Pathological margins and advanced cutaneous squamous cell carcinoma of the head and neck.

OBJECTIVE:The recommended treatment for cutaneous squamous cell cancer (CuSCC) of the head and neck is Mohs surgical excision or wide local excision. Excision is recommended to a gross surgical margin of 4-6 mm however this is based on limited evidence and specify a goal histologic margin. The objective of this study was therefore to examine the reported histological margin distance following WLE of advanced CuSCC and its association with recurrence and survival. STUDY DESIGN:Retrospective database review. SETTING:All patients included received treatment at UC Davis Department of Otolaryngology-Head and Neck Surgery and/or Radiation Oncology in Sacramento, California. SUBJECTS AND METHODS:The patients included were treated for advanced CuSCC with primary surgery with or without adjuvant therapy. Kaplan Meier survival curves with log rank analysis were then performed to compare 5-year recurrence free survival, and disease-specific survival for patients with different margin distances. RESULTS:Total number of subjects was 92. The overall 5-year DSS and RFS was 68.8 and 51.0% respectively. When the pathological margin distance was ≥5 mm, 5-year disease specific survival was improved when compared to margin distance less than 5 mm (94.7 vs 60.7 p = 0.034). CONCLUSION:The findings of this study suggest that a histologic margin of at least 5 mm may increase survival in advanced head and neck CuSCC patients

How well do CMIP5 climate simulations replicate historical trends and patterns of meteorological droughts?

Assessing the uncertainties and understanding the deficiencies of climate models are fundamental to developing adaptation strategies. The objective of this study is to understand how well Coupled Model Intercomparison-Phase 5 (CMIP5) climate model simulations replicate ground-based observations of continental drought areas and their trends. The CMIP5 multimodel ensemble encompasses the Climatic Research Unit (CRU) ground-based observations of area under drought at all time steps. However, most model members overestimate the areas under extreme drought, particularly in the Southern Hemisphere (SH). Furthermore, the results show that the time series of observations and CMIP5 simulations of areas under drought exhibit more variability in the SH than in the Northern Hemisphere (NH). The trend analysis of areas under drought reveals that the observational data exhibit a significant positive trend at the significance level of 0.05 over all land areas. The observed trend is reproduced by about three-fourths of the CMIP5 models when considering total land areas in drought. While models are generally consistent with observations at a global (or hemispheric) scale, most models do not agree with observed regional drying and wetting trends. Over many regions, at most 40% of the CMIP5 models are in agreement with the trends of CRU observations. The drying/wetting trends calculated using the 3 months Standardized Precipitation Index (SPI) values show better agreement with the corresponding CRU values than with the observed annual mean precipitation rates. Pixel-scale evaluation of CMIP5 models indicates that no single model demonstrates an overall superior performance relative to the other models

The importance of sea ice area biases in 21st century multimodel projections of Antarctic temperature and precipitation

This is the final version of the article. Available from the publisher via the DOI in this record.Climate models exhibit large biases in sea ice area (SIA) in their historical simulations. This study explores the impacts of these biases on multimodel uncertainty in Coupled Model Intercomparison Project phase 5 (CMIP5) ensemble projections of 21st century change in Antarctic surface temperature, net precipitation, and SIA. The analysis is based on time slice climatologies in the Representative Concentration Pathway 8.5 future scenario (2070-2099) and historical (1970-1999) simulations across 37 different CMIP5 models. Projected changes in net precipitation, temperature, and SIA are found to be strongly associated with simulated historical mean SIA (e.g., cross-model correlations of r = 0.77, 0.71, and -0.85, respectively). Furthermore, historical SIA bias is found to have a large impact on the simulated ratio between net precipitation response and temperature response. This ratio is smaller in models with smaller-than-observed SIA. These strong emergent relationships on SIA bias could, if found to be physically robust, be exploited to give more precise climate projections for Antarctica.We acknowledge the World Climate Research Programme’s Working Group on Coupled Modelling, which is responsible for CMIP, and we thank the climate modeling groups (listed in Table S1 of this paper) for producing and making available their model output. For CMIP the U.S. Department of Energy’s Program for Climate Model Diagnosis and Intercomparison provided the coordinating support and led development of software infrastructure in partnership with the Global Organization for Earth System Science Portals. The original CMIP5 data can be accessed through the ESGF data portals (see http://pcmdi-cmip.llnl.gov/cmip5/ availability.html). This study is part of the British Antarctic Survey Polar Science for Planet Earth Programme. It was funded by The UK Natural Environment Research Council (grant reference NE/K00445X/1). We would like to thank Paul Holland for his useful discussions and comments on an earlier version of this manuscript

Quantifying regeneration in patients following peripheral nerve injury

Healthy nerve function provides humans with the control of movement, sensation (such as pain, touch and temperature) and the quality of skin, hair and nails. Injury to this complex system creates a deficit in function which is slow to recover and rarely, if ever, returns to what patients consider to be normal. Despite promising preclinical experiments in animals, a significant limitation in the translation of emerging therapies is the lack of effective measures with which to quantify nerve regeneration in patients and to relate this to clinical recovery. In animal models, tissue can be obtained interventionally following treatment to quantify muscle mass and structure and the number of axons in nerve. This would incur a significant functional deficit if undertaken in humans, and furthermore, quantification of such biological features does not necessarily reflect patient experience of functional recovery. This article presents a combined commentary of current practice from a specialist clinical unit and research team in regard to laboratory and clinic quantification of nerve regeneration. We highlight how electrophysiological diagnostic methods (which are used with significant recognised limitations in assessment of clinical medicine) can potentially be used with more validity to interpret and assess the processes of neural regeneration in the clinical context. Thus throwing light on the factors at play in translating lab advances into the clinic

Strategies for Peripheral Nerve Repair

PURPPOSE AND REVIEW: This review focuses on biomechanical and cellular considerations required for development of biomaterials and engineered tissues suitable for implantation following PNI, as well as translational requirements relating to outcome measurements for testing success in patients. RECENT FINDINGS: Therapies that incorporate multiple aspects of the regenerative environment are likely to be key to improving therapies for nerve regeneration. This represents a complex challenge when considering the diversity of biological, chemical and mechanical factors involved. In addition, clinical outcome measures following peripheral nerve repair which are sensitive and responsive to changes in the tissue microenvironment following neural injury and regeneration are required. SUMMARY: Effective new therapies for the treatment of PNI are likely to include engineered tissues and biomaterials able to evoke a tissue microenvironment that incorporates both biochemical and mechanical features supportive to regeneration. Translational development of these technologies towards clinical use in humans drives a concomitant need for improved clinical measures to quantify nerve regeneration

Development, Validation, and Field-Testing of an Instrument for Clinical Assessment of HIV-Associated Neuropathy and Neuropathic Pain in Resource-Restricted and Large Population Study Settings

HIV-associated sensory peripheral neuropathy (HIV-SN) afflicts approximately 50% of patients on antiretroviral therapy, and is associated with significant neuropathic pain. Simple accurate diagnostic instruments are required for clinical research and daily practice in both high- and low-resource setting. A 4-item clinical tool (CHANT: Clinical HIV-associated Neuropathy Tool) assessing symptoms (pain and numbness) and signs (ankle reflexes and vibration sense) was developed by selecting and combining the most accurate measurands from a deep phenotyping study of HIV positive people (Pain In Neuropathy Study–HIV-PINS). CHANT was alpha-tested in silico against the HIV-PINS dataset and then clinically validated and field-tested in HIV-positive cohorts in London, UK and Johannesburg, South Africa. The Utah Early Neuropathy Score (UENS) was used as the reference standard in both settings. In a second step, neuropathic pain in the presence of HIV-SN was assessed using the Douleur Neuropathique en 4 Questions (DN4)-interview and a body map. CHANT achieved high accuracy on alpha-testing with sensitivity and specificity of 82% and 90%, respectively. In 30 patients in London, CHANT diagnosed 43.3% (13/30) HIV-SN (66.7% with neuropathic pain); sensitivity = 100%, specificity = 85%, and likelihood ratio = 6.7 versus UENS, internal consistency = 0.88 (Cronbach alpha), average item-total correlation = 0.73 (Spearman’s Rho), and inter-tester concordance > 0.93 (Spearman’s Rho). In 50 patients in Johannesburg, CHANT diagnosed 66% (33/50) HIV-SN (78.8% neuropathic pain); sensitivity = 74.4%, specificity = 85.7%, and likelihood ratio = 5.29 versus UENS. A positive CHANT score markedly increased of pre- to post-test clinical certainty of HIV-SN from 43% to 83% in London, and from 66% to 92% in Johannesburg. In conclusion, a combination of four easily and quickly assessed clinical items can be used to accurately diagnose HIV-SN. DN4-interview used in the context of bilateral feet pain can be used to identify those with neuropathic pain

The Milliarcsecond Structure of Radio Galaxies and Quasars

Hybrid maps of the nuclei of radio galaxies and quasars show a variety of morphologies. Among compact sources, two structures are common: an asymmetric, “core-jet” morphology (eg, 3C 273), and an “equal double” morphology with two separated, similar components (eg, CTD 93). The nuclei of extended, double radio galaxies generally have a core-jet morphology with the jet directed toward one of the outer components

Characterising cellular and molecular features of human peripheral nerve degeneration

Nerve regeneration is a key biological process in those recovering from neural trauma. From animal models it is known that the regenerative capacity of the peripheral nervous system (PNS) relies heavily on the remarkable ability of Schwann cells to undergo a phenotypic shift from a myelinating phenotype to one that is supportive of neural regeneration. In rodents, a great deal is known about the molecules that control this process, such as the transcription factors c-Jun and early growth response protein 2 (EGR2/KROX20), or mark the cells and cellular changes involved, including SOX10 and P75 neurotrophin receptor (p75NTR). However, ethical and practical challenges associated with studying human nerve injury have meant that little is known about human nerve regeneration. The present study addresses this issue, analysing 34 denervated and five healthy nerve samples from 27 patients retrieved during reconstructive nerve procedures. Using immunohistochemistry and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR), the expression of SOX10, c-Jun, p75NTR and EGR2 was assessed in denervated samples and compared to healthy nerve. Nonparametric smoothing linear regression was implemented to better visualise trends in the expression of these markers across denervated samples. It was found, first, that two major genes associated with repair Schwann cells in rodents, c-Jun and p75NTR, are also up-regulated in acutely injured human nerves, while the myelin associated transcription factor EGR2 is down-regulated, observations that encourage the view that rodent models are relevant for learning about human nerve injury. Second, as in rodents, the expression of c-Jun and p75NTR declines during long-term denervation. In rodents, diminishing c-Jun and p75NTR levels mark the general deterioration of repair cells during chronic denervation, a process thought to be a major obstacle to effective nerve repair. The down-regulation of c-Jun and p75NTR reported here provides the first molecular evidence that also in humans, repair cells deteriorate during chronic denervation

The Effects of Surgical Antiseptics and Time Delays on RNA Isolated From Human and Rodent Peripheral Nerves

Peripheral Nerve Injury (PNI) is common following blunt or penetrating trauma with an estimated prevalence of 2% among the trauma population. The resulting economic and societal impacts are significant. Nerve regeneration is a key biological process in those recovering from neural trauma. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) and RNA sequencing (RNA seq) are investigative methods that are often deployed by researchers to characterize the cellular and molecular mechanisms that underpin this process. However, the ethical and practical challenges associated with studying human nerve injury have meant that studies of nerve injury have largely been limited to rodent models of renervation. In some circumstances it is possible to liberate human nerve tissue for study, for example during reconstructive nerve repair. This complex surgical environment affords numerous challenges for optimizing the yield of RNA in sufficient quantity and quality for downstream RT-qPCR and/or RNA seq applications. This study characterized the effect of: (1) Time delays between surgical liberation and cryopreservation and (2) contact with antiseptic surgical reagents, on the quantity and quality of RNA isolated from human and rodent nerve samples. It was found that time delays of greater than 3 min between surgical liberation and cryopreservation of human nerve samples significantly decreased RNA concentrations to be sub-optimal for downstream RT-qPCR/RNA seq applications (<5 ng/μl). Minimizing the exposure of human nerve samples to antiseptic surgical reagents significantly increased yield of RNA isolated from samples. The detrimental effect of antiseptic reagents on RNA yield was further confirmed in a rodent model where RNA yield was 8.3-fold lower compared to non-exposed samples. In summary, this study has shown that changes to the surgical tissue collection protocol can have significant effects on the yield of RNA isolated from nerve samples. This will enable the optimisation of protocols in future studies, facilitating characterisation of the cellular and molecular mechanisms that underpin the regenerative capacity of the human peripheral nervous system

Estimating the size of "anti-vax" and vaccine hesitant populations in the US, UK, and Canada: comparative latent class modeling of vaccine attitudes

This is the final version. Available on open access from Taylor & Francis via the DOI in this recordVaccine hesitancy is a significant impediment to global efforts to vaccinate against the SARS-CoV-2 virus at levels that generate herd immunity. In this article, we show the utility of an inductive approach - latent class analysis (LCA) - that allows us to characterize the size and nature of different vaccine attitude groups; and to compare how these groups differ across countries as well as across demographic subgroups within countries. We perform this analysis using original survey data collected in the US, UK, and Canada. We also show that these classes are strongly associated with SARS-CoV-2 vaccination intent and perceptions of the efficacy and safety of the COVID-19 vaccines, suggesting that attitudes about vaccines to fight the novel coronavirus pandemic are well explained by latent vaccine attitudes that precede the pandemic. More specifically, we find four substantive classes of vaccine attitudes: strong supporters, supporters with concerns, vaccine hesitant, and "anti-vax" as well as a fifth measurement error class. The strong "anti-vax" sentiment class is small in all three countries, while the strong supporter class is the largest across all three countries. We observe different distributions of class assignments in different demographic groups - most notably education and political leaning (partisanship and ideology).Economic and Social Research Council (ESRC