Guided recall of positive autobiographical memories increases anticipated pleasure and psychological resources, and reduces depressive symptoms: a replication and extension of a randomised controlled trial of brief positive cognitive-reminiscence therapy.

Reminiscence-based interventions focus on recalling autobiographical memories and reflective reasoning to develop a healthy and adaptive view of oneself and one's life. This study aimed to replicate the effects of a three-session, group-based, positive-memory version of cognitive-reminiscence therapy (CRT) on psychological resources and mental well-being and extend the findings to anticipated pleasure. The participants (N = 75, Mage = 43.7 (SD = 16.7), 60% females) were randomised to CRT or control group. Anticipated pleasure, psychological resources (schemas of positive self-esteem, self-efficacy, meaning in life, optimism), mental well-being (depression, anxiety, and stress symptoms) and theorised change processes (automatic negative thoughts, awareness of narrative identity) were assessed. Relative to the control group, the CRT group reported significantly higher anticipated pleasure (d = 0.76-0.93) and psychological resources of self-esteem, self-efficacy, and optimism (d's = 0.58-0.99) at post-CRT and follow-up, and lower depressive symptoms post-CRT and at follow-up (d = 0.56-0.67). Findings on meaning in life and negative automatic thinking were partially replicated. This study replicates findings of the effectiveness of this intervention for improving psychological resources such as self-worth, confidence and optimism and depressive symptoms, and indicates additional effects on anticipated pleasure. CRT may serve as a standalone intervention, or as an adjunct "memory booster" for interventions focused on future thinking and related anticipated reward.

Improving usual care outcomes in major depression in youth by targeting memory specificity: A randomized controlled trial of adjunct computerized memory specificity training (c-MeST).

OBJECTIVE: Extending on previous findings that computerized Memory Specificity Training (c-MeST) improves memory specificity and depressive symptoms in Major Depressive Disorder (MDD) in adults, this study aimed to assess the effects of c-MeST in youth with MDD on memory specificity and depression in addition to other treatment. METHODS: Participants aged 15-25 (N = 359, 76 % female; M age = 19.2, SD = 3.1), receiving predominantly psychological therapy or counseling (85 %) and/or antidepressants (52 %) were randomized to usual care and c-MeST or usual care. Cognitive and clinical outcomes were assessed at baseline and at one, three, and six-month follow-ups. RESULTS: The usual care and c-MeST group reported higher memory specificity at one-month (d = 0.42, p = .022), but not at three or six months (d's < 0.15, p's > 0.05). The rate of MDE was numerically lower in the c-MeST group at each follow-up time-point, but group was not a statistically significant predictor at one month (64 % usual care and c-MeST vs. 68 % usual care, OR = 0.81, p = .606), three months (67 % usual care and c-MeST vs. 72 % usual care, OR = 0.64, p = .327) or six months (55 % usual care and c-MeST vs. 68 % usual care, OR = 0.56, p = .266). The usual care and c-MeST group did report lower depressive symptoms at one month (d = 0.42, p = .023) and six-months (d = 0.84, p = .001), but not three-months (d = 0.13, p > .05). CONCLUSIONS: c-MeST may reduce symptoms in youth with MDD when provided alongside other treatments. However, there are significant limitations to this inference, including high attrition in the study and a need for more data on the acceptability of the intervention.

Correction: Hamilton et al. Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2017, 18, 2305.

In the original publication [...].

Development of a Machine Learning Modelling Tool for Predicting HIV Incidence Using Public Health Data from a County in the Southern United States.

BACKGROUND: Recent advancements in Machine Learning (ML) have significantly improved the accuracy of models predicting HIV incidence. These models typically utilize electronic medical records and patient registries. This study aims to broaden the application of these tools by utilizing de-identified public health datasets for notifiable sexually transmitted infections (STIs) from a southern U.S. County known for high HIV incidence rates. The goal is to assess the feasibility and accuracy of ML in predicting HIV incidence, which could potentially inform and enhance public health interventions. METHODS: We analyzed two de-identified public health datasets, spanning January 2010 to December 2021, focusing on notifiable STIs. Our process involved data processing and feature extraction, including sociodemographic factors, STI cases, and social vulnerability index (SVI) metrics. Various ML algorithms were trained and evaluated for predicting HIV incidence, using metrics such as accuracy, precision, recall, and F1 score. RESULTS: The study included 85,224 individuals, with 2,027 (2.37%) newly diagnosed with HIV during the study period. The ML models demonstrated high performance in predicting HIV incidence among males and females. Influential predictive features for males included age at STI diagnosis, previous STI information, provider type, and SVI. For females, they included age, ethnicity, previous STIs information, overall SVI, and race. CONCLUSIONS: The high accuracy of our ML models in predicting HIV incidence highlights the potential of using public health datasets for public health interventions such as tailored HIV testing and prevention. While these findings are promising, further research is needed to translate these models into practical public health applications.

Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure.

Dapagliflozin in Myocardial InfarctionA total of 4017 patients with acute myocardial infarction, but no diabetes or chronic heart failure, were randomly assigned 10 mg of dapagliflozin or placebo. The primary outcome was a composite of death, hospitalization for heart failure, and five cardiometabolic outcomes analyzed using the win ratio method. There were significantly more wins for dapagliflozin than for placebo (win ratio, 1.34; 95% confidence interval, 1.20 to 1.50), which was driven by the cardiometabolic outcomes. The composite of time to cardiovascular death/hospitalization for heart failure was not different between the two groups.

Automated external defibrillator location and socioeconomic deprivation in Great Britain.

OBJECTIVE: The early use of automated external defibrillators (AEDs) improves outcomes in out-of-hospital cardiac arrest (OHCA). We investigated AED access across Great Britain (GB) according to socioeconomic deprivation. METHODS: Cross-sectional observational study using AED location data from The Circuit: the national defibrillator network led by the British Heart Foundation in partnership with the Association of Ambulance Chief Executives, Resuscitation Council UK and St John Ambulance. We calculated street network distances between all 1 677 466 postcodes in GB and the nearest AED and used a multilevel linear mixed regression model to investigate associations between the distances from each postcode to the nearest AED and Index of Multiple Deprivation, stratified by country and according to 24 hours 7 days a week (24/7) access. RESULTS: 78 425 AED locations were included. Across GB, the median distance from the centre of a postcode to an AED was 726 m (England: 739 m, Scotland: 743 m, Wales: 512 m). For 24/7 access AEDs, the median distances were further (991 m, 994 m, 570 m). In Wales, the average distance to the nearest AED and 24/7 AED was shorter for the most deprived communities. In England, the average distance to the nearest AED was also shorter in the most deprived areas. There was no association between deprivation and average distance to the nearest AED in Scotland. However, the distance to the nearest 24/7 AED was greater with increased deprivation in England and Scotland. On average, a 24/7 AED was in England and Scotland, respectively, 99.2 m and 317.1 m further away in the most deprived than least deprived communities. CONCLUSION: In England and Scotland, there are differences in distances to the nearest 24/7 accessible AED between the most and least deprived communities. Equitable access to 'out-of-hours' accessible AEDs may improve outcomes for people with OHCA.

ERK mediates interferon gamma-induced melanoma cell death.

BACKGROUND: Interferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway. METHODS: We performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death. RESULTS: We show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins. CONCLUSIONS: Our results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.

Fractalkine/CX3CR1 in Dilated Cardiomyopathy: A Potential Future Target for Immunomodulatory Therapy?

Dilated cardiomyopathy (DCM) is a cardiac condition with structural and functional impairment, where either the left ventricle or both ventricular chambers are enlarged, coinciding with reduced systolic pump function (reduced ejection fraction, rEF). The prevalence of DCM is more than 1:250 individuals, and mortality largely due to heart failure in two-third of cases, and sudden cardiac death in one-third of patients. Damage to the myocardium, whether from a genetic or environmental cause such as viruses, triggers inflammation and recruits immune cells to the heart to repair the myocardium. Examination of myocardial biopsy tissue often reveals an inflammatory cell infiltrate, T lymphocyte (T cell) infiltration, or other activated immune cells. Despite medical therapy, adverse outcomes for DCM remain. The evidence base and existing literature suggest that upregulation of CX3CR1, migration of immune cells, together with cytomegalovirus (CMV) seropositivity is associated with worse outcomes in patients with dilated cardiomyopathy. We hypothesise that this potentially occurs through cardiac inflammation and fibrosis, resulting in adverse remodelling. Immune modulators to target this pathway may potentially improve outcomes above and beyond current guideline-recommended therapy.

Conservative versus Invasive Strategy in Elderly Patients with Non-ST-Elevation Myocardial Infarction: Insights from the International POPular Age Registry.

This registry assessed the impact of conservative and invasive strategies on major adverse clinical events (MACE) in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). Patients aged ≥75 years with NSTEMI were prospectively registered from European centers and followed up for one year. Outcomes were compared between conservative and invasive groups in the overall population and a propensity score-matched (PSM) cohort. MACE included cardiovascular death, acute coronary syndrome, and stroke. The study included 1190 patients (median age 80 years, 43% female). CAG was performed in 67% (N = 798), with two-thirds undergoing revascularization. Conservatively treated patients had higher baseline risk. After propensity score matching, 319 patient pairs were successfully matched. MACE occurred more frequently in the conservative group (total population 20% vs. 12%, adjHR 0.53, 95% CI 0.37-0.77, p = 0.001), remaining significant in the PSM cohort (18% vs. 12%, adjHR 0.50, 95% CI 0.31-0.81, p = 0.004). In conclusion, an early invasive strategy was associated with benefits over conservative management in elderly patients with NSTEMI. Risk factors associated with ischemia and bleeding should guide strategy selection rather than solely relying on age.

Conversion of Patellofemoral Arthroplasty to Robotic-Assisted Total Knee Arthroplasty.

Conversion of patellofemoral arthroplasty to total knee arthroplasty (TKA) has been described as similar to primary TKA, although it may come with more challenges and worse outcomes. With the increased rate of revision following conversion TKA vs primary TKA, robotically assisted TKA provides an alternative technique to manual conversion. We present 3 cases of robot-assisted conversion of prior patellofemoral arthroplasty to TKA with good mechanical and clinical outcomes and no intraoperative complications.

Adaptation of the Tumor Antigen Presentation Machinery to Ionizing Radiation.

Ionizing radiation (IR) can reprogram proteasome structure and function in cells and tissues. In this article, we show that IR can promote immunoproteasome synthesis with important implications for Ag processing and presentation and tumor immunity. Irradiation of a murine fibrosarcoma (FSA) induced dose-dependent de novo biosynthesis of the immunoproteasome subunits LMP7, LMP2, and Mecl-1, in concert with other changes in the Ag-presentation machinery (APM) essential for CD8+ T cell-mediated immunity, including enhanced expression of MHC class I (MHC-I), ß2-microglobulin, transporters associated with Ag processing molecules, and their key transcriptional activator NOD-like receptor family CARD domain containing 5. In contrast, in another less immunogenic, murine fibrosarcoma (NFSA), LMP7 transcripts and expression of components of the immunoproteasome and the APM were muted after IR, which affected MHC-I expression and CD8+ T lymphocyte infiltration into NFSA tumors in vivo. Introduction of LMP7 into NFSA largely corrected these deficiencies, enhancing MHC-I expression and in vivo tumor immunogenicity. The immune adaptation in response to IR mirrored many aspects of the response to IFN-γ in coordinating the transcriptional MHC-I program, albeit with notable differences. Further investigations showed divergent upstream pathways in that, unlike IFN-γ, IR failed to activate STAT-1 in either FSA or NFSA cells while heavily relying on NF-κB activation. The IR-induced shift toward immunoproteasome production within a tumor indicates that proteasomal reprogramming is part of an integrated and dynamic tumor-host response that is specific to the stressor and the tumor and therefore is of clinical relevance for radiation oncology.

Fractalkine Signalling (CX3CL1/CX3CR1 Axis) as an Emerging Target in Coronary Artery Disease.

Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CX3CL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CX3CR1. We have shown previously that the fractalkine receptor CX3CR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CX3CR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CX3CR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.

Analysis of Adsorbed Polyphosphate Changes on Milled Titanium Dioxide, Using Low-Field Relaxation NMR and Photoelectron Spectroscopy.

In this study, changes in the adsorbed amount and surface structure of sodium hexametaphosphate (SHMP) were investigated for aluminum-doped TiO2 pigment undergoing milling. Relaxation NMR was utilized as a potential at-line technique to monitor the effect of milling on surface area and surface chemistry, while XPS was used primarily to consider the dispersant structure. Results showed that considerable amounts of weakly adsorbed SHMP could be removed with washing, and the level of dispersant removal increased with time, highlighting destructive effects of sustained high-energy milling. Nonetheless, there were no significant chemical changes to the dispersant, although increases to the bridging oxygen (BO) peak full width at half-maximum (FWHM) suggested some chemical degradation was occurring with excess milling. Relaxation NMR revealed a number of important features. Results with unmilled material indicated that dispersant adsorption could be tracked with pseudo-isotherms using the relative enhancement rate (Rsp), where the Rsp decreased with dispersant coverage, owing to partial blocking of the quadrupolar surface aluminum. Milled samples were also tracked, with very accurate calibrations of surface area possible from either T1 or T2 relaxation data for systems without dispersant. Behavior was considerably more complicated with SHMP, as there appeared to be an interplay between the dispersant surface coverage and relaxation enhancement from the surface aluminum. Nevertheless, findings highlight that relaxation NMR could be used as a real-time technique to monitor the extent of milling processes, so long as appropriate industrial calibrations can be achieved.

Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction.

Myocardial infarction (MI) accelerates immune ageing characterised by lymphopenia, expansion of terminally differentiated CD8+ T-lymphocytes (CD8+ TEMRA) and inflammation. Pre-clinical data showed that TA-65, an oral telomerase activator, reduced immune ageing and inflammation after MI. We conducted a double blinded randomised controlled pilot trial evaluating the use of TA-65 to reduce immune cell ageing in patients following MI. Ninety MI patients aged over 65 years were randomised to either TA-65 (16 mg daily) or placebo for 12 months. Peripheral blood leucocytes were analysed by flow cytometry. The pre-defined primary endpoint was the proportion of CD8+ T-lymphocytes which were CD8+ TEMRA after 12 months. Secondary outcomes included high-sensitivity C-reactive protein (hsCRP) levels. Median age of participants was 71 years. Proportions of CD8+ TEMRA did not differ after 12 months between treatment groups. There was a significant increase in mean total lymphocyte count in the TA-65 group after 12 months (estimated treatment effect: + 285 cells/µl (95% CI: 117-452 cells/ µ l, p < 0.004), driven by significant increases from baseline in CD3+, CD4+, and CD8+ T-lymphocytes, B-lymphocytes and natural killer cells. No increase in lymphocyte populations was seen in the placebo group. At 12 months, hsCRP was 62% lower in the TA-65 group compared to placebo (1.1 vs. 2.9 mg/L). Patients in the TA-65 arm experienced significantly fewer adverse events (130 vs. 185, p = 0.002). TA-65 did not alter CD8+ TEMRA but increased all major lymphocyte subsets and reduced hsCRP in elderly patients with MI after 12 months.

Saksenaea mucormycosis: a rare and dangerous cause of necrotising fasciitis.

Necrotising fasciitis is a rapidly progressing soft tissue infection requiring early and adequate surgical debridement and appropriate antibiotic cover. The present case highlights bacterial fasciitis associated with fungal (Mucor) infection with insidious angioinvasive nature (Saksenaea vasiformis) which required amputation, negative-pressure vacuum dressings and amphotericin B for definitive treatment. This demonstrates a relatively rare case of the group IV classification of necrotising fasciitis, which we must consider when there is slowly progressing tissue death despite seemingly adequate treatment.

Severe Maternal Morbidity in Georgia, 2009-2020.

BACKGROUND: The increasing focus of population surveillance and research on maternal-and not only fetal and infant-health outcomes is long overdue. The United States maternal mortality rate is higher than any other high-income country, and Georgia is among the highest rates in the country. Severe maternal morbidity (SMM) is conceived of as a "near miss" for maternal mortality, is 50 times more common than maternal death, and efforts to systematically monitor SMM rates in populations have increased in recent years. Much of the current population-based research on SMM has occurred in coastal states or large cities, despite substantial geographical variation with higher maternal and infant health burdens in the Southeast and rural regions. METHODS: This population-based study uses hospital discharge records linked to vital statistics to describe the epidemiology of SMM in Georgia between 2009 and 2020. RESULTS: Georgia had a higher SMM rate than the United States overall (189.2 vs. 144 per 10,000 deliveries in Georgia in 2014, the most recent year with US estimates). SMM was higher among racially minoritized pregnant persons and those at the extremes of age, of lower socioeconomic status, and with comorbid chronic conditions. SMM rates were 5 to 6 times greater for pregnant people delivering infants <1500 grams or <32 weeks' gestation as compared with those delivering normal weight or term infants. Since 2015, SMM has increased in Georgia. CONCLUSION: SMM represents a collection of life-threatening emergencies that are unevenly distributed in the population and require increased attention. This descriptive analysis provides initial guidance for programmatic interventions intending to reduce the burden of SMM and, subsequently, maternal mortality in the US South.

Impact of Sex on Clinical Outcomes in Patients undergoing Complex Percutaneous Coronary Angioplasty (from the e-ULTIMASTER Study).

Female gender has been shown to be associated with worse clinical outcomes after percutaneous coronary intervention (PCI). However, the impact of gender on the clinical outcomes of complex PCI is still poorly understood. This study examined the differences in patient and coronary lesion characteristics and longer-term clinical outcomes in male and female patients who underwent complex PCI. This was a sub-analysis of the e-ULTIMASTER study, which was a large, multicontinental, prospective, observational study enrolling 37,198 patients who underwent PCI with the Ultimaster stent. Patients who underwent complex PCI were stratified by gender. The primary outcome was target lesion failure at 12 months, defined as the composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target lesion revascularization at 12 months. A total of 13,623 patients underwent complex procedures, of which 35.7% were women. Women were twice as likely as men to be aged ≥80 years (17.6% vs 9%, p <0.0001) and had a higher prevalence of cardiovascular risk factors. Women had fewer lesions treated than men (1.5 ± 0.8 vs 1.6 ± 0.8, p <0.0001) and fewer stents implanted (2.0 ± 1.1 vs 2.1 ± 1.1, p <0.0001). There was no statistically significant difference in clinical outcomes at 12 months between women and men. Event rates were comparable in women and men for target lesion failure (4.7% vs 4.3%, p = 0.30), target vessel failure (5.1% vs 4.9%, p = 0.73), and cardiac death (1.8% vs 1.7%, p = 0.80).In conclusion, our findings suggest no significant differences in clinical outcomes between women and men who underwent complex PCI.

Preventing cardiotoxicity in patients with breast cancer and lymphoma: protocol for a multicentre randomised controlled trial (PROACT).

INTRODUCTION: Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin's lymphoma (NHL) receiving anthracycline-based chemotherapy. METHODS AND ANALYSIS: PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects. ETHICS AND DISSEMINATION: A favourable opinion was given following research ethics committee review by West Midlands-Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03265574.

Prognosis of PCI in AMI setting in the elderly population: Outcomes from the multicenter prospective e-ULTIMASTER registry.

BACKGROUND: Elderly patients with ST-elevation myocardial infarction (STEMI) who undergo percutaneous coronary intervention (PCI) are usually excluded from major trials. HYOPTHESIS: This study sought to assess 1-year clinical outcomes following PCI with a drug-eluting stent in patients older than 80 years old with STEMI. METHODS: The large all-comer, multicontinental e-ULTIMASTER registry included 7507 patients with STEMI who underwent PCI using the Ultimaster stent. The primary clinical endpoint was 1-year target lesion failure, a composite of cardiac death (CD), target vessel-related myocardial infarction (TV-MI), or clinically driven target lesion revascularization (CD-TLR). RESULTS: There were 457 (6.1%) patients in the elderly group (≥80 years old) that were compared to 7050 (93.9%) patients <80 years. The elderly patients included more female patients and had significantly more comorbidities and had more complex coronary anatomy. The primary endpoint occurred in 7.2% of the elderly, compared to 3.1% of the younger group (p < .001). All-cause mortality was significantly higher among the elderly group compared to the younger group (10.1% vs. 2.3%, p < .0001), as well as CD (6.1% vs. 1.6%, p < .0001), but not TV-MI (1.1% vs. 0.7%, p = .34) or CD-TLR (1.1% vs. 1.4%, p = .63). CONCLUSION: Elderly patients with STEMI presentation had a higher incidence of the composite endpoint than younger patients. All-cause and CD were higher for elderly patients compared to patients younger than 80 years old. However, there was no difference in the incidence of TV-MI or target lesion revascularizations. These findings suggest that PCI for STEMI in elderly patients is relatively safe.