Publications by authors named "Peter White"

758 Publications

Central sensitisation in chronic fatigue syndrome and fibromyalgia; a case control study.

J Psychosom Res 2021 Nov 21;150:110624. Epub 2021 Sep 21.

Wolfson Institute, Queen Mary University of London, UK.

Introduction: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are both complex conditions that are challenging to treat. This may be related to an incomplete understanding of their pathophysiology, itself obfuscated by their heterogeneity. The symptomatic overlap between them and their common comorbidity suggests a shared vulnerability, which might be explained by central sensitisation.

Methods: 19 CFS cases, 19 FM cases and 20 age and sex matched healthy controls (HC) were recruited primarily from secondary care clinics in London. Those with other pain disorders, psychiatric diagnoses and those taking centrally acting or opiate medications were excluded. Participants were asked to abstain from alcohol and over the counter analgaesia 48 h prior to assessment by static and dynamic quantitative sensory tests, including measures of temporal summation (TS) and conditioned pain modulation (CPM).

Results: CS, as defined by the presence of both enhanced TS and inefficient CPM, was present in 16 (84%) CFS cases, 18 (95%) FM cases, and none of the HC (p < 0.001). Pressure pain thresholds were lower in CFS (Median222kPaIQR 146-311; p = 0.04) and FM cases (Median 189 kPa; IQR 129-272; p = 0.003) compared to HC (Median 311 kPa; IQR 245-377). FM cases differed from HC in cold-induced (FM = 22.6 °C (15.3-27.7) vs HC = 14.2 °C (9.0-20.5); p = 0.01) and heat-induced (FM = 38.0 °C (35.2-44.0) vs HC = 45.3 °C (40.1-46.8); p = 0.03) pain thresholds, where CFS cases did not.

Conclusion: Central sensitisation may be a common endophenotype in chronic fatigue syndrome and fibromyalgia. Further research should address whether central sensitisation is a cause or effect of these disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychores.2021.110624DOI Listing
November 2021

Epidemiology and Clinical Outcomes of Foot and Ankle Trauma During the First Wave of the COVID-19 Pandemic in the New York Metropolitan Area.

Orthopedics 2021 Sep-Oct;44(5):313-319. Epub 2021 Sep 1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel respiratory virus that has rapidly changed the practice of medicine. The authors sought to evaluate the clinical presentation and clinical outcomes of patients presenting with foot and ankle (F&A) trauma to the emergency department during the first wave of the pandemic. The authors retrospectively studied all patients who presented to an emergency department within their multicenter institution during the first wave of the pandemic in their region from March 1 to June 30, 2020, with F&A trauma. They compared this cohort with a matched control group of patients who presented the prior year. Demographics, perioperative factors, coronavirus disease 2019 (COVID-19) polymerase chain reaction testing/positivity rates, 30-day readmissions, and 30-day mortalities were collected and analyzed. During the pandemic, the authors saw a 62.0% decrease in the total number of patients presenting with F&A trauma. Patients who presented during the pandemic were significantly older and a greater proportion were male. There was a greater proportion of ankle fractures, fewer ankle sprains, and more open fractures presenting during the pandemic. A greater proportion of patients presenting to the emergency department were admitted (18.2% vs 12.5%). The 30-day readmission (n=13 [5.8%] vs n=38 [9.3%]) and mortality (n=4 [1.8%] vs n=3 [0.7%]) rates for admitted patients were similar (=.114 and =.232, respectively). The authors found that 9.6% of patients who presented had a positive COVID-19 polymerase chain reaction test result and that these patients had 20% mortality and readmission rates. [. 2021;44(5):313-319.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3928/01477447-20210819-01DOI Listing
October 2021

Preliminary Investigation into a Novel Sustained-Release Formulation of Meloxicam in Sheep ()-Pharmacokinetic Profile.

Animals (Basel) 2021 Aug 24;11(9). Epub 2021 Aug 24.

Faculty of Science, Sydney School of Veterinary Science, University of Sydney, Sydney, NSW 2006, Australia.

This study is a preliminary investigation describing the pharmacokinetic profile of a novel subcutaneous sustained-release meloxicam formulation (SRMF) in sheep. Six merino ewe hoggets (41.5 ± 4.6 kg) were treated with a novel subcutaneous SRMF at 2 mg/kg bodyweight (BW). Blood samples were collected at t = 0, 2, 4, 6, 8, 10, 12, 24, 48, 96, 144, 168, 192, and 336 h following treatment, and interstitial (ISF) fluid samples were collected at periods of 8 to 12 h, 12 to 24 h, 24 to 48 h, 48 to 52 h, and 92 to 96 h following treatment. High-pressure liquid chromatography (HPLC) analysis with ultraviolet detection was utilised to determine the concentration of meloxicam in plasma and ISF. The SRMF exhibited the following mean (±SD) pharmacokinetic indices: C of 1.58 μg/mL (±0.82 μg/mL) at a T of 10.0 h (±1.79 h), and half life (t) of 31.4 h (±13.17 h) in sheep plasma. Interstitial fluid samples were collected from three of the six sheep, with a decrease in meloxicam concentration exhibited over 52 h. This study demonstrates a variable extended t, a delayed T, and a lower C of the SRMF, as compared to that of a conventional meloxicam formulation (CMF) in sheep, as previously referenced (t: 14.28 h; T: 5 h; C: 15.94 μg/mL). Further research to determine the clinical efficacy and safety of the SRMF in sheep is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ani11092484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466480PMC
August 2021

Lateral tilt during IVC filter placement does not predict the need for advanced filter retrieval techniques.

Diagn Interv Radiol 2021 Sep;27(5):644-648

Dotter Department of Interventional Radiology, Oregon Health and Science University, Portland, Oregon, USA.

Purpose: We aimed to determine if lateral inferior vena cava (IVC) filter tilt at placement predicts the need for subsequent advanced retrieval techniques.

Methods: A retrospective chart review was performed of all Gunther Tulip IVC filter placements with subsequent retrievals between February 2015 and October 2017. Chart and imaging review was performed for patient, filter placement, and filter retrieval demographics/characteristics. Degree of agreement between two measurement sets was evaluated with the intraclass correlation (ICC) analysis. Categorical variables were compared with chi-square or Fisher exact test, as appropriate. Kendall rank correlation was used to measure correlation between categorical variables.

Results: There was poor agreement between filter tilt angle at the time of placement and retrieval (ICC coefficient, 0.54). Mean difference ± standard deviation between tilt angle at the time of placement and retrieval was 4.6°±4.3° (p = 0.35). Among patient- or procedure-related factors, a common femoral vein access on placement (regression coefficient, -2.90; p = 0.039) was associated with a lower difference between placement and retrieval filter tilt angles compared to internal jugular vein access. Higher filter tilt angle measured at the time of retrieval (OR: 1.19, p = 0.025), hook embedment (OR: 77.3, p < 0.001), and a longer dwell time (OR: 1.25, p = 0.002) were associated with the need for advanced retrieval techniques. However, in univariate and multivariate analysis filter tilt angle at the time of placement was not associated with the subsequent need for advanced retrieval technique (p = 0.16).

Conclusion: Lateral tilt at the time of placement is poorly associated with lateral tilt at the time of retrieval and does not correlate with the need for advanced retrieval technique.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5152/dir.2021.19411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480951PMC
September 2021

The impact of the COVID-19 pandemic on patterns of attendance at emergency departments in two large London hospitals: an observational study.

BMC Health Serv Res 2021 Sep 23;21(1):1008. Epub 2021 Sep 23.

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, Norfolk Place, London, W2 1PG, UK.

Background: Hospitals in England have undergone considerable change to address the surge in demand imposed by the COVID-19 pandemic. The impact of this on emergency department (ED) attendances is unknown, especially for non-COVID-19 related emergencies.

Methods: This analysis is an observational study of ED attendances at the Imperial College Healthcare NHS Trust (ICHNT). We calibrated auto-regressive integrated moving average time-series models of ED attendances using historic (2015-2019) data. Forecasted trends were compared to present year ICHNT data for the period between March 12, 2020 (when England implemented the first COVID-19 public health measure) and May 31, 2020. We compared ICHTN trends with publicly available regional and national data. Lastly, we compared hospital admissions made via the ED and in-hospital mortality at ICHNT during the present year to the historic 5-year average.

Results: ED attendances at ICHNT decreased by 35% during the period after the first lockdown was imposed on March 12, 2020 and before May 31, 2020, reflecting broader trends seen for ED attendances across all England regions, which fell by approximately 50% for the same time frame. For ICHNT, the decrease in attendances was mainly amongst those aged < 65 years and those arriving by their own means (e.g. personal or public transport) and not correlated with any of the spatial dependencies analysed such as increasing distance from postcode of residence to the hospital. Emergency admissions of patients without COVID-19 after March 12, 2020 fell by 48%; we did not observe a significant change to the crude mortality risk in patients without COVID-19 (RR 1.13, 95%CI 0.94-1.37, p = 0.19).

Conclusions: Our study findings reflect broader trends seen across England and give an indication how emergency healthcare seeking has drastically changed. At ICHNT, we find that a larger proportion arrived by ambulance and that hospitalisation outcomes of patients without COVID-19 did not differ from previous years. The extent to which these findings relate to ED avoidance behaviours compared to having sought alternative emergency health services outside of hospital remains unknown. National analyses and strategies to streamline emergency services in England going forward are urgently needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12913-021-07008-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460185PMC
September 2021

Discovery of Novel Viruses Associated With the Invasive Cane Toad () in Its Native and Introduced Ranges.

Front Microbiol 2021 6;12:733631. Epub 2021 Sep 6.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.

Cane toads () are notoriously successful invaders: from 101 individuals brought to Australia in 1935, poisonous toads now cover an area >1.2 million km with adverse effects on native fauna. Despite extensive research on the role of macroparasites in cane toad invasion, viral research is lagging. We compared viral prevalence and diversity between toads in their native range (French Guiana, =25) and two introduced ranges: Australia (=151) and Hawai'i (=10) with a metatranscriptomic and metagenomic approach combined with PCR screening. Australian toads almost exclusively harbor one of seven viruses detected globally. Rhimavirus-A () exhibited low genetic diversity and likely actively infected 9% of sampled Australian toads extending across ~2,000km of Northern Australia and up to the current invasion front. In native range cane toads, we identified multiple phylogenetically distinct viruses (, , , and Nackedna-like virus). None of the same viruses was detected in both ranges, suggesting that Australian cane toads have largely escaped the viral infection experienced by their native range counterparts. The novel native range viruses described here are potential biocontrol agents, as Australian toads likely lack prior immunological exposure to these viruses. Overall, our evidence suggests that there may be differences between viruses infecting cane toads in their native vs. introduced ranges, which lays the groundwork for further studies on how these viruses have influenced the toads' invasion history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2021.733631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450580PMC
September 2021

Ancient viral integrations in marsupials: a potential antiviral defence.

Virus Evol 2021 2;7(2):veab076. Epub 2021 Sep 2.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, UNSW Sydney, Sydney, NSW 2052, Australia.

Marsupial viruses are understudied compared to their eutherian mammal counterparts, although they may pose severe threats to vulnerable marsupial populations. Genomic viral integrations, termed 'endogenous viral elements' (EVEs), could protect the host from infection. It is widely known past viral infections and EVEs play an active role in antiviral defence in invertebrates and plants. This study aimed to characterise actively transcribed EVEs in Australian marsupial species, because they may play an integral role in cellular defence against viruses. This study screened publicly available RNA sequencing data sets ( = 35) and characterised 200 viral transcripts from thirteen Australian marsupial species. Of the 200 transcripts, 188 originated from either , or EVEs. The other twelve transcripts were from putative active infections from members of the and , and . EVE transcripts ( = 188) were mapped to marsupial genomes (where available,  = 5/13) to identify the genomic insertion sites. Of the 188 transcripts, 117 mapped to 39 EVEs within the koala, bare-nosed wombat, tammar wallaby, brushtail possum, and Tasmanian devil genomes. The remaining eight animals had no available genome (transcripts  = 71). Every marsupial has , and EVEs, a trend widely observed in eutherian mammals. Whilst eutherian bornavirus EVEs are predominantly nucleoprotein-derived, marsupial bornavirus EVEs demonstrate a surprising replicase gene bias. We predicted these widely distributed EVEs were conserved within marsupials from ancient germline integrations, as many were over 65 million years old. One bornavirus replicase EVE, present in six marsupial genomes, was estimated to be 160 million years old, predating the American-Australian marsupial split. We considered transcription of these EVEs through small non-coding RNA as an ancient viral defence. Consistent with this, in koala small RNA sequence data sets, we detected replicase and nucleoprotein produced small RNA. These were enriched in testis tissue, suggesting they could protect marsupials from vertically transmitted viral integrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ve/veab076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449507PMC
September 2021

A Multi-Omics Approach Using a Mouse Model of Cardiac Malformations for Prioritization of Human Congenital Heart Disease Contributing Genes.

Front Cardiovasc Med 2021 24;8:683074. Epub 2021 Aug 24.

Center for Cardiovascular Research and Heart Center, Nationwide Children's Hospital, Columbus, OH, United States.

Congenital heart disease (CHD) is the most common type of birth defect, affecting ~1% of all live births. Malformations of the cardiac outflow tract (OFT) account for ~30% of all CHD and include a range of CHDs from bicuspid aortic valve (BAV) to tetralogy of Fallot (TOF). We hypothesized that transcriptomic profiling of a mouse model of CHD would highlight disease-contributing genes implicated in congenital cardiac malformations in humans. To test this hypothesis, we utilized global transcriptional profiling differences from a mouse model of OFT malformations to prioritize damaging, variants identified from exome sequencing datasets from published cohorts of CHD patients. mice display a spectrum of cardiac OFT malformations ranging from BAV, semilunar valve (SLV) stenosis to TOF. Global transcriptional profiling of the E13.5 mutant mouse OFTs and wildtype controls was performed by RNA sequencing (RNA-Seq). Analysis of the RNA-Seq dataset demonstrated genes belonging to the , , , and signaling pathways were differentially expressed in the mutant OFT. Mouse to human comparative analysis was then performed to determine if patients with TOF and SLV stenosis display an increased burden of damaging, genetic variants in gene homologs that were dysregulated in OFT. We found an enrichment of variants in the TOF population among the 1,352 significantly differentially expressed genes in mouse OFT but not the SLV population. This association was not significant when comparing only highly expressed genes in the murine OFT to variants in the TOF population. These results suggest that transcriptomic datasets generated from the appropriate temporal, anatomic and cellular tissues from murine models of CHD may provide a novel approach for the prioritization of disease-contributing genes in patients with CHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2021.683074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421733PMC
August 2021

Hypomorphic alleles pose challenges in rare disease genomic variant interpretation.

Clin Genet 2021 Sep 3. Epub 2021 Sep 3.

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

Exon skipping associated with an ATP7B intronic variant in a patient with Wilson's disease. (A) Sashimi plot visualization of aligned RNA sequencing data from proband liver tissue at ATP7B exons 14-13-12. The red track shows traditional RNA-seq data; the blue track shows RNA-seq enriched with exon capture (cDNA-cap) which achieves higher depth of protein-coding transcripts. The histogram indicates overall sequencing depth while arcs tabulate the number of junction-spanning reads supporting exon pairs. (B) The domain structure (top) and exon structure (bottom) of ATP7B. Loss of exon 13 (dashed box) would remove a transmembrane domain and disrupt the first phosphorylation domain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.14052DOI Listing
September 2021

The extended present: an informational context for perception.

Authors:
Peter A White

Acta Psychol (Amst) 2021 Aug 26;220:103403. Epub 2021 Aug 26.

School of Psychology, Cardiff University, Tower Building, Park Place, Cardiff CF10 3YG, Wales, UK. Electronic address:

Several previous authors have proposed a kind of specious or subjective present moment that covers a few seconds of recent information. This article proposes a new hypothesis about the subjective present, renamed the extended present, defined not in terms of time covered but as a thematically connected information structure held in working memory and in transiently accessible form in long-term memory. The three key features of the extended present are that information in it is thematically connected, both internally and to current attended perceptual input, it is organised in a hierarchical structure, and all information in it is marked with temporal information, specifically ordinal and duration information. Temporal boundaries to the information structure are determined by hierarchical structure processing and by limits on processing and storage capacity. Supporting evidence for the importance of hierarchical structure analysis is found in the domains of music perception, speech and language processing, perception and production of goal-directed action, and exact arithmetical calculation. Temporal information marking is also discussed and a possible mechanism for representing ordinal and duration information on the time scale of the extended present is proposed. It is hypothesised that the extended present functions primarily as an informational context for making sense of current perceptual input, and as an enabler for perception and generation of complex structures and operations in language, action, music, exact calculation, and other domains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actpsy.2021.103403DOI Listing
August 2021

Evidence of pioneer factor activity of an oncogenic fusion transcription factor.

iScience 2021 Aug 16;24(8):102867. Epub 2021 Jul 16.

Nationwide Children's Hospital, Center for Childhood Cancer and Blood Diseases, Columbus, OH 43205, USA.

Recent characterizations of pioneer transcription factors provide insights into their structures and patterns of chromatin recognition associated with their roles in cell fate commitment and transformation. Intersecting with these basic science concepts, identification of pioneer factors (PFs) fused together as driver translocations in childhood cancers raises questions of whether these fusions retain the fundamental ability to invade repressed chromatin, consistent with their monomeric PF constituents. This study defines the cellular and chromatin localization of PAX3-FOXO1, an oncogenic driver of childhood rhabdomyosarcoma (RMS), derived from a fusion of PFs. To quantitatively define its chromatin-targeting functions and capacity to drive epigenetic reprogramming, we developed a ChIP-seq workflow with per-cell normalization (pc-ChIP-seq). Our quantitative localization studies address structural variation in RMS genomes and reveal insights into inactive chromatin localization of PAX3-FOXO1. Taken together, our studies are consistent with pioneer function for a driver oncoprotein in RMS, with repressed chromatin binding and nucleosome-motif targeting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346656PMC
August 2021

Tempo-spatial patterns of PM measured using a portable particulate monitor around a mine complex in Canada's Arctic.

Environ Monit Assess 2021 Aug 11;193(9):560. Epub 2021 Aug 11.

CircumArctic Rangifer Monitoring and Assessment Network, Vancouver, Canada.

Mining activities in Canada's pristine Arctic (e.g., driving on unpacked roads, blasts, rock grinding, diesel combustion, and garbage incineration) could add local sources of airborne fine particulate matter with a diameter of < 2.5 μm (PM) to their surrounding area. The increase in PM above the background level around a mine represents a potential disturbance to caribou. To quantify the spatial distribution of the elevated PM, we investigated three different sampling schemes to measure PM concentration using a portable monitor. We found that the best sampling scheme was to use the regional background PM as the reference and analyze the anomaly of PM measured at sites around the mine complex from the background level. The regional background PM values were measured at the Daring Lake Tundra Research Station during 2018 and 2019. Our results indicated that the background PM was not a low and constant value but varied with rain events, wind direction, and the impacts of forest fire smoke. After excluding periods affected by forest fires smokes, we found the background PM was close to 0 μg m for the first few hours after rain, and then increased logistically with the time after rain (t) to the maximum of 5 (or 10) μg m when the wind came from the north (or south) of the NW-SE axis. The NW-SE axis in western Canada divides the tundra north with few anthropogenic PM sources from the forested south with many PM sources from forest fire smokes and human activities. Analyses of PM anomaly from the background (i.e., PM measured at a site around the mining complex-the background level at the corresponding t and wind direction) revealed that the zone of elevated PM around the mine (Z) expanded with t. In the first few hours after rain, PM was close to 0 everywhere except within meters of a source (e.g., a truck exhaust) in the downwind direction. During t = 6 to 96 h, Z expanded to 6.3 km in the downwind direction when the wind came from south of the NW-SE axis. A similar result was found in the downwind direction when the wind came from north of the NW-SE axis, with Z = 4.4 km. In the upwind direction, the value of Z was much smaller, being 0.7 km (or 1.0 km) when the wind came from the north (or south) of the NW-SE axis. For the period of t between 96 and 192 hours, Z further expanded to 21.2 km when the wind from the south of the NW-SE axis. The results from this study indicated that this reference paradigm that uses the regional background PM as the reference in combination with a portable PM monitor worked well for quantifying the tempo-spatial patterns of PM at locations in remote and mostly pristine Arctic. However, their effectiveness for other regions needs further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10661-021-09376-5DOI Listing
August 2021

L-Arabinose Transport and Metabolism in Influences Biofilm Formation.

Front Cell Infect Microbiol 2021 22;11:698146. Epub 2021 Jul 22.

Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.

L-arabinose inducible promoters are commonly used in gene expression analysis. However, nutrient source and availability also play a role in biofilm formation; therefore, L-arabinose metabolism could impact biofilm development. In this study we examined the impact of L-arabinose on serovar Typhimurium (. Typhimurium) biofilm formation. Using mutants impaired for the transport and metabolism of L-arabinose, we showed that L-arabinose metabolism negatively impacts Typhimurium biofilm formation . When L-arabinose metabolism is abrogated, biofilm formation returned to baseline levels. However, without the ability to import extracellular L-arabinose, biofilm formation significantly increased. Using RNA-Seq we identified several gene families involved in these different phenotypes including curli expression, amino acid synthesis, and L-arabinose metabolism. Several individual candidate genes were tested for their involvement in the L-arabinose-mediated biofilm phenotypes, but most played no significant role. Interestingly, in the presence of L-arabinose the diguanylate cyclase gene A was downregulated in wild type . Typhimurium. Meanwhile , encoding an adenylate cyclase, was downregulated in an L-arabinose transport mutant. Using an IPTG-inducible plasmid to deplete c-di-GMP expression, we were able to abolish the increased biofilm phenotype seen in the transport mutant. However, the mechanism by which the L-arabinose import mutant forms significantly larger biofilms remains to be determined. Regardless, these data suggest that L-arabinose metabolism influences intracellular c-di-GMP levels and therefore biofilm formation. These findings are important when considering the use of an L-arabinose inducible promoter in biofilm conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2021.698146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341724PMC
August 2021

Industry Payments to Adult Reconstruction-Trained Orthopedic Surgeons: An Analysis of the Open Payments Database From 2014 to 2019.

J Arthroplasty 2021 Jul 15. Epub 2021 Jul 15.

Department of Orthopaedic Surgery, Huntington Hospital, Huntington, NY.

Background: In recent time, there has been an increased push toward transparency in industry funding toward physicians. The Physician Payments Sunshine Act called for the creation of the Open Payments Database managed by the Centers for Medicare & Medicaid Services. To our knowledge, there have been no studies evaluating the trends in payments among adult reconstruction fellowship-trained orthopedic surgeons. The purpose of this study is to investigate trends in all payments to adult reconstruction-trained orthopedic surgeons from 2014 to 2019. Secondary outcomes included evaluating trends in yearly subpayment categories, regional variations, as well as characterizing the top 5 industry companies.

Methods: A review of the Centers for Medicare & Medicaid Services Open Payments Database was performed to identify all payments to adult reconstruction-trained orthopedic surgeons. A total of 94,265 payments were made to 4911 surgeons accounting for a total of $258,865,231.20 during the study period. Our primary outcome was to assess the trend in median payment per year to individual surgeons. Secondary outcomes included evaluating payment trends with respect to subtype, location as defined by United States Census regions, as well as specifics concerning the top 5 companies.

Results: Over the study period, there was a nonsignificant increasing trend in median payment per surgeon (r = 0.49, P = .096). However, there was also a significantly increasing trend in the number of payments per year (r = 0.83, P = .014), as well as the number of surgeons receiving payments (r = 0.88, P = .019). With respect to subcategory payments, there were significantly increasing trends in the median payment per surgeon for education (1054%, r = 0.942, P < .001) and entertainment/food and beverage expenses (20.2%, r = 0.49, P = .020), as well as a significantly decreasing trend for median honoraria payments per surgeon (20.2%, r = -0.04, P = .005). No significant regional trends were identified. Of the top 5 companies, one demonstrated a significantly decreasing trend in median payment per surgeon (21.6%, r = -0.109, P < .001), whereas the others remained unchanged.

Conclusion: In this study, we found a nonsignificant increasing trend in payments to adult reconstruction-trained surgeons as well as an increasing number of surgeons receiving payments. There were increasing trends in median payment per surgeon for education and entertainment expenses, but a decreasing trend for honoraria payments. No significant regional trends were identified. The majority of the top 5 companies had nonsignificant trends in their payments. Further studies are needed to characterize the disclosure of payments and the impact of industry payments on clinical outcomes.

Level Of Evidence: IV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arth.2021.07.004DOI Listing
July 2021

Delay in Treatment of a Bimalleolar Ankle Fracture during Coronavirus Disease-19 COVID-19 Pandemic Leading to Amputation.

J Orthop Case Rep 2021 Apr;11(4):28-32

Department of Adult Reconstruction Orthopaedic Surgery-ProHEALTH Care, Lake Success, New York, United States.

Introduction: Severe acute respiratory syndrome coronavirus-2 (SARs-CoV-2), also known as coronavirus disease-19 (COVID-19), is a novel respiratory disease which has fundamentally disrupted societal norms. Common responses to the pandemic have called for "social distancing" and national lockdowns. There is little evidence as to how public perception surrounding exposure to the virus may impact patient care. Here, we present a case of a patient who deferred medical treatment due to concerns regarding exposure to the virus.

Case Report: A 99-year-old female who presented to an emergency department of a community hospital on Long Island, New York, during the COVID-19 pandemic complaining of right ankle pain after a fall three 3 weeks ago. Fear of contracting COVID-19, led to initial avoidance of medical evaluation. On presentation, the patient presented with a Gustillo-Anderson Grade III A, bimalleolar ankle fracture with associated gangrene. After evaluation and a thorough discussion with the patient and her family, the patient underwent guillotine amputation.

Conclusion: Public perception surrounding COVID-19 has created a sense of fear that can impact patient behaviors, such as prevent them from seeking medical care when necessary. As physicians, we need to make patients feel safe and increase availability to patient care during this time to prevent similar issues as demonstrated in this case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.13107/jocr.2021.v11.i04.2138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310643PMC
April 2021

Endogenous retrovirus envelope as a tumor-associated immunotherapeutic target in murine osteosarcoma.

iScience 2021 Jul 19;24(7):102759. Epub 2021 Jun 19.

Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, 700 Children's Drive Columbus, OH 43205, USA.

Osteosarcoma remains one of the deadliest cancers in pediatrics and young adults. We administered two types of immunotherapies, oncolytic virotherapy and immune checkpoint inhibition, to two murine osteosarcoma models and observed divergent results. Mice bearing F420 showed no response, whereas those with K7M2 showed prolonged survival in response to combination therapy. K7M2 had higher expression of immune-related genes and higher baseline immune cell infiltrates, but there were no significant differences in tumor mutational burden or predicted MHC class I binding of nonsynonymous mutations. Instead, we found several mouse endogenous retrovirus sequences highly expressed in K7M2 compared with F420. T cell tetramer staining for one of them, gp70, was detected in mice with K7M2 but not F420, suggesting that endogenous retrovirus proteins are targets for the anti-tumor immune reaction. Given prior observations of endogenous retrovirus expression in human osteosarcomas, our findings may be translatable to human disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267546PMC
July 2021

Corrigendum to "Guided graded exercise self-help for chronic fatigue syndrome: Long term follow up and cost-effectiveness following the GETSET trial" [Journal of Psychosomatic Research 146 (2021) 110484].

J Psychosom Res 2021 Sep 1;148:110542. Epub 2021 Jul 1.

Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Bart's and the London School of Medicine and Dentistry, Queen Mary University, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychores.2021.110542DOI Listing
September 2021

Key epidemiological drivers and impact of interventions in the 2020 SARS-CoV-2 epidemic in England.

Sci Transl Med 2021 07 22;13(602). Epub 2021 Jun 22.

MRC Centre for Global Infectious Disease Analysis, Abdul Latif Jameel Institute for Disease and Emergency Analytics (J-IDEA), School of Public Health, Imperial College London, London W2 1PG, UK.

We fitted a model of SARS-CoV-2 transmission in care homes and the community to regional surveillance data for England. Compared with other approaches, our model provides a synthesis of multiple surveillance data streams into a single coherent modeling framework, allowing transmission and severity to be disentangled from features of the surveillance system. Of the control measures implemented, only national lockdown brought the reproduction number ( ) below 1 consistently; if introduced 1 week earlier, it could have reduced deaths in the first wave from an estimated 48,600 to 25,600 [95% credible interval (CrI): 15,900 to 38,400]. The infection fatality ratio decreased from 1.00% (95% CrI: 0.85 to 1.21%) to 0.79% (95% CrI: 0.63 to 0.99%), suggesting improved clinical care. The infection fatality ratio was higher in the elderly residing in care homes (23.3%, 95% CrI: 14.7 to 35.2%) than those residing in the community (7.9%, 95% CrI: 5.9 to 10.3%). On 2 December 2020, England was still far from herd immunity, with regional cumulative infection incidence between 7.6% (95% CrI: 5.4 to 10.2%) and 22.3% (95% CrI: 19.4 to 25.4%) of the population. Therefore, any vaccination campaign will need to achieve high coverage and a high degree of protection in vaccinated individuals to allow nonpharmaceutical interventions to be lifted without a resurgence of transmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abg4262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432953PMC
July 2021

Advancing leadership in Australasian emergency medicine: Taking stock and looking ahead.

Emerg Med Australas 2021 Oct 15;33(5):938-940. Epub 2021 Jun 15.

Australasian College for Emergency Medicine, Melbourne, Victoria, Australia.

Since 2018, the Australasian College for Emergency Medicine has collaborated with the Swinburne University of Technology on a research project to understand and enhance the leadership capacity of emergency physicians, beginning with Australasian Directors of Emergency Medicine (DEMs). Over the last 3 years, this research programme has revealed the complexity of leadership in emergency medicine, illuminating the strengths and limitations of extant research and suggesting promising new directions for emergency medicine leadership and leadership development research. This programme has also shed new light on the knowledge, skills and abilities that DEMs need to develop to catalyse change in the systems where DEMs practice both medicine and leadership. We propose that an approach to leadership development that reflects the diversity of DEMs' leadership challenges and the complexity of leadership in emergency medicine would go a long way to enhancing the sophistication, effectiveness and impact of the leadership in emergency medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1742-6723.13815DOI Listing
October 2021

Characteristics of Patients ≥ 10 Years of Age with Diffuse Intrinsic Pontine Glioma: A Report from the International DIPG Registry.

Neuro Oncol 2021 Jun 11. Epub 2021 Jun 11.

The Ohio State University College of Medicine, Columbus, OH.

Background: DIPG generally occurs in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR).

Methods: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months).

Results: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years [range 10-26.8]. Median OS was 13 [2-82] months. The 1-, 3- and 5- years OS was 61.9%, 3.7%, and 1.5%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P<0.01) and present with longer symptom duration (P<0.01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and one was a LTS. The presence or absence of H3 alterations did not affect survival.

Conclusion: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noab140DOI Listing
June 2021

Gastroblastoma with a novel EWSR1-CTBP1 fusion presenting in adolescence.

Genes Chromosomes Cancer 2021 Sep 7;60(9):640-646. Epub 2021 Jun 7.

Department of Pathology, The Ohio State University, Columbus, Ohio, USA.

Gastroblastomas are rare tumors with a biphasic epithelioid/spindle cell morphology that typically present in early adulthood and have recurrent MALAT1-GLI1 fusions. We describe an adolescent patient with Wiskott-Aldrich syndrome who presented with a large submucosal gastric tumor with biphasic morphology. Despite histologic features consistent with gastroblastoma, a MALAT1-GLI1 fusion was not found in this patient's tumor; instead, comprehensive molecular profiling identified a novel EWSR1-CTBP1 fusion and no other significant genetic alterations. The tumor also overexpressed NOTCH and FGFR by RNA profiling. The novel fusion and expression profile suggest a role for epithelial-mesenchymal transition in this tumor, with potential implications for the pathogenesis of biphasic gastric tumors such as gastroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22973DOI Listing
September 2021

Review of Industry Payments to General Orthopaedic Surgeons Reported by the Open Payments Database: 2014 to 2019.

J Am Acad Orthop Surg Glob Res Rev 2021 05 7;5(5):e21.00060. Epub 2021 May 7.

From the Zucker School of Medicine at Hofstra/Northwell Orthopaedic Surgery Residency Program, Plainview, NY (Dr. Braithwaite, Dr. Frane, Dr. Partan, Dr. White, and Dr. Bitterman), the Department of Orthopaedic Surgery, Northwell Health Huntington Hospital, Huntington, NY (Dr. Braithwaite, Dr. Frane, Dr. Partan, Dr. White, Dr. Iturriaga, and Dr. Bitterman), Nova Southeastern University (Mr. Gruber).

Introduction: The Physician Payments Sunshine Act was placed into law in 2010 in an effort to create transparency between physicians and industry. Along with many other specialties, orthopaedic surgeons have long worked intimately with medical industry companies. This study aimed to evaluate trends in industry payments to general orthopaedic surgeons from 2014 to 2019.

Methods: A retrospective review of the Center of Medicare and Medicaid Services' Open Payments Database was done to identify all industry payments to all general orthopaedic surgeons (ie, not subspecialty affiliated) from 2014 to 2019. The researchers analyzed total payments and subtype payments for yearly trends, and a regional analysis was done. The primary outcome was the overall trend in total median payments, which was assessed through the Jonckheere-Terpstra test. Descriptive statistics include medians with interquartile ranges. P < 0.05 was considered statistically significant.

Results: Between 2014 and 2019, a total of 1,330,543 payments totaling $1.79 billion dollars was paid to 108,041 general orthopaedic surgeons. During this time, the number of surgeons receiving payments increased with a significant uptrend in median payments per surgeon (P < 0.001; Table 1). The top 25% percentile of general orthopaedic surgeons received >95% of payments, whereas the bottom 25% received <0.1%. The general payment types all saw significant increases (P < 0.001) between 2014 and 2019, with the exception of "Ownership or Investment Interests" (P = 0.657) and "Royalty or License" (P = 0.517). Significant regional uptrends in median industry payments were also seen in the Midwest, Northeast, South, and West (P < 0.001). Four of the top five orthopaedic industry companies made payment increases between 2014 and 2019.

Conclusion: Industry payments to general orthopaedic surgeons between 2014 and 2019 have increased with a considerable disparity in payments among the top-paid orthopaedic surgeons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5435/JAAOSGlobal-D-21-00060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116034PMC
May 2021

Alpha-antitrypsin Disease, Treatment and Role for Lung Volume Reduction Surgery.

Thorac Surg Clin 2021 May;31(2):139-160

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Southern Illinois University School of Medicine, 801 North Rutledge Street, Room 1269, Springfield, IL 62702, USA.

Chronic obstructive pulmonary usually is subcategorized into 2 groups: chronic bronchitis and emphysema. The main cause of chronic bronchitis and emphysema is smoking; however, alpha1-antitrypsin also has been seen to cause emphysema in patients who are deficient. As symptoms and lung function decline, treatment modalities, such as lung volume reduction surgery, have been used in individuals with chronic obstructive pulmonary disease and upper lobe predominant emphysema. This article analyzes multiple published series where lung volume reduction surgery has been used in individuals with alpha1-antitrypsin deficiency and their overall outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thorsurg.2021.02.002DOI Listing
May 2021

Guided graded exercise self-help for chronic fatigue syndrome: Long term follow up and cost-effectiveness following the GETSET trial.

J Psychosom Res 2021 07 2;146:110484. Epub 2021 Apr 2.

Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Bart's and the London School of Medicine and Dentistry, Queen Mary University, London, UK.

Objective: The GETSET trial found that guided graded exercise self-help (GES) improved fatigue and physical functioning more than specialist medical care (SMC) alone in adults with chronic fatigue syndrome (CFS) 12 weeks after randomisation. In this paper, we assess the longer-term clinical and health economic outcomes.

Methods: GETSET was a randomised controlled trial of 211 UK secondary care patients with CFS. Primary outcomes were the Chalder fatigue questionnaire and the physical functioning subscale of the short-form-36 survey. Postal questionnaires assessed the primary outcomes and cost-effectiveness of the intervention 12 months after randomisation. Service costs and quality-adjusted life years (QALYs) were combined in a cost-effectiveness analysis.

Results: Between January 2014 and March 2016, 164 (78%) participants returned questionnaires 15 months after randomisation. Results showed no main effect of intervention arm on fatigue (chi(1) = 4.8, p = 0.03) or physical functioning (chi(1) = 1.3, p = 0.25), adjusting for multiplicity. No other intervention arm or time*arm effect was significant. The short-term fatigue reduction was maintained at long-term follow-up for participants assigned to GES, with improved fatigue from short- to long-term follow up after SMC, such that the groups no longer differed. Healthcare costs were £85 higher for GES and produced more QALYs. The incremental cost-effectiveness ratio was £4802 per QALY.

Conclusions: The short-term improvements after GES were maintained at long-term follow-up, with further improvement in the SMC group such that the groups no longer differed at long-term follow-up. The cost per QALY for GES compared to SMC alone was below the usual threshold indicating cost-effectiveness, but with uncertainty around the result.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychores.2021.110484DOI Listing
July 2021

Novel morphologic findings in PLAG1-rearranged soft tissue tumors.

Genes Chromosomes Cancer 2021 Aug 29;60(8):577-585. Epub 2021 Apr 29.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

Oncogenesis in PLAG1-rearranged tumors often results from PLAG1 transcription factor overexpression driven by promoter-swapping between constitutively expressed fusion partners. PLAG1-rearranged tumors demonstrate diverse morphologies. This study adds to this morphologic heterogeneity by introducing two tumors with PLAG1 rearrangements that display distinct histologic features. The first arose in the inguinal region of a 3-year-old, appeared well-circumscribed with a multinodular pattern, and harbored two fusions: ZFHX4-PLAG1 and CHCHD7-PLAG1. The second arose in the pelvic cavity of a 15-year-old girl, was extensively infiltrative and vascularized with an adipocytic component, and demonstrated a COL3A1-PLAG1 fusion. Both showed low-grade cytomorphology, scarce mitoses, no necrosis, and expression of CD34 and desmin. The ZFHX4-/CHCHD7-PLAG1-rearranged tumor showed no evidence of recurrence after 5 months. By contrast, the COL3A1-PLAG1-rearranged tumor quickly recurred following primary excision with positive margins; subsequent re-excision with adjuvant chemotherapy resulted in no evidence of recurrence after 2 years. While both tumors show overlap with benign and malignant fibroblastic and fibrovascular neoplasms, they also display divergent features. These cases highlight the importance of appropriate characterization in soft tissue tumors with unusual clinical and histologic characteristics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22953DOI Listing
August 2021

Nuclear localisation of West Nile virus NS5 protein modulates host gene expression.

Virology 2021 Jul 9;559:131-144. Epub 2021 Apr 9.

Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. Electronic address:

The involvement of the nucleus during flavivirus infection has been observed in only a small number of cases and can be limited to primarily two viral proteins; the structural protein C and the RNA polymerase NS5. Previously we observed that by blocking nuclear transport, WNV strain Kunjin (WNV) replication is severely affected and through mutation of the identified NLS in WNV NS5 protein. In this study, we interrogated the potential nuclear functions of WNV NS5 has on the host transcriptome, by means of RNA sequencing (RNAseq). In a direct comparison between wild type and mutant NS5, it can also be determined that the nuclear translocation of NS5 results in a significant down-regulation of host genes involved in the innate immune response. When compared to published RNAseq data from WNV infection, many of these genes were overlapping indicting the role of NS5 induced transcription during infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2021.03.018DOI Listing
July 2021

Modelling intensive care unit capacity under different epidemiological scenarios of the COVID-19 pandemic in three Western European countries.

Int J Epidemiol 2021 07;50(3):753-767

MRC Centre for Global Infectious Disease Analysis & WHO Collaborating Centre for Infectious Disease Modelling, Abdul Latif Jameel Institute for Disease and Emergency Analytics, Imperial College London, St Mary's Campus, Norfolk Place, London, UK.

Background: The coronavirus disease 2019 (COVID-19) pandemic has placed enormous strain on intensive care units (ICUs) in Europe. Ensuring access to care, irrespective of COVID-19 status, in winter 2020-2021 is essential.

Methods: An integrated model of hospital capacity planning and epidemiological projections of COVID-19 patients is used to estimate the demand for and resultant spare capacity of ICU beds, staff and ventilators under different epidemic scenarios in France, Germany and Italy across the 2020-2021 winter period. The effect of implementing lockdowns triggered by different numbers of COVID-19 patients in ICUs under varying levels of effectiveness is examined, using a 'dual-demand' (COVID-19 and non-COVID-19) patient model.

Results: Without sufficient mitigation, we estimate that COVID-19 ICU patient numbers will exceed those seen in the first peak, resulting in substantial capacity deficits, with beds being consistently found to be the most constrained resource. Reactive lockdowns could lead to large improvements in ICU capacity during the winter season, with pressure being most effectively alleviated when lockdown is triggered early and sustained under a higher level of suppression. The success of such interventions also depends on baseline bed numbers and average non-COVID-19 patient occupancy.

Conclusion: Reductions in capacity deficits under different scenarios must be weighed against the feasibility and drawbacks of further lockdowns. Careful, continuous decision-making by national policymakers will be required across the winter period 2020-2021.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyab034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083295PMC
July 2021

Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma.

Acta Neuropathol Commun 2021 04 7;9(1):61. Epub 2021 Apr 7.

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute At Nationwide Children's Hospital, 575 Children's Crossroad, Columbus, OH, 43215 , USA.

Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1. Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1. These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-021-01164-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025529PMC
April 2021

Synonymous variants that disrupt messenger RNA structure are significantly constrained in the human population.

Gigascience 2021 Apr;10(4)

Computational Genomics Group, The Institute for Genomic Medicine, Nationwide Children's Hospital, 575 Children's Crossroad, Columbus, OH 43215, USA.

Background: The role of synonymous single-nucleotide variants in human health and disease is poorly understood, yet evidence suggests that this class of "silent" genetic variation plays multiple regulatory roles in both transcription and translation. One mechanism by which synonymous codons direct and modulate the translational process is through alteration of the elaborate structure formed by single-stranded mRNA molecules. While tools to computationally predict the effect of non-synonymous variants on protein structure are plentiful, analogous tools to systematically assess how synonymous variants might disrupt mRNA structure are lacking.

Results: We developed novel software using a parallel processing framework for large-scale generation of secondary RNA structures and folding statistics for the transcriptome of any species. Focusing our analysis on the human transcriptome, we calculated 5 billion RNA-folding statistics for 469 million single-nucleotide variants in 45,800 transcripts. By considering the impact of all possible synonymous variants globally, we discover that synonymous variants predicted to disrupt mRNA structure have significantly lower rates of incidence in the human population.

Conclusions: These findings support the hypothesis that synonymous variants may play a role in genetic disorders due to their effects on mRNA structure. To evaluate the potential pathogenic impact of synonymous variants, we provide RNA stability, edge distance, and diversity metrics for every nucleotide in the human transcriptome and introduce a "Structural Predictivity Index" (SPI) to quantify structural constraint operating on any synonymous variant. Because no single RNA-folding metric can capture the diversity of mechanisms by which a variant could alter secondary mRNA structure, we generated a SUmmarized RNA Folding (SURF) metric to provide a single measurement to predict the impact of secondary structure altering variants in human genetic studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gigascience/giab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023685PMC
April 2021
-->