Pooling robustness in distance sampling: Avoiding bias when there is unmodelled heterogeneity.

The pooling robustness property of distance sampling results in unbiased abundance estimation even when sources of variation in detection probability are not modeled. However, this property cannot be relied upon to produce unbiased subpopulation abundance estimates when using a single pooled detection function that ignores subpopulations. We investigate by simulation the effect of differences in subpopulation detectability upon bias in subpopulation abundance estimates. We contrast subpopulation abundance estimates using a pooled detection function with estimates derived using a detection function model employing a subpopulation covariate. Using point transect survey data from a multispecies songbird study, species-specific abundance estimates are compared using pooled detection functions with and without a small number of adjustment terms, and a detection function with species as a covariate. With simulation, we demonstrate the bias of subpopulation abundance estimates when a pooled detection function is employed. The magnitude of the bias is positively related to the magnitude of disparity between the subpopulation detection functions. However, the abundance estimate for the entire population remains unbiased except when there is extreme heterogeneity in detection functions. Inclusion of a detection function model with a subpopulation covariate essentially removes the bias of the subpopulation abundance estimates. The analysis of the songbird point count surveys shows some bias in species-specific abundance estimates when a pooled detection function is used. Pooling robustness is a unique property of distance sampling, producing unbiased abundance estimates at the level of the study area even in the presence of large differences in detectability between subpopulations. In situations where subpopulation abundance estimates are required for data-poor subpopulations and where the subpopulations can be identified, we recommend the use of subpopulation as a covariate to reduce bias induced in subpopulation abundance estimates.

Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major.

BACKGROUND: The macrophage infectivity potentiator (Mip) protein, which belongs to the immunophilin superfamily, is a peptidyl-prolyl cis/trans isomerase (PPIase) enzyme. Mip has been shown to be important for virulence in a wide range of pathogenic microorganisms. It has previously been demonstrated that small-molecule compounds designed to target Mip from the Gram-negative bacterium Burkholderia pseudomallei bind at the site of enzymatic activity of the protein, inhibiting the in vitro activity of Mip. OBJECTIVES: In this study, co-crystallography experiments with recombinant B. pseudomallei Mip (BpMip) protein and Mip inhibitors, biochemical analysis and computational modelling were used to predict the efficacy of lead compounds for broad-spectrum activity against other pathogens. METHODS: Binding activity of three lead compounds targeting BpMip was verified using surface plasmon resonance spectroscopy. The determination of crystal structures of BpMip in complex with these compounds, together with molecular modelling and in vitro assays, was used to determine whether the compounds have broad-spectrum antimicrobial activity against pathogens. RESULTS: Of the three lead small-molecule compounds, two were effective in inhibiting the PPIase activity of Mip proteins from Neisseria meningitidis, Klebsiella pneumoniae and Leishmania major. The compounds also reduced the intracellular burden of these pathogens using in vitro cell infection assays. CONCLUSIONS: These results indicate that Mip is a novel antivirulence target that can be inhibited using small-molecule compounds that prove to be promising broad-spectrum drug candidates in vitro. Further optimization of compounds is required for in vivo evaluation and future clinical applications.

The effect of infliximab dose escalation in inflammatory bowel disease patients with antibodies to infliximab.

BACKGROUND: Infliximab dose escalation (DE) can be used in inflammatory bowel disease patient; however, the long-term benefit remains unclear, especially in those with antibodies to infliximab (ATI). The aim was to assess the effect of DE in patients with ATI on drug level, clinical response and ATI status. METHODS: All patients undergoing infliximab DE (a reduction in dose interval between infusions <8 weeks ± an increase in dose up to 10 mg/kg) at a referral centre between April 2016 and August 2019 were included. RESULTS: Ninety-two patients were DE: 51 were men, 50 had CD and 63 were receiving immunosuppression. A total of 87 people received DE for a median of 44 weeks (range 4-176). Five stopped infliximab after 1 dose of DE: 2 for loss of response and 3 for infusion reaction. In patients with ATI ≤10 vs. >10 AU/mL, DE significantly increased drug levels: median infliximab levels of 1.4 and 0.9 at baseline, respectively, to 3.2 and 3.5 at week 24. After DE, 21/35 ATI-positive patients had a fall in ATI ≤10 AU/mL. At week 24 following DE 62/92 patients were in clinical remission. Duration of clinical remission was shorter in those with ATI >10 AU/mL (median 24 weeks, range 0-88) than in those with transient/ATI ≤10 AU/mL (median 36 weeks, range 0-126, P = 0.06). CONCLUSIONS: A strategy of DE for selected patients receiving infliximab is associated with an increase in drug levels and reduced ATI positivity. This is associated with clinical remission in approximately 70% of patients at 6 months.

Pathways for Memory, Cognition and Emotional Context: Hippocampal, Subgenual Area 25, and Amygdalar Axons Show Unique Interactions in the Primate Thalamic Reuniens Nucleus.

The reuniens nucleus (RE) is situated at the most ventral position of the midline thalamus. In rats and mice RE is distinguished by bidirectional connections with the hippocampus and medial prefrontal cortex (mPFC) and a role in memory and cognition. In primates, many foundational questions pertaining to RE remain unresolved. We addressed these issues by investigating the composition of the rhesus monkey RE in both sexes by labeling for GABA, a marker of inhibitory neurons, and for the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR), which label thalamic excitatory neurons that project to cortex. As in rats and mice, the macaque RE was mostly populated by CB and CR neurons, characteristic of matrix-dominant nuclei, and had bidirectional connections with hippocampus and mPFC area 25 (A25). Unlike rodents, we found GABAergic neurons in the monkey RE and a sparser but consistent population of core-associated thalamocortical PV neurons. RE had stronger connections with the basal amygdalar complex than in rats or mice. Amygdalar terminations were enriched with mitochondria and frequently formed successive synapses with the same postsynaptic structures, suggesting an active and robust pathway to RE. Significantly, hippocampal pathways formed multisynaptic complexes that uniquely involved excitatory projection neurons and dendrites of local inhibitory neurons in RE, extending this synaptic principle beyond sensory to high-order thalamic nuclei. Convergent pathways from hippocampus, A25, and amygdala in RE position it to flexibly coordinate activity for memory, cognition, and emotional context, which are disrupted in several psychiatric and neurologic diseases in humans.SIGNIFICANCE STATEMENT The primate RE is a central node for memory and cognition through connections with the hippocampus and mPFC. As in rats or mice, the primate RE is a matrix-dominant thalamic nucleus, suggesting signal traffic to the upper cortical layers. Unlike rats or mice, the primate RE contains inhibitory neurons, synaptic specializations with the hippocampal pathway, and robust connections with the amygdala, suggesting unique adaptations. Convergence of hippocampal, mPFC, and amygdalar pathways in RE may help unravel a circuit basis for binding diverse signals for conscious flexible behaviors and the synthesis of memory with affective significance in primates, whereas disruption of distinct circuit nodes may occur in psychiatric disorders in humans.

Effects of Ketoprofen and Morphine on Pain-Related Depression of Nestlet Shredding in Male and Female Mice.

A primary goal in pain treatment is restoration of behaviors that are disrupted by pain. Measures of pain interference indicate the degree to which pain interferes with activities in pain patients, and these measures are used to evaluate the effects of analgesic drugs. As a result of the emphasis on the expression and treatment of functional impairment in clinical settings, preclinical pain researchers have attempted to develop procedures for evaluation of pain-related functional impairment in laboratory animals. The goal of the present study was to develop and validate a low cost procedure for the objective evaluation of pain-related depression of home cage behavior in mice. On test days, a 5 × 5 cm Nestlet was weighed prior to being suspended from the wire lid of the home cage of individually housed male and female ICR mice. Over the course of experimental sessions, mice removed pieces of the suspended Nestlet, and began to build a nest with the material they removed. Thus, the weight of the pieces of Nestlet that remained suspended at various time points in the session provided an indicator of the rate of this behavior. The results indicate that Nestlet shredding was stable with repeated testing, and shredding was depressed by intra-peritoneal injection of 0.32% lactic acid. The non-steroidal anti-inflammatory drug ketoprofen blocked 0.32% lactic acid-induced depression of shredding, but did not block depression of shredding by a pharmacological stimulus, the kappa opioid receptor agonist U69,593. The µ-opioid receptor agonist morphine did not block 0.32% lactic acid-induced depression of shredding when tested up to doses that depressed shredding in the absence of lactic acid. When noxious stimulus intensity was reduced by decreasing the lactic acid concentration to 0.18%, morphine was effective at blocking pain-related depression of behavior. In summary, the data from the present study support consideration of the Nestlet shredding procedure for use in studies examining mechanisms, expression, and treatment of pain-related functional impairment.

Retrospective evaluation of hyperproteinorrachia without pleocytosis (albuminocytologic dissociation) and survival in dogs.

BACKGROUND: Hyperproteinorrachia (raised cerebrospinal fluid total protein [CSF-TP]) without pleocytosis (HP) (also known as albuminocytologic dissociation) is identified in dogs with different neurologic diseases. However, the association between survival and increased CSF-TP is unknown. OBJECTIVES: (a) Identify conditions commonly associated with HP in dogs and (b) investigate whether higher CSF-TP concentrations or other relevant factors are associated with 1-year survival. METHODS: This is a retrospective study that identified dogs with HP (Cisternal CSF-TP >0.30 g/L, Lumbar CSF-TP >0.45 g/L with total nucleated cell concentrations [TNCCs] and RBC counts within RIs) from 2008 to 2019: recording signalment, weight, vital parameters, inflammation, neuroanatomic localization, CSF-TP, sampling site, final diagnosis, etiologic classification, and 1-year survival. Corrected CSF-TP was calculated as CSF-TP minus 0.3 (cisternal) or 0.45 (lumbar or unknown). Descriptive statistics were produced, CSF-TP differences between groups (eg, neuroanatomic localizations) were evaluated using the Mann-Whitney U test or Kruskal-Wallis test (post-hoc testing). The Cox proportional hazards model was used for survival data. Statistical significance was set at a P < 0.05. RESULTS: In all, 39 dogs had HP, associated with 17 conditions, including neoplasia (n = 6), meningoencephalitis of unknown origin (n = 4) (MUO), and intervertebral disc disease (n = 4) (IVDD) as the most common conditions. There was no significant difference between the CSF-TP/corrected CSF-TP between 1-year survivors and non-survivors, nor was there a difference between different neuroanatomic localizations or etiologic classifications (P > 0.05). Neoplasia, after adjustment for age, was the only variable associated with a worse survival (P = 0.01 HR: 2.08 (95% CI: 1.65-39.2). CSF-TP was not associated with age (P > 0.05). CONCLUSIONS: HP in dogs is associated with a wide range of conditions; the most common conditions are neoplasia, MUO, and IVDD. Higher CSF-TP levels do not correlate with a worse 1-year survival; however, they do correlate with neoplastic lesions.

Predicting survival in malignant pleural mesothelioma using routine clinical and laboratory characteristics.

INTRODUCTION: The prognosis of malignant pleural mesothelioma (MPM) is poor, with a median survival of 8-12 months. The ability to predict prognosis in MPM would help clinicians to make informed decisions regarding treatment and identify appropriate research opportunities for patients. The aims of this study were to examine associations between clinical and pathological information gathered during routine care, and prognosis of patients with MPM, and to develop a 6-month mortality risk prediction model. METHODS: A retrospective cohort study of patients diagnosed with MPM at Queen Alexandra Hospital, Portsmouth, UK between December 2009 and September 2013. Multivariate analysis was performed on routinely available histological, clinical and laboratory data to assess the association between different factors and 6-month survival, with significant associations used to create a model to predict the risk of death within 6 months of diagnosis with MPM. RESULTS: 100 patients were included in the analysis. Variables significantly associated with patient survival in multivariate analysis were age (HR 1.31, 95% CI 1.09 to 1.56), smoking status (current smoker HR 3.42, 95% CI 1.11 to 4.20), chest pain (HR 2.14, 95% CI 1.23 to 3.72), weight loss (HR 2.13, 95% CI 1.18 to 3.72), platelet count (HR 1.05, 95% CI 1.00 to 1.10), urea (HR 2.73, 95% CI 1.31 to 5.69) and adjusted calcium (HR 1.47, 95% CI 1.10 to 1.94). The resulting risk model had a c-statistic value of 0.76. A Hosmer-Lemeshow test confirmed good calibration of the model against the original dataset. CONCLUSION: Risk of death at 6 months in patients with a confirmed diagnosis of MPM can be predicted using variables readily available in clinical practice. The risk prediction model we have developed may be used to influence treatment decisions in patients with MPM. Further validation of the model requires evaluation of its performance on a separate dataset.

Values of cancer survivors and the supportive role of recreational video games.

Value-affirming activities have been linked to positive health outcomes and improved ability to cope. For cancer survivors who regularly play video games, might the games have potential to affirm values? We surveyed gameplaying survivors and included an open-ended question asking about values and the extent to which they perceived gameplaying as supporting values. A content analysis of responses (N = 533) using Schwartz's value typology revealed that a majority perceived gameplaying as supporting values or offering other benefits. Self-transcendence followed by openness to change were the most frequently coded higher-order categories. The results contribute to a richer understanding of survivors who gameplay.

Duration of American Football Play and Chronic Traumatic Encephalopathy.

OBJECTIVE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose-response relationship between duration of football played and CTE risk and severity. METHODS: In a convenience sample of 266 deceased American football players from the Veterans Affairs-Boston University-Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias. RESULTS: In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19-1.41; p = 3.8 × 10-9 ) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07-1.22; p = 3.1 × 10-4 ). Participants with CTE were 1/10th as likely to have played <4.5 years (negative likelihood ratio [LR] = 0.102, 95% CI = 0.100-0.105) and were 10 times as likely to have played >14.5 years (positive LR = 10.2, 95% CI = 9.8-10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios. INTERPRETATION: The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116-131.

Clinical audit research and evaluation of motor neuron disease (CARE-MND): a national electronic platform for prospective, longitudinal monitoring of MND in Scotland.

Objectives: Launched in 1989, the Scottish Motor Neuron Disease Register (SMNDR) has provided a resource for prospective clinical data collection. However, in 2015 we aimed to evolve a system to allow: i) A patient-centered approach to care based on recognized standards, ii) Harmonized data sharing between Scottish health professionals in "real-time", iii) Regular audit of care to facilitate timely improvements in service delivery, and iv) Patient participation in a diverse range of observational and interventional research studies including clinical trials. Methods: We developed a standardized national electronic data platform-Clinical Audit Research and Evaluation of MND (CARE-MND) which integrates clinical audit and research data fields. Data completion pre- and post-CARE-MND were compared, guided by recently published National Institute for Clinical Excellence (NICE) recommendations. Statistical difference in data capture between time periods was assessed using Z-test of proportions. Results: Data field completion for the historical 2011-2014 period ranged from 4 to 95%; median 50%. CARE-MND capture ranged from 32 to 98%; median 87%. 15/17 fields were significantly more complete post-CARE-MND (p < 0.001). All MND nurse/allied health specialists in Scotland use the CARE-MND platform. Management of MND in Scotland is now coordinated through a standardized template. Conclusions: Through CARE-MND, national audits of MND care and interventions have been possible, leading to protocols for harmonized service provision. Stratification of the MND population is facilitating participation in observational and interventional studies. CARE-MND can act as a template for other neurological disorders.

The impact of anxiety on chronic musculoskeletal pain and the role of astrocyte activation.

Anxiety and depression are associated with increased pain responses in chronic pain states. The extent to which anxiety drives chronic pain, or vice versa, remains an important question that has implications for analgesic treatment strategies. Here, the effect of existing anxiety on future osteoarthritis (OA) pain was investigated, and potential mechanisms were studied in an animal model. Pressure pain detection thresholds, anxiety, and depression were assessed in people with (n = 130) or without (n = 100) painful knee OA. Separately, knee pain and anxiety scores were also measured twice over 12 months in 4730 individuals recruited from the general population. A preclinical investigation of a model of OA pain in normo-anxiety Sprague-Dawley (SD) and high-anxiety Wistar Kyoto (WKY) rats assessed underlying neurobiological mechanisms. Higher anxiety, independently from depression, was associated with significantly lower pressure pain detection thresholds at sites local to (P < 0.01) and distant from (P < 0.05) the painful knee in patients with OA. Separately, high anxiety scores predicted increased risk of knee pain onset in 3274 originally pain-free people over the 1-year period (odds ratio = 1.71; 95% confidence interval = 1.25-2.34, P < 0.00083). Similarly, WKY rats developed significantly lower ipsilateral and contralateral hind paw withdrawal thresholds in the monosodium iodoacetate model of OA pain, compared with SD rats (P = 0.0005). Linear regressions revealed that baseline anxiety-like behaviour was predictive of lowered paw withdrawal thresholds in WKY rats, mirroring the human data. This augmented pain phenotype was significantly associated with increased glial fibrillary acidic protein immunofluorescence in pain-associated brain regions, identifying supraspinal astrocyte activation as a significant mechanism underlying anxiety-augmented pain behaviour.

Early specialist palliative care on quality of life for malignant pleural mesothelioma: a randomised controlled trial.

PURPOSE: Malignant pleural mesothelioma (MPM) has a high symptom burden and poor survival. Evidence from other cancer types suggests some benefit in health-related quality of life (HRQoL) with early specialist palliative care (SPC) integrated with oncological services, but the certainty of evidence is low. METHODS: We performed a multicentre, randomised, parallel group controlled trial comparing early referral to SPC versus standard care across 19 hospital sites in the UK and one large site in Western Australia. Participants had newly diagnosed MPM; main carers were additionally recruited. INTERVENTION: review by SPC within 3 weeks of allocation and every 4 weeks throughout the study. HRQoL was assessed at baseline and every 4 weeks with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30. PRIMARY OUTCOME: change in EORTC C30 Global Health Status 12 weeks after randomisation. RESULTS: Between April 2014 and October 2016, 174 participants were randomised. There was no significant between group difference in HRQoL score at 12 weeks (mean difference 1.8 (95% CI -4.9 to 8.5; p=0.59)). HRQoL did not differ at 24 weeks (mean difference -2.0 (95% CI -8.6 to 4.6; p=0.54)). There was no difference in depression/anxiety scores at 12 weeks or 24 weeks. In carers, there was no difference in HRQoL or mood at 12 weeks or 24 weeks, although there was a consistent preference for care, favouring the intervention arm. CONCLUSION: There is no role for routine referral to SPC soon after diagnosis of MPM for patients who are cared for in centres with good access to SPC when required. TRIAL REGISTRATION NUMBER: ISRCTN18955704.

Risk-based inspection as a cost-effective strategy to reduce human exposure to cysticerci of Taenia saginata in low-prevalence settings.

BACKGROUND: Taenia saginata cysticercus is the larval stage of the zoonotic parasite Taenia saginata, with a life-cycle involving both cattle and humans. The public health impact is considered low. The current surveillance system, based on post-mortem inspection of carcasses has low sensitivity and leads to considerable economic burden. Therefore, in the interests of public health and food production efficiency, this study aims to explore the potential of risk-based and cost-effective meat inspection activities for the detection and control of T. saginata cysticercus in low prevalence settings. METHODS: Building on the findings of a study on risk factors for T. saginata cysticercus infection in cattle in Great Britain, we simulated scenarios using a stochastic scenario tree model, where animals are allocated to different risk categories based on their age, sex and movement history. These animals underwent different types of meat inspection (alternative or current) depending on their risk category. Expert elicitation was conducted to assess feasibility of scenarios and provide data for economic analysis. The cost-effectiveness of these scenarios was calculated as an incremental cost-effectiveness ratio, using the number of infected carcasses detected as the technical outcome. RESULTS: Targeting the high-risk population with more incisions into the heart while abandoning incisions into the masseter muscles was found to reduce the total number of inspections and cost, while simultaneously increasing the number of infected carcasses found. CONCLUSIONS: The results suggest that, under reasonable assumptions regarding potential improvements to current inspection methods, a more efficient and sensitive meat inspection system could be used on animals categorised according to their risk of harbouring T. saginata cysticercus at slaughter. Such a system could reduce associated cost to the beef industry and lower microbial contamination of beef products, improving public health outcomes.

Traits associated with central pain augmentation in the Knee Pain In the Community (KPIC) cohort.

This study aimed to identify self-report correlates of central pain augmentation in individuals with knee pain. A subset of participants (n = 420) in the Knee Pain and related health In the Community (KPIC) baseline survey undertook pressure pain detection threshold (PPT) assessments. Items measuring specific traits related to central pain mechanisms were selected from the survey based on expert consensus, face validity, item association with underlying constructs measured by originating host questionnaires, adequate targeting, and PPT correlations. Pain distribution was reported on a body manikin. A "central pain mechanisms" factor was sought by factor analysis. Associations of items, the derived factor, and originating questionnaires with PPTs were compared. Eight self-report items measuring traits of anxiety, depression, catastrophizing, neuropathic-like pain, fatigue, sleep disturbance, pain distribution, and cognitive impact were identified as likely indices of central pain mechanisms. Pressure pain detection thresholds were associated with items representing each trait and with their originating scales. Pain distribution classified as "pain below the waist additional to knee pain" was more strongly associated with low PPT than were alternative classifications of pain distribution. A single factor, interpreted as "central pain mechanisms," was identified across the 8 selected items and explained variation in PPT (R = 0.17) better than did any originating scale (R = 0.10-0.13). In conclusion, including representative items within a composite self-report tool might help identify people with centrally augmented knee pain.

An O-Antigen Glycoconjugate Vaccine Produced Using Protein Glycan Coupling Technology Is Protective in an Inhalational Rat Model of Tularemia.

There is a requirement for an efficacious vaccine to protect people against infection from Francisella tularensis, the etiological agent of tularemia. The lipopolysaccharide (LPS) of F. tularensis is suboptimally protective against a parenteral lethal challenge in mice. To develop a more efficacious subunit vaccine, we have used a novel biosynthetic technique of protein glycan coupling technology (PGCT) that exploits bacterial N-linked glycosylation to recombinantly conjugate F. tularensis O-antigen glycans to the immunogenic carrier protein Pseudomonas aeruginosa exoprotein A (ExoA). Previously, we demonstrated that an ExoA glycoconjugate with two glycosylation sequons was capable of providing significant protection to mice against a challenge with a low-virulence strain of F. tularensis. Here, we have generated a more heavily glycosylated conjugate vaccine and evaluated its efficacy in a Fischer 344 rat model of tularemia. We demonstrate that this glycoconjugate vaccine protected rats against disease and the lethality of an inhalational challenge with F. tularensis Schu S4. Our data highlights the potential of this biosynthetic approach for the creation of next-generation tularemia subunit vaccines.

A simulation approach to assessing environmental risk of sound exposure to marine mammals.

Intense underwater sounds caused by military sonar, seismic surveys, and pile driving can harm acoustically sensitive marine mammals. Many jurisdictions require such activities to undergo marine mammal impact assessments to guide mitigation. However, the ability to assess impacts in a rigorous, quantitative way is hindered by large knowledge gaps concerning hearing ability, sensitivity, and behavioral responses to noise exposure. We describe a simulation-based framework, called SAFESIMM (Statistical Algorithms For Estimating the Sonar Influence on Marine Megafauna), that can be used to calculate the numbers of agents (animals) likely to be affected by intense underwater sounds. We illustrate the simulation framework using two species that are likely to be affected by marine renewable energy developments in UK waters: gray seal (Halichoerus grypus) and harbor porpoise (Phocoena phocoena). We investigate three sources of uncertainty: How sound energy is perceived by agents with differing hearing abilities; how agents move in response to noise (i.e., the strength and directionality of their evasive movements); and the way in which these responses may interact with longer term constraints on agent movement. The estimate of received sound exposure level (SEL) is influenced most strongly by the weighting function used to account for the specie's presumed hearing ability. Strongly directional movement away from the sound source can cause modest reductions (~5 dB) in SEL over the short term (periods of less than 10 days). Beyond 10 days, the way in which agents respond to noise exposure has little or no effect on SEL, unless their movements are constrained by natural boundaries. Most experimental studies of noise impacts have been short-term. However, data are needed on long-term effects because uncertainty about predicted SELs accumulates over time. Synthesis and applications. Simulation frameworks offer a powerful way to explore, understand, and estimate effects of cumulative sound exposure on marine mammals and to quantify associated levels of uncertainty. However, they can often require subjective decisions that have important consequences for management recommendations, and the basis for these decisions must be clearly described.

Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei.

The bacteria Burkholderia pseudomallei and Legionella pneumophila cause severe diseases like melioidosis and Legionnaire's disease with high mortality rates despite antibiotic treatment. Due to increasing antibiotic resistances against these and other Gram-negative bacteria, alternative therapeutical strategies are in urgent demand. As a virulence factor, the macrophage infectivity potentiator (Mip) protein constitutes an attractive target. The Mip proteins of B. pseudomallei and L. pneumophila exhibit peptidyl-prolyl cis/trans isomerase (PPIase) activity and belong to the PPIase superfamily. In previous studies, the pipecolic acid moiety proved to be a valuable scaffold for inhibiting this PPIase activity. Thus, a library of pipecolic acid derivatives was established guided by structural information and computational analyses of the binding site and possible binding modes. Stability and toxicity considerations were taken into account in iterative extensions of the library. Synthesis and evaluation of the compounds in PPIase assays resulted in highly active inhibitors. The activities can be interpreted in terms of a common binding mode obtained by docking calculations.

Cancer Survivors Who Play Recreational Computer Games: Motivations for Playing and Associations with Beneficial Psychological Outcomes.

OBJECTIVE: Playing recreational videogames is a common activity, yet little is known about its role in the lives of people who are coping with serious illness. These individuals may experience depression and isolation and may turn to games to help alleviate negative experiences and support well-being. We explored these possibilities in the context of cancer survivors. The study aimed to discover motivations underlying game play and the extent to which motivations are associated with psychological health and well-being. METHODS: We conducted a cross-sectional online survey of survivors who play recreational games (N = 794). Key variables were motivations and indicators of psychological health, including self-efficacy in cancer communications, resilient coping, and beliefs that one is living a fulfilling and meaningful life (flourishing). RESULTS: Participants were most likely to be motivated to play for stimulation and a sense of accomplishment (intrinsic rewards), followed by development of self, sense of community, and personal affirmation. Multiple regression analyses revealed positive associations between playing for intrinsic rewards and all three psychological health outcomes. Playing for a sense of community was also positively associated with coping and flourishing. CONCLUSION: Playing recreational videogames, particularly to receive intrinsic rewards and to connect with others, may play a supportive role in the psychological health of survivors. Findings suggest future areas for research and implications for development of serious games.

How Does Gameplaying Support Values and Psychological Well-Being Among Cancer Survivors?

OBJECTIVE: This qualitative study examined the extent to which playing recreational computer games and videogames is perceived by cancer survivors as supporting personal values. Values serve as behavioral guides and may thus impact health outcomes; therefore activities that have the potential to support values deserve further attention so their role in promoting health may be better understood. MATERIALS AND METHODS: We asked a sample of survivors who play recreational games (n = 73) open-ended questions about the types of recreational games they play, about something they really value in life, and the extent to which playing games supports the value. Data analysis used a grounded theory approach, supported by computer-assisted qualitative analysis software. RESULTS: Three major themes emerged linking gameplaying to survivors' values: the need to create and maintain social connections, the desire to help others, and the need to experience alternate realities (including escape and exploration). CONCLUSIONS: The present study offers a unique perspective by focusing on the intersection of values and gameplay among survivors. The findings suggest that playing recreational computer games and videogames may be congruent with survivors' personal values and may have potential to influence positive health outcomes among survivors. The findings have implications for developing effective values-based interventions for cancer survivors.

Perils and pitfalls for clinicians embarking on qualitative research in physiotherapy.

AIM: To consider the pros and cons of focus groups versus interviews for studies interested in examining patient experiences of clinical interventions. The paper looks at the hazards of being a clinician when collecting qualitative data and shares these experiences to provide useful learning for other clinicians embarking on qualitative approaches. BACKGROUND: Sub-acromial decompression surgery (SAD) is the accepted, surgical intervention for shoulder impingement syndrome. Evidence suggests that outcomes from SAD are no more superior to conservative management. This raises questions as to whether alternative explanations such as patient experience are at play when considering patient outcomes. DATA SOURCES: A study looking at patients' experiences of subacromial decompression surgery six months after the operation. REVIEW METHODS: One small focus group and one individual interview took place to explore patient experience following sub-acromial decompression shoulder surgery. DISCUSSION: Focus groups risk producing competitive and comparative discussions, and clinical researchers require sufficient training and mentoring to recognise and assist group dynamics. The study exposed ways in which clinicians involved in collecting data may be injured to aspects of patients' experiences, and accordingly may not explore in depth aspects important to patients. CONCLUSION: This paper highlights the importance of novice researchers thinking carefully about the capacity for 'practitioner eyes' to influence analytical decisions about study design and the direction of data collection. Focus group interactions are complex and risk being underestimated by inexperienced clinical researchers. IMPLICATIONS FOR RESEARCH/PRACTICE: Novice researchers are advised to be open to the possibility that unpredictable situations are likely to occur and expose assumptions about the study design. Preparation and guidance is required to avoid some of the challenges and manage group dynamics effectively in the first instance.