As time goes by: hippocampal connectivity changes with remoteness of autobiographical memory retrieval.

The hippocampus is crucial for episodic autobiographical memory retrieval. Functional neuroimaging evidence suggests that it is similarly engaged in recent and remote retrieval when memories are matched on vividness and personal importance. Far fewer studies have investigated the nature of hippocampal-neocortical coactivation in relation to memory remoteness. The purpose of this study was to examine hippocampal activity and functional connectivity as a function of memory age. Unlike most studies of autobiographical memory, we included autobiographical memories formed in the days and weeks before scanning, in addition to truly remote memories on the order of months and years. Like previous studies, we found that the hippocampus was active bilaterally regardless of memory age, with anterior activity increasing up to 1 yr and then decreasing, and with posterior activity being less sensitive to memory age. More importantly, hippocampal functional connectivity varied with memory age. Retrieving recent memories (≤1 yr) showed a late coactivation of the hippocampus and areas of the autobiographical memory network, whereas retrieving remote memories (10 yrs) showed an early negative coactivation of the hippocampus and left inferior frontal gyrus followed by a positive coactivation with anterior cingulate. This finding may reflect that the hippocampus is more strongly integrated with the autobiographical memory network for recent than for remote memories, and that more effort is required to recover remote memories.

Teaching medical professionalism.

Medical professionalism has been notoriously difficult to define and remains poorly understood. Because of this, graduates often have contrasting views on how it is best taught. These views should be considered and incorporated into teaching methods in order to enhance learning and development. Over a six-month consecutive period doctors and medical students in County Durham and Darlington Foundation Trust completed a questionnaire asking them to define professionalism, state where they felt they had learnt about professionalism and how important they feel professionalism is to them. They were also asked to identify how they felt teaching about professionalism was best delivered from a selection of educational resources. The findings highlight major differences between how the material is taught and how students and graduates feel they learn best about professionalism and more research into this field is needed.

A Handheld Gyroscopic Device for Haptics and Hand Rehabilitation.

We propose a novel, gyroscopic device for haptics and hand rehabilitation, named Gymball. It consists of a fully actuated rotor-gimbal assembly encased in an easy-to-grip appealing design. When held, the device generates a gyroscopic torque which causes the user's hand to move about the wrist. Interviews with occupational therapists, simulations, and proof-of-concept models helped determine the design specifications of Gymball. Compared to the existing gyroscopic devices, Gymball has the following advantages. (i) A smaller form-factor with better user appeal while achieving 0.5 Nm torque. (ii) A wire entanglement-free design allowing complete rotations of the rotor-gimbal assembly. (iii) Negligible rotary imbalances owing to a symmetrical design, resulting in haptic signals with minimal vibratory noise. In this paper, we detail the design and analysis of the device. A feasibility study was conducted to validate prospect of using the device for haptic feedback or therapy. Specifically, the study focused on (i) whether the gyroscopic torque generated by the device can passively move the user's hand about the wrist and (ii) whether the produced hand motion can be controlled. The results show that Gymball can successfully generate about 7° of hand oscillations. The amplitude and frequency of the hand oscillations can be controlled using the speed of rotor and gimbal.

Evaluating Knee Mechanisms for Assistive Devices.

State-of-the-art knee braces use a polycentric mechanism with a predefined locus of the instantaneous center of rotation (centrode) and most exoskeleton devices use a knee mechanism with a single axis of rotation. However, human knees do not share a common centrode nor do they have a single axis. This leads to misalignment between the assistive device's joint axis and the user's knee axis, resulting in device migration and interaction forces, which can lead to sores, pain, and abandonment of the device over time. There has been some research into self-aligning knee mechanisms; however, there is a lack of consensus on the benefit of these mechanisms. There is no research that looked purely at the impact of the knee mechanisms, either. In this article, we compare three different knee brace mechanisms: single axis (SA), polycentric with predefined centrode (PPC), and polycentric with a self-aligning center of rotation (PSC). We designed and conducted an experiment to evaluate different joint mechanisms on device migration and interaction forces. Brace material, weight, size, cuff design, fitment location, and tightness were consistent across trials, making the knee joint mechanism the sole variable. The brace mechanisms had no significant effect on walking kinematics or kinetics. However, the PPC brace had greater interaction forces on the top brace strap than the SA and PSC. The PSC and SA had significantly lower interaction forces on the bottom strap compared to the PPC brace. The PSC had significantly less migration than both the SA and PPC braces. These results show that a PPC mechanism may not be beneficial for a wide range of users. This also shows that the PSC mechanisms may improve mechanism alignment and lessen device migration.

Biomechanical Impacts of Toe Joint With Transfemoral Amputee Using a Powered Knee-Ankle Prosthesis.

Transfemoral amputees are currently forced to utilize energetically passive prostheses that provide little to no propulsive work. Among the several joints and muscles required for healthy walking, the ones most vital for push-off assistance include the knee, ankle, and metatarsophalangeal (MTP) joints. There are only a handful of powered knee-ankle prostheses (also called powered transfemoral prostheses) in literature and few of them comprise a toe-joint. However, no one has researched the impact of toe-joint stiffness on walking with a power transfemoral prosthesis. This study is aimed at filling this gap in knowledge. We conducted a study with an amputee and a powered transfemoral prosthesis consisting of a spring loaded toe-joint. The prosthesis's toe-joint stiffness was varied between three values: 0.83 Nm/deg, 1.25 Nm/deg, and infinite (rigid). This study found that 0.83 Nm/deg stiffness reduced push-off assistance and resulted in compensatory movements that could lead to issues over time. While the joint angles and moments did not considerably vary across 1.25 Nm/deg and rigid stiffness, the latter led to greater power generation on the prosthesis side. However, the 1.25 Nm/deg joint stiffness resulted in the least power production from the intact side. We, thus, concluded that the use of a stiff toe-joint with a powered transfemoral prosthesis can reduce the cost of transport of the intact limb.

Control Framework for Sloped Walking With a Powered Transfemoral Prosthesis.

User customization of a lower-limb powered Prosthesis controller remains a challenge to this date. Controllers adopting impedance control strategies mandate tedious tuning for every joint, terrain condition, and user. Moreover, no relationship is known to exist between the joint control parameters and the slope condition. We present a control framework composed of impedance control and trajectory tracking, with the transitioning between the two strategies facilitated by Bezier curves. The impedance (stiffness and damping) functions vary as polynomials during the stance phase for both the knee and ankle. These functions were derived through least squares optimization with healthy human sloped walking data. The functions derived for each slope condition were simplified using principal component analysis. The weights of the resulting basis functions were found to obey monotonic trends within upslope and downslope walking, proving the existence of a relationship between the joint parameter functions and the slope angle. Using these trends, one can now design a controller for any given slope angle. Amputee and able-bodied walking trials with a powered transfemoral prosthesis revealed the controller to generate a healthy human gait. The observed kinematic and kinetic trends with the slope angle were similar to those found in healthy walking.

Should we teach and train in smaller hospitals?

In the NHS, training occurs in nearly all our hospitals, and this is part of the NHS service model. As the shortage of doctors is increasingly recognised, so has the pull from remote, rural and smaller places to large urban centres. We discuss whether this is inevitable and what else could be done to ensure equitable access to healthcare for all, by making better use of the excellent clinical training the UK has in place in smaller as well as larger centres.

Electroconvulsive therapy "corrects" the neural architecture of visuospatial memory: Implications for typical cognitive-affective functioning.

Although electroconvulsive therapy (ECT) is a widely used and effective treatment for refractory depression, the neural underpinnings of its therapeutic effects remain poorly understood. To address this issue, here, we focused on a core cognitive deficit associated with depression, which tends to be reliably ameliorated through ECT, specifically, the ability to learn visuospatial information. Thus, we pursued three goals. First, we tested whether ECT can "normalize" the functional brain organization patterns associated with visuospatial memory and whether such corrections would predict post-ECT improvements in learning visuospatial information. Second, we investigated whether, among healthy individuals, stronger expression of the neural pattern, susceptible to adjustments through ECT, would predict reduced incidence of depression-relevant cognition and affect. Third, we sought to quantify the heritability of the ECT-correctable neural profile. Thus, in a task fMRI study with a clinical and a healthy comparison sample, we characterized two functional connectome patterns: one that typifies trait depression (i.e., differentiates patients from healthy individuals) and another that is susceptible to "normalization" through ECT. Both before and after ECT, greater expression of the trait depression neural profile was associated with more frequent repetitive thinking about past personal events (affective persistence), a hallmark of depressogenic cognition. Complementarily, post-treatment, stronger expression of the ECT-corrected neural profile was linked to improvements in visuospatial learning, a mental ability which is markedly impaired in depression. Subsequently, using data from the Human Connectome Project (HCP) (N = 333), we demonstrated that the functional brain organization of healthy participants with greater levels of subclinical depression and higher incidence of its associated cognitive deficits (affective persistence, impaired learning) shows greater similarity to the trait depression neural profile and reduced similarity to the ECT-correctable neural profile, as identified in the patient sample. These results tended to be specific to learning-relevant task contexts (working memory, perceptual relational processing). Genetic analyses based on HCP twin data (N = 128 pairs) suggested that, among healthy individuals, a functional brain organization similar to the one normalized by ECT in the patient sample is endogenous to cognitive contexts that require visuospatial processing that extends beyond the here-and-now. Broadly, the present findings supported our hypothesis that some of the therapeutic effects of ECT may be due to its correcting the expression of a naturally occurring pattern of functional brain organization that facilitates integration of internal and external cognition beyond the immediate present. Given their substantial susceptibility to both genetic and environmental effects, such mechanisms may be useful both for identifying at risk individuals and for monitoring progress of interventions targeting mood-related pathology.

Utility of Detecting sof Gene as Evidence of Streptococcus pyogenes Infection in Acute Rheumatic Fever.

OBJECTIVE: To determine the diagnostic accuracy of polymerase chain reaction-based detection of sof gene compared to throat swab culture for S. pyogenes infection in patients with acute rheumatic fever and those with recurrence of rheumatic activity. METHODS: 40 patients between 3 to 18 years of age, with clinical diagnosis of acute rheumatic fever or new activity in established rheumatic heart disease were included. The amplicon of 228bp of sof gene was detected using a polymerase chain reaction-based technique and the results were compared with throat swab culture for Streptococcus pyogenes. RESULTS: 10 patients had a positive throat swab culture and 11 had sof gene detected. The sensitivity and specificity of the test was 100% and 96.7%, respectively compared to throat swab culture (P=0.001). The positive predictive value and the negative predictive value was 90.9% and 100% respectively. CONCLUSION: Polymerase chain reaction-based detection of sof gene provides an alternative to throat swab culture in diagnosing activity in Acute Rheumatic Fever or established Rheumatic heart disease.

Author Correction: Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cardiovascular disease--the silent killer in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a multisystem disease with high rates of morbidity and mortality. In recent years, there has been increasing focus on the growing rates of cardiovascular disease (CVD) in RA, over and above expected levels allowing for 'traditional' risk factors. In this paper the impact of CVD in RA, the relative contributions of traditional risk factors and novel risk factors (including homocysteine, oxidised low-density lipoprotein, high-sensitivity C-reactive protein and leptin), and the need to address cardiovascular risk in the fight against premature death from coronary artery and stroke disease in RA are discussed.

Treatment of Rheumatoid Arthritis with Certolizumab Pegol: Results from PROACTIVE, a Non-Interventional Study in the UK and Ireland.

INTRODUCTION: The objective of this non-interventional study was to investigate the long-term safety and effectiveness of certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) in the UK and Ireland. METHODS: Patients were prescribed CZP at their physicians' discretion and followed during routine clinical practice for up to 88 weeks. DAS28(ESR) response (defined as at least a 1.2-point reduction from baseline) was measured in the full analysis set (FAS) at week 12, and patients were categorized by week 12 responder status in all subsequent analyses. The primary outcome was DAS28(ESR) response at week 78. Secondary outcomes included change from baseline in DAS28(ESR), HAQ-DI, and RADAI scores at week 78, and EULAR response at week 78. Adverse drug reactions (ADRs) were recorded for all patients who received at least one dose of CZP. RESULTS: A total of 149 patients were enrolled, of whom 111 (74.5%) formed the FAS. At week 12, 80 patients (72.1%) were DAS28(ESR) responders and 31 (27.9%) non-responders. Compared to non-responders, a greater proportion of week 12 responders had a DAS28(ESR) response at week 78 (43.8% versus 22.6%). Improvements in DAS28(ESR), HAQ-DI, and RADAI scores were also greater on average among week 12 responders, as was the proportion of patients meeting EULAR criteria. Overall, 9 patients (6.1%) experienced 13 ADRs during the study. CONCLUSION: These data demonstrate the safety and effectiveness of CZP in adult patients with RA treated during routine clinical practice in the UK and Ireland. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01288287. FUNDING: UCB Pharma.

Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.

Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERαWT and ERαMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs.Significance: Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERαWT and ERαMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176-93. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.

Delusions and processing of discrepant information: an event-related brain potential study.

One possible explanation for why delusions persist despite the awareness of contradictory information is that the new information fails to be integrated. Interestingly, the amplitude of the N400 event-related brain potential (ERP) has been proposed as an index of the integration of information that is discrepant with expectancies whatever the task in which the potential is found. Thus, delusions may persist because of a deficit in integration as indexed by the N400. To test this hypothesis, ERPs were recorded in 35 schizophrenia patients (mean age=30.5+/-5.6 years) and 26 normal controls during a task in which they either had to decide whether or not each target word could be integrated into the category "animal", or had no decision to make, according to the prompt "animal?" or the prompt "inaction". In these conditions, the amplitudes of the N400s to target words that were discrepant with the category were found to be negatively correlated with delusion severity. The patient group was then dichotomized according to a median split of delusion severity, excluding the 5 patients with delusion scores at the median. Mean age, sex ratio, and severity of conceptual disorganization and hallucinations of the two subgroups differed. Controlling for these 4 covariates, the N400s for discrepant targets were found smaller in the 14 More-Delusional patients than in the 16 Less-Delusional patients. These results support the hypothesis that delusions are associated with smaller N400s in patients. Further studies should thus be done to test whether a deficit of N400 processes could have a causal role in the persistence of delusions.

Synergistic Effects on the Elderly People's Motor Control by Wearable Skin-Stretch Device Combined with Haptic Joystick.

Cutaneous sensory feedback can be used to provide additional sensory cues to a person performing a motor task where vision is a dominant feedback signal. A haptic joystick has been widely used to guide a user by providing force feedback. However, the benefit of providing force feedback is still debatable due to performance dependency on factors such as the user's skill-level, task difficulty. Meanwhile, recent studies have shown the feasibility of improving a motor task performance by providing skin-stretch feedback. Therefore, a combination of two aforementioned feedback types is deemed to be promising to promote synergistic effects to consistently improve the person's motor performance. In this study, we aimed at identifying the effect of the combined haptic and skin-stretch feedbacks on the aged person's driving motor performance. For the experiment, 15 healthy elderly subjects (age 72.8 ± 6.6 years) were recruited and were instructed to drive a virtual power-wheelchair through four different courses with obstacles. Four augmented sensory feedback conditions were tested: no feedback, force feedback, skin-stretch feedback, and a combination of both force and skin-stretch feedbacks. While the haptic force was provided to the hand by the joystick, the skin-stretch was provided to the steering forearm by a custom-designed wearable skin-stretch device. We tested two hypotheses: (i) an elderly individual's motor control would benefit from receiving information about a desired trajectory from multiple sensory feedback sources, and (ii) the benefit does not depend on task difficulty. Various metrics related to skills and safety were used to evaluate the control performance. Repeated measure ANOVA was performed for those metrics with two factors: task scenario and the type of the augmented sensory feedback. The results revealed that elderly subjects' control performance significantly improved when the combined feedback of both haptic force and skin-stretch feedback was applied. The proposed approach suggest the feasibility to improve people's task performance by the synergistic effects of multiple augmented sensory feedback modalities.

Junior doctor psychiatry placements in hospital and community settings: a phenomenological study.

OBJECTIVES: The proportion of junior doctors required to complete psychiatry placements in the UK has increased, due in part to vacant training posts and psychiatry career workforce shortages, as can be seen across the world. The aim of this study was to understand the lived experience of a Foundation Year 1 junior doctor psychiatry placement and to understand how job components influence attitudes. DESIGN: The study was conducted using a cross-sectional qualitative phenomenological approach. SETTING: Hospital and community psychiatry department settings in the North East of England, UK. PARTICIPANTS: In total, 14 Foundation Year 1 junior doctors were interviewed including seven men and seven women aged between 23 and 34 years. The majority had completed their medical degree in the UK and were White British. RESULTS: The lived experience of a junior doctor psychiatry placement was understood by three core themes: exposure to patient recovery, connectedness with others in the healthcare team and subjective interpretations of psychiatry. The experiences were moderated by instances of role definition, reaction to the specialty and the organisational fit of the junior doctor capacity in the specialty. CONCLUSIONS: The study reinforces and adds to the literature by identifying connectedness as being important for both job satisfaction and morale, which is currently damaged within the junior doctor population. The study provides in-depth insights into the lived experience of psychiatry placements and can be taken forward by educationalists to ensure the placements are meaningful experiences for junior doctors by developing role definition, belonging, structure and psychiatric care responsibility.

EP4 Antagonism by E7046 diminishes Myeloid immunosuppression and synergizes with Treg-reducing IL-2-Diphtheria toxin fusion protein in restoring anti-tumor immunity.

Reprogramming of immunosuppressive tumor microenvironment (TME) by targeting alternatively activated tumor associated macrophages (M2TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite and mediator of chronic inflammation, has emerged as a powerful immunosuppressor in the TME through engagement with one or more of its 4 receptors (EP1-EP4). We have developed E7046, an orally bioavailable EP4-specific antagonist and show here that E7046 has specific and potent inhibitory activity on PGE2-mediated pro-tumor myeloid cell differentiation and activation. E7046 treatment reduced the growth or even rejected established tumors in vivo in a manner dependent on both myeloid and CD8+ T cells. Furthermore, co-administration of E7046 and E7777, an IL-2-diphtheria toxin fusion protein that preferentially kills Tregs, synergistically disrupted the myeloid and Treg immunosuppressive networks, resulting in effective and durable anti-tumor immune responses in mouse tumor models. In the TME, E7046 and E7777 markedly increased ratios of CD8+granzymeB+ cytotoxic T cells (CTLs)/live Tregs and of M1-like/M2TAM, and converted a chronic inflammation phenotype into acute inflammation, shown by substantial induction of STAT1/IRF-1 and IFNγ-controlled genes. Notably, E7046 also showed synergistic anti-tumor activity when combined with anti-CTLA-4 antibodies, which have been reported to diminish intratumoral Tregs. Our studies thus reveal a specific myeloid cell differentiation-modifying activity by EP4 blockade and a novel combination of E7046 and E7777 as a means to synergistically mitigate both myeloid and Treg-derived immunosuppression for cancer treatment in preclinical models.

Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.

Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγHigh/RXRαS427F/Y impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic "immuno-oncogenes" that modulate the immune microenvironment of cancer.Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease. Here the authors characterize diverse genetic alterations in MIBC that convergently lead to constitutive activation of PPARgamma/RXRalpha and result in immunosurveillance escape by inhibiting CD8+ T-cell recruitment.

Threat of death and autobiographical memory: a study of passengers from Flight AT236.

We investigated autobiographical memory in a group of passengers onboard a trans-Atlantic flight that nearly ditched at sea. The consistency of traumatic exposure across passengers, some of whom developed post-traumatic stress disorder (PTSD), provided a unique opportunity to assess verified memory for life-threatening trauma. Using the Autobiographical Interview, which separates episodic from non-episodic details, passengers and healthy controls (HCs) recalled three events: the airline disaster (or a highly negative event for HCs), the September 11, 2001 attacks, and a non-emotional event. All passengers showed robust mnemonic enhancement for episodic details of the airline disaster. Although neither richness nor accuracy of traumatic recollection was related to PTSD, production of non-episodic details for traumatic and non-traumatic events was elevated in PTSD passengers. These findings indicate a robust mnemonic enhancement for trauma that is not specific to PTSD. Rather, PTSD is associated with altered cognitive control operations that affect autobiographical memory in general.