Search

PurposeProcess mining (PM) specialises in extracting insights from event logs to facilitate the improvement of an organisation's business processes. Industry trends show the proliferation and continued growth of PM techniques. To address the minimal attention given to developing empirically supported frameworks to assess the nature of impact in the PM domain, this study proposes a framework that identifies the key categories of PM impacts and their interrelationships.Design/methodology/approachThe qualitatively derived framework is built, re-specified and validated from a diverse collection of 62 PM case reports. With multiple rounds of coding supported by coder corroborations, inductively extracted concepts relating to impact from a first set of 12 case reports were grouped into themes and sub-themes to derive an a-priori framework by adopting the balanced scorecard as a theoretical lens. Concepts from the remaining 50 case reports were deductively grouped to re-specify and validate the proposed PM impacts framework. Further analysis identified interrelationships between impacts, which extends our understanding of the identified PM impacts.FindingsThe proposed framework captures PM impacts in four main categories: (a) impact on the process, (b) customer impact, (c) financial impact, and (d) impact on innovation and learning. The authors extended this analysis to identify the interrelationships between these categories, which vividly demonstrates how impact on the process mediates the attainment of the other three impact types.Originality/valueThe need for a deeper understanding of PM impacts within the context of contemporary PM practice is addressed by this work. The PM impacts framework provides a classification of PM impacts into four categories with 19 subcategories. It also identifies direct, moderating and mediating relationships between categories and subcategories whilst highlighting the role of impact on the process as a precursor to the other types of PM impact.

STUDY OBJECTIVES: To evaluate (determinants of) treatment success of mandibular advancement device application in a selected phenotype of patients with obstructive sleep apnea (OSA). METHODS: Ninety nonobese patients with moderate OSA (obstructive apnea-hypopnea index [OAHI] ≥ 15 and < 30 events/h) without comorbidities were prospectively included. Polysomnography was performed at baseline and with a mandibular advancement device. A drug-induced sleep endoscopy with jaw thrust was performed in 83%. RESULTS: OAHI reduction ≥ 50% was observed in 73%, OAHI reduction ≥ 50% with OAHI < 10 events/h in 70%, and complete OSA resolution (OAHI < 5 events/h) in 40%. Patients with nonpositional OSA showed a significantly higher rate of complete OSA resolution: Posttest probability increased to 67%. In patients with total disappearance of collapse at velum level and at all levels during drug-induced sleep endoscopy with jaw thrust, the drop in OAHI was impressive with an infinitively high positive likelihood ratio. However, the proportion of patients having nonpositional OSA or the drug-induced sleep endoscopy characteristics as described above was < 20%. The change in snoring disturbance based on a visual analog scale was 76% (interquartile range 40-89%, P < .001) and a statistically significant amelioration in Epworth Sleepiness Scale (especially in somnolent subjects) was observed. High adherence was reported. CONCLUSIONS: In this predefined OSA phenotype, a mandibular advancement device was effective in reduction of OAHI and in amelioration of symptoms. Stratification by nonpositional OSA and findings on drug-induced sleep endoscopy with jaw thrust increased treatment success defined as reduction in OAHI. However, the clinical relevance can be questioned because only a small number of patients demonstrated these characteristics. CITATION: Buyse B, Nguyen PAH, Leemans J, et al. Short-term positive effects of a mandibular advancement device in a selected phenotype of patients with moderate obstructive sleep apnea: a prospective study. J Clin Sleep Med. 2023;19(1):5-16. ispartof: J Clin Sleep Med vol:19 issue:1 pages:5-16 ispartof: location:United States status: published

Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13–16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS− group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS− group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation.

Previously, researchers used functional MRI to identify regional brain activations associated with sensory processing sensitivity (SPS), a proposed normal phenotype trait. To further validate SPS as a behavioral entity, to characterize it anatomically, and to test the usefulness in psychology of methodologies that assess axonal properties, the present study correlated SPS proxy questionnaire scores (adjusted for neuroticism) with diffusion tensor imaging measures. Participants (n=408) from the Young Adult Human Connectome Project that are free of neurologic and psychiatric disorders were investigated. We computed mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) and fractional anisotropy (FA). A voxelwise, exploratory analysis showed that MD and RD correlated positively with SPS proxy scores in the right and left subcallosal and anterior ventral cingulum bundle, and the right forceps minor of the corpus callosum (peak Cohen’s D effect size = 0.269). Further analyses showed correlations throughout the entire right and left ventromedial prefrontal cortex, including the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate and arcuate fasciculus. These prefrontal regions are generally involved in emotion, reward and social processing. FA was negatively correlated with SPS proxy scores in white matter of the right premotor/motor/somatosensory/supramarginal gyrus regions, which are associated with empathy, theory of mind, primary and secondary somatosensory processing. Region of interest (ROI) analysis, based-on previous fMRI results and Freesurfer atlas-defined areas, showed small effect sizes, (+0.151 to -0.165) in white matter of the precuneus and inferior frontal gyrus. Other ROI effects were found in regions of the dorsal and ventral visual pathways and primary auditory cortex. The results reveal that in a large, diverse group of participants axonal microarchitectural differences can be identified with SPS traits that are subtle and in the range of typical behavior. The results suggest that the heightened sensory processing in people who show SPS may be influenced by the microstructure of white matter in specific neocortical regions. Although previous fMRI studies had identified most of these general neocortical regions, the DTI results put a new focus on brain areas related to attention and cognitive flexibility, empathy, emotion and low-level sensory processing, as in the primary sensory cortex. Psychological trait characterization may benefit from diffusion tensor imaging methodology by identifying influential brain systems for traits.

ispartof: pages:96-109 ispartof: Beyond Metropolization: Exploring New Hybrids pages:96-109 ispartof: 10th International U&U PhD Seminar location:Lille, France date:28 Jun - 30 Jun 2023 status: published

This chapter introduces neuroimaging researchers to the concepts and techniques of diffusion magnetic resonance imaging data processing. Using the freely available ExploreDTI software, we provide a step-by-step guide for processing multi-shell High Angular Resolution Diffusion Imaging data and generating tractography based on constrained deconvolution. Brief explanations of the rationale behind each processing step are provided to aid the researcher in understanding the concepts and principles involved. Potential processing pitfalls will be discussed, and tips for troubleshooting common issues will be provided. An addtional step-by-step guide for processing DTI data using the open-access AOMIC data set is also provided, demonstrating command-line that can also be applied to process other large neuroimaging datasets.

Contains fulltext : 273921.pdf (Publisher’s version ) (Open Access) BACKGROUND: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti. METHODS: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated. RESULTS: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass. CONCLUSION: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC.

Background Several neurologic complications have been reported in close temporal association with both severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and following vaccination against SARS-CoV-2. Specifically, several cases of Guillain-Barré syndrome (GBS) have been reported in temporal relationship with COVID-19 vaccination, with two small case series describing a specific phenotype with bifacial weakness and paresthesia in the limbs. Methods We retrospectively collected patients who developed a new-onset neuromuscular disorder in the first 6 weeks after receiving a COVID-19 vaccine (either first or second dose). The patients were collected from one tertiary care centre and one secondary care centre from February to July 2021. Results We report eight patients who developed phenotypically diverse neuromuscular disorders in the weeks following COVID-19 vaccination, with a presumed immune-mediated etiology. In our case series, we report three patients with classical GBS, one patient with bifacial weakness with paresthesia variant of GBS, two patients with subacute-onset chronic inflammatory demyelinating polyneuropathy (CIDP), one patient with brachial plexopathy and one patient with subacute axonal sensorimotor polyneuropathy. Conclusions New-onset neuromuscular disorders with onset in the weeks after COVID-19 vaccination can include diverse phenotypes. A causal relationship between these disorders and the vaccine cannot be proven at present, and further epidemiological studies are needed to further investigate this association.

Background Long COVID is suggested to be present in 14 to 43% of COVID 19-survivors. Literature on this new condition states a need for a multidisciplinary approach including physical exercise and nutrition. The aim of the current UNLOCK study is to investigate the feasibility of the proposed protocol to prepare for a randomized controlled study that addresses the effectiveness of a personalized multimodal treatment compared to standard physiotherapy. Methods This is a protocol of a pragmatic, single-center, randomized controlled pilot trial with two groups. Patients with persisting symptoms related to a proven SARS-CoV-2 infection will be recruited from the Universitair Ziekenhuis Brussel, Belgium. Patients will receive either standard physiotherapy or an individualized physical exercise program combined with nutritional counseling. They will be followed-up at 6, 12 and 18 weeks after randomization. Discussion a multidisciplinary approach for dealing with long COVID is needed. Because of the lack of clear data and the fact that this is a very heterogenic group, we aim to prepare and optimize a randomized controlled study that addresses the effectiveness of a personalized multimodal treatment. Protocol version number and date Version number: 2.0 Version date: 10 June 2022 Trial registration: ClinicalTrials.gov Identifier: NCT05254301 (since February 24, 2022)

The uncovering of genes involved in susceptibility to the sporadic cancer types is a great challenge. It is well established that the way in which an individual deals with DNA damage is related to the chance to develop cancer. Mutagen sensitivity is a phenotype that reflects an individual's susceptibility to the major sporadic cancer types, including colon, lung, and head and neck cancer. A standard test for mutagen sensitivity is measuring the number of chromatid breaks in lymphocytes after exposure to bleomycin. The aim of the present study was to search for the pathways involved in mutagen sensitivity. Lymphoblastoid cell lines of seven individuals with low mutagen sensitivity were compared with seven individuals with a high score. RNA was isolated from cells exposed to bleomycin (4 hours) and from unexposed cells. Microarray analysis (19K) was used to compare gene expression of insensitive and sensitive cells. The profile of most altered genes after bleomycin exposure, analyzed in all 14 cell lines, included relatively many genes involved in biological processes, such as cell growth and/or maintenance, proliferation, and regulation of cell cycle, as well as some genes involved in DNA repair. When comparing the insensitive and sensitive individuals, other differentially expressed genes were found that are involved in signal transduction and cell growth and/or maintenance (e.g., BUB1 and DUSP4). This difference in expression profiles between mutagen-sensitive and mutagen-insensitive individuals justifies further studies aimed at elucidating the genes responsible for the development of sporadic cancers. (Mol Cancer Res 2006;4(2):71–7)

Supplementary Table S5. Characteristics of the patient groups extracted from Wichmann et al.(64) and used in Figure 4. Patients were selected on basis of a negative HPV test result as HPV will confound the prognostic associations. All patients were treated with multimodality therapy regimens with curative intent.

Gene list: bleo comparison

Supplementary figures S1-S4

Frequency plots of CNAs detected in tumor and precancer samples. (A) A frequency plot of the 22 tumor cell lines. Note that almost all samples contained a loss at chromosome 3p and a gain at 3q. (B) The same plot was made for 12 precancer cultures originating from the margins, including VU-preSCC-M3 (HN439-M1 was excluded). Although the number of samples is low, there is a clear peak visible at chromosome 9p, where CDKN2A is located. (C) A similar plot was made for the five (erythro)leukoplakia cultures. Again the numbers are low, but a trend towards HNSCC-associated CNAs is clearly visible. All graphs represent the frequency of losses and gains in the group of samples, where blue represent gains and red losses.

Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectedly not responding to cisplatin may better be treated with surgery and postoperative radiation or cetuximab and radiation, but biomarkers to personalize chemoradiotherapy are not available. We performed an unbiased genome-wide functional genetic screen in vitro to identify genes that influence the response to cisplatin in HNSCC cells. By siRNA-mediated knockdown, we identified the Fanconi anemia/BRCA pathway as the predominant pathway for cisplatin response in HNSCC cells. We also identified the involvement of the SHFM1 gene in the process of DNA cross-link repair. Furthermore, expression profiles based on these genes predict the prognosis of radiation- and chemoradiation-treated head and neck cancer patients. This genome-wide functional analysis designated the genes that are important in the response of HNSCC to cisplatin and may guide further biomarker validation. Cisplatin imaging as well as biomarkers that indicate the activity of the Fanconi anemia/BRCA pathway in the tumors are the prime candidates. Mol Cancer Ther; 16(3); 540–50. ©2016 AACR.

Supplementary Figure S4: CN profiles of cultures HN539-M2 and HN433-M1. (A) HN539-M2 is one of the cultures with only CNAs and no mutations. Cells of this culture contained a focal loss at chromosome 7q, however targeted sequencing revealed no mutations in any of the genes of our cancer-panel. (B) CN profile of HN433-M1 made at passage 3, with 6 PDs. We also generated a CN profile when the cells reached 30 PDs (Figure 2B). In both profiles a similar gain at chromosome 5q, a loss of chromosome 9p and a gain at the same arm were detected.

Figure S3. Visible lesions in non-transplanted FA patients. Visible lesions were found in 27 of 110 patients (25%) with follow-up. Five patients with visible lesions (4 with LOH, 1 without LOH) developed HNSCC.

LOH at chromosome arms 3p, 9p, 11q, and 17p are well-established oncogenetic aberrations in oral precancerous lesions and promising biomarkers to monitor the development of oral cancer. Noninvasive LOH screening of brushed oral cells is a preferable method for precancer detection in patients at increased risk for head and neck squamous cell carcinoma (HNSCC), such as patients with Fanconi anemia. We determined the prevalence of LOH in brushed samples of the oral epithelium of 141 patients with Fanconi anemia and 144 aged subjects, and studied the association between LOH and HNSCC. LOH was present in 14 (9.9%) nontransplanted patients with Fanconi anemia, whereas LOH was not detected in a low-risk group (n = 50, >58 years, nonsmoking/nonalcohol history) and a group with somewhat increased HNSCC risk (n = 94, >58 years, heavy smoking/excessive alcohol use); Fisher exact test, P = 0.023 and P = 0.001, respectively. Most frequent genetic alteration was LOH at 9p. Age was a significant predictor of LOH (OR, 1.13, P = 0.001). Five patients with Fanconi anemia developed HNSCC during the study at a median age of 39.6 years (range, 24.8–53.7). LOH was significantly associated with HNSCC (Fisher exact test, P = 0.000). Unexpectedly, the LOH assay could not be used for transplanted patients with Fanconi anemia because donor DNA in brushed oral epithelium, most likely from donor leukocytes present in the oral cavity, disturbed the analysis. Noninvasive screening using a LOH assay on brushed samples of the oral epithelium has a promising outlook in patients with Fanconi anemia. However, assays need to be adapted in case of stem cell transplantation, because of contaminating donor DNA. Cancer Prev Res; 8(11); 1102–11. ©2015 AACR.

Supplementary Table S3 from Microarray Analysis of Bleomycin-Exposed Lymphoblastoid Cells for Identifying Cancer Susceptibility Genes

Genetic characterization of the five established tumor cultures. The five tumor cultures we generated contained multiple CNAs, three samples showed a loss of CDKN2A and all contained a mutation in TP53.

Figure S2. Picture of a FA patient (F06-84) with squamous cell carcinoma of the gingiva LOH at chromosome arm 9p in brush C was detected in the first brush of patient F06-84.

Head and neck squamous cell carcinomas (HNSCC) develop in fields of genetically altered cells. These fields are often dysplastic and a subset can be recognized as (erythro)leukoplakia, but most are macroscopically invisible. There is a lack of adequate treatment options to eradicate these fields, whereas they underlie the development of primary tumors as well as part of the local relapses. Unfortunately, there are almost no representative cellular models available to identify suitable treatment options. To this end, clinical biopsy specimens (n = 98) were cultured from normal appearing mucosa of the surgical margins of patients with primary HNSCCs (n = 32) to generate precancer cell culture models. This collection was extended with six previously established precancer cell cultures. Genetic analysis was performed on cultures with an extended life span (≥20 population doublings), the previously established cultures, and some randomly selected cultures. In total, cancer-associated changes were detected in 18 out of 34 (53%) cultures analyzed, which appeared to be independent of life span. A variety of genetic changes were identified, including somatic mutations as well as chromosomal copy-number aberrations (CNA). Loss of CDKN2A/p16Ink4A and mutations in TP53/p53 were most prominent. Remarkably, in some of these precancer cell cultures only chromosomal CNAs were detected, and none of the frequently occurring driver mutations.Implications:The precancer cell cultures, characterized herein, form a representative collection of field models that can be exploited to identify and validate new therapeutic strategies to prevent primary HNSCCs and local relapses.

Supplementary Table S1. Primer sequences for quantitative real-time PCR.

CN profiles of the cultures of patient HN472 revealed multiple fields, not related to the tumor. (A) CN profile of culture HN472-M1 showed two focal aberrations, a loss at chromosome 7p and an gain at chromosome 18p. In addition, a loss at chromosome 18p was detected. (B) The CN profile of culture HN472-M4 had different CNAs, namely two focal losses at 9p (CDKN2A) and 12q, and a more extensive loss at chromosome 6q. (C) The CN profile of the tumor culture generated of this patient displayed numerous CNAs, however none related to the ones found in the precancer samples. For instance, the deletion at chromosome 9p was not at the location of CDKN2A¸but at the location of another HNSCC-annotated gene; PTPRD (Leemans et al. 2011).

Figure S1. Follow-up of non-transplanted FA patients Follow-up of the 141 non-transplanted FA patients. Four of 10 patients with LOH and 1 of 100 patients without LOH developed HNSCC.

CN profiles of noncancer control UPPP50 revealed a germ-line loss at chromosome 17p. (A) CN profile of the fibroblast culture from UPPP50, with a loss at 17p12. (B) CN profile of the keratinocyte culture from the same sample, showing the same loss at chromosome 17p12. This is the location of the PMP22 gene, known to be affected in HNPP. Both graphs represent the median-normalized log2 transformed read count corresponding to chromosome position.

Supplementary Table S4. Overview of selected probes that target the 102 genes found to sensitize HNSCC cells with two different statistical methods.

Supplementary Table S3. Number of siRNAs that were confirmed to cause the cisplatin sensitizing phenotype after deconvolution of the siRNA pool.

Supplementary Table S2. List of siRNA SMARTpools that significantly sensitized VU-SCC-120 cells to cisplatin as identified by at least one of two separate statistical analyses.

Overview of the origin of the five visible (erythro)leukoplakia cultures we obtained from others. These five samples were cultured and genetically characterized.

Gene list: sensitive vs insensitive comparison

Overview of all detected genetic alterations. (A) Overview of the locations of all detected CNAs in the cultured margin samples generated in our lab. (B). Overview of the mutations detected in the precancerous samples that were assessed. Validation revealed that some mutations appeared to be germline, those were excluded from further analysis.

Supplementary tables and figure legends

Legends to supplementary figures S1-S4

Patient characteristics

Table with detailed follow-up data of the complete CRT treated patient cohort.

PDF file, 96K, Supplementary Figure S1 First validation of the identified 19 microRNAs that seemed to elicit a tumor-selective lethal effect. Supplementary Figure S2 Effect of the six tumor-selective microRNAs on non-HNSCC cell lines. Supplementary Figure S3 Phenotypic effect of miR-181a overexpression in time, either when introduced by retroviral transduction or transient transfection in HNSCC cell line VU-SCC-120. Supplementary Figure S4 ATM expression after transient transfection of expression constructs with ATM and a kinase-dead ATM mutant lacking the 3'UTR of ATM.

Purpose: The 5-year survival rates of head and neck squamous cell carcinomas (HNSCC) remain disappointing. HNSCCs develop in precursor fields of genetically altered cells that are often not completely resected when the tumor is excised, causing local relapse. These precursor fields are mostly recognized as dysplasia, but histologic grading cannot reliably predict malignant transformation. Our aim was to discover and validate protein biomarkers that can detect precursor fields and predict local relapse in HNSCC using immunostaining of surgical margins.Experimental Design: We compared paired and genetically characterized normal, precursor, and tumor tissues of eight patients by proteome analysis to identify differentially expressed proteins. The prognostic value of candidate protein biomarkers was evaluated by immunohistochemical analysis of 222 surgical margins of 46 HNSCC patients who developed local relapse or remained disease free. Significant associations were determined by Kaplan-Meier survival analysis and Cox-proportional hazards models.Results: Forty proteins showed significant differential expression (false discovery rate–corrected P < 0.05). Most discriminative markers suited for immunostaining were keratin 4 and cornulin. Low expression in the surgical margins of keratin 4 (hazard ratio, 3.8; P = 0.002), cornulin (hazard ratio, 2.7; P = 0.025), and their combination (hazard ratio, 8.8; P = 0.0005) showed a highly significant association with the development of local relapse. Dysplasia grading had no prognostic relevance.Conclusions: Immunohistochemical assessment of keratin 4 and cornulin expression in surgical margins of HNSCC patients outperforms histopathologic grading in predicting the risk for local relapse. These markers can be used to initiate more frequent and lifelong surveillance of patients at high risk of local relapse, and enable selection for adjuvant treatment or tertiary prevention trials. (Clin Cancer Res 2009;15(24):7666–75)