Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

Geometrical benchmarking and analysis of redox potentials of copper(I/II) guanidine-quinoline complexes: Comparison of semi-empirical tight-binding and DFT methods and the challenge of describing the entatic state (part III).

Copper guanidine-quinoline complexes are an important class of bioinorganic complexes that find utilization in electron and atom transfer processes. By substitution of functional groups on the quinoline moiety the electron transfer abilities of these complexes can be tuned. In order to explore the full substitution space by simulations, the accurate theoretical description of the effect of functional groups is essential. In this study, we compare three different methods for the theoretical description of the structures. We use the semi-empirical tight-binding method GFN2-xTB, the density functional TPSSh and the double-hybrid functional B2PLYP. We evaluate the methods on five different complex pairs (Cu(I) and Cu(II) complexes), and compare how well calculated energies can predict the redox potentials. We find even though B2PLYP and TPSSh yield better accordance with the experimental structures. GFN2-xTB performs surprisingly well in the geometry optimization at a fraction of the computational cost. TPSSh offers a good compromise between computational cost and accuracy of the redox potential for real-life complexes.

CLIN-X: pre-trained language models and a study on cross-task transfer for concept extraction in the clinical domain.

MOTIVATION: The field of natural language processing (NLP) has recently seen a large change toward using pre-trained language models for solving almost any task. Despite showing great improvements in benchmark datasets for various tasks, these models often perform sub-optimal in non-standard domains like the clinical domain where a large gap between pre-training documents and target documents is observed. In this article, we aim at closing this gap with domain-specific training of the language model and we investigate its effect on a diverse set of downstream tasks and settings. RESULTS: We introduce the pre-trained CLIN-X (Clinical XLM-R) language models and show how CLIN-X outperforms other pre-trained transformer models by a large margin for 10 clinical concept extraction tasks from two languages. In addition, we demonstrate how the transformer model can be further improved with our proposed task- and language-agnostic model architecture based on ensembles over random splits and cross-sentence context. Our studies in low-resource and transfer settings reveal stable model performance despite a lack of annotated data with improvements of up to 47 F1 points when only 250 labeled sentences are available. Our results highlight the importance of specialized language models, such as CLIN-X, for concept extraction in non-standard domains, but also show that our task-agnostic model architecture is robust across the tested tasks and languages so that domain- or task-specific adaptations are not required. AVAILABILITY AND IMPLEMENTATION: The CLIN-X language models and source code for fine-tuning and transferring the model are publicly available at https://github.com/boschresearch/clin_x/ and the huggingface model hub.

The extent to which cancer patients trust in cancer-related online information: a systematic review.

BACKGROUND: The use of the internet to satisfy information needs is widespread among cancer patients. Patients' decisions regarding whether to act upon the information they find strongly depend on the trustworthiness of the information and the medium. Patients who are younger, more highly educated and female are more likely to trust online information. The objectives of this systematic review were to examine the extent to which cancer patients trust in cancer-related online information, internet websites as a source of cancer-related information or the internet as a medium of cancer information. METHODS: A systematic review was conducted using five databases (PROSPERO registration number: CRD42017070190). Studies of any kind were included if they measured cancer patients' trust in online health information. Study quality was assessed using the Research Triangle Institute (RTI) item bank. A narrative synthesis was undertaken to examine the included studies. RESULTS: Of the 7,314 citations obtained by the search, seven cross-sectional studies were included in the synthesis. A total of 1,054 patients reported having some or a great deal of trust in online cancer information; 154 patients reported moderately trusting such information; and 833 patients reported having no or little trust in online cancer information, internet websites as a source of cancer-related information or the internet as a medium of cancer-related information. Two of the seven studies reported between group comparisons for the above-stated patient characteristics. The methodological quality of the included studies was diverse. CONCLUSION: The results of the included studies indicates that approximately half of cancer patients appear to trust cancer-specific online information, internet websites as a source of cancer-related information or the internet as an information medium. However, the small number of included studies, high heterogeneity of participants, methods and outcomes calls for further systematic research. It is important to understand that cancer patients do and will increasingly use trusted cancer information websites to search for information concerning their disease. Therefore, physicians and other health care providers should provide more support and advice to these patients.

Views of psycho-oncologists, physicians, and nurses on cancer care-A qualitative study.

BACKGROUND: As worldwide cancer prevalence continues to increase, the challenges facing cancer care are also increasing. Various topics related to deficiencies in cancer care have been discussed repeatedly in the literature. The most frequently stated topics are the unmet psychosocial support needs of cancer patients, difficulties in multidisciplinary teamwork, difficulties in communication between physicians and patients, and issues in palliative care settings. However, there is little research regarding the views of health care providers on these topics. With the aim of gaining abundant information regarding the care of German cancer patients, this study explores the stances of psycho-oncologists, physicians, and nurses regarding the quality of cancer care. MATERIALS AND METHODS: Semi-structured interviews were conducted at the University Medical Center Hamburg-Eppendorf (UKE) and in different oncological outpatient offices in Hamburg; twenty-five interviews in total were conducted with health care providers. Interviews were semi-structured to gain a broad range of information on cancer care. The data were analyzed using thematic analysis by Braun and Clarke with an inductive, constant comparison approach to identify themes and categorized codes. RESULTS: The following five principle themes were identified in the interviews: "psycho-oncological care", "cooperation of health care providers", "palliative care", "health care provider-patient contact", and "coordination and organization of care". Participants seemed satisfied with the overall quality of cancer care in Germany. Nevertheless, the results showed deficiencies regarding communication among different health care providers and between health care providers and patients. Important findings in conjunction with these communication problems were a lack of psycho-oncological support, shortages in the oncology work force, language and cultural barriers, and deficient education in the communication of providers. CONCLUSIONS: The statements of psycho-oncologists, physicians, and nurses on cancer care provide a suitable basis to conduct further focused research on the studied deficiencies in cancer care. In particular, communication in psycho-oncological care, communication within multidisciplinary teams, and health care provider-patient communication should be further explored with the aim of developing new ideas for improvements and thereby enhancing the quality of cancer care.

Effectiveness, acceptance and satisfaction of guided chat groups in psychosocial aftercare for outpatients with prostate cancer after prostatectomy.

BACKGROUND: Physical and psychological symptoms associated with prostate cancer and its treatment can cause patients to feel distressed. Furthermore, patients still experience a range of unmet support needs. Online interventions have the potential to fill a gap in cancer care by augmenting the limited available mental health services. OBJECTIVE: The main goal of the study was to evaluate the effectiveness of guided chat groups in psychosocial aftercare for outpatients with prostate cancer. Additionally, the participants' satisfaction with and acceptance of the intervention was measured and evaluated. METHODS: A quasi-experimental design was used to analyze the research questions. 18 prostate cancer patients followed five web-based chat-group sessions. 26 patients received treatment as usual. The guided chat group enabled patients to exchange concerns, problems and support with fellow patients. The intervention group and control patients had to fill in self-reported questionnaires before the intervention and at a follow-up. Outcome measures include distress, anxiety, depression, anger, need for help, quality of life (QoL), fear of progression (FoP) and coping with cancer. To analyze the effectiveness of the chat groups, an analysis of covariance was conducted. RESULTS: The analysis of covariance revealed one significant difference between the two groups for the outcome anger. The difference had a large effect size (η2 = 0.160) with higher scores for the intervention group. Further differences with a medium effect size were found for coping with cancer, the physical component of quality of life and depression. The intervention group scored higher on all three outcomes.Additionally, participants reported that the atmosphere in the chat sessions was confidential and believed that the chat program worked as a bridge between inpatient treatment and daily life. CONCLUSIONS: Intervention participants reported poorer results for the primary and secondary outcomes in comparison to the control group patients at follow up, which indicates that web based chat groups may not be an effective way to decrease prostate cancer perceived distress even if the intervention participants seem to accept the intervention.

Using the Three-Step Test Interview to understand how patients perceive the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C).

PURPOSE: The aim of this study was to assess the experiences of patients with chronic obstructive pulmonary disease (COPD) while they were completing the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C), using qualitative research methods. METHODS: Twenty Dutch COPD patients were recruited through pulmonary physicians [13 women; mean age = 63.3 years (SD = 11.4)]. A trained interviewer applied the Three-Step Test Interview which allowed the interviewer to follow the thought process of the patient filling out the SGRQ-C. The official Dutch translation of the SGRQ-C was used. RESULTS: Patients missed a recall period for the Symptoms subscale; were uncertain how to interpret specific words and phrases like "good days", "games", and "housework"; were confused by long-item stems that included a list of activities; and were frustrated by the dichotomous format used for the majority of SGRQ-C items (true/false). CONCLUSIONS: Overall, patients were satisfied with the SGRQ-C. Nevertheless, making minor adjustments could further increase its quality. This includes reintroducing a recall period in the first set of items such as used in the previous version and splitting up items consisting of multiple activities. Furthermore, we recommend using the same response format (4 or 5 response categories) for all items.

Rechargeability of Li-air cathodes pre-filled with discharge products using an ether-based electrolyte solution: implications for cycle-life of Li-air cells.

The instability of currently used electrolyte solutions and of the carbon support during charge-discharge in non-aqueous lithium-oxygen cells can lead to discharge products other than the desired Li2O2, such as Li2CO3, which is believed to reduce cycle-life. Similarly, discharge in an O2 atmosphere which contains H2O and CO2 impurities would lead to LiOH and Li2CO3 discharge products. In this work we therefore investigate the rechargeability of model cathodes pre-filled with four possible Li-air cell discharge products, namely Li2O2, Li2CO3, LiOH, and Li2O. Using Online Electrochemical Mass Spectrometry (OEMS), we determined the charge voltages and the gases evolved upon charge of pre-filled electrodes, thus determining the reversibility of the formation/electrooxidation reactions. We show that Li2O2 is the only reversible discharge product in ether-based electrolyte solutions, and that the formation of Li2CO3, LiOH, or Li2O is either irreversible and/or reacts with the electrolyte solution or the carbon during its oxidation.