Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis.

PURPOSE: A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival. PATIENTS AND METHODS: A total of 460 OPC tumor specimens from two large United States medical centers (1980-2017) underwent HPV16 whole-genome sequencing. Site-specific variable positions [single nucleotide polymorphisms (SNPs)] across the HPV16 genome were identified. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival. RESULTS: A total of 384 OPC tumor specimens (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. Some 284 HPV16 SNPs with a minor allele frequency ≥1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate correction (individual prevalence: 1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 [HR for overall survival (HRos): 3.75, 95% CI 1.77-7.95; Pfdr = 0.0099]; L2 gene positions 4410 (HRos: 5.32, 95% CI 1.91-14.81; Pfdr = 0.0120), 4539 (HRos: 6.54, 95% CI 2.03-21.08; Pfdr = 0.0117); 5050 (HRos: 6.53, 95% CI 2.34-18.24; Pfdr = 0.0030), and 5254 (HRos: 7.76, 95% CI 2.41-24.98; Pfdr = 0.0030); and L1 gene positions 5962 (HRos: 4.40, 95% CI 1.88-10.31; Pfdr = 0.0110) and 6025 (HRos: 5.71, 95% CI 2.43-13.41; Pfdr = 0.0008) and position 7173 within the upstream regulatory region (HRos: 9.90, 95% CI 3.05-32.12; Pfdr = 0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared with 18.67 years for patients without a high-risk SNP; log-rank test P < 0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment); increase in C-index was 0.069 (95% CI 0.019-0.119, P < 0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95% CI 0.015-0.111, P = 0.008). CONCLUSIONS: HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.

A case series study of an innovative community-based brief psychological model for men in suicidal crisis.

OBJECTIVES: To conduct a 1-year evaluation of James' Place, a suicidal crisis centre delivering a clinical intervention in a community setting. DESIGN: A case series study, following men entering the service during the first year of operation. PARTICIPANTS: Men experiencing a suicidal crisis referred to the service (N = 265), with N = 176 going on to engage in therapy. INTERVENTION: The James' Place Model is a therapeutic intervention offered to men who are in a suicidal crisis. Trained therapists provide a range of therapeutic approaches and interventions, focusing on decreasing suicidal distress and supporting men to develop resilience and coping strategies. MAIN OUTCOME MEASURES: CORE-34 Clinical Outcome Measure (CORE-OM). RESULTS: For all subscales of the CORE-OM there was a significant reduction in mean scores between assessment and discharge (p < 0.001), with all outcomes demonstrating a large effect size. All reductions illustrated a clinically significant change or a reliable change. CONCLUSIONS: Our results support the use of the James' Place Model for men in suicidal distress to aid in potentially preventing suicides in this high-risk group of the population.HighlightsEvaluates a brief psychological clinical intervention delivered in the community.Model effectively reduces suicide risk and findings can inform future services.Accessed men receiving an innovative intervention at the time of suicidal crisis.

Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD.

Stimulant medication has long been effective in treating attention-deficit/hyperactivity disorder (ADHD) and is currently the first-line pharmacological treatment for children. Both methylphenidate and amphetamine modulate extracellular catecholamine levels through interaction with dopaminergic, adrenergic and serotonergic system components; it is therefore likely that catecholaminergic molecular components influence the effects of ADHD treatment. Using meta-analysis, we sought to identify predictors of pharmacotherapy to further the clinical implementation of personalized medicine. We identified 36 studies (3647 children) linking the effectiveness of methylphenidate treatment with DNA variants. Pooled-data revealed a statistically significant association between single nucleotide polymorphisms (SNPs) rs1800544 ADRA2A (odds ratio: 1.69; confidence interval: 1.12-2.55), rs4680 COMT (odds ratio (OR): 1.40; confidence interval: 1.04-1.87), rs5569 SLC6A2 (odds ratio: 1.73; confidence interval: 1.26-2.37) and rs28386840 SLC6A2 (odds ratio: 2.93; confidence interval: 1.76-4.90), and, repeat variants variable number tandem repeat (VNTR) 4 DRD4 (odds ratio: 1.66; confidence interval: 1.16-2.37) and VNTR 10 SLC6A3 (odds ratio: 0.74; confidence interval: 0.60-0.90), whereas the following variants were not statistically significant: rs1947274 LPHN3 (odds ratio: 0.95; confidence interval: 0.71-1.26), rs5661665 LPHN3 (odds ratio: 1.07; confidence interval: 0.84-1.37) and VNTR 7 DRD4 (odds ratio: 0.68; confidence interval: 0.47-1.00). Funnel plot asymmetry among SLC6A3 studies was identified and attributed largely to small study effects. Egger's regression test and Duval and Tweedie's 'trim and fill' were used to examine and correct for publication bias. These findings have major implications for advancing our therapeutic approach to childhood ADHD treatment.

Phosphaturic mesenchymal tumors: what an endocrinologist should know.

Tumor-induced osteomalacia (TIO), also known as "oncogenic osteomalacia", is a rare cause of osteomalacia. TIO often has an insidious onset characterized clinically by progressive muscle weakness and bone pain with fractures. The hallmark biochemical finding is a persistent low serum phosphorus concentration due to renal phosphate wasting. The vast majority of cases of TIO result from production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) by a histologically distinctive mesenchymal tumor, termed "phosphaturic mesenchymal tumor" (PMT). Circulating FGF23 induces internalization of renal sodium/phosphate co-transporters resulting in reduced proximal tubular phosphate reabsorption. FGF23 also inhibits production of 1α,25-dihydroxyvitamin D which is inappropriately low or normal in the context of hypophosphatemia. Diagnosis is often delayed owing to the rarity of the condition and an underappreciation for the role of phosphorus as a cause for the constellation of symptoms. Primary treatment for TIO is identification of the offending tumor and surgical removal. However, these tumors are notoriously difficult to find, precluding the opportunity for a curative surgery in many. In such cases, phosphate and calcitriol therapy is used to improve symptoms and heal the osteomalacia. Recently, molecular genetic studies have shown recurrent genetic events in PMT, including the novel fusions FN1-FGFR1 and less commonly FN1-FGF1. These fusion events are hypothesized to result in autocrine/paracrine signaling loops within the tumor, spurring tumorigenesis. This review will cover the clinical features, imaging characteristics, pathologic features, molecular genetic aspects, and therapy of PMT, with a brief discussion of other neoplasms that may cause TIO.

Implementation of the Needs Assessment Tool for patients with interstitial lung disease (NAT:ILD): facilitators and barriers.

A Needs Assessment Tool (NAT) was developed previously to help clinicians identify the supportive/palliative needs of people with interstitial lung disease (ILD) (NAT:ILD). This letter presents barriers and facilitators to clinical implementation. Data from (1) a focus group of respiratory clinicians and (2) an expert consensus group (respiratory and palliative clinicians, academics, patients, carers) were analysed using Framework Analysis. Barriers related to resources and service reconfiguration, and facilitators to clinical need, structure, objectiveness, flexibility and benefits of an 'aide-memoire'. Identified training needs included communication skills and local service knowledge. The NAT:ILD was seen as useful, necessary and practical in everyday practice.

Material characterisation of nanowires with intrinsic stress.

When fabricating nanowires (NWs) in a doubly-clamped beam configuration it is possible for a residual axial stress to be generated. Here, we show that material characterisation of metal and semiconductor NWs subjected to residual axial stress can be problematic. Benchmark measurements of the Young's modulus of NWs are performed by sectioning a doubly-clamped NW into two cantilevered wires, eliminating residual axial stress. Use of models for doubly-clamped beams that incorporate the effects of residual stress are found to lead to ambiguity in the extracted Young's modulus as a function of displacement fit range, even for NWs with no residual stress. This is due to coupling of bending and axial stress effects at small displacements, and the limited displacement range of force curves prior to fracture or plastic deformation. This study highlights the importance of fabricating metal and semiconductor NWs that exhibit little or no residual axial stress for materials characterisation.

Effects of opioids on immunologic parameters that are relevant to anti-tumour immune potential in patients with cancer: a systematic literature review.

BACKGROUND: The immune system has a central role in controlling cancer, and factors that influence protective antitumour immunity could therefore have a significant impact on the course of malignant disease. Opioids are essential for the management of cancer pain, and preclinical studies indicate that opioids have the potential to influence these tumour immune surveillance mechanisms. The aim of this systematic literature review is to evaluate the clinical effects of opioids on the immune system of patients with cancer. METHODS: A systematic search of Ovid MEDLINE (PubMed) and Embase, Cochrane database and Web of Knowledge for clinical studies, which evaluated the effects of opioids on the immune system in patients with cancer, was performed. RESULTS: Five human studies, which have assessed the effects of opioids on the immune system in patients with cancer, were identified. Although all of these evaluated the effect of morphine on immunologic end points in patients with cancer, none measured the clinical effects. CONCLUSIONS: Evidence from preclinical, healthy volunteer and surgical models suggests that different opioids variably influence protective anti-tumour immunity; however, actual data derived from cancer populations are inconclusive and definitive recommendations cannot be made. Appropriately designed and powered studies assessing clinical outcomes of opioid use in people with cancer are therefore required to inform oncologists and others involved in cancer care about the rational use of opioids in this patient group.

Holistic needs assessment in advanced, intensively treated multiple myeloma patients.

PURPOSE: It is recommended that patients with multiple myeloma should be assessed for unmet holistic needs at key times in their disease trajectory. The aim of this exploratory study was to characterise the holistic needs of advanced, intensively treated multiple myeloma using a structured assessment tool. METHODS: Patients with multiple myeloma who had undergone a haematopoietic stem cell transplantation and subsequent treatment for at least one episode of progressive disease but were in stable plateau phase were included in the study. Patients' holistic needs were assessed using the self-reporting tool, Sheffield Profile for Assessment and Referral for Care (SPARC). RESULTS: Thirty-two patients with a median age of 60 years at assessment and a median of 5.5 years from diagnosis were recruited. Using the SPARC, half of the patients reported tiredness as 'quite a bit/very much,' while one third complained that daytime somnolence and insomnia were 'quite a bit/very much.' Forty-four percent of patients reported pain. One third of patients were bothered and distressed by the side effects from their treatment and were worried about long-term effects of their treatment. Thirty-one percent of patients felt that the effect of their condition had an impact on their sexual life, and 40 % were worried about the effect that their illness was having on their family or other people. CONCLUSION: This is the first study to use a self-reported holistic needs assessment tool in multiple myeloma. A multidimensional structured questionnaire like the SPARC could provide a useful first step in the effective delivery of supportive and palliative care for patients with multiple myeloma.

Thermo-electro-optical properties of seamless metallic nanowire networks for transparent conductor applications.

Rapid reaction time, high attainable temperatures, minimum operating voltage, excellent optical transmittance, and tunable sheet resistance are all desirable properties of transparent conductors, which are important thin-film components in numerous electronic devices. A seamless nanowire network (NWN) refers to a structure composed of nanowires that lack interwire contact junctions, resulting in a continuous and uninterrupted network arrangement. This seamless nature leads to unique properties, including high conductivity and surface area-to-volume ratios, which make it a promising candidate for a vast application range in nanotechnology. Here, we have conducted an in-depth computational investigation to study the thermo-electro-optical properties of seamless nanowire networks and understand their geometrical features using in-house computational implementations and a coupled electrothermal model built in COMSOL Multiphysics software. Sheet resistance calculations were performed using Ohm's law combined with Kirchhoff circuit laws for a random resistor network and compared with those obtained employing COMSOL. In this work, aluminium, gold, copper, and silver nanowires are the materials of choice for testing the transparent conduction performance of our systems. We have studied a wide range of tuning parameters, including the network area fraction, the width-to-depth aspect ratio, and the length of the nanowire segments. We obtained corresponding figures of merit (optical transmittance versus sheet resistance) and temperature distributions to provide a complete characterization of the performance of real-world transparent conductors idealized with seamless NWNs. Our analysis accounted for the thermo-electro-optical responses of the NWNs and the inspection of various controlling parameters depending on system design considerations to shed light on how the electrical transport, optical qualities, and thermal management of these systems can be optimized.

Design and delivery of an e-learning curriculum for physicians involved in the management of pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a condition that affects more than 25 million individuals worldwide and causes premature disability and death. Despite advances in our understanding of this condition, education and training of health professionals has not kept pace with the rapid changes in diagnosis and treatment. The net effects of this gap between advancing knowledge and limited educational opportunity likely include clinically significant delays in both the diagnosis and commencement of effective evidence-based treatment - an unacceptable outcome for patients with a lethal condition. AIM: The Actelion Clinical Excellence Programme (ACEP) is an e-learning postgraduate curriculum, the purpose of which is to educate and mentor healthcare professionals, both theoretically and practically, in the diagnosis and treatment of patients with all forms of PH. This article reports on the development and delivery of the programme and outcomes from its first year of operation. RESULTS: Forty-three healthcare professionals from 22 institutions were enroled in the first iteration of the programme. In the 6 months from May to October 2011, participants successfully completed 285 lectures and/or activities. Overall, the programme was considered easily accessible, comprehensive in terms of both quality and quantity, provided an efficient means of self-paced learning, and was a highly regarded as reference source. Ninety-five per cent of participants said that they intended to change their clinical practice as a result of the information presented in the programme. CONCLUSION: ACEP represents a successful physician-industry partnership, which has resulted in a significant impact on clinical teaching and awareness of PH.

Stormwater runoff reduction benefits of distributed curbside infiltration devices in an urban catchment.

Distributed infiltration systems can benefit downstream water bodies by reducing the runoff flowrate and volume discharges from the catchment. Investigating their runoff flowrate and volume reduction potential at the catchment scale will inform decision makers regarding their efficacy for managing catchment outflows. To this end, we conducted field investigations at the residential catchment scale for three years. The study monitored the catchment for one year before the installation of leaky well systems (preinstallation) and two years after installation (postinstallation). The hydrological model, calibrated to preinstallation catchment outflows, acted as a virtual control tool. Runoff flow outputs from the control model and two years of monitored runoff flow data from the postinstallation period were analysed using statistical methods. The statistical tests showed a significant 13% reduction in average flowrates in storms with a corresponding runoff flowrate of up to 50 L/s. The study further reported the ability of infiltration systems to reduce runoff volume in the catchment by 9%. This reduction was not significant, however, as per the results of the statistical analysis. We then fitted the generalized linear model (GLM) to the monitored and simulated runoff volume data. This enabled us to break down the effect of curbside infiltration systems on runoff volume according to corresponding peak flowrates during the storm. The results of the two-way ANOVA performed to detect significant differences in the regression slopes of the GLM indicated that curbside infiltration systems significantly reduced runoff volume for storms when the runoff flowrates remained below 100 L/s.

Implementation lessons learnt when trialling palliative care interventions in the intensive care unit: relationships between determinants, implementation strategies, and models of delivery-a systematic review protocol.

BACKGROUND: Heterogeneity amongst palliative care interventions in the intensive care unit (ICU) and their outcomes has meant that, even when found to be effective, translation of evidence into practice is hindered. Previous evidence reviews have suggested that the field of ICU-based palliative care would benefit from well-designed, targeted interventions, with explicit knowledge translation research demonstrating valid implementation strategies. Reviewing effectiveness studies alongside process evaluations for these interventions will give insight into the implementation barriers or constraints identified, and the implementation strategies adopted. METHODS: A systematic review to identify and synthesise knowledge on how models of integrating palliative care into the ICU have been implemented and provide critical recommendations for successful future development and implementation of complex interventions in the field. The search will be carried out using MEDLINE, Embase, Cochrane, CINAHL, and PsycINFO. The search strategy will combine terms related to palliative care, intensive care, and implementation. Only full-text articles will be considered and conference abstracts excluded. There will be no date or language restrictions. The Implementation Research Logic Model will be used as a framework for synthesis. Findings will be reported following the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. DISCUSSION: This review will provide understanding of implementation facilitators, barriers, and strategies, when employing palliative care interventions within the ICU. This will provide valuable recommendations for successful future development of complex interventions using implementation frameworks or theories. This can increase the potential for sustained change in practice, reduce heterogeneity in interventions, and therefore help produce measurable and comparable outcomes. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic reviews PROSPERO (CRD42022311052).

Complete genome sequence of the animal pathogen Listeria ivanovii, which provides insights into host specificities and evolution of the genus Listeria.

We report the complete and annotated genome sequence of the animal pathogen Listeria ivanovii subsp. ivanovii strain PAM 55 (serotype 5), isolated in 1997 in Spain from an outbreak of abortion in sheep. The sequence and its analysis are available at an interactive genome browser at the Institut Pasteur (http://genolist.pasteur.fr/LivaList/).

Long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction: the Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) study.

BACKGROUND: Knowledge about the incidence of cardiac arrhythmias after acute myocardial infarction has been limited by the lack of traditional ECG recording systems to document and confirm asymptomatic and symptomatic arrhythmias. The Cardiac Arrhythmias and Risk Stratification After Myocardial Infarction (CARISMA) trial was designed to study the incidence and prognostic significance of arrhythmias documented by an implantable cardiac monitor among patients with acute myocardial infarction and reduced left ventricular ejection fraction. METHODS AND RESULTS: A total of 1393 of 5869 patients (24%) screened in the acute phase (3 to 21 days) of an acute myocardial infarction had left ventricular ejection fraction ≤40%. After exclusions, 297 patients (21%) (mean±SD age, 64.0±11.0 years; left ventricular ejection fraction, 31±7%) received an implantable cardiac monitor within 11±5 days of the acute myocardial infarction and were followed up every 3 months for an average of 1.9±0.5 years. Predefined bradyarrhythmias and tachyarrhythmias were recorded in 137 patients (46%); 86% of these were asymptomatic. The implantable cardiac monitor documented a 28% incidence of new-onset atrial fibrillation with fast ventricular response (≥125 bpm), a 13% incidence of nonsustained ventricular tachycardia (≥16 beats), a 10% incidence of high-degree atrioventricular block (≤30 bpm lasting ≥8 seconds), a 7% incidence of sinus bradycardia (≤30 bpm lasting ≥8 seconds), a 5% incidence of sinus arrest (≥5 seconds), a 3% incidence of sustained ventricular tachycardia, and a 3% incidence of ventricular fibrillation. Cox regression analysis with time-dependent covariates revealed that high-degree atrioventricular block was the most powerful predictor of cardiac death (hazard ratio, 6.75; 95% confidence interval, 2.55 to 17.84; P<0.001). CONCLUSIONS: This is the first study to report on long-term cardiac arrhythmias recorded by an implantable loop recorder in patients with left ventricular ejection fraction ≤40% after myocardial infarction. Clinically significant bradyarrhythmias and tachyarrhythmias were documented in a substantial proportion of patients with depressed left ventricular ejection fraction after acute myocardial infarction. Intermittent high-degree atrioventricular block was associated with a very high risk of cardiac death. Clinical Trial Registration- URL: http://www.ClinicalTrials.gov, Unique identifier: NCT00145119.

Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study.

BACKGROUND: Probiotic treatment strategy based on the hygiene hypothesis, such as administration of ova from the non-pathogenic helminth, Trichuris suis, (TSO) has proven safe and effective in autoimmune inflammatory bowel disease. OBJECTIVE: To study the safety and effects of TSO in a second autoimmune disease, multiple sclerosis (MS), we conducted the phase 1 Helminth-induced Immunomodulatory Therapy (HINT 1) study. METHODS: Five subjects with newly diagnosed, treatment-naive relapsing-remitting multiple sclerosis (RRMS) were given 2500 TSO orally every 2 weeks for 3 months in a baseline versus treatment control exploratory trial. RESULTS: The mean number of new gadolinium-enhancing magnetic resonance imaging (MRI) lesions (n-Gd+) fell from 6.6 at baseline to 2.0 at the end of TSO administration, and 2 months after TSO was discontinued, the mean number of n-Gd+ rose to 5.8. No significant adverse effects were observed. In preliminary immunological investigations, increases in the serum level of the cytokines IL-4 and IL-10 were noted in four of the five subjects. CONCLUSION: TSO was well tolerated in the first human study of this novel probiotic in RRMS, and favorable trends were observed in exploratory MRI and immunological assessments. Further investigations will be required to fully explore the safety, effects, and mechanism of action of this immunomodulatory treatment.

Imaging of human colon cancer cells using He-Ion scanning microscopy.

Due to its low beam current and charge compensation mechanism He-Ion scanning microscopy is a very promising tool for imaging biological cells. However, to obtain relevant information, the method used for sample preparation is also critical. In this work, we have used a Carl Zeiss Orion Plus helium-ion microscope to study the effect of sample gold coating on the morphology of human colorectal adenocarcinoma Caco2 cells. The fixative glutaraldehyde was used and the selective gold coating of the samples was investigated. A comparative study with standard scanning electron microscopy is presented.

The 2021 ultrafast spectroscopic probes of condensed matter roadmap.

In the 60 years since the invention of the laser, the scientific community has developed numerous fields of research based on these bright, coherent light sources, including the areas of imaging, spectroscopy, materials processing and communications. Ultrafast spectroscopy and imaging techniques are at the forefront of research into the light-matter interaction at the shortest times accessible to experiments, ranging from a few attoseconds to nanoseconds. Light pulses provide a crucial probe of the dynamical motion of charges, spins, and atoms on picosecond, femtosecond, and down to attosecond timescales, none of which are accessible even with the fastest electronic devices. Furthermore, strong light pulses can drive materials into unusual phases, with exotic properties. In this roadmap we describe the current state-of-the-art in experimental and theoretical studies of condensed matter using ultrafast probes. In each contribution, the authors also use their extensive knowledge to highlight challenges and predict future trends.

The Mars Environmental Dynamics Analyzer, MEDA. A Suite of Environmental Sensors for the Mars 2020 Mission.

NASA's Mars 2020 (M2020) rover mission includes a suite of sensors to monitor current environmental conditions near the surface of Mars and to constrain bulk aerosol properties from changes in atmospheric radiation at the surface. The Mars Environmental Dynamics Analyzer (MEDA) consists of a set of meteorological sensors including wind sensor, a barometer, a relative humidity sensor, a set of 5 thermocouples to measure atmospheric temperature at ∼1.5 m and ∼0.5 m above the surface, a set of thermopiles to characterize the thermal IR brightness temperatures of the surface and the lower atmosphere. MEDA adds a radiation and dust sensor to monitor the optical atmospheric properties that can be used to infer bulk aerosol physical properties such as particle size distribution, non-sphericity, and concentration. The MEDA package and its scientific purpose are described in this document as well as how it responded to the calibration tests and how it helps prepare for the human exploration of Mars. A comparison is also presented to previous environmental monitoring payloads landed on Mars on the Viking, Pathfinder, Phoenix, MSL, and InSight spacecraft.