Profiles of objective and subjective cognitive function in Post-COVID Syndrome, COVID-19 recovered, and COVID-19 naïve individuals.

Post-COVID Syndrome has emerged as a significant public health concern worldwide with increasing evidence to suggest that individuals who have had an acute COVID-19 infection report lingering memory and attention difficulties, even in individuals who have fully recovered and no longer experiencing symptoms of COVID-19. The present study sought to investigate the profile of objective and subjective cognitive difficulties in people who have Post-COVID Syndrome, people who have fully recovered from an acute COVID infection and people who have never had COVID-19. We further sought to explore the extent to which self-reported fatigue and stress are related to subjective and objective cognitive difficulties. 162 participants including 50 people living with Post-COVID Syndrome, 59 people who have had COVID-19 but have fully recovered and 53 people who have never experienced symptoms of COVID-19 and had never tested positive for COVID-19 were recruited from Academic Prolific to complete a series of online questionnaires and neurocognitive tasks. Subjective cognitive function was measured using the Cognitive Failures Questionnaire and objective cognitive function was measured using the Cognitron cognitive test battery. We found that objective and subjective measures of cognitive function were not significantly related, suggesting that self-reports of "brain fog" are not reflecting objectively measured cognitive dysfunction. A MANOVA revealed that subjective cognitive deficits were driven by heightened perceived stress and fatigue and not significantly related to COVID-19 status. Objective cognitive function, however, was significantly related to perceived stress and COVID status whereby we observed significant objective cognitive deficits in people who have been exposed to an acute COVID-19 infection regardless of whether they had Post-COVID Syndrome or had fully recovered, as compared to people who had never had COVID-19. This suggests that an acute infection can have long term effects on cognitive function, even without persistent COVID-19 symptoms. Encouragingly, objective cognitive function was significantly associated with time since initial infection showing that cognitive deficits improved over time for people who had recovered from COVID-19. However, we did not observe the same improvement in individuals with Post-COVID Syndrome and observed that cognitive dysfunction was significantly related to the number of neurological symptoms presently experienced. These results add to the accumulating literature that COVID-19 is associated with significant cognitive difficulties following a COVID-19 infection, which appear to improve over time for those who have recovered from COVID-19 yet persist in people living with Post-COVID Syndrome.

Courage, camaraderie and compassion: a qualitative exploration into UK military veterans' experiences of self-compassion within the context of alcohol use disorders and recovery.

INTRODUCTION: UK veterans are at increased risk of mental health and alcohol use disorders (AUDs), experiencing specific challenges such as combat exposure and re-integration which may contribute to treatment barriers. Experiences of shame and AUDs, which may precede or become exacerbated during military service, may be mitigated by self-compassion (SC). This study sought to understand how UK veterans make sense of their SC experiences within the context of their relationships with alcohol and recovery. METHODS: Interpretative phenomenological analysis was used to interpret the SC experiences of five ex-military veterans (one female). Semistructured face-to-face interviews were audio-recorded and transcribed verbatim, with a double hermeneutic approach used to interpret meaningful issues which influenced participants' self-perceptions in relation to their alcohol use and wider social world. RESULTS: Two key themes were identified. 'Searching for Safety', which illustrated veterans' SC sense-making within the context of their evolving lifeworld and alcohol use, and 'Healing with Honour' which reflected the significance of purpose and identity within experiences of recovery and SC. Findings were interpreted through the lens of the six bipolar elements of SC, which identified SC as salient within veterans' experiences of AUD and recovery. Although experiences of SC were sometimes perceived as challenging or incongruent to military identity, this was influenced by positive reframing and meaning-making, supported by compassionate narratives and informed trusted relationships. CONCLUSIONS: Veterans' AUD recovery and support-seeking may be impacted by the experience of SC and enhanced by the early implementation of acceptable and feasible interventions which draw on veterans' unique military identities and experience. This may include compassion-focussed interventions which reframe SC as fierce SC, peer support models and educational strategies which support healthcare professionals to understand and identify veterans' military experiences.

Mechanisms of synergistic suppression of ALK-positive lung cancer cell growth by the combination of ALK and SHP2 inhibitors.

Lung cancer is a major cause of cancer-related deaths. Alectinib is the first line of treatment for patients with ALK-positive lung cancer, but the survival rate beyond 2-3 years is low. Co-targeting secondary oncogenic drivers such as SHP2 is a potential strategy for improving drug efficacy. This is because SHP2 is expressed ubiquitously, but ALK expression is largely restricted to cancer cells. Thus, the combination of ALK and SHP2 inhibitors may provide a way to restrict synergistic cytotoxicity to cancer cells only, by reducing the dose of SHP2 inhibitors required for anticancer action and minimising SHP2-dependent systemic toxicity. The objective of this study was to investigate whether the combination of a SHP2 inhibitor (SHP099) with alectinib would synergistically suppress the growth of ALK-positive lung cancer cells. Our results demonstrated that the drug combination significantly and synergistically decreased cell viability at relatively low concentrations in ALK-positive H3122 and H2228 cells, due to G1 cell cycle arrest and increased apoptosis because of suppressed downstream RAS/MAPK signalling. The drug combination also induced the expression of mediators of the intrinsic apoptotic pathway, Bim and cleaved caspase-3, and modulated the expression of cell cycle mediators cyclin D1, cyclin B1, and phosphorylated CDK1.

Patrolling the boundaries of social domains: Neural activations to violations of expectations for romantic and work relationships.

According to the social domains hypothesis, we reduce the information-processing demands of complex social cues by classifying them into a limited number of domains, each with distinct sets of expectations. This requires rapid identification of violations of the boundaries between social domains. We hypothesized that these violations are likely to be associated with neural activation of the salience system. Using fMRI we compared responses of 20 adults to expected and unexpected everyday social scenarios in personal and work interactions. The vignettes exemplified different kinds of scenarios presented in the work setting, i.e., task-focused scenarios which are expected at work and scenarios with a personal focus, which are unexpected at work. The key contrast between task and personal focussed scenarios presented in the work setting was associated with fronto-insular activation. Perceived inappropriateness of the unexpected scenarios, and shorter response time to judgment of inappropriateness were also associated with fronto-insular activation, after controlling for unpleasantness. This study indicates specific neural responses to violations of expectations in different social situations. Our findings suggest that the fronto-insular region is implicated in rapid detection of behaviors that cross the boundaries of social domains, which are hypothesized to be necessary for efficient social information processing.

The effect of metformin in EML4-ALK+ lung cancer alone and in combination with crizotinib in cell and rodent models.

Cell based studies have suggested that the diabetes drug metformin may combine with the anaplastic lymphoma kinase receptor (ALK) inhibitor crizotinib to increase ALK positive lung cancer cell killing and overcome crizotinib resistance. We therefore tested metformin alone and in combination with crizotinib in vivo, by employing a xenograft mouse model of ALK positive lung cancer. We found that 14 days of daily oral metformin (100 mg/kg) alone had a moderate but statistically significant effect on tumour growth suppression, but in combination with crizotinib, produced no greater tumour suppression than crizotinib (25 mg/kg) alone. We also reassessed the effect of metformin on EML4-ALK positive lung cancer (H3122) cell viability. Although metformin alone did have a moderate effect on cell viability (30% suppression) this was only at a clinically irrelevant concentration (5 mM) and there was no additive effect with cytotoxic concentrations of crizotinib. Moreover, metformin did not overcome crizotinib resistance in our resistant cells. Nevertheless, we were able to show that metformin induces a G1-cell cycle arrest and apoptosis alone and in combination with crizotinib. Also, consistent with earlier work, the addition of insulin-like growth factor-1 (IGF-1) to EML4-ALK positive cancer cells reduced cell killing by crizotinib. We therefore hypothesised that the effect of metformin in vivo was not due to direct cytotoxicity on cancer cells, but by modulation of IGF-1 expression. We therefore measured levels of IGF-1 in plasma taken from mice treated with metformin, but found no difference between the drug treatment and control groups. We further hypothesised that the effect of metformin could be due to modulation of thrombospondin 1 (TSP-1), which metformin has been proposed to regulatein vivo, but again we found no difference between the experimental groups. Finally, we investigated the potential for liver and kidney toxicity, as well as CYP3A based interactions, from the combination of metformin with crizotinib.

Inhibition of Mitogen-Activated Protein Kinase Kinase Alone and in Combination with Anaplastic Lymphoma Kinase (ALK) Inhibition Suppresses Tumor Growth in a Mouse Model of ALK-Positive Lung Cancer.

Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer most commonly arises through EML4 (Echinoderm Microtuble Like 4)-ALK chromosomal fusion. We have previously demonstrated that combination of the ALK inhibitor crizotinib with the MEK inhibitor selumetinib was highly effective at reducing cell viability of ALK-positive non-small-cell lung cancer (H3122) cells. In this study, we further investigated the efficacy of crizotinib and selumetinib combination therapy in an in vivo xenograft model of ALK-positive lung cancer. Crizotinib decreased tumor volume by 52% compared with control, and the drug combination reduced tumor growth compared with crizotinib. In addition, MEK inhibition alone reduced tumor growth by 59% compared with control. Crizotinib and selumetinib alone and in combination were nontoxic at the dose of 25 mg/kg, with values for ALT (<80 U/l) and creatinine (<2 mg/dl) within the normal range. Our results support the combined use of crizotinib with selumetinib in ALK-positive lung cancer but raise the possibility that a sufficient dose of an MEK inhibitor alone may be as effective as adding an MEK inhibitor to an ALK inhibitor. SIGNIFICANCE STATEMENT: This study contains in vivo evidence supporting the use of combination MEK inhibitors in ALK+ lung cancer research, both singularly and in combination with ALK inhibitors. Contrary to previously published reports, our results suggest that it is possible to gain much of the benefit from combination treatment with an MEK inhibitor alone, at a tolerable dose.

Individuals living with lupus: findings from the LUPUS UK Members Survey 2014.

Systemic lupus erythematosus (SLE) is a complex and unpredictable disease which varies greatly among patients and has a significant impact on an individual's daily living and quality of life. A better understanding of the patients' experiences with the disease is vital to the effective management of the disease. LUPUS UK, a national UK-registered charity supporting people with systemic and discoid lupus, conducted a UK-wide survey of individuals living with lupus in order to provide foundation information to support and identify gaps needing further research. An anonymous survey was sent to 5660 LUPUS UK members in order to obtain demographic, diagnosis, symptom and treatment information. A total of 2527 surveys were returned by 2371 females (mean age 56.9 years, SD 13.6) and 156 males, (mean age 60.9 years, SD 15.7). Individuals reported a mean (SD) time to diagnosis from the first symptom of 6.4 (9.5) years, with 47% ( n = 1186) initially being given a different diagnosis prior to lupus. Fatigue/weakness (91%, n = 2299) and joint pain/swelling (77.4%, n = 1957) were the most common symptoms that interfere with daily activities, while 73% ( n = 1836) noted having some problems that make them unable to carry out their usual daily activities. Thirty-two per cent ( n = 806) were also seeking support beyond traditional pharmacological treatments, such as acupuncture and massage. This study highlights the range and frequency of symptoms difficult to live with on a daily basis and support areas needing further research to improve patients' well-being.