Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models.

Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (LeY)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, LeY CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although LeY CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.

Short- and long-term mortality following acute medical admission.

BACKGROUND: Short-term in-hospital mortality following acute medical admission has been widely investigated. Longer term mortality, particularly out-of-hospital mortality, has been less well studied. AIM: The aim of this study is to evaluate short- and long-term mortality, and predictors of such, following acute medical admission. DESIGN: Retrospective database study. METHODS: We evaluated all acute medical admissions to our institution over 10 years (2002-11) with a minimum of a further 10 years follow-up to 2021 using the Irish National Death Register. Predictors of 30-day in-hospital and long-term mortality were analysed with logistic and Cox regression, with loss of life years estimated. RESULTS: The 2002-11 cohort consisted of 62 184 admissions in 35 140 patients. 30-Day in hospital mortality (n = 3646) per patient was 10.4% and per admission was 5.9%. There were an additional 11 440 longer-term deaths by 2021-total mortality was 15 086 (42.9%). Deaths post hospital discharge had median age at admission of 75.4 years [interquartile range (IQR) 63.7, 82.8] and died at median age of 80 years (IQR 69, 87). The half-life of survival following admission was 195 months-representing a short fall of 8 life years (32.9%) compared with the projected population reference of 24.3 years. Age [odds ratio (OR) 1.73 (95% confidence interval (CI) 1.64, 1.81)], acute illness severity score [OR 1.39 (95% CI 1.36, 1.43)] and comorbidity score [OR 1.09 (95% CI 1.08, 1.10)] predicted long-term mortality. CONCLUSION: Similar factors influence both short- and long-term mortality following acute medical admission, the magnitude of effect is attenuated over time.

Yield of brain MRI in children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition. The American Academy of Paediatrics and American Academy of Neurology do not recommend routine brain magnetic resonance imaging (MRI) in the assessment of ASD. The need for a brain MRI should be decided on atypical features in the clinical history and examination. However, many physicians continue to use brain MRI routinely in the assessment process. We performed a retrospective review of indications for requesting brain MRI in our institution over a 5-year period. The aim was to identify the yield of MRI in children with ASD and calculate the prevalence of significant neuroimaging abnormalities in children with ASD and identify clinical indications for neuroimaging. One hundred eighty-one participants were analysed. An abnormal brain MRI was identified in 7.2% (13/181). Abnormal brain MRI was more likely with an abnormal neurological examination (OR 33.1, p = 0.001) or genetic/metabolic abnormality (OR 20, p = 0.02). In contrast, abnormal MRI was not shown to be more likely in children with a variety of other indications such as behavioural issues and developmental delay.      Conclusion: Thus, our findings support that MRI should not be a routine investigation in ASD, without additional findings. The decision to arrange brain MRI should be made on a case-by-case basis following careful evaluation of potential risks and benefits. The impact of any findings on the management course of the child should be considered prior to arranging imaging. What is Known: • Incidental brain MRI findings are common in children with and without ASD. • Many children with ASD undergo brain MRI in the absence of neurological comorbidities. What is New: • Brain MRI abnormalities in ASD are more likely with an abnormal neurological examination and genetic or metabolic conditions. • Prevalence of significant brain MRI abnormalities in ASD alone is low.

Imagined eating - An investigation of priming and sensory-specific satiety.

While obesity remains a pressing issue, the wider population continues to be exposed to more digital food content than ever before. Much research has demonstrated the priming effect of visual food content, i.e., exposure to food cues increasing appetite and food intake. In contrast, some recent research points out that repeated imagined consumption can facilitate satiate and decrease food intake. Such findings have been suggested as potential remedies to excessive food cue exposure. However, the practically limitless variety of digital food content available today may undermine satiation attempts. The present work aims to replicate and extend prior findings by introducing a within-subjects baseline comparison, disentangling general and (sensory-) specific eating desires, as well as considering the moderating influence of visual and flavour stimulus variety. Three online studies (n = 1149 total) manipulated food colour and flavour variety and reproducibly revealed a non-linear dose-response pattern of imagined eating: 3 repetitions primed, while 30 repetitions satiated. Priming appeared to be specific to the taste of the exposed stimulus, and satiation, contrary to prior literature, appeared to be more general. Neither colour nor flavour variety reliably moderated any of the responses. Therefore, the results suggest that a more pronounced variety may be required to alter imagery-induced satiation.

Outcomes for Emergency Department Final Diagnosis of Non-specific Complaint compared to Dyspnoea and Pain.

AIM: To compare outcomes in Emergency Department (ED) final diagnoses of (non-specific complaint) NSC, dyspnoea and pain. METHODS: We studied all ED final diagnoses of NSC, dyspnoea, and pain over 6 years (2015-2020). Multivariable logistic regression was performed. RESULTS: There were 49,965 admissions. 30-day in-hospital mortality was significantly lower for pain, 3.0% (95%CI 2.4%, 3.6%), compared to NSC, 4.2% (95%CI 3.8%, 4.7%), and dyspnoea, 4.6% (95%CI 4.2%, 5.0%). NSC did not predict 30-day in-hospital mortality- univariate OR 1.05 (95%CI 0.93, 1.19), multivariable OR 1.07 (95%CI 0.93, 1.23). Comorbidity and Acute Illness Severity Scores demonstrated a curvilinear relationship with 30-day in-hospital mortality. CONCLUSION: An ED final diagnosis of NSC did not predict 30-day in-hospital mortality.

Developing Irelands first National Student Mental Health and Suicide Prevention Framework for Higher Education.

This article focuses on the development of Ireland's first National Student Mental Health and Suicide Prevention Framework for Higher Education. There is growing concern for student mental health in higher education nationally and globally. The majority of students are aged between 18 and 24, which is identified as a high-risk group for mental health difficulties. Recent surveys of student mental illness, mental distress, and low well-being have been recognized by the World Health Organization, the Union of Students in Ireland National Report on Student Mental Health in Third Level Education, the My World survey and the My World 2 study. The Higher Education Authority in Ireland made a commitment to the Department of Health Connecting for Life (Ireland's National Strategy to Reduce Suicide 2015-2020) to form national guidelines for suicide prevention in higher education. In order to deliver on this commitment, The National Student Mental Health and Suicide Prevention Framework was developed. The Framework is informed by international evidence and was the product of a collaborative cross sector and cross disciplinary team including health professionals, government representatives, educators, students, policy makers, community organizations, researchers and clinicians.

The 'Unwell' clinical presentation- an opportunity for admission avoidance?

BACKGROUND: An 'unwell' patient is a common presentation. METHODS: We studied all ED 'unwell' admissions over 6 years, assessing factors influencing mortality with logistic regression. RESULTS: From 49,965 admissions, the ED diagnosis was 'unwell' in 3650 (7.3%). 'Unwell' presentations were older and had longer length of stay. Mortality was not different 4.2% vs 4.6 % (p=0.28). Respiratory patients and those >=70 years had increased mortality, 8.3% (95%CI: 5.9%, 10.6%) and 7.1% (5.7%, 8.4%) respectively. Being unwell predicted a better outcome - univariate OR 0.35 (95%CI: 0.24, 0.52), multivariable OR 0.68 (95%CI: 0.44, 1.03). CONCLUSION: A diagnosis of 'unwell' applied to a heterogenous group; clinical trajectories and outcomes were sufficiently different to preclude targeted admission avoidance as a strategy.

Blood Culture and Troponin Testing in Suspected Bacteraemic Admissions - Example of Risk Stratification Based on Clinical Testing.

AIM: To investigate the clinical predictive value of troponin (hscTnT) and blood culture testing. METHODS: We examined all medical admissions from 2011-2020. Prediction of 30-day in-hospital mortality, dependent on blood culture and hscTnT requests/results, was evaluated using multiple variable logistic regression. Length of stay was related to utilization of procedures/services with truncated Poisson regression. RESULTS: There were 77,566 admissions in 42,325 patients. With both blood cultures and hscTnT requested, 30-day in-hospital mortality increased to 20.9% (95%CI: 19.7, 22.1) vs 8.9% (95%CI: 8.5, 9.4) for blood cultures alone and 2.3% (95%CI: 2.2, 2.4) with neither. Blood culture 3.93 (95%CI: 3.50, 4.42) or hsTnT requests 4.58 (95%CI: 4.10, 5.14) were prognostic. CONCLUSION: Blood culture and hscTnT requests and results predict worse outcomes.

Impact of the COVID-19 pandemic on surgery for severe endometriosis in the UK: a national database study.

Background: The COVID-19 pandemic has had a significant effect on healthcare services, particularly affecting patients who suffer from chronic conditions. However, the pandemic's effect on endometriosis surgery is not yet known. Objectives: To determine the impact of the COVID-19 pandemic on surgery for severe endometriosis in the UK at a national, regional and centre-level. Materials and Methods: The British Society for Gynaecological Endoscopy (BSGE) collects data nationally on all operations for severe endometriosis which involve dissection of the pararectal space. Annual audits of this database were obtained from the BSGE. Publicly available data on COVID-19 cases and population were obtained from the UK Office for National Statistics. Main outcome measures: Numbers of annual BSGE-registered endometriosis operations. Results: A total of 8204 operations were performed. The number of operations decreased by 49.4% between 2019 and 2020 and then increased in 2021, but remained 10.5% below average pre-pandemic levels, indicating at least 980 missed operations between 2019-2020. Median operations per centre decreased by 51.0% in 2020 (IQR 29.4% - 75.0%) and increased in 2021 but remained 33% below pre-pandemic levels. There was no change in the type of surgery performed. All 11 administrative regions of Great Britain had reduced numbers of operations in 2020 compared with the average for 2017-2019, with a median 44.2% decrease (range 13.3% - 67.5%). Regional reduction in operations was correlated with COVID-19 infection rates (r=0.54, 95% CI of r 0.022 - 1.00, p=0.043). Conclusion: The number of operations performed annually in the UK for severe endometriosis fell dramatically during the COVID-19 pandemic and is yet to normalise. What's new?: This study shows the dramatic effect that the COVID-19 pandemic has had on UK services for endometriosis surgery, which may continue to affect patients and clinicians for a considerable time to come.

Rapid microbial methanogenesis during CO2 storage in hydrocarbon reservoirs.

Carbon capture and storage (CCS) is a key technology to mitigate the environmental impact of carbon dioxide (CO2) emissions. An understanding of the potential trapping and storage mechanisms is required to provide confidence in safe and secure CO2 geological sequestration1,2. Depleted hydrocarbon reservoirs have substantial CO2 storage potential1,3, and numerous hydrocarbon reservoirs have undergone CO2 injection as a means of enhanced oil recovery (CO2-EOR), providing an opportunity to evaluate the (bio)geochemical behaviour of injected carbon. Here we present noble gas, stable isotope, clumped isotope and gene-sequencing analyses from a CO2-EOR project in the Olla Field (Louisiana, USA). We show that microbial methanogenesis converted as much as 13-19% of the injected CO2 to methane (CH4) and up to an additional 74% of CO2 was dissolved in the groundwater. We calculate an in situ microbial methanogenesis rate from within a natural system of 73-109 millimoles of CH4 per cubic metre (standard temperature and pressure) per year for the Olla Field. Similar geochemical trends in both injected and natural CO2 fields suggest that microbial methanogenesis may be an important subsurface sink of CO2 globally. For CO2 sequestration sites within the environmental window for microbial methanogenesis, conversion to CH4 should be considered in site selection.

Inhibiting Type VI Secretion System Activity with a Biomimetic Peptide Designed To Target the Baseplate Wedge Complex.

Human health is threatened by bacterial infections that are increasingly resistant to multiple drugs. A recently emerged strategy consists of disarming pathogenic bacteria by targeting and blocking their virulence factors. The type VI secretion system (T6SS) is a widespread secretion nanomachine encoded and employed by pathogenic strains to establish their virulence process during host invasion. Given the conservation of T6SS in several human bacterial pathogens, the discovery of an effective broad-spectrum T6SS virulence blocker represents an attractive target for development of antivirulence therapies. Here, we identified and validated a protein-protein interaction interface, TssK-TssG, as a key factor in the assembly of the T6SS baseplate (BP) complex in the pathogen enteroaggregative Escherichia coli (EAEC). In silico and biochemical studies revealed that the determinants of the interface are broadly conserved among pathogenic species, suggesting a role for this interface as a target for T6SS inhibition. Based on the high-resolution structure of the TssKFGE wedge complex, we rationally designed a biomimetic cyclic peptide (BCP) that blocks the assembly of the EAEC BP complex and inhibits the function of T6SS in bacterial cultures. Our BCP is the first compound completely designed from prior structural knowledge with anti-T6SS activity that can be used as a model to target human pathogens. IMPORTANCE New therapeutic options are urgently needed to fight drug-resistant and life-threatening infections. In contrast to antibiotics that inhibit the growth pathways of bacteria, the antivirulence strategy is a promising approach to disarm pathogens by interfering with bacterial virulence factors without exerting evolutionary pressure. The type VI secretion system (T6SS) is used by many pathogens, including members of the antibiotic-resistant ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), to establish their virulence during the invasion of the human host. Although the T6SS is undoubtedly involved in pathogenesis, strategies targeting this virulence factor are crucially lacking. Here, we used a combination of genetics, microbiology, biochemical, biophysics, and bioinformatics approaches to rationally design a biomimetic peptide that interferes with T6SS assembly and functioning. This study represents a novel proof of concept for an antivirulence strategy which aims to interfere with the assembly of the T6SS.

Analysis of factors that could affect symptomatic outcome in patients having laparoscopic excision of deep rectovaginal endometriosis in BSGE endometriosis centres.

OBJECTIVE: Investigate factors that influence quality of life after laparoscopic excision of deep rectovaginal endometriosis. STUDY DESIGN: A multicentre prospective cohort study involving 63 hospitals accredited as British Society for Gynaecological Endoscopy specialist endometriosis centres was conducted. The study population comprised of 8368 women who had undergone laparoscopic surgical excision of deep rectovaginal endometriosis requiring dissection of the pararectal space. The main outcome assessed was mean quality of life measured using the EuroQol 100 mm visual analogue score at 6 and 24 months after surgery according to potential prognostic factors. These factors included patient characteristics (age, smoking status, BMI), previous treatments for endometriosis, concomitant bowel surgery and surgical complications. RESULTS: Quality of life improved from a mean pre-operative score of 55/100 to 72/100 (p < 0.01), at 6 months following surgery and this elevated score was sustained at 24 months (mean VAS = 71/100; p < 0.01). Smoking and previous surgery for endometriosis were associated with significantly reduced quality of life at both 6 months (mean difference -7.7 (standard error (SE) 1.0); P < 0.01 and -2.8 (SE 0.7); P < 0.01 respectively) and 24 months after surgery (mean difference -6.8 (SE 1.8); P < 0.01 and -4.5 (SE 1.2); P < 0.01 respectively). Age over 45 years was predictive of greater clinical improvement at 6 and 24 months (mean difference 5.5 (SE 1.2); P < 0.01 and 9.7 (SE 2.2); P < 0.01) as was the use of gonadotrophin analogues (GnRHa) (mean difference 7.6 (SE 1.2); P < 0.01 and 8.9 (SE 2.0); P < 0.01). CONCLUSION(S): Laparoscopic excision of deep endometriosis in specialist centres improves quality of life. Women should be advised to stop smoking and consider pre-operative ovarian suppression. Surgery should be avoided prior to referral to a specialist centre in women diagnosed with deep rectovaginal endometriosis to achieve a better quality of life outcome.

Limited Prognostic Utility of a Simplified Vital Sign Based Risk Calculator in Acute Medical Admissions.

BACKGROUND: Accurate efficient prognostication in acute medical admissions remains challenging. METHODS: We constructed a Vital Sign based Risk Calculator using vital parameters and Major Disease Categories to predict 30-day in-hospital mortality using a multivariable fractional polynomial model. RESULTS: We evaluated 113,807 admissions in 58,126 patients. The Vital Sign based Risk Calculator predicted 30-day inhospital mortality to increase from 2 points - 3.6% (95%CI 3.4, 3.7) to 12 points - 14.8% (95%CI 14.0, 15.7). AUROC was 0.74 (95%CI 0.72, 0.74). The addition of illness severity and comorbidity data improved AUROC to 0.90 (95%CI 0.89, 0.90). CONCLUSION: The Vital Sign based Risk Calculator is limited by its simplicity; inclusion of illness severity and comorbidity data improve prediction.

Prognostic Value Of Blood Cultures as an Illness Severity Marker In Emergency Medical Admissions.

BACKGROUND: Positive blood cultures predict mortality. The prognostic value of blood culture performance itself has not been fully defined. METHODS: We evaluated medical admissions from 2002-2017. We defined blood culture category as 1) no culture 2) negative culture 3) positive culture. We employed a multivariable logistic regression model to evaluate outcomes. RESULTS: We evaluated 78,568 blood cultures in 106,586 admissions. 30-day in-hospital mortality for no culture was 2.8% (95%CI 2.7, 2.9), culture negative 8.9% (95%CI 8.5, 9.3) and culture positive 16.7% (95%CI 15.5, 17.9). There was significant interaction between blood culture category and illness severity, OR 1.06 (95%CI 1.05, 1.08), and comorbidity, OR 1.09 (95%CI 1.09, 1.10). CONCLUSION: Performance and results of blood cultures are independently associated with increased mortality.