THE SIGNIFICANCE OF INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-ALPHA LEVELS IN COGNITIVE IMPAIRMENT AMONG FIRST-EVER ACUTE ISCHAEMIC STROKE PATIENTS

Background: Acute ischemic stroke (AIS) frequently results in the development of cognitive impairment, which quite often persists. The pathophysiological mechanisms involved in the development of cognitive impairment are only partially elucidated. The aim of this study was to evaluate the correlation between interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-) serum levels with cognitive impairment in AIS patients. Subjects and methods: This hospital-based case-control study was performed during December 2014 May 2018. A total number of 130 randomly selected patients were prospectively recruited from the Department of Neurology, Clinical Center University of Sarajevo. The study examined 100 first-ever AIS patients, while 30 comprised the non-stroke control group of patients with discogenic lumbosacral radiculopathy. All participants were evaluated using the Mini-Mental State Examination, the Montreal Cognitive Assessment, the Frontal Assessment Battery, and the Addenbrooke\u27s Cognitive Examination-Revised. Cognitive testing and laboratory analyses were performed within the first three days of admission in all patients while AIS patients were reassessed on the 15th day of hospitalization. Results: Female stroke patients with cognitive impairment had significantly higher baseline levels of IL-6 (p<0.017), and TNF- (p<0.017) than those without cognitive impairment. In the control measurement, a significant difference in IL-6 levels (p=0.037) in male and TNF-=0.042) in female stroke patients with cognitive impairment was observed. Conclusions: These findings indicate that pro-inflammatory cytokines are probably implicated in the pathogenesis of cognitive decline in AIS patients

THE SIGNIFICANCE OF INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-ALPHA LEVELS IN COGNITIVE IMPAIRMENT AMONG FIRST-EVER ACUTE ISCHAEMIC STROKE PATIENTS

Background: Acute ischemic stroke (AIS) frequently results in the development of cognitive impairment, which quite often persists. The pathophysiological mechanisms involved in the development of cognitive impairment are only partially elucidated. The aim of this study was to evaluate the correlation between interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-) serum levels with cognitive impairment in AIS patients. Subjects and methods: This hospital-based case-control study was performed during December 2014 May 2018. A total number of 130 randomly selected patients were prospectively recruited from the Department of Neurology, Clinical Center University of Sarajevo. The study examined 100 first-ever AIS patients, while 30 comprised the non-stroke control group of patients with discogenic lumbosacral radiculopathy. All participants were evaluated using the Mini-Mental State Examination, the Montreal Cognitive Assessment, the Frontal Assessment Battery, and the Addenbrooke\u27s Cognitive Examination-Revised. Cognitive testing and laboratory analyses were performed within the first three days of admission in all patients while AIS patients were reassessed on the 15th day of hospitalization. Results: Female stroke patients with cognitive impairment had significantly higher baseline levels of IL-6 (p<0.017), and TNF- (p<0.017) than those without cognitive impairment. In the control measurement, a significant difference in IL-6 levels (p=0.037) in male and TNF-=0.042) in female stroke patients with cognitive impairment was observed. Conclusions: These findings indicate that pro-inflammatory cytokines are probably implicated in the pathogenesis of cognitive decline in AIS patients

Application of Building Typologies for Modelling the Energy Balance of the Residential Building Stock

Building typologies can serve as a basis for analysing the national housing sector. During the TABULA project which was introducing or further developing building typologies in thirteen EU countries, six of the European partners have carried out model calculations which aim at imaging the energy consumption and estimating the energy saving potentials of their national residential building stocks (IWU / Germany, NOA / Greece, POLITO / Italy, VITO / Belgium, STU-K / Czech Republic, SBi / Denmark). The results show that the model calculations can provide plausible projections of the energy consumption of the national residential buildings stock. The fit of model calculations and national energy statistics is satisfactory, deviations can often be explained and corrected by adapting standard boundary conditions of the applied calculation models to more realistic values. In general, the analysis shows that building typologies can be a helpful tool for modelling the energy consumption of national building stocks and for carrying out scenario analysis beyond the TABULA project. The consideration of a set of representative buildings makes it possible to have a detailed view on various packages of measures for the complete buildings stock or for its sub-categories. The effects of different insulation measures at the respective construction elements as well as different heat supply measures including renewable energies can be considered in detail. The quality of future model calculations will depend very much on the availability of statistical data. For reliable scenario analysis information is necessary about the current state of the building stock (How many buildings and heating systems have been refurbished until now?) and about the current trends (How many buildings and heating systems are being refurbished every year?). The availability and regular update of the relevant statistical data will be an important basis for the development and evaluation of national climate protection strategies in the building secto

Application of Building Typologies for Modelling the Energy Balance of the Residential Building Stock.

Building typologies can serve as a basis for analysing the national housing sector. During the TABULA project which was introducing or further developing building typologies in thirteen EU countries, six of the European partners have carried out model calculations which aim at imaging the energy consumption and estimating the energy saving potentials of their national residential building stocks (IWU / Germany, NOA / Greece, POLITO / Italy, VITO / Belgium, STU-K / Czech Republic, SBi / Denmark). The results show that the model calculations can provide plausible projections of the energy consumption of the national residential buildings stock. The fit of model calculations and national energy statistics is satisfactory, deviations can often be explained and corrected by adapting standard boundary conditions of the applied calculation models to more realistic values. In general, the analysis shows that building typologies can be a helpful tool for modelling the energy consumption of national building stocks and for carrying out scenario analysis beyond the TABULA project. The consideration of a set of representative buildings makes it possible to have a detailed view on various packages of measures for the complete buildings stock or for its sub-categories. The effects of different insulation measures at the respective construction elements as well as different heat supply measures including renewable energies can be considered in detail. The quality of future model calculations will depend very much on the availability of statistical data. For reliable scenario analysis information is necessary about the current state of the building stock (How many buildings and heating systems have been refurbished until now?) and about the current trends (How many buildings and heating systems are being refurbished every year?). The availability and regular update of the relevant statistical data will be an important basis for the development and evaluation of national climate protection strategies in the building sector

Type of mRNA COVID-19 vaccine and immunomodulatory treatment influence humoral immunogenicity in patients with inflammatory rheumatic diseases

Patients with inflammatory rheumatic diseases (IRD) are at increased risk for worse COVID-19 outcomes. Identifying whether mRNA vaccines differ in immunogenicity and examining the effects of immunomodulatory treatments may support COVID-19 vaccination strategies. We aimed to conduct a long-term, model-based comparison of the humoral immunogenicity following BNT162b2 and mRNA-1273 vaccination in a cohort of IRD patients. Patients from the Swiss IRD cohort (SCQM), who assented to mRNA COVID-19 vaccination were recruited between 3/2021-9/2021. Blood samples at baseline, 4, 12, and 24 weeks post second vaccine dose were tested for anti-SARS-CoV-2 spike IgG (anti-S1). We examined differences in antibody levels depending on the vaccine and treatment at baseline while adjusting for age, disease, and past SARS-CoV-2 infection. 565 IRD patients provided eligible samples. Among monotherapies, rituximab, abatacept, JAKi, and TNFi had the highest odds of reduced anti-S1 responses compared to no medication. Patients on specific combination therapies showed significantly lower antibody responses than those on monotherapy. Irrespective of the disease, treatment, and past SARS-CoV-2 infection, the odds of higher antibody levels at 4, 12, and 24 weeks post second vaccine dose were, respectively, 3.4, 3.8, and 3.8 times higher with mRNA-1273 versus BNT162b2 (p < 0.0001). With every year of age, the odds ratio of higher peak humoral immunogenicity following mRNA-1273 versus BNT162b2 increased by 5% (p < 0.001), indicating a particular benefit for elderly patients. Our results suggest that in IRD patients, two-dose vaccination with mRNA-1273 versus BNT162b2 results in higher anti-S1 levels, even more so in elderly patients

Type of mRNA COVID-19 vaccine and immunomodulatory treatment influence humoral immunogenicity in patients with inflammatory rheumatic diseases.

Patients with inflammatory rheumatic diseases (IRD) are at increased risk for worse COVID-19 outcomes. Identifying whether mRNA vaccines differ in immunogenicity and examining the effects of immunomodulatory treatments may support COVID-19 vaccination strategies. We aimed to conduct a long-term, model-based comparison of the humoral immunogenicity following BNT162b2 and mRNA-1273 vaccination in a cohort of IRD patients. Patients from the Swiss IRD cohort (SCQM), who assented to mRNA COVID-19 vaccination were recruited between 3/2021-9/2021. Blood samples at baseline, 4, 12, and 24 weeks post second vaccine dose were tested for anti-SARS-CoV-2 spike IgG (anti-S1). We examined differences in antibody levels depending on the vaccine and treatment at baseline while adjusting for age, disease, and past SARS-CoV-2 infection. 565 IRD patients provided eligible samples. Among monotherapies, rituximab, abatacept, JAKi, and TNFi had the highest odds of reduced anti-S1 responses compared to no medication. Patients on specific combination therapies showed significantly lower antibody responses than those on monotherapy. Irrespective of the disease, treatment, and past SARS-CoV-2 infection, the odds of higher antibody levels at 4, 12, and 24 weeks post second vaccine dose were, respectively, 3.4, 3.8, and 3.8 times higher with mRNA-1273 versus BNT162b2 (p < 0.0001). With every year of age, the odds ratio of higher peak humoral immunogenicity following mRNA-1273 versus BNT162b2 increased by 5% (p < 0.001), indicating a particular benefit for elderly patients. Our results suggest that in IRD patients, two-dose vaccination with mRNA-1273 versus BNT162b2 results in higher anti-S1 levels, even more so in elderly patients

Technomass and cooling demand in South America: a superlinear relationship?

The impact of the increasing technomass (TM) on cooling demand in buildings is explored for cities in South America. The entangled double nature of the building–environment interrelation in an urban context is analyzed. The research question is whether an increase in the building density produces a superlinear increase of energy consumption at the urban scale. Advanced spatially explicit quantitative methods are used to select representative samples of the urban environment and to quantify the volumes of TM in four South American cities. Principal component analysis is used to extract representative urban tissue categories. The Urban Weather Generator tool is used to produce the urban weather data used in building performance simulations. The results confirm the superlinear dependence of the total cooling consumption of each sample in relation to the existing TM in areas with high-rise buildings due to the combined primary and secondary effects, namely, the increase of the total energy needs and the increase of air temperature due to the urban heat island effect. The great significance of the second-order effect poses challenges to current assessments performed on the basis of consumption per m2. The use of the TM indicator can promote the development of climate-sensible urban planning

Genetic and immune landscape evolution in MMR-deficient colorectal cancer.

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/β-catenin, mitogen-activated protein kinase, and TGF-β receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

The Society for Immunotherapy of Cancer statement on best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) staining and validation.

OBJECTIVES: The interaction between the immune system and tumor cells is an important feature for the prognosis and treatment of cancer. Multiplex immunohistochemistry (mIHC) and multiplex immunofluorescence (mIF) analyses are emerging technologies that can be used to help quantify immune cell subsets, their functional state, and their spatial arrangement within the tumor microenvironment. METHODS: The Society for Immunotherapy of Cancer (SITC) convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the optimization and validation of mIHC/mIF assays across platforms. RESULTS: Representative outputs and the advantages and disadvantages of mIHC/mIF approaches, such as multiplexed chromogenic IHC, multiplexed immunohistochemical consecutive staining on single slide, mIF (including multispectral approaches), tissue-based mass spectrometry, and digital spatial profiling are discussed. CONCLUSIONS: mIHC/mIF technologies are becoming standard tools for biomarker studies and are likely to enter routine clinical practice in the near future. Careful assay optimization and validation will help ensure outputs are robust and comparable across laboratories as well as potentially across mIHC/mIF platforms. Quantitative image analysis of mIHC/mIF output and data management considerations will be addressed in a complementary manuscript from this task force