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Objectives: We used quality improvement methods to implement a care bundle for children presenting to a pediatric emergency department (ED) with mental health concerns. A bundle novelty was that it included an option for assessment in a partnered clinic, not in the ED, to families of children assessed as having no medical or safety concerns. The primary aim of this study was to establish successful implementation of the bundle prior to studying its impact., Methods: The bundle included the Ask Suicide-Screening Questions to standardize risk assessment at triage, the HEADS-ED (Home, Education, Activities/Peers, Drug/Alcohol, Suicidality, Emotions/Behavior, Discharge Resources) tool for brief, scored mental health assessments, and offering an urgent appointment within 96 h for low-risk children as an alternative to ED-based assessment or as a follow-up option for patients assessed in the ED. We developed aims, driver diagrams, and outcome measures for each bundle element. Each element was introduced with small tests of change using iterative plan-do-study-act cycles. Run charts were used to determine successful completion of aims., Results: Rules for special cause were met through detection of shifts in performance 5 months after bundle implementation for the Ask Suicide-Screening Questions and HEADS-ED. These bundle elements were consistently used with ≥ 80% of eligible patients, representing aim achievement. During the 6 months of providing urgent appointments, 89.3% of 159 referred families received an appointment within 96 h., Conclusions: Using quality improvement methods, we were able to successfully ensure reliable implementation of a new care bundle for pediatric patients presenting to the ED with mental health concerns and allow eligible low-risk patients to receive full assessments in a partnered clinic instead of the ED., (© 2023. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

BQ.1.1 has dominated the Europe and Americas COVID-19 wave across the 2022-2023 winter, and further viral evolution is expected to escape the consolidating immune responses. We report here the emergence of the BQ.1.1.37 variant in Italy, peaking in January 2022 before suffering competition by XBB.1.*. We attempted to correlate the potential fitness of BQ.1.1.37 with a unique two-amino acid insertion within the Spike protein.

Nirmatrelvir/ritonavir (N/R) is one of the most effective antiviral drugs against SARS-CoV-2. The preclinical development, pharmacodynamics and pharmacokinetics of N/R are reviewed herein. Randomized clinical trials have been conducted exclusively with pre-Omicron variants of concern, but in vitro studies show that efficacy against all Omicron sublineages is preserved, as confirmed by post-marketing observational studies. Nevertheless, investigations of large viral genome repositories have shown that mutation in the main protease causing resistance to N/R are increasingly frequent. In addition, virological and clinical rebounds after N/R discontinuation have been reported in immunocompetent patients. This finding is of concern when translated to immunocompromised patients, in whom N/R efficacy has not been formally investigated in clinical trials. Economical sustainability and perspectives for this therapeutic arena are discussed., (Copyright © 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

The first 2 years of the COVID-19 pandemic were mainly characterized by recurrent mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 emerging independently across different variants of concern (Alpha, Beta, Gamma, and Delta). Such homoplasy is a marker of convergent evolution. Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and refocus antibody-mediated therapeutic efforts on polyclonal preparations that are less likely to allow for viral immune escape.

This article provides an authentic, student-centred account of how law students develop their commercial awareness on their journey to graduate employment. Drawing on data collected from a two year research study involving law students going through the graduate interview process, this article presents the first detailed empirical findings on how, when and why law students develop their commercial awareness. This data is important because law students have a wide range of available career options and commercial awareness is required across a range of graduate professions, including the legal sector. The findings of this study indicate that the law school played a part in developing law students' commercial awareness but that its role was limited due to a lack of explicit guidance on what commercial awareness meant and how teaching and learning activities supported development. Students identified development much more frequently and explicitly through their own independent developmental activities. As well as providing valuable insight into law student perceptions of the role of the law school and the law student in developing commercial awareness, this article makes recommendations for legal educators on how to support students in developing their commercial awareness., Competing Interests: Conflict of InterestThe author states that there is no conflict of interest. Approval for this research study was obtained from the ethics committee at Northumbria University., (© The Author(s) 2023.)

Background: Reports of HLA incompatible (HLAi) kidney transplant outcomes are inconclusive, especially in the context of lower level Donor Specific Antibodies (DSA)., Methods: Multi-centre national cohort study of HLAi kidney transplant recipients matched in 1:2 ratio with HLA compatible (HLAc) kidney transplant recipients. HLAi defined as DSA identified by Luminex. Antibody mediated rejection (AMR) and transplant-survival were analysed using Kaplan-Meier plots. Propensity score (PS) matching was used to compare recipient and transplant survival between groups., Results: We included 61 HLAi and 122 HLAc recipients; mean age 46 years; 60% female. MFI T0 : 3327 (IQR 1352-6458), 23 (38%) were Flow cytometry crossmatch positive (FC-XM POS ). DSA POS /FC-XM POS transplantation carried an increased risk of AMR at 1 year (52%) compared to DSA POS /FC-XM NEG (27%) and HLAc (0%). Unadjusted death censored graft loss at 3 years was 13% (HLAi) and 8% (HLAc). Three-year patient survival was 95% in HLAc, 84% in DSA POS /FC-XM NEG and 69% in DSA POS /FC-XM POS recipients; 58% of HLAi deaths were infection-related. HLA incompatibility was associated with a decreased 3-year survival in our PS-matched cohort., Conclusion: In kidney transplantation, DSA and positive FC-XM carries an increased risk of AMR. Despite inferior transplant and survival outcomes compared to HLAc transplantation, it remains a realistic option for highly sensitized patients facing prolonged waiting times and reduced survival on dialysis., (© 2022 Asian Pacific Society of Nephrology.)

WHO-defined SARS-CoV-2 variants of concern (VOC) drive therapeutics and vaccine development. The Omicron VOC is dominating the arena since November 2021, but the number of its sublineages is growing in complexity. Omicron represent a galaxy with a myriad of stars that suddenly rise and expand before collapsing into apparent extinction when a more fit sublineage appears. This has already happened with BA.1, BA.2, and BA.4/5 and is happening with BA.2.75. We review here the current PANGO phylogeny, focusing on sublineages with Spike mutations, and show how frequently xxxxxxxx convergent evolution has occurred in these sublineages. We finally summarize how Omicron evolution has progressively defeated the anti-Spike monoclonal antibodies authorized so far, leaving clinicians to again fall back on COVID19 convalescent plasma from vaccinated donors as the only antibody-based therapy available., Competing Interests: Conflict of Interest We declare we have no conflict of interest related to this manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Monoclonal antibodies (mAbs) targeting the spike protein of SARS-CoV-2 have been widely used in the ongoing COVID-19 pandemic. In this paper, we review the properties of mAbs and their effect as therapeutics in the pandemic, including structural classification, outcomes in clinical trials that led to the authorisation of mAbs, and baseline and treatment-emergent immune escape. We show how the omicron (B.1.1.529) variant of concern has reset treatment strategies so far, discuss future developments that could lead to improved outcomes, and report the intrinsic limitations of using mAbs as therapeutic agents., Competing Interests: Declaration of interests AC is the Chair of the US National COVID-19 Convalescent Plasma Project and reports being part of the scientific advisory board of SAB Therapeutics, a company developing cow polyclonal antibodies. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Luminex single antigen bead (SAB) assays used to detect HLA antibodies may artificially increase sensitisation in highly sensitised patients (HSP). The presence of denatured HLA (dHLA) within the assay enables antibodies specific to cryptic HLA epitopes to bind, such antibodies are not clinically relevant. We sought to exclude dHLA reactivity in a cohort of very HSP, calculated reaction frequency (cRF) 95%-100% and determine the effect upon sensitisation. Such patients have limited access to suitable donors and small changes in their HLA antibody profile, particularly where their cRF is 100%, can increase their opportunity of a transplant. We determined the presence of dHLA by aligning antibody reactivity which did not correspond to known HLA class I epitope mismatches with the results of assays modified to detect class I dHLA. 130 class I dHLA reactions were identified within 11 HSP, all of whom had clear sensitising events. cRF was corrected for dHLA, mean cRF 98.2% (93-100) pre and 95.5% (87-100) post correction (p = 0.0156). An increase in the number of predicted compatible donors (p = 0.0078) after dHLA correction was demonstrated. Two manufacturers SAB assays were used. A reduction of patients with 100% cRF was observed for both manufactures. dHLA is contributing to sensitisation in HSP and is detrimental to their chances of receiving a compatible transplant. The observed dHLA reactivity varied according to kit manufacturers (p = 0.0001), this is potentially a useful finding for laboratories wishing to discriminate between nHLA and dHLA, but without the resources required to regularly perform dHLA assay and epitope analyses., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.

Digital technologies are increasingly available and are reducing in cost. There is an opportunity to move to a digital health approach in vestibular rehabilitation (VR), but there is a paucity of suitable systems available and a consequent lack of evidence to support their use. This study aimed to investigate a novel digital platform developed specifically for VR (comprising clinician software, a wearable sensor, and a patient-facing app). Participants ( n = 14, 9F:5M, mean age 59) with vestibular dysfunction and imbalance used the app for treatment, and therapists ( n = 4) used the platform to deliver VR in the form of individualized exercise programmes over a mean of 17.4 ± 8.8 weeks. Outcomes included the system usability scale, the patient enablement instrument (PEI), change in subjective symptoms (numerical rating scales), percentage adherence to prescribed exercise, and a semi-structured interview on utility. A significant reduction was found in symptoms of vertigo/dizziness ( p < 0.004), imbalance ( p < 0.002), oscillopsia ( p < 0.04), and anxiety ( p < 0.02) after use. System usability scores were high for both clinicians (mean 85/100) and participants (mean 82.7/100) and high enablement was reported (mean PEI 6.5/12). Overall percentage adherence to the exercise prescription was highly variable and ranged from 4 to 78% when measured digitally. At semi-structured interviews, participants reported a high level of acceptance and satisfaction with digital delivery, and no adverse events were recorded. When COVID-19 restrictions eased, 2 participants trialed the head sensor with the application and found it highly usable. Further research is required to investigate the efficacy and how the wearable sensor impacts the delivery of care., Competing Interests: DMe is the inventor of the digital intervention that was employed in the study. It is patent pending and she is named on the patent. This research is being commercialized and she is a shareholder in a start-up company formed before the end of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Meldrum, Murray, Vance, Coleman, McConnell, Hardiman and McConn Walsh.)

Massive usage of antiviral compounds during a pandemic creates an ideal ground for emergence of resistant strains. Remdesivir, a broad-spectrum inhibitor of the viral RNA-dependent RNA polymerase (RdRp), was extensively prescribed under emergency use authorization during the first 18 months of the COVID19 pandemic, before randomized controlled trials showed poor efficacy in hospitalized patients. RdRp mutations conferring resistance to remdesivir are well known from in vitro studies, and the huge SARS-CoV-2 sequencing effort during the ongoing COVID19 pandemic represents an unprecedented opportunity to assess emergence and fitness of antiviral resistance in vivo. We mined the GISAID database to extrapolate the frequency of remdesivir escape mutations. Our analysis reveals very low levels of remdesivir resistance worldwide despite massive usage., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Training and quality assurance in oesophagogastroduodenoscopy (OGD) is important to ensure competent practice. A national evidence-based review was undertaken to update and develop standards and recommendations for OGD training and certification., Methods: Under the oversight of the Joint Advisory Group (JAG), a modified Delphi process was conducted with stakeholder representation from British Society of Gastroenterology, Association of Upper Gastrointestinal Surgeons, trainees and trainers. Recommendations on OGD training and certification were formulated following literature review and appraised using Grading of Recommendations Assessment, Development and Evaluation. These were subjected to electronic voting to achieve consensus. Accepted statements were incorporated into the updated certification pathway., Results: In total, 32 recommendation statements were generated for the following domains: definition of competence (4 statements), acquisition of competence (12 statements), assessment of competence (10 statements) and post-certification support (6 statements). The consensus process led to following certification criteria: (1) performing ≥250 hands-on procedures; (2) attending a JAG-accredited basic skills course; (3) attainment of relevant minimal performance standards defined by British Society of Gastroenterology/Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, (4) achieving physically unassisted D2 intubation and J-manoeuvre in ≥95% of recent procedures, (5) satisfactory performance in formative and summative direct observation of procedural skills assessments., Conclusion: The JAG standards for diagnostic OGD have been updated following evidence-based consensus. These standards are intended to support training, improve competency assessment to uphold standards of practice and provide support to the newly-independent practitioner., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID-19-convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), a few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of the spike protein (e.g., ΔHV69-70, ΔLGVY141-144 and ΔAL243-244). The continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and the fitness of emerging variants.

The Common Rock Rat Zyzomys argurus is an abundant small- to medium-sized Murid rodent that is endemic to Australia. It is a nocturnal mammal with a mostly herbivorous diet. This species is native to the wet/dry tropics of Northern Australia and can be identified from other rock rats on the basis of its small size and its tail length (which is at least equivalent to its head-body length). Here, we describe the complete mitochondrial genome of Z. argurus and compare it to other Rodentia. The Z. argurus circular mitogenome was 16,261 bp and contained 13 protein-coding genes, two rRNA genes, 22 tRNAs and a control region (D-loop) of 859 bp. Phylogenetic analysis of selected, published sequenced mitogenomes reveal it is most closely related to the Lakeland Downs mouse Leggadina lakedownensis in the order Rodentia., Competing Interests: The authors report no conflict of interest., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Evidence demonstrates there is a need for innovation and further investigation on how to best prepare nursing students for practice. A consistent framework is necessary to guide students, theory faculty, and clinical instructors., Method: A tool was created to transform the student learning experience. This tool, the Clinical Compass, provides opportunity to better integrate didactic knowledge within the clinical experience. The tool was evaluated by creating a questionnaire for both students and faculty., Results: Survey data were collected from both student and instructor groups via an anonymous electronic survey. Both student and instructor surveys yielded positive results reflecting improved connection between theoretical and clinical knowledge., Conclusion: Data support continued use and ongoing revisions of the Clinical Compass tool. The tool will be adapted for use in the classroom, specialty areas, and virtual and simulation environments. [ J Nurs Educ . 2021;60(5):286-288.] .

Objective: Training in gastrointestinal endoscopy in the UK occurs predominantly in a real world one-to-one trainer to trainee interaction. Previous surveys have shown surgical and gastroenterology trainees have had mixed experiences of supervision and training, and no surveys have explored specifically the role of trainee to trainer feedback. This study aimed to explore the experience of training and of providing trainer feedback for all disciplines of endoscopy trainees., Design/method: An online survey designed in collaboration with Joint Advisory Committee training committee and trainee representatives was distributed from January 2020 but was interrupted by the COVID-19 pandemic and hence terminated early., Results: There were 129 responses, including trainees from all disciplines and regions, of which 86/129 (66.7%) rated the culture in their endoscopy units favourably-either good or excellent. 65/129 (50.4%) trainees reported having one or more training lists allocated per week, with 41/129 (31.8%) reporting only ad hoc lists. 100/129 (77.5%) respondents were given feedback and 97/129 (75.2%) were provided with learning points from the list. 65/129 (50.4%) respondents reported their trainer completed a direct observation of procedure or direct observation of polypectomies. 73/129 (56.6%) respondents reported that they felt able to give feedback to their trainer, with 88/129 (68.2%) feeling they could do this accurately. Barriers to trainer feedback cited included time constraints, lack of anonymity and concerns about affecting the trainer-trainee relationship., Conclusion: Overall, the training environment has improved since previous surveys. There are still issues around interdisciplinary differences with some surgical trainees finding the training environment less welcoming, and trainee perceptions of hierarchical barriers and trainer responsiveness to feedback limiting the accuracy of their feedback., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients' experience of symptoms often goes undetected during consultation in an outpatient clinic, and the use of a patient-reported outcome measure (PRO) in such a setting could be useful to aid treatment decision-making. A new PRO measure, the HM-PRO (Hematological Malignancy Specific Patient-Reported Outcome Measure) has been recently developed to evaluate hematological malignancy (HM) patients' health-related quality of life (HRQoL) and their symptom experience in daily clinical practice as well as in research. The objectives of the study were to assess: the internal consistency of the scores for Part A (impact) and its four domains (physical behavior; social well-being; emotional behavior; and eating and drinking habits) and Part B (signs and symptoms); and the test-retest reliability of the individual items of the newly developed hematological malignancy specific composite measure, the HM-PRO., Methods: This was a prospective longitudinal observational study where 150 patients with different HMs and different stage of disease (male n = 98 (65.3%); mean age 64.9 ± 14.4 years, range 17.9-89.2 years; mean time since diagnosis 3.7 ± 4.9 years, range 0.04-25.8 years) completed the HM-PRO at baseline (assessment 1 at t1) and after 7 days (assessment 2 at t2). Data analysis was performed using IBMSPSS 23 statistical software., Results: The Cronbach's alpha estimates of the HM-PRO for both assessment points (t1 and t2) were above 0.9 for Part A, and above 0.8 for Part B, showing strong stability of the measurement. The level of agreement for the reproducibility between the two assessments, using intra-class correlation coefficients (ICC), was very strong with Part A: ICC = 0.93 (95% CI = 0.90-0.95), and Part B: ICC = 0.91 (0.88-0.93). The ICC for the four domains of Part A ranged from 0.85-0.91. The ICC was greater than 0.8 for overall score of Part A and Part B for all the 10 diagnoses, confirming strong reliability., Conclusion: This study clearly indicates that the HM-PRO possesses strong test-retest reliability for both Part A and Part B. The Cronbach's alpha confirmed acceptable internal consistency. The extensive reliability testing described in this study supports the generic nature of the HM-PRO for use in hematological malignancies in both routine clinical practice, to aid treatment decisions, as well as in research., (Copyright © 2020 Goswami, Oliva, Ionova, Else, Kell, Fielding, Jennings, Karakantza, Al-Ismail, Collins, McConnell, Langton, Al-Obaidi, Oblak and Salek.)

Background: Our aim was to identify health-related quality-of-life (HRQoL) issues and symptoms in patients with haematological malignancies (HMs) and develop a conceptual framework to reflect the inter-relation between them., Methods: A total of 129 patients with HMs were interviewed in a UK multicentre qualitative study. All interviews were audio recorded, transcribed and analysed using NVivo-11., Results: Overall, 34 issues were reported by patients and were grouped into two parts: quality of life (QoL) and symptoms. The most prevalent HRQoL issues were: eating and drinking habits; social life; physical activity; sleep; and psychological well-being. Furthermore, most prevalent disease-related symptoms were: tiredness; feeling unwell; breathlessness; lack of energy; and back pain. The most prevalent treatment side effects were: tiredness; feeling sick; disturbance in sense of taste; and breathlessness., Conclusions: Both HMs and their treatments have a significant impact on patients' HRQoL, in particular on issues such as job-role change, body image and impact on finances., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: Validity is the ability of an instrument to measure what it claims to measure. It means the degree to which the empirical evidence supports the trustworthiness of interpretations based on the calculated scores. The hematological malignancy (HM) specific patient reported outcome measure (HM-PRO), is a newly developed instrument for use in daily clinical practice as well as in research. This study, provides the evidence for construct validity of the HM-PRO, specifically focusing on the convergent and divergent validity compared to the other established instruments used in hematology., Methods: This validation study adopted a prospective cross-sectional design where a heterogeneous group of patients diagnosed with different HMs and different disease state were recruited. A total of 905 patients were recruited from seven secondary care hospitals in the UK and online through five patient organizations. Patients were asked to complete the HM-PRO and other cancer specific PRO's, FACT-G and EORTC QLQ C-30. Data analysis was performed using IBM SPSS 23 statistical software., Results: A total of 486 males (53.7%) and 419 females (46.3%), with a mean age of 64.3 (± 12.4) years and mean time since diagnosis of 4.6 ( ± 5.2) were recruited. The total score of Part A of the HM-PRO highly correlated with the five functional scales of the EORTC QLQ-C30 (Physical = -0.71, Role = -0.72, Emotional = -0.64, Cognitive = -0.58, Social = -0.74-p < 0.001). With respect to correlation with FACT-G, the total score of Part A of the HM-PRO highly correlated with Physical (-0.74), Emotional (-0.57), Functional (-0.66) domains and overall score of FACT-G (-0.74). Similarly, the total score of Part B of the HM-PRO highly correlated with three symptoms scales of EORTC QLQ-C30 (Fatigue scale = -0.74, Nausea and Vomiting = -0.52, Pain = -0.59-p < 0.001) and individual symptom items (Dyspnea = 0.51, Insomnia= 0.43, Appetite loss = 0.54-p < 0.001)., Conclusion: The construct validity evidence presented in this research is a testimony to the HM-PRO's ability to measure HRQoL issues which it intends to measure. This is of utmost importance when a PRO is used in routine clinical practice so that the interpretation of the scores or response to an individual item is understood by the clinicians/nurses as intended by the patients., (Copyright © 2020 Goswami, Oliva, Ionova, Else, Kell, Fielding, Jennings, Karakantza, Al-Ismail, Collins, McConnell, Langton, Al-Obaidi, Oblak and Salek.)

Background: The quality of life of patients at all stages of hematological malignancy is greatly affected by the disease and its treatment. There is a wide range of health-related quality of life (HRQoL) issues important to these patients. Any new instrument developed to measure HRQoL of such patients should be content valid, i.e., the items should be comprehensively relevant to the patients and their health condition. The aim of the present study was to examine content validity of a hematological malignancy specific patient reported outcome measure (HM-PRO) developed for use in routine clinical practice., Methods: Following literature review and semi-structured interviews, the generated themes and sub-themes were discussed to develop the prototype version of the HM-PRO. A 4-step approach was used for content validation: initial testing and cognitive interviewing; item rating; content validity panel meeting; final field testing and cognitive interviewing. Additional questions related to patients' perception of recall period and preferred sentence structure (i.e., question or statement) of the items were also asked during cognitive interviews., Results: The content analysis of 129 transcribed semi-structured interviews resulted in the prototype version of the instrument consisting of 58 items grouped into two parts: Part A (impact/HRQoL - 34 items) and Part B (signs and symptoms - 24 items). The initial testing showed intra-class correlation coefficient (ICC) of >0.8 for both Part A and Part B. Item rating for language clarity, completeness, relevance, and response scale by experts and patients showed content validity index for scales average >0.8 for both Part A and Part B, except 0.64 for relevance for Part A by the patient panel. The final testing of the revised version of the instrument showed the Cronbach's alpha value of 0.91 for Part A and 0.76 for Part B, suggesting high internal consistency, and ICC of 0.91 for Part A and 0.76 for Part B. The recall period of "today" for Part-A and "last 3 days" for Part-B were the patients' preferred "recall period." Furthermore, the patients expressed preference to the HM-PRO items as statements., Conclusion: The findings of this study confirm that the HM-PRO possesses a strong content validity, includes all the issues important to patients and is easy to read, understand and respond to spontaneously., (Copyright © 2020 Goswami, Oliva, Ionova, Else, Kell, Fielding, Jennings, Karakantza, Al-Ismail, Collins, McConnell, Langton and Salek.)

Background: The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible., Methods: This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment., Results: An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response., Conclusion: This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.

Aim: To determine measurement equivalence of paper and electronic application of the hematological malignancy-patient-reported outcome (HM-PRO), a specific measure for the evaluation of patient-reported outcomes in HMs. Patients & methods: Following International Society of Pharmacoeconomics and Outcomes Research ePRO Good Research Practice Task Force guidelines, a total of 193 adult patients with different HMs were recruited into a multicenter prospective study. The paper and the electronic version of the instrument were completed in the outpatient clinics in a randomized crossover design with a 30 min time interval to minimize the learning effect. Those who completed the paper version first, completed the electronic version after 30 min and vice versa. Instrument version and order effects were tested on total score of the two parts of the HM-PRO (Part A: quality of life and Part B: signs & symptoms) in a two-way ANOVA with patients as random effects. Intraclass correlation coefficients (95% CI) and Spearman's rank correlation coefficients were used to evaluate test-retest reliability and reproducibility. The effects of instrument version and order were tested on total score of the two parts of HM-PRO. Results: The questionnaire version and administration order effects were not significant at the 5% level. There were no interactions found between these two factors for HM-PRO (Part A [quality of life]; p = 0.95); and (part B [signs and symptoms]; p = 0.72]. Spearman's rank correlation coefficients were greater than 0.9, and intraclass correlation coefficients ranged from 0.94 to 0.98; furthermore, the scores were not statistically different between the two versions, showing acceptable reliability indexes. Noteworthy, the difference between the completion time for both paper (mean = 6:38 min) and electronic version (mean = 7:29 min) was not statistically significant (n = 100; p = 0.11). Patients did not report any difficulty in completing the electronic version during cognitive interviews and were able to understand and respond spontaneously. Conclusion: Measurement equivalence has been demonstrated for the paper and electronic application of the HM-PRO.

Lice infestation is a common health issue affecting 6 to 12 million school-age children in the United States each year, impacting all members of the household. The home care nurse can be a valuable resource in the management of lice in the home and can assist the family in understanding the various myths and misconceptions about lice. This article provides an overview of lice management, including identification and treatment of a lice infestation as well as recommendations for environmental control strategies in the home. It includes an overview of the various over-the-counter and prescription treatment options and highlights the social stigma that is often associated with a lice infestation.

Background: High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity., Objective: The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy., Methods: A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m 2 by intravenous infusion. The determinant-optimal sampling strategy was explored with PopED software. Individual area under the curve estimates were generated by Bayesian estimation using full and the proposed sparse sampling data. The predictive performance of the optimal sampling strategy was evaluated based on bias and precision estimates. The feasibility of the optimal sampling strategy was tested using pharmacokinetic data from five pediatric patients., Results: A two-compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33-0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R 2  = 0.98; p < 0.01) with a mean bias of -2.2% and precision of 9.4%. A similar relationship was observed in children (R 2  = 0.99; p < 0.01)., Conclusions: The developed pharmacokinetic model-based sparse sampling strategy promises to achieve the target area under the curve as part of precision dosing.

Canonical instanton theory is known to overestimate the rate constant close to a system-dependent crossover temperature and is inapplicable above that temperature. We compare the accuracy of the reaction rate constants calculated using recent semi-classical rate expressions to those from canonical instanton theory. We show that rate constants calculated purely from solving the stability matrix for the action in degrees of freedom orthogonal to the instanton path is not applicable at arbitrarily low temperatures and use two methods to overcome this. Furthermore, as a by-product of the developed methods, we derive a simple correction to canonical instanton theory that can alleviate this known overestimation of rate constants close to the crossover temperature. The combined methods accurately reproduce the rate constants of the canonical theory along the whole temperature range without the spurious overestimation near the crossover temperature. We calculate and compare rate constants on three different reactions: H in the Müller-Brown potential, methylhydroxycarbene → acetaldehyde and H 2  + OH → H + H 2 O. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Duchenne Muscular Dystrophy (DMD) is a genetic disorder caused by dystrophin protein deficiency. Muscle biopsy is the gold standard to determine the disease severity and progression. MRI has shown potential for monitoring disease progression or assessing the treatment effectiveness. In this study, multiple quantitative MRI parameters were used to classify the tissue components in a canine model of DMD disease using histoimmunochemistry analysis as a "ground truth". Results show that multiple MRI parameters may be used to reliably classify the muscular tissue and generate a high-resolution tissue type maps, which can be used as potential non-invasive imaging biomarkers for the DMD.

Objective: To identify effective mind-body exercise programs and provide clinicians and patients with updated, high-quality recommendations concerning non-traditional land-based exercises for knee osteoarthritis., Methods: A systematic search and adapted selection criteria included comparative controlled trials with mind-body exercise programs for patients with knee osteoarthritis. A panel of experts reached consensus on the recommendations using a Delphi survey. A hierarchical alphabetical grading system (A, B, C+, C, D, D+, D-) was used, based on statistical significance ( P < 0.5) and clinical importance (⩾15% improvement)., Results: The four high-quality studies identified demonstrated that various mind-body exercise programs are promising for improving the management of knee osteoarthritis. Hatha Yoga demonstrated significant improvement for pain relief (Grade B) and physical function (Grade C+). Tai Chi Qigong demonstrated significant improvement for quality of life (Grade B), pain relief (Grade C+) and physical function (Grade C+). Sun style Tai Chi gave significant improvement for pain relief (Grade B) and physical function (Grade B)., Conclusion: Mind-body exercises are promising approaches to reduce pain, as well as to improve physical function and quality of life for individuals with knee osteoarthritis.

Objectives: To identify effective aerobic exercise programs and provide clinicians and patients with updated, high-quality recommendations concerning traditional land-based exercises for knee osteoarthritis., Methods: A systematic search and adapted selection criteria included comparative controlled trials with strengthening exercise programs for patients with knee osteoarthritis. A panel of experts reached consensus on the recommendations using a Delphi survey. A hierarchical alphabetical grading system (A, B, C+, C, D, D+, or D-) was used, based on statistical significance ( P < 0.5) and clinical importance (⩾15% improvement)., Results: The five high-quality studies included demonstrated that various aerobic training exercises are generally effective for improving knee osteoarthritis within a 12-week period. An aerobic exercise program demonstrated significant improvement for pain relief (Grade B), physical function (Grade B) and quality of life (Grade C+). Aerobic exercise in combination with strengthening exercises showed significant improvement for pain relief (3 Grade A) and physical function (2 Grade A, 2 Grade B)., Conclusion: A short-term aerobic exercise program with/without muscle strengthening exercises is promising for reducing pain, improving physical function and quality of life for individuals with knee osteoarthritis.

Objective: To identify effective strengthening exercise programs and provide rehabilitation teams and patients with updated, high-quality recommendations concerning traditional land-based exercises for knee osteoarthritis., Methods: A systematic search and adapted selection criteria included comparative controlled trials with strengthening exercise programs for patients with knee osteoarthritis. A panel of experts reached consensus on the recommendations using a Delphi survey. A hierarchical alphabetical grading system (A, B, C+, C, D, D+ or D-) was based on statistical significance ( p < 0.5) and clinical importance (⩾15% improvement)., Results: The 26 high-quality studies identified demonstrated that various strengthening exercise programs with/without other types of therapeutic exercises are generally effective for improving knee osteoarthritis management within a six-month period. Strengthening exercise programs demonstrated a significant improvement for pain relief (four Grade A, ten Grade B, two Grade C+), physical function (four Grade A, eight Grade B) and quality of life (three Grade B). Strengthening in combination with other types of exercises (coordination, balance, functional) showed a significant improvement in pain relief (three Grade A, 11 Grade B, eight Grade C+), physical function (two Grade A, four Grade B, three Grade C+) and quality of life (one Grade A, one Grade C+)., Conclusion: There are a variety of choices for strengthening exercise programs with positive recommendations for healthcare professionals and knee osteoarthritis patients. There is a need to develop combined behavioral and muscle-strengthening strategies to improve long-term maintenance of regular strengthening exercise programs.

The processes leading to genetic isolation influence a population's local extinction risk, and should thus be identified before conservation actions are implemented. Natural or human-induced circumstances can result in historical or contemporary barriers to gene flow and/or demographic bottlenecks. Distinguishing between these hypotheses can be achieved by comparing genetic diversity and differentiation in isolated vs. continuous neighboring populations. In Ontario, American black bears (Ursus americanus) are continuously distributed, genetically diverse, and exhibit an isolation-by-distance structuring pattern, except on the Bruce Peninsula (BP). To identify the processes that led to the genetic isolation of BP black bears, we modelled various levels of historical and contemporary migration and population size reductions using forward simulations. We compared simulation results with empirical genetic indices from Ontario black bear populations under different levels of geographic isolation, and conducted additional simulations to determine if translocations could help achieve genetic restoration. From a genetic standpoint, conservation concerns for BP black bears are warranted because our results show that: i) a recent demographic bottleneck associated with recently reduced migration best explains the low genetic diversity on the BP; and ii) under sustained isolation, BP black bears could lose between 70% and 80% of their rare alleles within 100 years. Although restoring migration corridors would be the most effective method to enhance long-term genetic diversity and prevent inbreeding, it is unrealistic to expect connectivity to be re-established. Current levels of genetic diversity could be maintained by successfully translocating 10 bears onto the peninsula every 5 years. Such regular translocations may be more practical than landscape restoration, because areas connecting the peninsula to nearby mainland black bear populations have been irreversibly modified by humans, and form strong barriers to movement.

Objective: The purpose of this retrospective registry data analysis was to explore the effectiveness of a novel multivalent topical ointment (Terrasil Infection Control Wound Care Ointment; Aspiera Medical, Woonsocket, Rhode Island), containing a patented mineral complex and 0.2% benzethonium chloride in the treatment of nonhealing acute and chronic wounds., Design: Aspiera Medical designed a registry to capture physician experiences and treatment results with Terrasil Infection Control Wound Care Ointment. Physicians were asked to enter deidentified patient data into an online registry., Setting: Wound clinics in the United States were asked to participate in the registry., Patients: Physicians at 4 wound clinics treated 30 patients (26 of whom completed the treatment) with various chronic wounds that had persisted for an average of 6 months and entered treatment data into the registry., Interventions: Patients applied the ointment according to physician orders. Concurrent treatments used by patients included offloading, compression wraps, and dressings, such as collagen and calcium alginate. Patients were treated until complete wound closure or lost to follow-up., Main Outcome Measures: Physicians calculated each patient's percentage wound reduction at each visit., Main Results: Thirty patients were entered into the registry. Pretreatment and posttreatment measurements were available for 26 of them. Patients achieved an average surface area reduction of 84% in a mean of 23 days' treatment., Conclusion: The antimicrobial and moisturizing ointment studied appears to be effective in promoting wound closure in a variety of acute and chronic wounds. Wounds studied included diabetic foot ulcers, venous leg ulcers, venous stasis ulcers, surgical infections, burns, and insect bites. The results of this registry data analysis will be used to inform planned clinical trials.

Duchenne Muscular Dystrophy (DMD) is a fatal X-linked disorder. Therapeutic assessments currently require muscle biopsy to ascertain information about the status of disease progression. MRI shows potential to be used in place of muscle biopsy for therapeutic assessments. In this work, localized histological data and various MRI parameters were correlated in a canine model of DMD. The results indicate several MRI parameters may be useful as biomarkers of disease progression.

Parallel factor (PARAFAC) analysis of dissolved organic matter (DOM) fluorescence has facilitated a surge of investigation into its biogeochemical cycling. However, rigorous, PARAFAC-based methods for holistically distinguishing DOM sources are lacking. This study classified 1029 PARAFAC-analyzed excitation-emission matrices (EEMs) measured using DOM isolated from 24 different leaf leachates, rivers, and organic matter standards using four machine learning methods (MLM). EEMs were also divided into subsets to assess the impact of experimental treatments (i.e. whole EEMs, size fractionation, mixtures, quenching) and dataset properties (i.e. different numbers of EEMs from each leachate/river) on classification. A split-half validated, 10-component PARAFAC model was extended to 12 components to remove consistent peaks evident in model residuals. The 12-component model performed better than the 10-component model, correctly classifying up to 80 additional EEMs, when the dataset included size-fractionated DOM or several different sources (i.e. many leaf species and rivers); however, the 10-component model performed better for whole-sample EEMs when comparing leaf leachates to rivers. The MLM correctly classified whole EEMs of riverine DOM by source with up to 87.0% accuracy, leachates with up to 92.5% accuracy, and distinguished leachates from rivers with 97.2% accuracy. A difference of up to 17.3% in classification accuracy was observed depending on the MLM method used with the following order: multilayer perceptron = support vector machine > k-nearest neighbours ≫ decision tree; however, performances differed widely depending on the data subset. Classification accuracy for whole and size-fractionated rivers compared to whole and size-fractionated leachates using N-way partial least-squares discriminant analysis (NPLS-DA; 97.7%) was similar to that achieved using MLM. Combining MLM with PARAFAC is an effective method for classifying DOM based on its fluorescence signature because PARAFAC can isolate meaningful fluorescent species and unlike PLSDA, MLM constructs a single model which simultaneously classifies EEMs as belonging to one of several categories. A complete accounting of carbon flows through ecosystems should include the processes and sources that contribute to the disparate fluorescence signatures of riverine and leached DOM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Context: Compassion is frequently referenced as a hallmark of quality care by patients, health care providers, health care administrators, and policy makers. Despite its putative centrality, including its institution in recent health care reform, an empirical understanding based on the perspectives of patients, the recipients of compassion, is lacking-making compassion one of the most referenced yet poorly understood elements of quality care., Objectives: The objective of this study was to investigate palliative cancer patients' understanding and experiences of compassion to provide a critical perspective on the nature and importance of compassion., Methods: This grounded theory study used semi-structured interviews to investigate how patients understand and experience compassion in clinical care. Using convenience and theoretical sampling, 53 advanced cancer inpatients were recruited over a seven-month period from a specialized palliative care unit and hospital-wide palliative care service within a Canadian urban setting. Data were analyzed by four members of the research team through the three stages of Straussian grounded theory., Results: Qualitative analysis yielded seven categories, each containing distinct themes and subthemes. Together, they constitute components of the compassion model-the first empirically based clinical model of compassion. The model defines compassion as a virtuous response that seeks to address the suffering and needs of a person through relational understanding and action., Conclusion: The components of the compassion model provide insight into how patients understand and experience compassion, providing the necessary empirical foundation to develop future research, measures, training, and clinical care based on this vital feature of quality care., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether land-based therapeutic exercise is beneficial for people with knee osteoarthritis (OA) in terms of reduced joint pain or improved physical function and quality of life., Methods: Five electronic databases were searched, up until May 2013. Randomised clinical trials comparing some form of land-based therapeutic exercise with a non-exercise control were selected. Three teams of two review authors independently extracted data and assessed risk of bias for each study. Standardised mean differences immediately after treatment and 2-6 months after cessation of formal treatment were separately pooled using a random effects model., Results: In total, 54 studies were identified. Overall, 19 (35%) studies reported adequate random sequence generation, allocation concealment and adequately accounted for incomplete outcome data. However, research results may be vulnerable to selection, attrition and detection bias. Pooled results from 44 trials indicated that exercise significantly reduced pain (12 points/100; 95% CI 10 to 15) and improved physical function (10 points/100; 95% CI 8 to 13) to a moderate degree immediately after treatment, while evidence from 13 studies revealed that exercise significantly improved quality of life immediately after treatment with small effect (4 points/100; 95% CI 2 to 5). In addition, 12 studies provided 2-month to 6-month post-treatment sustainability data which showed significantly reduced knee pain (6 points/100; 95% CI 3 to 9) and 10 studies which showed improved physical function (3 points/100; 95% CI 1 to 5)., Conclusions: Among people with knee osteoarthritis, land-based therapeutic exercise provides short-term benefit that is sustained for at least 2-6 months after cessation of formal treatment., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objectives: The purpose of this study was to use a qualitative approach to better understand the importance and efficacy of addressing spiritual issues within an interdisciplinary bone marrow transplant clinic from the perspectives of patients and healthcare providers., Setting: Participants were recruited from the bone marrow transplant clinic of a large urban outpatient cancer care centre in western Canada., Participants: Focus groups were conducted with patients (n=7) and healthcare providers (n=9) to explore the importance of addressing spiritual issues across the treatment trajectory and to identify factors associated with effectively addressing these needs., Results: Data were analysed using the qualitative approach of latent content analysis. Addressing spiritual issues was understood by patients and healthcare providers, as a core, yet under addressed, component of comprehensive care. Both sets of participants felt that addressing basic spiritual issues was the responsibility of all members of the interdisciplinary team, while recognising the need for specialised and embedded support from a spiritual care professional. While healthcare providers felt that the impact of the illness and treatment had a negative effect on patients' spiritual well-being, patients felt the opposite. Skills, challenges, key time points and clinical indicators associated with addressing spiritual issues were identified., Conclusions: Despite a number of conceptual and clinical challenges associated with addressing spiritual issues patients and their healthcare providers emphasised the importance of an integrated approach whereby basic spiritual issues are addressed by members of the interdisciplinary team and by an embedded spiritual care professional, who in addition also provides specialised support. The identification of clinical issues associated with addressing spiritual needs provides healthcare providers with clinical guidance on how to better integrate this aspect of care into their clinical practice, while also identifying acute incidences when a more targeted and specialised approach may be of benefit., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Aims and Objectives: To provide a critical review of nursing literature about compassion, identifying major themes, questions arising and directions for future investigation of the topic., Background: Compassion has emerged as a topic of broad social concern in recent years and is particularly pertinent to nurses., Design: Critical review was selected as the most appropriate way of analysing literature from both qualitative research studies and conceptual articles., Methods: An electronic database search was conducted, discovering articles published between 1952 and 2013. The search was then limited to publications since 2000 to capture recent development of the concept. The search was limited to peer-reviewed literature, excluding a large body of editorial material, resulting in 20 relevant articles. Two books were also added that contributed important perspective to the analysis. Critical analysis of the resulting material was undertaken to identify themes, tensions and implications in the literature., Results: Major themes were compassion as practice and compassion as a moral virtue, holding implications for how nurses can demonstrate compassion in relation to contemporary healthcare values. A third major theme was the influence of institutional environments in facilitating or limiting the expression of compassion., Conclusions: Compassion is a human experience of deep significance to nursing and needs understanding in the context of healthcare environments dominated by discourses of efficiency and rationalisation. There is an emergent literature about how compassion may be understood, taught and sustained among nurses but it is a topic that requires continued attention., Relevance to Clinical Practice: More precise understanding of compassion will support nurses in advocating for compassionate care, participating in interdisciplinary dialogue, and contributing to the design of healthcare environments that are conducive to compassionate care., (© 2015 John Wiley & Sons Ltd.)

Bioavailability has been used as a key indicator in chemical risk assessment yet poorly quantified risk factor. Worldwide, the framework used to assess potentially contaminated sites is similar, and the decisions are based on threshold contaminant concentration. The uncertainty in the definition and measurement of bioavailability had limited its application to environment risk assessment and remediation. Last ten years have seen major developments in bioavailability research and acceptance. The use of bioavailability in the decision making process as one of the key variables has led to a gradual shift towards a more sophisticated risk-based approach. Now a days, many decision makers and regulatory organisations 'more readily accept' this concept. Bioavailability should be the underlying basis for risk assessment and setting remediation goals of those contaminated sites that pose risk to environmental and human health. This paper summarises the potential application of contaminant bioavailability and bioaccessibility to the assessment of sites affected by different contaminants, and the potential for this to be the underlying basis for sustainable risk assessment and remediation in Europe, North America and Australia over the coming decade.

We propose and analyze a two-state valence-bond model of non-equilibrium solvation effects on the excited-state twisting reaction of monomethine cyanines. Suppression of this reaction is thought responsible for environment-dependent fluorescence yield enhancement in these dyes. Fluorescence is quenched because twisting is accompanied via the formation of dark twisted intramolecular charge-transfer (TICT) states. For monomethine cyanines, where the ground state is a superposition of structures with different bond and charge localizations, there are two possible twisting pathways with different charge localizations in the excited state. For parameters corresponding to symmetric monomethines, the model predicts two low-energy twisting channels on the excited-state surface, which leads to a manifold of TICT states. For typical monomethines, twisting on the excited state surface will occur with a small barrier or no barrier. Changes in the solvation configuration can differentially stabilize TICT states in channels corresponding to different bonds, and that the position of a conical intersection between adiabatic states moves in response to solvation to stabilize either one channel or the other. There is a conical intersection seam that grows along the bottom of the excited-state potential with increasing solvent polarity. For monomethine cyanines with modest-sized terminal groups in moderately polar solution, the bottom of the excited-state potential surface is completely spanned by a conical intersection seam.

Background: Knee osteoarthritis (OA) is a major public health issue because it causes chronic pain, reduces physical function and diminishes quality of life. Ageing of the population and increased global prevalence of obesity are anticipated to dramatically increase the prevalence of knee OA and its associated impairments. No cure for knee OA is known, but exercise therapy is among the dominant non-pharmacological interventions recommended by international guidelines., Objectives: To determine whether land-based therapeutic exercise is beneficial for people with knee OA in terms of reduced joint pain or improved physical function and quality of life., Search Methods: Five electronic databases were searched, up until May 2013., Selection Criteria: All randomised controlled trials (RCTs) randomly assigning individuals and comparing groups treated with some form of land-based therapeutic exercise (as opposed to exercise conducted in the water) with a non-exercise group or a non-treatment control group., Data Collection and Analysis: Three teams of two review authors independently extracted data, assessed risk of bias for each study and assessed the quality of the body of evidence for each outcome using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. We conducted analyses on continuous outcomes (pain, physical function and quality of life) immediately after treatment and on dichotomous outcomes (proportion of study withdrawals) at the end of the study; we also conducted analyses on the sustained effects of exercise on pain and function (two to six months, and longer than six months)., Main Results: In total, we extracted data from 54 studies. Overall, 19 (20%) studies reported adequate random sequence generation and allocation concealment and adequately accounted for incomplete outcome data; we considered these studies to have an overall low risk of bias. Studies were largely free from selection bias, but research results may be vulnerable to performance and detection bias, as only four of the RCTs reported blinding of participants to treatment allocation, and, although most RCTs reported blinded outcome assessment, pain, physical function and quality of life were participant self-reported.High-quality evidence from 44 trials (3537 participants) indicates that exercise reduced pain (standardised mean difference (SMD) -0.49, 95% confidence interval (CI) -0.39 to -0.59) immediately after treatment. Pain was estimated at 44 points on a 0 to 100-point scale (0 indicated no pain) in the control group; exercise reduced pain by an equivalent of 12 points (95% CI 10 to 15 points). Moderate-quality evidence from 44 trials (3913 participants) showed that exercise improved physical function (SMD -0.52, 95% CI -0.39 to -0.64) immediately after treatment. Physical function was estimated at 38 points on a 0 to 100-point scale (0 indicated no loss of physical function) in the control group; exercise improved physical function by an equivalent of 10 points (95% CI 8 to 13 points). High-quality evidence from 13 studies (1073 participants) revealed that exercise improved quality of life (SMD 0.28, 95% CI 0.15 to 0.40) immediately after treatment. Quality of life was estimated at 43 points on a 0 to 100-point scale (100 indicated best quality of life) in the control group; exercise improved quality of life by an equivalent of 4 points (95% CI 2 to 5 points).High-quality evidence from 45 studies (4607 participants) showed a comparable likelihood of withdrawal from exercise allocation (event rate 14%) compared with the control group (event rate 15%), and this difference was not significant: odds ratio (OR) 0.93 (95% CI 0.75 to 1.15). Eight studies reported adverse events, all of which were related to increased knee or low back pain attributed to the exercise intervention provided. No study reported a serious adverse event.In addition, 12 included studies provided two to six-month post-treatment sustainability data on 1468 participants for knee pain and on 1279 (10 studies) participants for physical function. These studies indicated sustainability of treatment effect for pain (SMD -0.24, 95% CI -0.35 to -0.14), with an equivalent reduction of 6 (3 to 9) points on 0 to 100-point scale, and of physical function (SMD -0.15 95% CI -0.26 to -0.04), with an equivalent improvement of 3 (1 to 5) points on 0 to 100-point scale.Marked variability was noted across included studies among participants recruited, symptom duration, exercise interventions assessed and important aspects of study methodology. Individually delivered programmes tended to result in greater reductions in pain and improvements in physical function, compared to class-based exercise programmes or home-based programmes; however between-study heterogeneity was marked within the individually provided treatment delivery subgroup., Authors' Conclusions: High-quality evidence indicates that land-based therapeutic exercise provides short-term benefit that is sustained for at least two to six months after cessation of formal treatment in terms of reduced knee pain, and moderate-quality evidence shows improvement in physical function among people with knee OA. The magnitude of the treatment effect would be considered moderate (immediate) to small (two to six months) but comparable with estimates reported for non-steroidal anti-inflammatory drugs. Confidence intervals around demonstrated pooled results for pain reduction and improvement in physical function do not exclude a minimal clinically important treatment effect. Since the participants in most trials were aware of their treatment, this may have contributed to their improvement. Despite the lack of blinding we did not downgrade the quality of evidence for risk of performance or detection bias. This reflects our belief that further research in this area is unlikely to change the findings of our review.

Background: Current international treatment guidelines recommending therapeutic exercise for people with symptomatic hip osteoarthritis (OA) report are based on limited evidence., Objectives: To determine whether land-based therapeutic exercise is beneficial for people with hip OA in terms of reduced joint pain and improved physical function and quality of life., Search Methods: We searched five databases from inception up to February 2013., Selection Criteria: All randomised controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based therapeutic exercise (as opposed to exercises conducted in water) with a non-exercise group., Data Collection and Analysis: Four review authors independently selected studies for inclusion. We resolved disagreements through consensus. Two review authors independently extracted data, assessed risk of bias and the quality of the body of evidence for each outcome using the GRADE approach. We conducted analyses on continuous outcomes (pain, physical function and quality of life) and dichotomous outcomes (proportion of study withdrawals)., Main Results: We considered that seven of the 10 included RCTs had a low risk of bias. However, the results may be vulnerable to performance and detection bias as none of the RCTs were able to blind participants to treatment allocation and, while most RCTs reported blinded outcome assessment, pain, physical function and quality of life were participant self reported. One of the 10 RCTs was only reported as a conference abstract and did not provide sufficient data for the evaluation of bias risk.High-quality evidence from nine trials (549 participants) indicated that exercise reduced pain (standardised mean difference (SMD) -0.38, 95% confidence interval (CI) -0.55 to -0.20) and improved physical function (SMD -0.38, 95% CI -0.54 to -0.05) immediately after treatment. Pain and physical function were estimated to be 29 points on a 0- to 100-point scale (0 was no pain or loss of physical function) in the control group; exercise reduced pain by an equivalent of 8 points (95% CI 4 to 11 points; number needed to treat for an additional beneficial outcome (NNTB) 6) and improved physical function by an equivalent of 7 points (95% CI 1 to 12 points; NNTB 6). Only three small studies (183 participants) evaluated quality of life, with overall low quality evidence, with no benefit of exercise demonstrated (SMD -0.07, 95% CI -0.23 to 0.36). Quality of life was estimated to be 50 points on a norm-based mean (standard deviation (SD)) score of 50 (10) in the general population in the control group; exercise improved quality of life by 0 points. Moderate-quality evidence from seven trials (715 participants) indicated an increased likelihood of withdrawal from the exercise allocation (event rate 6%) compared with the control group (event rate 3%), but this difference was not significant (risk difference 1%; 95% CI -1% to 4%). Of the five studies reporting adverse events, each study reported only one or two events and all were related to increased pain attributed to the exercise programme.The reduction in pain was sustained at least three to six months after ceasing monitored treatment (five RCTs, 391 participants): pain (SMD -0.38, 95% CI -0.58 to -0.18). Pain was estimated to be 29 points on a 0- to 100-point scale (0 was no pain) in the control group, the improvement in pain translated to a sustained reduction in pain intensity of 8 points (95% CI 4 to 12 points) compared with the control group (0 to 100 scale). The improvement in physical function was also sustained (five RCTs, 367 participants): physical function (SMD -0.37, 95% CI -0.57 to -0.16). Physical function was estimated to be 24 points on a 0- to 100-point scale (0 was no loss of physical function) in the control group, the improvement translated to a mean of 7 points (95% CI 4 to 13) compared with the control group.Only five of the 10 RCTs exclusively recruited people with symptomatic hip OA (419 participants). There was no significant difference in pain or physical function outcomes compared with five studies recruiting participants with hip or knee OA (130 participants)., Authors' Conclusions: Pooling the results of these 10 RCTs demonstrated that land-based therapeutic exercise programmes can reduce pain and improve physical function among people with symptomatic hip OA.

Background: In preparation for the initial offering of the University of Alaska Fairbanks (UAF), Interior-Aleutians Campus Rural Nutrition Services (RNS) program, a literature review was conducted to establish the need for the proposed program and to substantiate the methodology for delivering integrated, culturally tailored postsecondary education and extension to Alaska Natives and rural Alaskans. There was a striking absence of peer-reviewed journal articles describing culturally tailored postsecondary health curricula for indigenous populations., Objective: To complete and discuss a current (November 2012) literature review for culturally tailored postsecondary health curricula designed and delivered for indigenous populations., Methods/design: The author conducted an expanded online search that employed multiple configurations of key terms using Google and Google Scholar, as well as pertinent sources. The author located archived reports in person and contacted authors by email., Results: The expanded search produced a modest amount of additional literature for review. A disappointing number of publications describing or evaluating culturally tailored postsecondary health curricula in mainstream institutions are available. Related resources on culturally tailored extension and resources for the development and delivery of culturally tailored nutrition and health curricula were identified., Conclusions: The present results demonstrate a significant absence of literature on the topic, which may or may not indicate the absence of sufficient culturally tailored postsecondary health curricula for indigenous populations. There are indications that culturally tailored postsecondary health curricula for indigenous populations have the potential to effectively address certain issues of health literacy and health disparities.

Voriconazole (VCZ) is frequently utilized for prevention and treatment of invasive fungal infections in peripheral stem cell transplant (PSCT) patients. We performed an open-label pharmacokinetic study to compare VCZ and N-oxide voriconazole (N-oxide VCZ) pharmacokinetics in patients pre- and post-PSCT. Ten patients completed both sampling periods. The pharmacokinetics of VCZ were unchanged; however, those of N-oxide VCZ were significantly different pre- and post-PSCT.

Preschool experience plays a role in children's development. However, for programs with language and early literacy goals, the question remains whether or not preschool instructional experiences are sufficiently effective to achieve these goals for all children. In a multisite study, we conducted a process-product description of preschool instruction and children's growth and outcomes in typical programs (i.e., Pre-Kindergarten, Title 1, Head Start, Tuition-Based) using a Response to Intervention (RTI) perspective. Results indicated that (a) students in their preschool year prior to kindergarten made small gains, but students starting the year in lower Tier 2 and 3 performance levels did not close initial skills gaps, (b) variations were noted by program types with varying socio-demographics and instructional processes, and (c) the quality of instruction (Tier 1) received by all was low with room for improvement. Implications for future research on the application of the RTI approach and potential benefits are discussed.

Sheep infected with the triclabendazole-susceptible Cullompton isolate of Fasciola hepatica were treated with compound alpha at a dosage of 15 mg/kg at 12 weeks post-infection. Adult flukes were recovered from the bile ducts at 24h, 48 h and 72 h post-treatment (pt). They were processed for whole mount analysis, histology and transmission electron microscopy of the female reproductive system: specifically, the uterus, Mehlis' gland, ovary and vitellaria. As judged by the appearance of the uterus, normal egg production ceased within 24h of treatment; this phenomenon preceded significant changes to the other reproductive organs. Over the 3-day pt period, there was a progressive decline in the number of oogonia in the ovary, together with an increase in the number of eosinophilic and apoptotic oocytes and vacuolation and shrinkage of the ovarian tubules. There was a shift in the cell population within the vitelline follicles at 48 h pt, with relatively greater numbers of mature vitelline cells and fewer immature cells. The follicles were vacuolated and the shell globule clusters in the mature cells were disorganised. Greater disruption was seen at 72 h pt, with a reduction in the size of the follicles and rupture of cells, releasing their content into the lumen of the follicles. These histological observations were confirmed and extended at the TEM level. Thus, examination of electron micrographs showed that disruption of the shell globule clusters was evident at 48 h pt, which coincided with the start of the breakdown of the mature cells and of the nurse cell network. These degenerative changes were more conspicuous at 72 h pt. In the Mehlis' gland, shrinkage and vacuolation of the cells and their cytoplasmic extensions became progressively greater from 48 h to 72 h pt, and secretory activity declined. The changes in the reproductive organs and inhibition of egg production are put in context of the overall time-course of drug action., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Lambs infected with the Cullompton triclabendazole (TCBZ)-susceptible isolate of Fasciola hepatica were treated with TCBZ at a dosage of 10mg/kg at 16 weeks post-infection. Adult flukes were recovered from the liver at 3h, 24h, 48 h and 60 h post-treatment (pt). They were processed for histological analysis of the uterus, Mehlis' gland, vitellaria, ovary and testis. At 3h pt, the flukes were essentially similar to the controls and were producing normal eggs. Egg production had ceased by 24h pt. At this time period, the cells of the Mehlis' gland showed some evidence of vacuolation, but otherwise were relatively normal. A shift in the population of vitelline cells towards mature cells was observed at 24h pt, and this trend continued at later time-periods. It was accompanied by a breakdown of the cells and the presence of apoptotic bodies. Marked changes to the ovary were first noted at 48 h pt, as evidenced by vacuolation and the presence of apoptotic bodies. Some disruption to the testis was seen at 24h pt, with a reduction in the population of spermatogenic cells, the appearance of apoptotic bodies and some peripheral vacuolation of the tubules. These abnormalities increased in severity with longer time periods pt. The results bring forward the time-line of cessation of egg production by 24h, demonstrating that this process is affected very rapidly pt., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background/aims: Radiotherapy (XRT) is the gold standard treatment for cancer-induced bone pain (CIBP), but only 50% of patients achieve adequate pain relief within 6 weeks. No predictors of analgesic response to XRT are known. The aim of this preliminary study was to explore the effect of XRT on sensory changes in CIBP with a view to predicting response., Methods: After ethics committee approval, patients with CIBP were assessed prior to and 4-6 weeks after palliative XRT. This included completion of the Brief Pain Inventory (BPI) and bedside Quantitative Sensory Testing (QST) measuring evoked sensations to quantified stimuli on the skin over the area of CIBP and a control site., Results: Twenty-three patients were assessed pre and post XRT. Thirteen (57%) had an analgesic response (defined as ≥30% reduction in total BPI). Those patients who had normalisation of abnormal warm sensation ("warm responders", n = 6) were different in that they had higher baseline functional BPI pain scores (median score (IQR) in warm responders = 43 (31.75-58) compared to 31 (12-39.5) in the remaining patients, p = 0.039), larger reductions in pain scores (median difference of 33.5 in total BPI, p = 0.027) and increased likelihood of resolution of sensitivity to pinprick., Conclusions: This is the first clinical study to demonstrate alterations in sensory responses in CIBP. Alterations in specific sensory characteristics seem to be associated with an increased likelihood of successful analgesia from palliative XRT. This supports the use of QST in further biomarker studies to predict response to therapy and aid clinical decision making., (© 2011 European Federation of International Association for the Study of Pain Chapters.)

We present a model of the galactic habitable zone (GHZ), described in terms of the spatial and temporal dimensions of the Galaxy that may favor the development of complex life. The Milky Way galaxy was modeled using a computational approach by populating stars and their planetary systems on an individual basis by employing Monte Carlo methods. We began with well-established properties of the disk of the Milky Way, such as the stellar number density distribution, the initial mass function, the star formation history, and the metallicity gradient as a function of radial position and time. We varied some of these properties and created four models to test the sensitivity of our assumptions. To assess habitability on the galactic scale, we modeled supernova rates, planet formation, and the time required for complex life to evolve. Our study has improved on other literature on the GHZ by populating stars on an individual basis and modeling Type II supernova (SNII) and Type Ia supernova (SNIa) sterilizations by selecting their progenitors from within this preexisting stellar population. Furthermore, we considered habitability on tidally locked and non-tidally locked planets separately and studied habitability as a function of height above and below the galactic midplane. In the model that most accurately reproduces the properties of the Galaxy, the results indicate that an individual SNIa is ∼5.6× more lethal than an individual SNII on average. In addition, we predict that ∼1.2% of all stars host a planet that may have been capable of supporting complex life at some point in the history of the Galaxy. Of those stars with a habitable planet, ∼75% of planets are predicted to be in a tidally locked configuration with their host star. The majority of these planets that may support complex life are found toward the inner Galaxy, distributed within, and significantly above and below, the galactic midplane.