBackground: Nijmegen breakage syndrome (NBS) is an autosomal recessive DNA repair disorder that manifests through increased genomic instability, malignancy, and cellular and humoral immunodeficiencies. The prognosis for NBS patients is poor due to their increased susceptibility to fatal infections and lymphoproliferative malignancies. Currently, there is no specific treatment for NBS, though allogeneic hematopoietic stem cell transplantation (HSCT) has been performed and documented as case series to demonstrate the utility of transplantation. Methods: A 14-year-old girl with NBS and haploidentical HSCT from her older brother due to recurrent lung infection was referred for liver transplantation (LT) due to liver cirrhosis, hepatopulmonary syndrome (HPS), and suspicion of liver malignancy. It was decided to perform LT using the living donor who had previously donated for HSCT. Results: Living donor left lobe LT was successfully performed from her brother. The patient experienced no complications in the early postoperative period and was discharged on the seventh postoperative day. Pathological examination of extracted liver has shown “intermediate cell carcinoma” in two foci. After 1 year LT, the patient has had an uneventful course in terms of LT complications and infection, with minimal immunosuppression. Conclusions: NBS patients have an increased prevalence of malignancies, including primary hepatic malignancy, but most are managed medically or with limited resections. Transplantation in these patients can be curative for hepatic malignancy with a favorable safety profile. © 2024 Wiley Periodicals LLC.Publication Metadata only Neuropeptides affecting social behavior in mammals: oxytocin(Elsevier Inc., 2024) Zhou, Hong; Zhu, Rui; Xia, Yuqing; Zhang, Xinming; Wang, Zixu; Lorimer, George H.; Ghiladi, Reza A.; Wang, Jun; Bayram, Hasan; ; School of Medicine;Oxytocin (OXT), a neuropeptide consisting of only nine amino acids, is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Although OXT is best known for its role in lactation and parturition, recent research has shown that it also has a significant impact on social behaviors in mammals. However, a comprehensive review of this topic is still lacking. In this paper, we systematically reviewed the effects of OXT on social behavior in mammals. These effects of OXT from the perspective of five key behavioral dimensions were summarized: parental behavior, anxiety, aggression, attachment, and empathy. To date, researchers have agreed that OXT plays a positive regulatory role in a wide range of social behaviors, but there have been controversially reported results. In this review, we have provided a detailed panorama of the role of OXT in social behavior and, for the first time, delved into the underlying regulatory mechanisms, which may help better understand the multifaceted role of OXT. Levels of OXT in previous human studies were also summarized to provide insights for diagnosis of mental disorders. © 2024 Elsevier Inc.Publication Metadata only Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network(Springer, 2024) Patry, Christian; Webb, Nicholas J. A.; Feisst, Manuel; Krupka, Kai; Becker, Jan; Bald, Martin; Antoniello, Benedetta; Gulhan, Bora; Hogan, Julien; Kanzelmeyer, Nele; Ozkaya, Ozan; Buescher, Anja; Sellier-Leclerc, Anne-Laure; Shenoy, Mohan; Weber, Lutz T.; Fichtner, Alexander; Hoecker, Britta; Meier, Matthias; Toenshoff, Burkhard; Bilge, İlmay; ; School of Medicine;BackgroundComplement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation.MethodsIn this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20).ResultsEleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective.ConclusionsThese data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary informationPublication Metadata only Neurocognitive impairment in patients with ataxia telangiectasia and their unaffected parents: is it similar?(Elsevier Inc., 2024) Uyar, Emel; Usanmaz, Sevil; Kiykim, Ayca; Tufan, Ali Evren; Alibas, Hande; Aydiner, Omer; Somer, Ayper; Ozen, Ahmet; Baris, Safa; Karakoc-Aydiner, Elif; Aktürk, Hacer; ; School of Medicine;Background: Ataxia telangiectasia (AT) is a genetic multisystemic disorder affecting the nervous system. Data on neurocognitive functioning in AT are limited and focused on patients at various stages of disease. Because of the genetic nature of the disorder, parents of patients may also display subtle neurological problems. This study aimed to evaluate neurocognitive functioning in patients with AT and their unaffected parents. Methods: The study included 26 patients with AT and 41 parents among which 13 patients and 18 parents were evaluated with neurocognitive tests. Clinical and radiological data were reviewed retrospectively. Data were analyzed with descriptive statistics. Results: The median ages of patients and parents were 12.5 years (interquartile range [IQR] = 9.5) and 38.0 years (IQR = 12.0), respectively. Median intelligence quotients were 62.0 (IQR = 21.3) and 82.5 (IQR = 16.8), respectively, for patients and parents. Rates of intellectual disability for patients and parents were 100.0% and 83.3%, respectively. Areas of impairment in patients in decreasing order of frequency were motor skills, visual perception/memory, visual-manual coordination, spontaneous/focused and sustained attention (100.0% for each), social judgment, as well as vocabulary and arithmetic skills (75.0% for each). Areas of impairment in unaffected parents in decreasing order of frequency were visualmanual coordination (77.8%), working memory (76.5%), and visual perception and motor skills (66.7% for each). Conclusion: Intellectual disabilities, visual-spatial disabilities, and reduced visual-motor coordination seem to be similar in patients with AT and their parents. These results should be replicated with larger samples from multiple centers and may form putative cognitive endophenotypes for the disorder. (c) 2024 Elsevier Inc. All rights reserved.Publication Metadata only Development of a low allergenic product for patients with milk allergy and assessment of its specific IgE reactivity(Wiley, 2024) Nemutlu, Emirhan; Kocak, Engin; Yazıcı, Duygu; Süer, Hande; Bülbüloğlu, Cemre Naz; Güzar, Elif; Büyüktiryaki, Ayşe Betül; Saçkesen, Cansın; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of Medicine;Background: Milk oral immunotherapy is the riskiest and most unpredictable form of oral immunotherapy. We aimed to produce a low allergenic product than conventional once baked-cake/muffin, to develop indirect in-house ELISA to check the tolerance status with milk products and evaluate IgE reactivity of patients' sera via western blotting (WB) and indirect in-house ELISA. Method: A low allergenic product named biscotti-twice baked-cake was developed, and the total protein concentration was determined. The protein content was studied by SDS-PAGE and proteomics. Milk-specific IgE (sIgE) binding assays were performed by WB and indirect in-house ELISA by using patients' sera. Results: Casein band intensity was observed to be lower in the biscotti-twice baked-cake than in the once baked-cake (p = .014). Proteomics analysis and alpha S1-casein measurement showed that the lowest intensity of casein was found in biscotti. The low binding capacity of milk sIgE to biscotti compared with once baked-cake was shown by WB (p = .0012) and by indirect in-house ELISA (p = .0001). In the ROC analysis, the area under the curve (AUC) of the in-house ELISA IgE was comparable with Uni-CAP milk and casein sIgE. The AUC of the in-house ELISA IgE for cake (0.96) and biscotti (1) was slightly better than Uni-CAP milk sIgE (0.94; 0.97) and casein sIgE (0.96; 0.97), respectively. Conclusion: The low allergenicity of the newly developed low allergenic product "biscotti-twice baked-cake" has been demonstrated by in vitro experiments. Biscotti could be a safe treatment option than once baked-cake/muffin in patients who are reactive to once baked-milk products.Publication Metadata only Splicing variants of versican in CD133+/CD44+ prostate cancer stem cells(Elsevier GMBH, 2024) Ayla, Sule; Karakoc, Emre; Byrne, Yasemin Yozgat; Parlayan, Cuneyd; Keskin, Ilknur; Taskiran, Aysegul; Oktem, Gulperi; Karahüseyinoğlu, Serçin; ; School of Medicine;A cancer mass is composed of a heterogeneous group of cells, a small part of which constitutes the cancer stem cells since they are less differentiated and have a high capacity to develop cancer. Versican is an extracellular matrix protein located in many human tissues. The mRNA of versican has been shown to have "splicing patterns" as detected by RT-PCR, northern blot analysis, and cDNA sequencing. Based on this knowledge this study aims to reveal the splice variants of versican molecules, which are thought to be involved in the pathogenesis of the DU145 human prostatic carcinoma cell line and prostatic cancer stem cells isolated from this cell line. In this study, RWPE-1 normal prostatic and DU-145 human prostate cancer cell lines have been used. Prostatic cancer stem cells and the remaining group of non-prostatic-cancer stem cells (bulk population) were isolated according to their CD133+/CD44+. RNA was isolated in all groups, and sequence analysis was accomplished for splicing variants by Illumina NextSeq 500 sequencing system. The results were analyzed by bioinformatic evaluation. As five isoforms of the versican gene in the differential transcript expression are analyzed, it was observed that a significant change was only found in the isoforms Versican 0 and Versican 1. In this study, we explored the function of this molecule which we think to be effective in cancer progression, and suggested that more valuable results can be obtained after the accomplishment of in vivo experiments.