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Tumor necrosis factor (TNF) is a protein produced by activated macrophages (immune system cells) in response to circulating toxins. One important physiological effect of TNF is to produce necrosis (tissue death) of experimentally induced tumors. With the cloning of the gene for human TNF, large quantities of the substance have become available, and experiments have been carried out investigating its possible use as an anti-cancer agent. The authors discuss previous studies of TNF performed by themselves and others. Complications of this treatment regimen, especially alterations in the levels of liver enzymes, were reported. Patients developed hyperbilirubinemia (high blood levels of bilirubin, a liver bile constituent), as well as jaundice induced by inhibition of bile flow (cholestatic jaundice). The possibility that these effects were caused by spread of the cancer to the liver was ruled out by noting the abatement of liver symptoms with cessation of TNF treatment. Liver biopsies were not performed, so no biochemical or microscopic analysis of liver tissue was possible in these cases. The observations suggest that TNF has direct pathogenic effects on the liver, and the hypothesis is put forward that disruptions in liver function seen in conditions where TNF levels would be increased (following viral infections, in liver failure, and in chronic liver disease) may be directly attributable to TNF. (Consumer Summary produced by Reliance Medical Information, Inc.)

Laboratory data suggest a synergistic interaction between carmustine (BCNU) and tumour necrosis factor (TNF) in melanoma. We therefore studied the activity of 200 mg/m2 BCNU given alone or in combination with 88 micrograms/m2 recombinant human TNF-alpha (rhTNF alpha) as a daily i.v. infusion for 5 days at 48-day intervals to patients with metastatic melanoma. In this randomised phase II trial, the rate of response to BCNU alone was 20% [95% confidence interval (CI), 2%-38%], and this was not improved by the addition of TNF (response rate, 10.5%; 95% CI, 1.3%-33%). Toxicity was higher in the combination arm, and there was no difference in survival. [ABSTRACT FROM AUTHOR]

A "priming" injection of cyclophosphamide (400 mg/m2 given i.v. on day -7) has been shown to reduce intestinal permeability and thus gut toxicity in patients receiving high-dose melphalan. To determine the optimal timing for this injection, patients receiving 200 mg/m2 melphalan with an autologous bone marrow transplant were randomly assigned to receive cyclophosphamide at 5, 7 or 9 days before the melphalan. The median percentage of [51Cr]-ethylenediaminetetraacetic acid excretion was similar (9.1% vs 7.1% vs 7.7%, respectively), with equivalent duration of WHO grade 2-4 mucositis and diarrhoea being recorded for each group. Thus, the timing of the cyclophosphamide prime is not critical, and the priming injection may be given between 5 and 9 days prior to high-dose melphalan. [ABSTRACT FROM AUTHOR]

Introduction: Children with special educational needs are more likely to have vision problems than peers in mainstream education. Reports focus on visual acuity and refraction, overlooking visuoperceptual difficulties, including cerebral visual impairment. This article reports on the feasibility and outcomes of visual function testing performed during in-school visual assessments., Method: A retrospective chart review was undertaken of children participating in a special school vision programme. The testing strategy included acuity, fields, contrast sensitivity, eye movements, accommodation, stereopsis, visual attention, refraction and a parent-completed questionnaire. The testing method was chosen based on the child's ability to engage with testing., Results: 78 cases were identified (mean age 9.6 years). Low vision (worse than 6/19) was identified in 31%. All six tests of visual function were completed by 44% (mean 5.1; range 2-6). The mean number of atypical responses was 1 (range 0-4). Almost half (49%) showed at least one atypical response, most commonly visual attention (35%) and 25% had atypical eye movements., Discussion: Overall, only 20% of children in the special school setting demonstrated a normal response to each test they were able to complete. Acuity testing alone does not demonstrate the atypical visual function of a child with special needs. Using techniques which require minimal cognitive, speech or motor function, a range of visual functions can be elicited during in-school testing. This testing strategy has the advantage of demonstrating areas of visual (dys)function impacting on the child's ability to access learning which can be immediately fed back to teaching staff and carers., Competing Interests: RFP is a trustee of See Ability, a charity which has campaigned for the development of a special school eye service. RFP represents the Royal College of Ophthalmologists on the NHS England Special School Eye Service Stakeholder group. RFP is co-creator of the Bradford Visual Function Box. The remaining authors do not declare any conflict of interest., (Copyright: © 2024 The Author(s).)

Background: Transcription factors bind DNA in specific sequence contexts. In addition to distinguishing one nucleobase from another, some transcription factors can distinguish between unmodified and modified bases. Current models of transcription factor binding tend not to take DNA modifications into account, while the recent few that do often have limitations. This makes a comprehensive and accurate profiling of transcription factor affinities difficult., Results: Here, we develop methods to identify transcription factor binding sites in modified DNA. Our models expand the standard A/C/G/T DNA alphabet to include cytosine modifications. We develop Cytomod to create modified genomic sequences and we also enhance the MEME Suite, adding the capacity to handle custom alphabets. We adapt the well-established position weight matrix (PWM) model of transcription factor binding affinity to this expanded DNA alphabet. Using these methods, we identify modification-sensitive transcription factor binding motifs. We confirm established binding preferences, such as the preference of ZFP57 and C/EBPβ for methylated motifs and the preference of c-Myc for unmethylated E-box motifs., Conclusions: Using known binding preferences to tune model parameters, we discover novel modified motifs for a wide array of transcription factors. Finally, we validate our binding preference predictions for OCT4 using cleavage under targets and release using nuclease (CUT&RUN) experiments across conventional, methylation-, and hydroxymethylation-enriched sequences. Our approach readily extends to other DNA modifications. As more genome-wide single-base resolution modification data becomes available, we expect that our method will yield insights into altered transcription factor binding affinities across many different modifications., (© 2023. The Author(s).)

Summary: Chromatin immunoprecipitation-sequencing is widely used to find transcription factor binding sites, but suffers from various sources of noise. Knocking out the target factor mitigates noise by acting as a negative control. Paired wild-type and knockout (KO) experiments can generate improved motifs but require optimal differential analysis. We introduce peaKO-a computational method to automatically optimize motif analyses with KO controls, which we compare to two other methods. PeaKO often improves elucidation of the target factor and highlights the benefits of KO controls, which far outperform input controls., Availability and Implementation: PeaKO is freely available at https://peako.hoffmanlab.org., Contact: michael.hoffman@utoronto.ca., (© The Author(s) 2023. Published by Oxford University Press.)

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

Economic evaluations performed alongside randomized controlled trials benefit from the protections against bias inherent in randomization. In this systematic review, we assessed the frequency and quality of economic assessments alongside randomized controlled trials of interventions in neonates published between 1990 and 2016. Over that period, 58 economic assessments were published, corresponding to approximately 2% of RCTs. We noted significant methodological limitations of these studies, including limitation of included costs to the health sector or payer rather than broader categories such as family or community expenditures (81%), short time horizon for cost measurement (less than one year in 60%), lack of reporting of uncertainty (26%), and infrequent analysis of costs and effects in a single metric (combined in 45%). Strategies for improving the quality and frequency of economic evaluations in neonatology are discussed, including selection of appropriate trials, funding, and peer review., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to investigate the views of young people (YP) with gender dysphoria and their parents concerning fertility preservation and reproductive and life priorities., Design: A cross-sectional questionnaire-based study assessed knowledge of potential effects of treatments for gender dysphoria on fertility, current and future life priorities and preferences regarding future fertility/parenting options among YP and parents., Results: A total of 79 YP (81% assigned female at birth [AFAB], 19% assigned male at birth [AMAB], aged 12-18 years, 68% between ages 16 years and 18 years) and 73 parents participated. The top current life priority for YP among eight options was being in good health ; the least important priority was having children . Anticipated life priorities 10 years from now were ranked similarly. Parents' rankings paralleled the YP responses; however, parents ranked having children as a significantly higher priority for AFAB compared with AMAB YP in 10 years. The majority of YP (66% AFAB, 67% AMAB) want to be a parent in the future. However, most do not envision having a biological child. A large majority (72% AFAB, 80% AMAB) were open to adoption. None of the YP surveyed pursued fertility preservation., Conclusion: Fertility is a low current and future life priority for transgender YP. The majority of YP wish to become parents but are open to alternative strategies for building a family. These data may explain in part the reported low rates of fertility preservation among this population. Further studies are needed to assess if life priorities change over time., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Covalent DNA modifications, such as 5-methylcytosine (5mC), are increasingly the focus of numerous research programs. In eukaryotes, both 5mC and 5-hydroxymethylcytosine (5hmC) are now recognized as stable epigenetic marks, with diverse functions. Bacteria, archaea, and viruses contain various other modified DNA nucleobases. Numerous databases describe RNA and histone modifications, but no database specifically catalogues DNA modifications, despite their broad importance in epigenetic regulation. To address this need, we have developed DNAmod: the DNA modification database. DNAmod is an open-source database ( https://dnamod.hoffmanlab.org ) that catalogues DNA modifications and provides a single source to learn about their properties. DNAmod provides a web interface to easily browse and search through these modifications. The database annotates the chemical properties and structures of all curated modified DNA bases, and a much larger list of candidate chemical entities. DNAmod includes manual annotations of available sequencing methods, descriptions of their occurrence in nature, and provides existing and suggested nomenclature. DNAmod enables researchers to rapidly review previous work, select mapping techniques, and track recent developments concerning modified bases of interest.

Mindfulness-based interventions (MBIs) have been shown to improve health and well-being in adolescents with chronic illnesses. Because they are most often delivered in person in a group setting, there are several barriers that limit access to MBIs for youth with limited mobility or who cannot access in-person MBIs in their communities. The objective of this study was to determine if eHealth is a viable platform to increase accessibility to MBIs for teens with chronic illnesses. This study reports the qualitative results of a mixed method randomized trial describing the experience of the Mindful Awareness and Resilience Skills for Adolescents (MARS-A) program, an eight-week MBI, delivered either in person or via eHealth. Participants were adolescents between the ages of 13 and 18 with a chronic illness recruited at a tertiary pediatric hospital in Toronto, Canada. Individual semi-structured post-participation audio-video interviews were conducted by a research assistant. A multiple-pass inductive process was used to review interview transcripts and interpret emergent themes from the participants' lived experiences. Fifteen participants (8 online and 7 in person) completed post-participation interviews. Four distinct themes emerged from participants in both groups: Creation of a safe space, fostering peer support and connection, integration of mindfulness skills into daily life, and improved well-being through the application of mindfulness. Direct quotations representative of those four themes are reported. Results from this study suggest that eHealth delivery of an adapted MBI for adolescents with chronic illnesses may be an acceptable and feasible mode of delivery for MBIs in this population. EHealth should be considered in future studies of MBIs for adolescents with chronic illnesses as a promising avenue to increase access to MBIs for youth who might not be able to access in-person programs.

Background: Eight-week mindfulness-based interventions (MBIs) have a beneficial impact on mental health and well-being in adolescents with chronic health conditions. Usually delivered in person in a group setting, these programs are difficult to access for teens with disabilities or who do not have in-person MBIs available in their communities., Objective: This paper outlines the rationale, development, and design of a randomized controlled trial comparing the effects of an MBI delivered in person or via eHealth in adolescents with a chronic illness. Quantitative outcomes will include mindfulness skills acquisition (primary outcome), effects of the MBI on self-reported mood, anxiety, self-esteem, illness perception, and physiological stress (via salivary cortisol), and qualitative outcomes will include individual practice, participant appreciation, and adaptation of the MBI for eHealth., Methods: This is a randomized noninferiority mixed methods study comparing 2 MBI arms: in-person and eHealth. Participants are eligible to participate if they are aged 13 to 18 years, have a diagnosis of chronic medical condition, live close enough to the recruitment hospital to participate in the in-person arm of the study, and are currently followed by a health care provider. Each participant will receive an adapted 8-week MBI delivered either in person at a tertiary pediatric hospital or via a secure audio-visual platform allowing group interactions in real time. Groups will be facilitated by 2 experienced mindfulness providers. Quantitative and qualitative data will be collected through standardized research questionnaires administered via a secure, youth-friendly online platform and through semistructured interviews, participant log books, facilitator log books, and salivary cortisol analysis. Qualitative data will be analyzed using a grounded theory model., Results: Data collection is currently underway. Data analysis, manuscript writing, and additional publications are expected to be completed in the winter and spring of 2018., Conclusions: Based on previous results from in-person trials conducted in adolescents and eHealth trials conducted in adults, we anticipate that both modes of delivery will significantly improve mindfulness skills acquisition, mood, anxiety, self-esteem, illness perception, and stress and that the magnitude of the effects will be correlated to the level of home practice. We predict that participants in both arms will show similar levels of home practice and that both modes of delivery will have high levels of feasibility and acceptability. If successful, this study could provide evidence for the use of eHealth in the delivery of 8-week MBIs in clinical adolescent populations, potentially increasing availability to MBIs for a large group of youth with mobility issues or living away from large urban centers., Trial Registration: ClinicalTrials.org NCT03067207; https://clinicaltrials.gov/ct2/show/NCT03067207 (archived by WebCite at http://www.webcitation.org/6v4ZK8RBH)., (©Nicholas Chadi, Miriam Kaufman, Elli Weisbaum, Catherine Malboeuf-Hurtubise, Sara Ahola Kohut, Christine Viner, Jake Locke, Dzung X Vo. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 27.11.2017.)

Purpose: The purpose of this study was to develop a convenient test of stereopsis in the clinic that is both robust and reliable and capable of providing a measure of variability necessary to make valid comparisons between measurements obtained at different occasions or under different conditions., Methods: Stereo acuity was measured based on principles derived from the laboratory measurement of stereopsis (i.e., staircase method). Potential premeasurement compensations are described if there is a significant degree of ocular misalignment, reduced visual acuity, or aniseikonia. Forty-six adults at McGill University, 44 adults at Auckland University, and 51 adults from the University of Bradford, with an age range of 20 to 65 years old and normal or corrected-to-normal vision participated in this study., Results: Stereo acuity within this normal population was widely distributed, with a significant percentage (28%) of the population with only coarse stereo (>300 arc seconds). Across subjects, the SD was approximately 25% of the mean. Measurements at two different times were strongly (r = 0.79) and significantly (P < 0.001) correlated, with little to no significant (P = 0.79) bias (0.01) between test and retest measures of stereopsis., Conclusions: The application enables measurements over the wide disparity range and not just at the finest disparities. In addition, it allows changes in stereopsis of the order of 1.9 to be statistically distinguished.

Somatic mutations reported in large-scale breast cancer (BC) sequencing studies primarily consist of protein coding mutations. mRNA splicing mutation analyses have been limited in scope, despite their prevalence in Mendelian genetic disorders. We predicted splicing mutations in 442 BC tumour and matched normal exomes from The Cancer Genome Atlas Consortium (TCGA). These splicing defects were validated by abnormal expression changes in these tumours. Of the 5,206 putative mutations identified, exon skipping, leaky or cryptic splicing was confirmed for 988 variants. Pathway enrichment analysis of the mutated genes revealed mutations in 9 NCAM1-related pathways, which were significantly increased in samples with evidence of lymph node metastasis, but not in lymph node-negative tumours. We suggest that comprehensive reporting of DNA sequencing data should include non-trivial splicing analyses to avoid missing clinically-significant deleterious splicing mutations, which may reveal novel mutated pathways present in genetic disorders.

Interpretation of variants present in complete genomes or exomes reveals numerous sequence changes, only a fraction of which are likely to be pathogenic. Mutations have been traditionally inferred from allele frequencies and inheritance patterns in such data. Variants predicted to alter mRNA splicing can be validated by manual inspection of transcriptome sequencing data, however this approach is intractable for large datasets. These abnormal mRNA splicing patterns are characterized by reads demonstrating either exon skipping, cryptic splice site use, and high levels of intron inclusion, or combinations of these properties. We present, Veridical, an in silico method for the automatic validation of DNA sequencing variants that alter mRNA splicing. Veridical performs statistically valid comparisons of the normalized read counts of abnormal RNA species in mutant versus non-mutant tissues. This leverages large numbers of control samples to corroborate the consequences of predicted splicing variants in complete genomes and exomes.

High-dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high-dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 x 10(6) units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high-dose chemotherapy (melphalan 140-200 mg/m2 or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression-free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow-up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu-like symptoms and malaise which were usually self-limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multicentre studies in the setting of minimal residual disease following autologous transplantation.

The use of infusional ambulatory chemotherapy is increasing. Careful patient selection and a structured programme of teaching and home support is required. Continuous ambulatory chemotherapy can improve clinical outcomes and provide both psychological and financial benefits.

In a sequential nonrandomized study, 204 consecutive unselected patients aged < 70 years received induction chemotherapy with infusional vincristine and adriamycin with oral methyl prednisolone (VAMP: n = 75) or with additional cyclophosphamide, C-VAMP (n = 129). 38/129 C-VAMP patients also received verapamil during induction as part of a controlled trial with the aim to overcome drug resistance. A median of five courses (range 1-11) of chemotherapy were required before maximal response was attained and this was similar in both groups. An over-all response rate of 71% was noted at the end of induction. The complete remission (CR) rate with C-VAMP was 24%, which was significantly higher (P = 0.04) than the CR rate with VAMP alone (8%). The addition of verapamil did not alter the response rate of C-VAMP. Compliance to VAMP was overall 83% and not affected by the addition of cyclophosphamide. The proportion of patients going on to receive high-dose chemotherapy and an autograft was the same for VAMP and C-VAMP treated patients (71%). The median overall survival (OS) and progression-free survival (PFS) for the whole group were 4.4 years and 2.0 years and no difference in outcome was observed between the different treatment groups. Therefore the addition of weekly cyclophosphamide to VAMP induction therapy has significantly improved the response rates of previously untreated myeloma patients. C-VAMP was not more toxic and did not compromise the chances of receiving an autograft. Verapamil was without influence on any parameters in this study.

Interferon (INF) has been incorporated as part of maintenance therapy after high dose treatment in order to make remissions more durable. In this study we have compared peripheral blood stem cell transplant (PBSCT) versus autologous bone marrow transplant (ABMT) with respect to INF tolerance. Thirty nine PBSCT patients have been compared to 37 ABMT patients for INF tolerance. This is followed by a comparison of 15 PBSCT patients versus 21 ABMT patients for engraftment details, response and survival. INF was started at a median of 61 days in the PBSCT and 58 days in the ABMT patients (P = NS). It was well tolerated in both groups without a significant difference in toxicity in the two arms. Engraftment was more rapid in the PBSCT patients with platelet recovery being significantly faster. Response and survival showed a favourable trend for ABMT patients though statistical significance was not reached and the cost of PBSCT was 12% cheaper. We were thus able to conclude that PBSCT grafts were as durable and could tolerate INF just as well as ABMT. Engraftment was more rapid and the procedure of PBSCT was also cheaper. Further studies with a larger group of patients will be required before comments on the efficacy of treatment can be made.