Real-world implications of aphantasia: episodic recall of eyewitnesses with aphantasia is less complete but no less accurate than typical imagers.

Individuals with aphantasia report an inability to voluntarily visually image and reduced episodic memory, yet episodic accounts provided by witnesses and victims are fundamental for criminal justice. Using the mock-witness paradigm, we investigated eyewitness memory of individuals with aphantasia versus typical imagers. Participants viewed a mock crime and 48 hours later were interviewed about the event, randomly allocated to one of three conditions. Two interview conditions included techniques designed to support episodic retrieval mode, namely (i) Mental Reinstatement of Context (MRC) and (ii) Sketch Reinstatement of Context (Sketch-RC). A third Control condition did not include retrieval support. Aphantasic mock-eyewitnesses recalled 30% less correct information and accounts were less complete, but they made no more errors and were as accurate as typical imagers. Interaction effects revealed reduced correct recall and less complete accounts for aphantasic participants in MRC interviews versus Sketch-RC and Control. Aphantaisic participants in the Control outperformed those in both the Sketch-RC and MRC, although Sketch-RC improved completeness by 15% versus MRC. Our pattern of results indicates reduced mental imagery ability might be compensated for by alternative self-initiated cognitive strategies. Findings offer novel insights into episodic recall performance in information gathering interviews when ability to voluntarily visualize is impoverished.

Cross cultural verbal cues to deception: truth and lies in first and second language forensic interview contexts.

Introduction: The verbal deception literature is largely based upon North American and Western European monolingual English speaker interactions. This paper extends this literature by comparing the verbal behaviors of 88 south Asian bilinguals, conversing in either first (Hindi) or second (English) languages, and 48 British monolinguals conversing in English. Methods: All participated in a live event following which they were interviewed having been incentivized to be either deceptive or truthful. Event details, complications, verifiable sources, and plausibility ratings were analyzed as a function of veracity, language and culture. Results: Main effects revealed cross cultural similarities in both first and second language interviews whereby all liar's verbal responses were impoverished and rated as less plausible than truthtellers. However, a series of cross-cultural interactions emerged whereby bi-lingual South Asian truthtellers and liars interviewed in first and second languages exhibited varying patterns of verbal behaviors, differences that have the potential to trigger erroneous assessments in practice. Discussion: Despite limitations, including concerns centered on the reductionary nature of deception research, our results highlight that while cultural context is important, impoverished, simple verbal accounts should trigger a 'red flag' for further attention irrespective of culture or interview language, since the cognitive load typically associated with formulating a deceptive account apparently emerges in a broadly similar manner.

Parental experiences of the impact of grooming and criminal exploitation of children for county lines drug trafficking.

BACKGROUND: County lines is used to describe the illicit drug supply model whereby drugs are transported from one area of the country to another, often by children believed to have been physically and psychologically coerced to do so. County lines is a serious threat to public health, with significant negative impacts on the physical and psychological health and wellbeing of children and families. METHODS: We conducted in-depth interviews with parents of children involved in county lines to understand their experiences and the impact of grooming and recruitment. Interviews were conducted between December 2019 and January 2021. Thematic analysis identified four primary themes: (i) out of nowhere behaviour change, (ii) escalation and entrenchment, (iii) impact of intervention failures and (iv) destructive lifestyle choices. RESULTS: Parents from across England all reported similar experiences, and so these data offer novel insight into potential grooming and recruitment indicators. All were frustrated by the prevailing vulnerable narrative, which they argued hindered understanding. A lack of consultation, and reports of numerous intervention failures was common. CONCLUSION: The importance of giving parents a voice and involving them as a potential first line of defence, and how the current vulnerability narrative appears to be closing impactful education opportunities are discussed.

Selecting Portable Ankle/Toe Brachial Pressure Index Systems for a Peripheral Arterial Disease Population Screening Programme: a Systematic Review, Clinical Evaluation Exercise, and Consensus Process.

OBJECTIVE: To provide an overview of systems available for peripheral arterial disease (PAD) screening, together with respective accuracies and a clinical evaluation to identify a system suitable for use in a community screening programme. METHODS: A systematic review of the diagnostic accuracy of six ankle brachial pressure index (ABPI) and toe brachial pressure index (TBPI) devices deemed to be portable, which were Conformité Européenne (CE) marked, and were automated or semi-automated was carried out compared with gold standard handheld Doppler and duplex ultrasound. The devices were MESI-ABPI-MD, Huntleigh Dopplex Ability, Huntleigh ABPI and TBPI systems, Systoe TBPI system, and BlueDop. Seven databases (MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials (CENTRAL), and Cumulative Index to Nursing and Allied Health Literature (CINAHL)) were searched, and 11 studies were identified as eligible for review. This was followed by hands on clinical evaluation by abdominal aortic aneurysm (AAA) screening staff (n = 39). During this, devices were demonstrated to staff which they then tested on volunteers and gave feedback using pre-designed questionnaires on their suitability for use in a screening programme. Finally, accuracy data and staff preferences were combined during a consensus conference that was held between study and screening staff to determine the most appropriate device to use in a community screening programme. RESULTS: Generally, the evaluated systems have a moderate level of sensitivity and a high level of specificity: Dopplex ability sensitivity 20% - 70%, specificity 86% - 96%; MESI sensitivity 57% - 74%, specificity 85% - 99%; BlueDop sensitivity 95%, specificity 89%; and Systoe sensitivity 71%, specificity 77%. Clinical evaluation by screening staff identified a preference for the MESI system. The consensus conference concluded that the MESI device was a good candidate for use in a community PAD screening programme. CONCLUSION: The MESI system is a good candidate to consider for community PAD screening.

Effect of high-pain versus low-pain structured exercise on walking ability in people with intermittent claudication: meta-analysis.

BACKGROUND: The aim was to determine the comparative benefits of structured high-pain exercise, structured low-pain exercise, and usual-care control, to identify which has the largest effect on walking ability in people with intermittent claudication (IC). METHODS: A network meta-analysis was undertaken to assess two outcomes: pain-free walking ability (PFWA) and maximal walking ability (MWA). Nine electronic databases were searched. Trials were included if they were: RCTS; involved adults with IC; had at least two of the following arms-structured low-pain exercise, structured high--pain exercise or usual-care control; and a maximal or pain-free treadmill walking outcome. RESULTS: Some 14 trials were included; results were pooled using the standardized mean difference (MD). Structured low-pain exercise had a significant large positive effect on MWA (MD 2.23, 95 percent c.i. 1.11 to 3.35) and PFWA (MD 2.26, 1.26 to 3.26) compared with usual-care control. Structured high-pain exercise had a significant large positive effect on MWA (MD 0.95, 0.20 to 1.70) and a moderate positive effect on PFWA (0.77, 0.01 to 1.53) compared with usual-care control. In an analysis of structured low- versus high pain exercise, there was a large positive effect in favour of low-pain exercise on MWA (MD 1.28, -0.07 to 2.62) and PFWA (1.50, 0.24 to 2.75); however, this was significant only for PFWA. CONCLUSION: There is strong evidence in support of use of structured high-pain exercise, and some evidence in support of structured low-pain exercise, to improve walking ability in people with IC compared with usual-care control (unstructured exercise advice).

Sorting Insiders From Co-Workers: Remote Synchronous Computer-Mediated Triage for Investigating Insider Attacks.

OBJECTIVE: Develop and investigate the potential of a remote, computer-mediated and synchronous text-based triage, which we refer to as InSort, for quickly highlighting persons of interest after an insider attack. BACKGROUND: Insiders maliciously exploit legitimate access to impair the confidentiality and integrity of organizations. The globalisation of organisations and advancement of information technology means employees are often dispersed across national and international sites, working around the clock, often remotely. Hence, investigating insider attacks is challenging. However, the cognitive demands associated with masking insider activity offer opportunities. Drawing on cognitive approaches to deception and understanding of deception-conveying features in textual responses, we developed InSort, a remote computer-mediated triage. METHOD: During a 6-hour immersive simulation, participants worked in teams, examining password protected, security sensitive databases and exchanging information during an organized crime investigation. Twenty-five percent were covertly incentivized to act as an 'insider' by providing information to a provocateur. RESULTS: Responses to InSort questioning revealed insiders took longer to answer investigation relevant questions, provided impoverished responses, and their answers were less consistent with known evidence about their behaviours than co-workers. CONCLUSION: Findings demonstrate InSort has potential to expedite information gathering and investigative processes following an insider attack. APPLICATION: InSort is appropriate for application by non-specialist investigators and can be quickly altered as a function of both environment and event. InSort offers a clearly defined, well specified, approach for use across insider incidents, and highlights the potential of technology for supporting complex time critical investigations.

Molecular transduction in receptor-ligand systems by planar electromagnetic fields / Transdução molecular em sistemas receptor-ligante por campos electromagnéticos planares

The coupling of a ligand with a molecular receptor induces a signal that travels through the receptor, reaching the internal domain and triggering a response cascade. In previous work on T-cell receptors and their coupling with foreign antigens, we observed the presence of planar molecular patterns able to generate electromagnetic fields within the proteins. These planes showed a coherent (synchronized) behavior, replicating immediately in the intracellular domain that which occurred in the extracellular domain as the ligand was coupled. In the present study, we examined this molecular transduction - the capacity of the coupling signal to penetrate deep inside the receptor molecule and induce a response. We verified the presence of synchronized behavior in diverse receptorligand systems. To appreciate this diversity, we present four biochemically different systems - TCR-peptide, calcium pump-ADP, haemoglobin-oxygen, and gp120-CD4 viral coupling. The confirmation of synchronized molecular transduction in each of these systems suggests that the proposed mechanism would occur in all biochemical receptor-ligand systems.

A ligação de um ligante com um receptor molecular induz um sinal que viaja através do receptor, chegando ao domínio interno e disparando uma cascata de resposta. Em trabalhos anteriores em receptores de células T e sua ligação com antígenos estranhos, observamos a presença de padrões moleculares planares capazes de gerar campos eletromagnéticos dentro das proteínas. Esses planos mostraram um comportamento coerente (sincronizado), replicando, instantaneamente, no domínio intracelular o que ocorreu no domínio extracelular, enquanto o ligante era acoplado. No presente estudo, examinamos essa transdução ­ a capacidade de um sinal de acoplamento de penetrar profundamente a molécula receptora e induzir uma resposta. Verificamos a presença de um comportamento coerente em sistemas diversos de receptor-ligante. Para apreciar essa diversidade, apresentamos quatro sistemas bioquímicos diferentes: TCR-peptídeo, ADP-bomba de cálcio, hemoglobina-oxigênio e gp120-CD4 acoplamento viral. A confirmação de transdução molecular sincronizada em cada um desses sistemas sugere que o mecanismo proposto ocorreria em todos os sistemas bioquímicos receptor-ligante.

Molecular transduction in receptor-ligand systems by planar electromagnetic fields / Transdução molecular em sistemas receptor-ligante por campos electromagnéticos planares

The coupling of a ligand with a molecular receptor induces a signal that travels through the receptor, reaching the internal domain and triggering a response cascade. In previous work on T-cell receptors and their coupling with foreign antigens, we observed the presence of planar molecular patterns able to generate electromagnetic fields within the proteins. These planes showed a coherent (synchronized) behavior, replicating immediately in the intracellular domain that which occurred in the extracellular domain as the ligand was coupled. In the present study, we examined this molecular transduction - the capacity of the coupling signal to penetrate deep inside the receptor molecule and induce a response. We verified the presence of synchronized behavior in diverse receptor ligand systems. To appreciate this diversity, we present four biochemically different systems - TCR-peptide, calcium pump-ADP, haemoglobin-oxygen, and gp120-CD4 viral coupling. The confirmation of synchronized molecular transduction in each of these systems suggests that the proposed mechanism would occur in all biochemical receptor-ligand systems.

A ligação de um ligante com um receptor molecular induz um sinal que viaja através do receptor, chegando ao domínio interno e disparando uma cascata de resposta. Em trabalhos anteriores em receptores de células T e sua ligação com antígenos estranhos, observamos a presença de padrões moleculares planares capazes de gerar campos eletromagnéticos dentro das proteínas. Esses planos mostraram um comportamento coerente (sincronizado), replicando, instantaneamente, no domínio intracelular o que ocorreu no domínio extracelular, enquanto o ligante era acoplado. No presente estudo, examinamos essa transdução – a capacidade de um sinal de acoplamento de penetrar profundamente a molécula receptora e induzir uma resposta. Verificamos a presença de um comportamento coerente em sistemas diversos de receptor-ligante. Para apreciar essa diversidade, apresentamos quatro sistemas bioquímicos diferentes: TCR-peptídeo, ADP-bomba de cálcio, hemoglobina-oxigênio e gp120-CD4 acoplamento viral. A confirmação de transdução molecular sincronizada em cada um desses sistemas sugere que o mecanismo proposto ocorreria em todos os sistemas bioquímicos receptor-ligante.

Molecular transduction in receptor-ligand systems by planar electromagnetic fields

Abstract The coupling of a ligand with a molecular receptor induces a signal that travels through the receptor, reaching the internal domain and triggering a response cascade. In previous work on T-cell receptors and their coupling with foreign antigens, we observed the presence of planar molecular patterns able to generate electromagnetic fields within the proteins. These planes showed a coherent (synchronized) behavior, replicating immediately in the intracellular domain that which occurred in the extracellular domain as the ligand was coupled. In the present study, we examined this molecular transduction - the capacity of the coupling signal to penetrate deep inside the receptor molecule and induce a response. We verified the presence of synchronized behavior in diverse receptor-ligand systems. To appreciate this diversity, we present four biochemically different systems - TCR-peptide, calcium pump-ADP, haemoglobin-oxygen, and gp120-CD4 viral coupling. The confirmation of synchronized molecular transduction in each of these systems suggests that the proposed mechanism would occur in all biochemical receptor-ligand systems.

Resumo A ligação de um ligante com um receptor molecular induz um sinal que viaja através do receptor, chegando ao domínio interno e disparando uma cascata de resposta. Em trabalhos anteriores em receptores de células T e sua ligação com antígenos estranhos, observamos a presença de padrões moleculares planares capazes de gerar campos eletromagnéticos dentro das proteínas. Esses planos mostraram um comportamento coerente (sincronizado), replicando, instantaneamente, no domínio intracelular o que ocorreu no domínio extracelular, enquanto o ligante era acoplado. No presente estudo, examinamos essa transdução a capacidade de um sinal de acoplamento de penetrar profundamente a molécula receptora e induzir uma resposta. Verificamos a presença de um comportamento coerente em sistemas diversos de receptor-ligante. Para apreciar essa diversidade, apresentamos quatro sistemas bioquímicos diferentes: TCR-peptídeo, ADP-bomba de cálcio, hemoglobina-oxigênio e gp120-CD4 acoplamento viral. A confirmação de transdução molecular sincronizada em cada um desses sistemas sugere que o mecanismo proposto ocorreria em todos os sistemas bioquímicos receptor-ligante.

Understanding variations in reported epidemiology of major lower extremity amputation in the UK: a systematic review.

OBJECTIVE: Estimate the prevalence/incidence/number of major lower extremity amputations (MLEAs) in the UK; identify sources of routinely collected electronic health data used; assess time trends and regional variation; and identify reasons for variation in reported incidence/prevalence of MLEA. DESIGN: Systematic review and narrative synthesis. DATA SOURCES: Medline, Embase, EMcare, CINAHL, The Cochrane Library, AMED, Scopus and grey literature sources searched from 1 January 2009 to 1 August 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Reports that provided population-based statistics, used routinely collected electronic health data, gave a measure of MLEA in adults in the general population or those with diabetes in the UK or constituent countries were included. DATA EXTRACTION AND SYNTHESIS: Data extraction and quality assessment using the Joanna Briggs Institute Critical Appraisal Instruments were performed by two reviewers independently. Due to considerable differences in study populations and methodology, data pooling was not possible; data were tabulated and narratively synthesised, and study differences were discussed. RESULTS: Twenty-seven reports were included. Incidence proportion for the general population ranged from 8.2 to 51.1 per 100 000 and from 70 to 291 per 100 000 for the population with diabetes. Evidence for trends over time was mixed, but there was no evidence of increasing incidence. Reports consistently found regional variation in England with incidence higher in the north. No studies reported prevalence. Differences in database use, MLEA definition, calculation methods and multiple procedure inclusion which, together with identified inaccuracies, may account for the variation in incidence. CONCLUSIONS: UK incidence and trends in MLEA remain unclear; estimates vary widely due to differences in methodology and inaccuracies. Reasons for regional variation also remain unexplained and prevalence uninvestigated. International consensus on the definition of MLEA and medical code list is needed. Future research should recommend standards for the reporting of such outcomes and investigate further the potential to use primary care data in MLEA epidemiology. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020165592.

Rapport building and witness memory: Actions may 'speak' louder than words.

Building rapport during police interviews is argued as important for improving on the completeness and accuracy of information provided by witnesses and victims. However, little experimental research has clearly operationalised rapport and investigated the impact of rapport behaviours on episodic memory. Eighty adults watched a video of a mock crime event and 24-hours later were randomly allocated to an interview condition where verbal and/or behavioural (non-verbal) rapport techniques were manipulated. Memorial performance measures revealed significantly more correct information, without a concomitant increase in errors, was elicited when behavioural rapport was present, a superiority effect found in both the free and probed recall phase of interviews. The presence of verbal rapport was found to reduce recall accuracy in the free recall phase of interviews. Post-interview feedback revealed significant multivariate effects for the presence of behavioural (only) rapport and combined (behavioural + verbal) rapport. Participants rated their interview experience far more positively when these types of rapport were present compared to when verbal (only) rapport or no rapport was present. These findings add weight to the importance of rapport in supporting eyewitness cognition, highlighting the potential consequences of impoverished social behaviours for building rapport during dyadic interactions, suggesting 'doing' rather than simply 'saying' may be more beneficial.

Molecular transduction in receptor-ligand systems by planar electromagnetic fields.

The coupling of a ligand with a molecular receptor induces a signal that travels through the receptor, reaching the internal domain and triggering a response cascade. In previous work on T-cell receptors and their coupling with foreign antigens, we observed the presence of planar molecular patterns able to generate electromagnetic fields within the proteins. These planes showed a coherent (synchronized) behavior, replicating immediately in the intracellular domain that which occurred in the extracellular domain as the ligand was coupled. In the present study, we examined this molecular transduction - the capacity of the coupling signal to penetrate deep inside the receptor molecule and induce a response. We verified the presence of synchronized behavior in diverse receptor-ligand systems. To appreciate this diversity, we present four biochemically different systems - TCR-peptide, calcium pump-ADP, haemoglobin-oxygen, and gp120-CD4 viral coupling. The confirmation of synchronized molecular transduction in each of these systems suggests that the proposed mechanism would occur in all biochemical receptor-ligand systems.

Reducing acetylated tau is neuroprotective in brain injury.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Characterization of the Jet-Flow Overpressure Model of Traumatic Brain Injury in Mice.

The jet-flow overpressure chamber (OPC) has been previously reported as a model of blast-mediated traumatic brain injury (bTBI). However, rigorous characterization of the features of this injury apparatus shows that it fails to recapitulate exposure to an isolated blast wave. Through combined experimental and computational modeling analysis of gas-dynamic flow conditions, we show here that the jet-flow OPC produces a collimated high-speed jet flow with extreme dynamic pressure that delivers a severe compressive impulse. Variable rupture dynamics of the diaphragm through which the jet flow originates also generate a weak and infrequent shock front. In addition, there is a component of acceleration-deceleration injury to the head as it is agitated in the headrest. Although not a faithful model of free-field blast exposure, the jet-flow OPC produces a complex multi-modal model of TBI that can be useful in laboratory investigation of putative TBI therapies and fundamental neurophysiological processes after brain injury.

Prevalence of Cognitive Impairment in Individuals with Vascular Surgical Pathology: a Systematic Review and Meta-Analysis.

OBJECTIVE: A significant proportion of vascular surgery patients may have undiagnosed cognitive impairment; however, its true prevalence and impact on outcomes are unknown. The aim of this review was to estimate the prevalence of cognitive impairment among individuals with clinically significant vascular surgical pathology and investigate its associations with post-operative outcomes in those undergoing vascular surgery. METHODS: MEDLINE, EMBASE, EMCare, CINAHL, PsycINFO, and Scopus were searched for relevant studies. Included studies assessed cognitive function among individuals with either symptomatic vascular surgical pathology, or disease above threshold for intervention, using a validated cognitive assessment tool. The primary outcome measure was prevalence of cognitive impairment. Secondary outcomes included incidence of post-operative delirium (POD). Two reviewers independently extracted relevant study data and assessed risk of bias (ROBINS-E or RoB 2 tool). Prevalence (%) of cognitive impairment was calculated for individual studies and presented with 95% confidence intervals (CI). Prevalence data from comparable studies were pooled using the Mantel-Haenszel method (random effects model) for separate vascular disease types. Certainty of effect estimates was assessed using the GRADE criteria. RESULTS: Twenty-four studies (2 564 participants) were included in the systematic review, and nine studies (1 310 participants) were included in the meta-analyses. The prevalence of cognitive impairment was 61% (95% CI 48 - 74; 391 participants; low certainty) in studies including multiple vascular surgical pathologies, 38% (95% CI 32 - 44; 278 participants; very low certainty) in carotid artery disease, and 19% (95% CI 10 - 33; 641 participants; low certainty) in those with intermittent claudication. Lower cognitive assessment scores were associated with POD (five studies; 841 participants), but data were not suitable for pooling. CONCLUSION: Screening elective vascular surgery patients for cognitive impairment may be appropriate given its high prevalence, and the association of worse cognition with POD, among individuals with clinically significant vascular surgical pathology.

Maternal P7C3-A20 Treatment Protects Offspring from Neuropsychiatric Sequelae of Prenatal Stress.

Aims: Impaired embryonic cortical interneuron development from prenatal stress is linked to adult neuropsychiatric impairment, stemming in part from excessive generation of reactive oxygen species in the developing embryo. Unfortunately, there are no preventive medicines that mitigate the risk of prenatal stress to the embryo, as the underlying pathophysiologic mechanisms are poorly understood. Our goal was to interrogate the molecular basis of prenatal stress-mediated damage to the embryonic brain to identify a neuroprotective strategy. Results: Chronic prenatal stress in mice dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis enzymes and cortical interneuron development in the embryonic brain, leading to axonal degeneration in the hippocampus, cognitive deficits, and depression-like behavior in adulthood. Offspring were protected from these deleterious effects by concurrent maternal administration of the NAD+-modulating agent P7C3-A20, which crossed the placenta to access the embryonic brain. Prenatal stress also produced axonal degeneration in the adult corpus callosum, which was not prevented by maternal P7C3-A20. Innovation: Prenatal stress dysregulates gene expression of NAD+-synthesis machinery and GABAergic interneuron development in the embryonic brain, which is associated with adult cognitive impairment and depression-like behavior. We establish a maternally directed treatment that protects offspring from these effects of prenatal stress. Conclusion: NAD+-synthesis machinery and GABAergic interneuron development are critical to proper embryonic brain development underlying postnatal neuropsychiatric functioning, and these systems are highly susceptible to prenatal stress. Pharmacologic stabilization of NAD+ in the stressed embryonic brain may provide a neuroprotective strategy that preserves normal embryonic development and protects offspring from neuropsychiatric impairment. Antioxid. Redox Signal. 35, 511-530.

Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress.

Post-traumatic stress disorder (PTSD) is characterized by persistent fear memory of remote traumatic events, mental re-experiencing of the trauma, long-term cognitive deficits, and PTSD-associated hippocampal dysfunction. Extinction-based therapeutic approaches acutely reduce fear. However, many patients eventually relapse to the original conditioned fear response. Thus, understanding the underlying molecular mechanisms of this condition is critical to developing new treatments for patients. Mutations in the neuropsychiatric risk gene CACNA1C, which encodes the Cav1.2 isoform of the L-type calcium channel, have been implicated in both PTSD and highly comorbid neuropsychiatric conditions, such as anxiety and depression. Here, we report that male mice with global heterozygous loss of cacna1c exhibit exacerbated contextual fear that persists at remote time points (up to 180 days after shock), despite successful acute extinction training, reminiscent of PTSD patients. Because dopamine has been implicated in contextual fear memory, and Cav1.2 is a downstream target of dopamine D1-receptor (D1R) signaling, we next generated mice with specific deletion of cacna1c from D1R-expressing neurons (D1-cacna1cKO mice). Notably, D1-cacna1cKO mice also show the same exaggerated remote contextual fear, as well as persistently elevated anxiety-like behavior and impaired spatial memory at remote time points, reminiscent of chronic anxiety in treatment-resistant PTSD. We also show that D1-cacna1cKO mice exhibit elevated death of young hippocampal neurons, and that treatment with the neuroprotective agent P7C3-A20 eradicates persistent remote fear. Augmenting survival of young hippocampal neurons may thus provide an effective therapeutic approach for promoting durable remission of PTSD, particularly in patients with CACNA1C mutations or other genetic aberrations that impair calcium signaling or disrupt the survival of young hippocampal neurons.

Different forms of traumatic brain injuries cause different tactile hypersensitivity profiles.

ABSTRACT: Chronic complications of traumatic brain injury represent one of the greatest financial burdens and sources of suffering in the society today. A substantial number of these patients suffer from posttraumatic headache (PTH), which is typically associated with tactile allodynia. Unfortunately, this phenomenon has been understudied, in large part because of the lack of well-characterized laboratory animal models. We have addressed this gap in the field by characterizing the tactile sensory profile of 2 nonpenetrating models of PTH. We show that multimodal traumatic brain injury, administered by a jet-flow overpressure chamber that delivers a severe compressive impulse accompanied by a variable shock front and acceleration-deceleration insult, produces long-term tactile hypersensitivity and widespread sensitization. These are phenotypes reminiscent of PTH in patients, in both cephalic and extracephalic regions. By contrast, closed head injury induces only transient cephalic tactile hypersensitivity, with no extracephalic consequences. Both models show a more severe phenotype with repetitive daily injury for 3 days, compared with either 1 or 3 successive injuries in a single day, providing new insight into patterns of injury that may place patients at a greater risk of developing PTH. After recovery from transient cephalic tactile hypersensitivity, mice subjected to closed head injury demonstrate persistent hypersensitivity to established migraine triggers, including calcitonin gene-related peptide and sodium nitroprusside, a nitric oxide donor. Our results offer the field new tools for studying PTH and preclinical support for a pathophysiologic role of calcitonin gene-related peptide in this condition.

P7C3-A20 treatment one year after TBI in mice repairs the blood-brain barrier, arrests chronic neurodegeneration, and restores cognition.

Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood-brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer's disease, Parkinson's disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions.

Frailty Factors and Outcomes in Vascular Surgery Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: To describe and critique tools used to assess frailty in vascular surgery patients, and investigate its associations with patient factors and outcomes. BACKGROUND: Increasing evidence shows negative impacts of frailty on outcomes in surgical patients, but little investigation of its associations with patient factors has been undertaken. METHODS: Systematic review and meta-analysis of studies reporting frailty in vascular surgery patients (PROSPERO registration: CRD42018116253) searching Medline, Embase, CINAHL, PsycINFO, and Scopus. Quality of studies was assessed using Newcastle-Ottawa scores (NOS) and quality of evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria. Associations of frailty with patient factors were investigated by difference in means (MD) or expressed as risk ratios (RRs), and associations with outcomes expressed as odds ratios (ORs) or hazard ratios (HRs). Data were pooled using random-effects models. RESULTS: Fifty-three studies were included in the review and only 8 (15%) were both good quality (NOS ≥ 7) and used a well-validated frailty measure. Eighteen studies (62,976 patients) provided data for the meta-analysis. Frailty was associated with increased age [MD 4.05 years; 95% confidence interval (CI) 3.35, 4.75], female sex (RR 1.32; 95% CI 1.14, 1.54), and lower body mass index (MD -1.81; 95% CI -2.94, -0.68). Frailty was associated with 30-day mortality [adjusted OR (AOR) 2.77; 95% CI 2.01-3.81), postoperative complications (AOR 2.16; 95% CI 1.55, 3.02), and long-term mortality (HR 1.85; 95% CI 1.31, 2.62). Sarcopenia was not associated with any outcomes. CONCLUSION: Frailty, but not sarcopenia, is associated with worse outcomes in vascular surgery patients. Well-validated frailty assessment tools should be preferred clinically, and in future research.