Contributions of Human Prefrontal Cortex to the Recogitation of Thought

Human beings have a unique ability to not only verbally articulate past and present experiences, as well as potential future ones, but also evaluate the mental representations of such things. Some evaluations do little good, in that they poorly reflect facts, create needless emotional distress, and contribute to the obstruction of personal goals, whereas some evaluations are the converse: They are grounded in logic, empiricism, and pragmatism and, therefore, are functional rather than dysfunctional. The aim of non-pharmacological mental health interventions is to revise dysfunctional thoughts into more adaptive, healthier ones; however, the neurocognitive mechanisms driving cognitive change have hitherto remained unclear. Therefore, this thesis examines the role of the prefrontal cortex (PFC) in this aspect of human higher cognition using the relatively new method of functional near-infrared spectroscopy (fNIRS). Chapter 1 advances recogitation as the mental ability on which cognitive restructuring largely depends, concluding that, as a cognitive task, it is a form of open-ended human problem-solving that uses metacognitive and reasoning faculties. Because these faculties share similar executive resources, Chapter 2 discusses the systems in the brain involved in controlled information processing, specifically the nature of executive functions and their neural bases. Chapter 3 builds on these ideas to propose an information-processing model of recogitation, which predicts the roles of different subsystems localized within the PFC and elsewhere in the context of emotion regulation. This chapter also highlights several theoretical and empirical challenges to investigating this neurocognitive theory and proposes some solutions, such as to use experimental designs that are more ecologically valid. Chapter 4 focuses on a neuroimaging method that is best suited to investigating questions of spatial localization in ecological experiments, namely functional near-infrared spectroscopy (fNIRS). Chapter 5 then demonstrates a novel approach to investigating the neural bases of interpersonal interactions in clinical settings using fNIRS. Chapter 6 explores physical activity as a ‘bottom-up’ approach to upregulating the PFC, in that it might help clinical populations with executive deficits to regulate their mental health from the ‘top-down’. Chapter 7 addresses some of the methodological issues of investigating clinical interactions and physical activity in more naturalistic settings by assessing an approach to recovering functional events from observed brain data. Chapter 8 draws several conclusions about the role of the PFC in improving psychological as well as physiological well-being, particularly that rostral PFC is inextricably involved in the cognitive effort to modulate dysfunctional thoughts, and proposes some important future directions for ecological research in cognitive neuroscience; for example, psychotherapy is perhaps too physically stagnant, so integrating exercise into treatment environments might boost the effectiveness of intervention strategies

Cavitation in shock wave lithotripsy: the critical role of bubble activity in stone breakage and kidney trauma

Objective: Shock Wave Lithotripsy (SWL) is the use of shock waves to fragment kidney stones. We have undertaken a study of the physical mechanisms responsible for stone comminution and tissue injury in SWL. SWL was originally developed on the premise that stone fragmentation could be induced by a short duration, high amplitude positive pressure pulse. Even though the SWL waveform carries a prominent tensile component, it has long been thought that SW damage to stones could be explained entirely on the basis of mechanisms such as spallation, pressure gradients, and compressive fracture. We contend that not only is cavitation also involved in SWL, bubble activity plays a critical role in stone breakage and is a key mechanism in tissue damage. Methods: Our evidence is based upon a series of experiments in which we have suppressed or minimized cavitation, and discovered that both stone comminution and tissue injury is similarly suppressed or minimized. Some examples of these experiments are (1) application of overpressure, (2) time reversal of acoustic waveform, (3) acoustically-transparent, cavitation-absorbing films, and (4) dual pulses. In addition, using passive and active ultrasound, we have observed the existence of cavitation, in vivo, and at the site of tissue injury. Results: Numerical and experimental results showed mitigation of bubble collapse intensity by time-reversing the lithotripsy pulse and in vivo treatment showed a corresponding drop from 6.1% ± 1.7% to 0.0% in the hemorrhagic lesion. The time-reversed wave did not break stones. Stone comminution and hemolysis were reduced to levels very near sham levels with the application of hydrostatic pressure greater than the near 10-MPa amplitude of the negative pressure of the lithotripter shock wave. A Mylar sheet 3-mm from the stone surface did not inhibit erosion and internal cracking, but a sheet in contact with the stone did. In water, mass lost from stones in a dual pulse lithotripter is 8 times greater than with a single lithotripter, but in glycerol, which reduces the pressures generated in bubble implosion, the enhancement is lost. Conclusion: This cavitation-inclusive mechanistic understanding of SWL is gaining acceptance and has had clinical impact. Treatment at slower SW rate gives cavitation bubble clusters time to dissolve between pulses and increases comminution. Some SWL centers now treat patients at slower SW rate to take advantage of this effect. An elegant cavitation-aware strategy to reduce renal trauma in SWL is being tested in experimental animals. Starting treatment at low amplitude causes vessels to constrict and this interferes with cavitation-mediated vascular injury. Acceptance of the role of cavitation in SWL is beginning to be embraced by the lithotripter industry, as new dual-pulse lithotripters—based on the concept of cavitation control— have now been introduced

Avian oncogenesis induced by lymphoproliferative disease virus: a neglected or emerging retroviral pathogen?

Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we describe the widespread distribution, genetic diversity, pathogenesis, and evolution of LPDV in the United States. Characterization of the provirus genome of the index LPDV case from North America demonstrated an 88% nucleotide identity to the Israeli prototype strain. Although phylogenetic analysis indicated that the majority of viruses fell into a single North American lineage, a small subset of viruses from South Carolina were most closely related to the Israeli prototype. These results suggest that LPDV was transferred between continents to initiate outbreaks of disease. However, the direction (New World to Old World or vice versa), mechanism, and time frame of the transcontinental spread currently remain unknown

Understanding variation in ambulance service non-conveyance rates: a mixed methods study

Background In England in 2015/16, ambulance services responded to nearly 11 million calls. Ambulance Quality Indicators show that half of the patients receiving a response by telephone or face to face were not conveyed to an emergency department. A total of 11% of patients received telephone advice only. A total of 38% of patients were sent an ambulance but were not conveyed to an emergency department. For the 10 large ambulance services in England, rates of calls ending in telephone advice varied between 5% and 17%. Rates of patients who were sent an ambulance but not conveyed to an emergency department varied between 23% and 51%. Overall non-conveyance rates varied between 40% and 68%. Objective To explain variation in non-conveyance rates between ambulance services. Design A sequential mixed methods study with five work packages. Setting Ten of the 11 ambulance services serving > 99% of the population of England. Methods (1) A qualitative interview study of managers and paramedics from each ambulance service, as well as ambulance commissioners (totalling 49 interviews undertaken in 2015). (2) An analysis of 1 month of routine data from each ambulance service (November 2014). (3) A qualitative study in three ambulance services with different published rates of calls ending in telephone advice (120 hours of observation and 20 interviews undertaken in 2016). (4) An analysis of routine data from one ambulance service linked to emergency department attendance, hospital admission and mortality data (6 months of 2013). (5) A substudy of non-conveyance for people calling 999 with breathing problems. Results Interviewees in the qualitative study identified factors that they perceived to affect non-conveyance rates. Where possible, these perceptions were tested using routine data. Some variation in non-conveyance rates between ambulance services was likely to be due to differences in the way rates were calculated by individual services, particularly in relation to telephone advice. Rates for the number of patients sent an ambulance but not conveyed to an emergency department were associated with patient-level factors: age, sex, deprivation, time of call, reason for call, urgency level and skill level of attending crew. However, variation between ambulance services remained after adjustment for patient-level factors. Variation was explained by ambulance service-level factors after adjustment for patient-level factors: the percentage of calls attended by advanced paramedics [odds ratio 1.05, 95% confidence interval (CI) 1.04 to 1.07], the perception of ambulance service staff and commissioners that advanced paramedics were established and valued within the workforce of an ambulance service (odds ratio 1.84, 95% CI 1.45 to 2.33), and the perception of ambulance service staff and commissioners that senior management was risk averse regarding non-conveyance within an ambulance service (odds ratio 0.78, 95% CI 0.63 to 0.98). Limitations Routine data from ambulance services are complex and not consistently collected or analysed by ambulance services, thus limiting the utility of comparative analyses. Conclusions Variation in non-conveyance rates between ambulance services in England could be reduced by addressing variation in the types of paramedics attending calls, variation in how advanced paramedics are used and variation in perceptions of the risk associated with non-conveyance within ambulance service management. Linking routine ambulance data with emergency department attendance, hospital admission and mortality data for all ambulance services in the UK would allow comparison of the safety and appropriateness of their different non-conveyance rates. Funding The National Institute for Health Research Health Services and Delivery Research programme

Cavitation in shock wave lithotripsy: the critical role of bubble activity in stone breakage and kidney trauma

Objective: Shock Wave Lithotripsy (SWL) is the use of shock waves to fragment kidney stones. We have undertaken a study of the physical mechanisms responsible for stone comminution and tissue injury in SWL. SWL was originally developed on the premise that stone fragmentation could be induced by a short duration, high amplitude positive pressure pulse. Even though the SWL waveform carries a prominent tensile component, it has long been thought that SW damage to stones could be explained entirely on the basis of mechanisms such as spallation, pressure gradients, and compressive fracture. We contend that not only is cavitation also involved in SWL, bubble activity plays a critical role in stone breakage and is a key mechanism in tissue damage. Methods: Our evidence is based upon a series of experiments in which we have suppressed or minimized cavitation, and discovered that both stone comminution and tissue injury is similarly suppressed or minimized. Some examples of these experiments are (1) application of overpressure, (2) time reversal of acoustic waveform, (3) acoustically-transparent, cavitation-absorbing films, and (4) dual pulses. In addition, using passive and active ultrasound, we have observed the existence of cavitation, in vivo, and at the site of tissue injury. Results: Numerical and experimental results showed mitigation of bubble collapse intensity by time-reversing the lithotripsy pulse and in vivo treatment showed a corresponding drop from 6.1% ± 1.7% to 0.0% in the hemorrhagic lesion. The time-reversed wave did not break stones. Stone comminution and hemolysis were reduced to levels very near sham levels with the application of hydrostatic pressure greater than the near 10-MPa amplitude of the negative pressure of the lithotripter shock wave. A Mylar sheet 3-mm from the stone surface did not inhibit erosion and internal cracking, but a sheet in contact with the stone did. In water, mass lost from stones in a dual pulse lithotripter is 8 times greater than with a single lithotripter, but in glycerol, which reduces the pressures generated in bubble implosion, the enhancement is lost. Conclusion: This cavitation-inclusive mechanistic understanding of SWL is gaining acceptance and has had clinical impact. Treatment at slower SW rate gives cavitation bubble clusters time to dissolve between pulses and increases comminution. Some SWL centers now treat patients at slower SW rate to take advantage of this effect. An elegant cavitation-aware strategy to reduce renal trauma in SWL is being tested in experimental animals. Starting treatment at low amplitude causes vessels to constrict and this interferes with cavitation-mediated vascular injury. Acceptance of the role of cavitation in SWL is beginning to be embraced by the lithotripter industry, as new dual-pulse lithotripters—based on the concept of cavitation control— have now been introduced

A point mutation in cpsE renders Streptococcus pneumoniae nonencapsulated and enhances its growth, adherence and competence.

BACKGROUND: The polysaccharide capsule is a major virulence factor of the important human pathogen Streptococcus pneumoniae. However, S. pneumoniae strains lacking capsule do occur. RESULTS: Here, we report a nasopharyngeal isolate of Streptococcus pneumoniae composed of a mixture of two phenotypes; one encapsulated (serotype 18C) and the other nonencapsulated, determined by serotyping, electron microscopy and fluorescence isothiocyanate dextran exclusion assay.By whole genome sequencing, we demonstrated that the phenotypes differ by a single nucleotide base pair in capsular gene cpsE (C to G change at gene position 1135) predicted to result in amino acid change from arginine to glycine at position 379, located in the cytoplasmic, enzymatically active, region of this transmembrane protein. This SNP is responsible for loss of capsule production as the phenotype is transferred with the capsule operon. The nonencapsulated variant is superior in growth in vitro and is also 117-fold more adherent to and more invasive into Detroit 562 human epithelial cells than the encapsulated variant.Expression of six competence pathway genes and one competence-associated gene was 11 to 34-fold higher in the nonencapsulated variant than the encapsulated and transformation frequency was 3.7-fold greater. CONCLUSIONS: We identified a new single point mutation in capsule gene cpsE of a clinical S. pneumoniae serotype 18C isolate sufficient to cause loss of capsule expression resulting in the co-existence of the encapsulated and nonencapsulated phenotype. The mutation caused phenotypic changes in growth, adherence to epithelial cells and transformability. Mutation in capsule gene cpsE may be a way for S. pneumoniae to lose its capsule and increase its colonization potential

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.

Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits

Association between the 2008–09 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring–Summer 2009: Four Observational Studies from Canada

In three case-control studies and a household transmission cohort, Danuta Skowronski and colleagues find an association between prior seasonal flu vaccination and increased risk of 2009 pandemic H1N1 flu

A synthesis of evidence for policy from behavioural science during COVID-19

Scientific evidence regularly guides policy decisions1, with behavioural science increasingly part of this process2. In April 2020, an influential paper3 proposed 19 policy recommendations (‘claims’) detailing how evidence from behavioural science could contribute to efforts to reduce impacts and end the COVID-19 pandemic. Here we assess 747 pandemic-related research articles that empirically investigated those claims. We report the scale of evidence and whether evidence supports them to indicate applicability for policymaking. Two independent teams, involving 72 reviewers, found evidence for 18 of 19 claims, with both teams finding evidence supporting 16 (89%) of those 18 claims. The strongest evidence supported claims that anticipated culture, polarization and misinformation would be associated with policy effectiveness. Claims suggesting trusted leaders and positive social norms increased adherence to behavioural interventions also had strong empirical support, as did appealing to social consensus or bipartisan agreement. Targeted language in messaging yielded mixed effects and there were no effects for highlighting individual benefits or protecting others. No available evidence existed to assess any distinct differences in effects between using the terms ‘physical distancing’ and ‘social distancing’. Analysis of 463 papers containing data showed generally large samples; 418 involved human participants with a mean of 16,848 (median of 1,699). That statistical power underscored improved suitability of behavioural science research for informing policy decisions. Furthermore, by implementing a standardized approach to evidence selection and synthesis, we amplify broader implications for advancing scientific evidence in policy formulation and prioritization

A synthesis of evidence for policy from behavioural science during COVID-19

Scientific evidence regularly guides policy decisions 1, with behavioural science increasingly part of this process 2. In April 2020, an influential paper 3 proposed 19 policy recommendations (‘claims’) detailing how evidence from behavioural science could contribute to efforts to reduce impacts and end the COVID-19 pandemic. Here we assess 747 pandemic-related research articles that empirically investigated those claims. We report the scale of evidence and whether evidence supports them to indicate applicability for policymaking. Two independent teams, involving 72 reviewers, found evidence for 18 of 19 claims, with both teams finding evidence supporting 16 (89%) of those 18 claims. The strongest evidence supported claims that anticipated culture, polarization and misinformation would be associated with policy effectiveness. Claims suggesting trusted leaders and positive social norms increased adherence to behavioural interventions also had strong empirical support, as did appealing to social consensus or bipartisan agreement. Targeted language in messaging yielded mixed effects and there were no effects for highlighting individual benefits or protecting others. No available evidence existed to assess any distinct differences in effects between using the terms ‘physical distancing’ and ‘social distancing’. Analysis of 463 papers containing data showed generally large samples; 418 involved human participants with a mean of 16,848 (median of 1,699). That statistical power underscored improved suitability of behavioural science research for informing policy decisions. Furthermore, by implementing a standardized approach to evidence selection and synthesis, we amplify broader implications for advancing scientific evidence in policy formulation and prioritization