What is the relative impact of nudging and online coupling on meteorological variables, pollutant concentrations and aerosol optical properties?

Meteorological and chemical modelling at the regional scale often involve the nudging of the modelled meteorology towards reanalysis fields and meteo-chemical coupling to properly consider the interactions between aerosols, clouds and radiation. Both types of processes can change the meteorology, but not for the same reasons and not necessarily in the same way. To assess the possible interactions between nudging and online coupling, several simulations are carried out with the WRF–CHIMERE (Weather Research and Forecasting) model in its offline and online configurations. Through comparison with measurements, we show that the use of nudging significantly improves the model performances. We also show that coupling changes the results much less than nudging. Finally, we show that when nudging is used, it limits the variability in the results due to coupling.</p

Two decades of recipient and donor referrals for heart transplantation to Groote Schuur Hospital, Cape Town, South Africa: A retrospective study

Background. Heart transplantation in South Africa faces numerous challenges related to organ scarcity and unequal access to advanced heart therapy. There is an urgent need to analyse the current transplant referral pathway to optimise equitable access to transplantation. Objectives. To provide an audit of heart transplant referrals to Groote Schuur Hospital, Cape Town, over a 23-year period, focusing on patient demographics, indications for referral, waiting-list dynamics, and transplant referral outcomes. Methods. The study utilised a retrospective patient folder review for the period 1 January 1997 - 31 December 2019 and audited the trends in heart transplant referrals and associated outcomes of the referral at a tertiary academic hospital. Results. A total of 625 recipients were referred for heart transplantation, with the majority being male (n=412; 65.9%), while gender was undocumented for 69 cases (11.0%). The mean age was 38.1 (14.6) years, and 153 (24.5%) were listed for transplant, while 215 (34.4%) were deemed ineligible for listing. Contraindications for listing included social (n=106; 49.3%), medical (n=83; 38.6%) and psychological (n=26; 12.0%) factors, while 134 patients (21.4%) were considered too well. Poor social circumstances (n=38; 39.6%), poor insight (n=28; 29.2%) and poor compliance (n=21; 21.9%) were the most common non-medical reasons for not listing recipients, while obesity (n=30; 31.3%) and smoking (n=23; 24.0%) were notable medical contraindications. Forty-nine patients (7.8%) died during work-up, while 130 (85.0%) of the listed patients received a heart transplant. Of the 429 donor referrals, 139 (32.4%) were accepted for organ procurement. Reasons for declining donors included unsuitability for transplantation (30.3%), lack of capacity (1.8%), and recipient-donor mismatch (66.9%). Conclusion. Three-quarters of the referred patients were deemed unsuitable for heart transplantation for medical and/or social reasons. The ratio of referral to listing has decreased over time. However, once listed, the likelihood of receiving a transplant was high

Primary retroperitoneal mucinous cystadenoma with sarcoma-like mural nodule: A case report and review of the literature

Primary retroperitoneal cystadenomas are extremely rare. This is the first report in literature to describe a primary retroperitoneal cystadenoma with a sarcoma-like mural nodule. A 45-year-old woman complained of a left-sided abdominal mass. A computed tomography scan revealed a cystic mass with a mural nodule, which seemed to originate from the tail of the pancreas. At laparotomy the cyst was not adhered to the pancreas but localized retroperitoneally. Histologic examination showed a mucinous cystadenoma with only foci of borderline malignancy with a mural “sarcoma-like” nodule. In view of the surgical and histopathological findings, the mucinous cystadenoma was regarded as primary retroperitoneal. This case demonstrates that in the era of radiological preoperative refinement, pathological diagnosis remains of utmost importance, especially for rare cases

Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer

The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM‐3, LAG‐3 and PD‐1 in patients with stage I–III colorectal cancer. Immunohistochemistry was employed to detect TIM‐3, LAG‐3, PD‐1 and PD‐L1 in 773 patients with stage I–III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG‐3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00–2.09, p = 0.049) and PD‐1 (HR 1.34 95% CI 1.00–1.78, p = 0.047) associated with poor survival, whereas high TIM‐3 (HR 0.60 95% CI 0.42–0.84, p = 0.003), LAG‐3 (HR 0.58 95% CI 0.40–0.87, p = 0.006) and PD‐1 (HR 0.65 95% CI 0.49–0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD‐L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG‐3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42–0.78, p = 0.001). The results suggest that individual and combined high expression of TIM‐3, LAG‐3, and PD‐1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously

Investigation of three alternative histopathological scoring methods at the invasive tumour front in colorectal cancer

Although the characteristics at the invasive tumour front in colorectal cancer (CRC) are simple to assess, they are not included in routine pathology reports because they lack reproducibility and standardisation. In this study, we aimed to validate alternative scoring methods at the invasive tumour front in a large cohort of stage I–III CRC. The retrospective analysis was performed on haematoxylin and eosin–stained sections from 538 patients. At the invasive tumour front, tumour characteristics were scored using three alternative methods: the Karamitopoulou method, which evaluates the percentage of infiltrative tumour; the Taskin method, a five-point grading scale; and the tumour growth pattern (TGP) method, which classifies patterns as pushing, intermediate, or infiltrative. For interobserver assessment, the Karamitopoulou and TGP methods showed good agreement while the Taskin method presented fair agreement. High scores with the Karamitopoulou and Taskin methods correlated significantly with adverse prognostic factors, particularly advanced T stage (p &lt; 0.001), N stage (p &lt; 0.001), and the presence of peritoneal involvement (p &lt; 0.001). The survival rate of the TGP method demonstrated that patients with an infiltrative growth pattern had significantly worse CRC survival compared to those with pushing and intermediate growth patterns (p &lt; 0.001) and the TGP method retained its independence as a prognostic factor in multivariable Cox regression analysis only for colon cancer-specific survival (p &lt; 0.001). The TGP scoring method is an independent prognostic factor only for colon cancer with simple and inexpensive assessment, underlining its practicality in routine reporting. Additionally, this method could be included as an additional histopathological risk indicator with the potential to guide therapeutic decision making

Spatially resolved transcriptomics deconvolutes prognostic histological subgroups in patients with colorectal cancer and synchronous liver metastases

Background: Patients demonstrating strong immune responses to primary colorectal cancer (CRC) have a survival benefit following surgery, while those with predominantly stromal microenvironments do poorly. Biomarkers to identify patients with colorectal cancer liver metastases (CRLM) who have good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary CRC and CRLM, and to interrogate the underlying functional biology that drives disease progression. Methods: Patients undergoing synchronous resection of primary CRC and CRLM underwent detailed histological assessment, panel genomic and bulk transcriptomic assessment, immunohistochemistry (IHC) and GeoMx Spatial Transcriptomics (ST) analysis. Integration with genomic features, pathway enrichment analysis and immune deconvolution were performed. Results: High-immune metastases were associated with improved cancer specific survival (HR, 0.36, P=0.01). Bulk transcriptomic analysis was confounded by stromal content but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for Type II Interferon signalling (NES=-2.05 P.Adj&lt;0.005) and MHC-Class II Antigen Presentation (NES=-2.09 P.Adj&lt;0.005). In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T-cells and neutrophils with enrichment of Notch (NES=2.2 P.Adj=0.022) and TGF-β (NES=2.2 P.Adj=0.02) signalling pathways at the metastatic tumor centre. Conclusions: Histological assessment stratifies outcome in patients undergoing synchronous resection of CRLM. ST analysis reveals significant intra-tumoral and inter-lesional heterogeneity with underlying transcriptomic programmes identified in driving each phenotype

Diastolic dysfunction in diabetes and the metabolic syndrome: promising potential for diagnosis and prognosis

Cardiac disease in diabetes mellitus and in the metabolic syndrome consists of both vascular and myocardial abnormalities. The latter are characterised predominantly by diastolic dysfunction, which has been difficult to evaluate in spite of its prevalence. While traditional Doppler echocardiographic parameters enable only semiquantitative assessment of diastolic function and cannot reliably distinguish perturbations in loading conditions from altered diastolic functions, new technologies enable detailed quantification of global and regional diastolic function. The most readily available technique for the quantification of subclinical diastolic dysfunction is tissue Doppler imaging, which has been integrated into routine contemporary clinical practice, whereas cine magnetic resonance imaging (CMR) remains a promising complementary research tool for investigating the molecular mechanisms of the disease. Diastolic function is reported to vary linearly with age in normal persons, decreasing by 0.16 cm/s each year. Diastolic function in diabetes and the metabolic syndrome is determined by cardiovascular risk factors that alter myocardial stiffness and myocardial energy availability/bioenergetics. The latter is corroborated by the improvement in diastolic function with improvement in metabolic control of diabetes by specific medical therapy or lifestyle modification. Accordingly, diastolic dysfunction reflects the structural and metabolic milieu in the myocardium, and may allow targeted therapeutic interventions to modulate cardiac metabolism to prevent heart failure in insulin resistance and diabetes

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC

NFκB signalling in colorectal cancer: examining the central dogma of IKKα and IKKβ signalling

The NFκB pathway, known as the central regulator of inflammation, has a well-established role in colorectal cancer (CRC) initiation, progression, and therapy resistance. Due to the pathway’s overarching roles in CRC, there have been efforts to characterise NFκB family members and target the pathway for therapeutic intervention. Initial research illustrated that the canonical NFκB pathway, driven by central kinase IKKβ, was a promising target for drug intervention. However, dose limiting toxicities and specificity concerns have resulted in failure of IKKβ inhibitors in clinical trials. The field has turned to look at targeting the less dominant kinase, IKKα, which along with NFκB inducing kinase (NIK), drives the lesser researched non-canonical NFκB pathway. However prognostic studies of the non-canonical pathway have produced conflicting results. There is emerging evidence that IKKα is involved in other signalling pathways, which lie outside of canonical and non-canonical NFκB signalling. Evidence suggests that some of these alternative pathways involve a truncated form of IKKα, and this may drive poor cancer-specific survival in CRC. This review aims to explore the multiple components of NFκB signalling, highlighting that NIK may be the central kinase for non-canonical NFκB signalling, and that IKKα is involved in novel pathways which promote CRC