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| 2. |
- Mullins, N., et al.
(author)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Journal article (peer-reviewed)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 3. |
- Jonsson, Lina, 1982, et al.
(author)
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Characterisation of age and polarity at onset in bipolar disorder
- 2021
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In: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
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Journal article (peer-reviewed)abstract
- Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (beta = -0.34 years, s.e. = 0.08), major depression (beta = -0.34 years, s.e. = 0.08), schizophrenia (beta = -0.39 years, s.e. = 0.08), and educational attainment (beta = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
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| 5. |
- Jones, Lesley, et al.
(author)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Journal article (peer-reviewed)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 6. |
- da Silva, R., et al.
(author)
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Oxygen, sulfur, and iron radial abundance gradients of classical Cepheids across the Galactic thin disk
- 2023
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 678, s. A195-A195
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Journal article (peer-reviewed)abstract
- Context. Classical Cepheids (CCs) are solid distance indicators and tracers of young stellar populations. Dating back to the beginning of the 20th century, they have been safely adopted to trace the rotation, kinematics, and chemical enrichment history of the Galactic thin disk.Aims. The main aim of this investigation is to provide iron, oxygen, and sulfur abundances for the largest and most homogeneous sample of Galactic CCs analyzed so far (1118 spectra of 356 objects). The current sample, containing 70 CCs for which spectroscopic metal abundances are provided for the first time, covers a wide range in galactocentric distances, pulsation modes, and pulsation periods.Methods. Optical high-resolution spectra with a high signal-to-noise ratio that were collected with different spectrographs were adopted to provide homogeneous estimates of the atmospheric parameters (effective temperature, surface gravity, and microturbulent velocity) that are required to determine the abundance. Individual distances were based either on trigonometric parallaxes by the Gaia Data Release 3 (Gaia DR3) or on distances based on near-infrared period-luminosity relations.Results. We found that iron and α-element radial gradients based on CCs display a well-defined change in the slope for galactocentric distances larger than ~12 kpc. We also found that logarithmic regressions account for the variation in [X/H] abundances from the inner to the outer disk. Radial gradients for the same elements, but based on open clusters covering a wide range in cluster ages, display similar trends. This means that the flattening in the outer disk is an intrinsic feature of the radial gradients because it is independent of age. Empirical evidence indicates that the S radial gradient is steeper than the Fe radial gradient. The difference in the slope is a factor of two in the linear fit (−0.081 vs. −0.041 dex kpc−1) and changes from −1.62 to −0.91 in the logarithmic distance. Moreover, we found that S (explosive nucleosynthesis) is underabundant on average when compared with O (hydrostatic nucleosynthesis). The difference becomes clearer in the metal-poor regime and for the [O/Fe] and [S/Fe] abundance ratios. We performed a detailed comparison with Galactic chemical evolution models and found that a constant star formation efficiency for galactocentric distances larger than 12 kpc accounts for the flattening observed in both iron and α-elements. To further constrain the impact of the predicted S yields for massive stars on radial gradients, we adopted a toy model and found that the flattening in the outermost regions requires a decrease of a factor of four in the current S predictions.Conclusions. CCs are solid beacons for tracing the recent chemical enrichment of young stellar populations. Sulfur photospheric abundances, when compared with other α-elements, have the key advantage of being a volatile element. Therefore, stellar S abundances can be directly compared with nebular sulfur abundances in external galaxies.
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| 7. |
- Mazzeschi, M., et al.
(author)
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The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer
- 2022
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In: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 41:1
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Journal article (peer-reviewed)abstract
- Background In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). Methods In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use. Results ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo. Conclusions Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.
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| 8. |
- Penney, K. L., et al.
(author)
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mRNA expression signature of Gleason grade predicts lethal prostate cancer
- 2011
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In: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 29:17, s. 2391-2396
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Journal article (peer-reviewed)abstract
- PURPOSE: Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis.PATIENTS AND METHODS: Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases.RESULTS: We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006).CONCLUSION: Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.
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| 14. |
- Aggarwal, R, et al.
(author)
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2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative
- 2017
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 76:5, s. 792-801
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Journal article (peer-reviewed)abstract
- To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0–100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.
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| 17. |
- Calvert, Clara, et al.
(author)
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Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries
- 2023
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In: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 7:4, s. 529-544
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Journal article (peer-reviewed)abstract
- Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.
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| 18. |
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| 19. |
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| 20. |
- KC, Ashish, 1982-, et al.
(author)
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Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.
- 2023
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In: Nature human behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 7:4, s. 529-544
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Journal article (peer-reviewed)abstract
- Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.
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| 21. |
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| 23. |
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| 24. |
- Zhang, Yiwen, et al.
(author)
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A prospective study of intraprostatic inflammation, focal atrophy, and progression to lethal prostate cancer
- 2019
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 28:12, s. 2047-2054
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Journal article (peer-reviewed)abstract
- BACKGROUND: Inflammation and focal atrophy are common features adjacent to prostate tumors. Limited evidence exists on whether these features have prognostic significance.METHODS: In the Health Professionals Follow-Up Study and Physicians' Health Study, we studied 1,035 men diagnosed with prostate cancer. A genitourinary pathologist centrally reviewed tumor and normal areas of hematoxylin and eosin slides from prostate cancer specimens for the presence of acute and chronic inflammation, and four subtypes of focal atrophy. Cox proportional hazards models adjusted for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of these features with lethal prostate cancer, defined as development of metastatic disease or death during follow-up.RESULTS: During a median of 12 years of follow-up, 153 men developed lethal prostate cancer. Eighty-four percent of men had histologic evidence of chronic inflammation and 30% had acute inflammation. Both chronic and acute inflammation were inversely associated with lethal prostate cancer in age- and lifestyle-adjusted models. Chronic inflammation remained inversely associated with lethal prostate cancer after additionally adjusting for prognostic clinical features (HR=0.45, 95% CI 0.30 to 0.69 for mild, HR=0.51, 95% CI 0.33 to 0.80 for moderate to severe). None of the atrophic lesions were associated with lethal prostate cancer.CONCLUSIONS: Our data suggest that the presence of inflammation, particularly chronic inflammation, in prostate cancer tissue is associated with better prognosis among prostate cancer patients.IMPACT: This is the largest prospective cohort study to examine the association between inflammation, focal atrophy, and lethal prostate cancer.
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| 29. |
- Fiorentino, M., et al.
(author)
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Immunohistochemical Expression of BRCA1 in Prostate Cancer
- 2009
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In: Laboratory Investigation. - : Nature Publishing Group. - 0023-6837 .- 1530-0307. ; 22, s. 169A-169A
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Journal article (other academic/artistic)abstract
- Background: BRCA1 is a multifunctional protein involved in DNA repair, gene transcription and the regulation of cell-cycle check-points. While germline mutations of BRCA1 are rare in prostate cancer and seem to play a limited role in tumor susceptibility, BRCA1 expression has not been investigated to date.Design: We analyzed the immunohistochemical expression of BRCA1 in paraffin embedded samples from 524 men with prostate cancer belonging to the Physicians’ Health Study and the Swedish Watchful Waiting cohorts of prostate cancer patients. High density tissue micro-arrays (TMA) including at least three tumor cores for each case were utilized for the immunohistochemical staining with the monoclonal MS110 antibody specific for the N-terminus of the 220 kDa BRCA1 protein. Cases were scored as negative or positive for BRCA1 immunostaining. The Ki67 proliferation index was also assessed on the same TMAs and evaluated by quantitative image analysis.Results: A positive nuclear immunostaining for BRCA1 was revealed in 62 of 524 (11.9%) patients while normal prostate control cores were all negative. BRCA1 positive tumors were associated with 4 times greater proliferation rate compared to BRCA1 negative tumors (p ∼ 0.0003). In addition, we found a linear trend such that tumors with greater number of TMA cores expressing BRCA1 had stronger extent of proliferation. Men with BRCA1 positive tumors had a slightly higher Gleason’s score (mean 7.5) compared to those negative for BRCA1 (mean 7) No significant correlation was found between BRCA1 staining and cancer-specific death.Conclusions: BRCA1 protein is expressed in a small subset of prostate cancers characterized by high proliferation index but not in normal prostate tissue. Expression of BRCA1 might be acquired in selected tumors to prevent DNA damage in actively replicating cells. A different role independent of germline mutations might be disclosed for BRCA1 as cell cycle regulator in prostate cancer.
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| 38. |
- Rong, Y., et al.
(author)
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High speed optical modulation in Ge quantum wells using quantum confined stark effect
- 2012
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In: Frontiers of Optoelectronics. - : Springer Science and Business Media LLC. - 2095-2759 .- 2095-2767. ; 5:1, s. 82-89
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Journal article (peer-reviewed)abstract
- We focus on the optimization of SiGe material deposition, the minimization of the parasitic capacitance of the probe pads for high speed, low voltage and high contrast ratio operation. The device fabrication is based on processes for standard Si electronics and is suitable for mass-production. We present observations of quantum confinement and quantum-confined Stark effect (QCSE) electroabsorption in Ge quantum wells (QWs) with SiGe barriers grown on Si substrates. Though Ge is an indirect gap semiconductor, the resulting effects are at least as clear and strong as seen in typical III-V QWstructures at similar wavelengths. We also demonstrated a modulator, with eye diagrams of up to 3. 5 GHz, a small driving voltage of 2. 5 V and a modulation bandwidth at about 10 GHz. Finally, carrier dynamics under ultra-fast laser excitation and high-speed photocurrent response are investigated.
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| 42. |
- Bergman, Michael, et al.
(author)
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International Diabetes Federation Position Statement on the 1-hour post-load plasma glucose for the diagnosis of intermediate hyperglycaemia and type 2 diabetes
- 2024
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In: Diabetes Research and Clinical Practice. - 0168-8227. ; 209
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Journal article (peer-reviewed)abstract
- Many individuals with intermediate hyperglycaemia (IH), including impaired fasting glycaemia (IFG) and impaired glucose tolerance (IGT), as presently defined, will progress to type 2 diabetes (T2D). There is confirmatory evidence that T2D can be prevented by lifestyle modification and/or medications, in people with IGT diagnosed by 2-h plasma glucose (PG) during a 75-gram oral glucose tolerance test (OGTT). Over the last 40 years, a wealth of epidemiological data has confirmed the superior value of 1-h plasma glucose (PG) over fasting PG (FPG), glycated haemoglobin (HbA1c) and 2-h PG in populations of different ethnicity, sex and age in predicting diabetes and associated complications including death. Given the relentlessly rising prevalence of diabetes, a more sensitive, practical method is needed to detect people with IH and T2D for early prevention or treatment in the often lengthy trajectory to T2D and its complications. The International Diabetes Federation (IDF) Position Statement reviews findings that the 1-h post-load PG ≥ 155 mg/dL (8.6 mmol/L) in people with normal glucose tolerance (NGT) during an OGTT is highly predictive for detecting progression to T2D, micro- and macrovascular complications, obstructive sleep apnoea, cystic fibrosis-related diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and mortality in individuals with risk factors. The 1-h PG of 209 mg/dL (11.6 mmol/L) is also diagnostic of T2D. Importantly, the 1-h PG cut points for diagnosing IH and T2D can be detected earlier than the recommended 2-h PG thresholds. Taken together, the 1-h PG provides an opportunity to avoid misclassification of glycaemic status if FPG or HbA1c alone are used. The 1-h PG also allows early detection of high-risk people for intervention to prevent progression to T2D which will benefit the sizeable and growing population of individuals at increased risk of T2D. Using a 1-h OGTT, subsequent to screening with a non-laboratory diabetes risk tool, and intervening early will favourably impact the global diabetes epidemic. Health services should consider developing a policy for screening for IH based on local human and technical resources. People with a 1-h PG ≥ 155 mg/dL (8.6 mmol/L) are considered to have IH and should be prescribed lifestyle intervention and referred to a diabetes prevention program. People with a 1-h PG ≥ 209 mg/dL (11.6 mmol/L) are considered to have T2D and should have a repeat test to confirm the diagnosis of T2D and then referred for further evaluation and treatment. The substantive data presented in the Position Statement provides strong evidence for redefining current diagnostic criteria for IH and T2D by adding the 1-h PG.
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| 43. |
- Biancari, Fausto, et al.
(author)
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Multicenter study on postcardiotomy venoarterial extracorporeal membrane oxygenation
- 2020
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In: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier BV. - 0022-5223 .- 1097-685X. ; 159:5, s. 1844-1854
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Journal article (peer-reviewed)abstract
- Objectives: The aim of this study was to identify the risk factors associated with early mortality after postcardiotomy venoarterial extracorporeal membrane oxygenation. Methods: This is an analysis of the postcardiotomy extracorporeal membrane oxygenation registry, a retrospective multicenter cohort study including 781 patients aged more than 18 years who required venoarterial extracorporeal membrane oxygenation for cardiopulmonary failure after cardiac surgery from 2010 to 2018 at 19 cardiac surgery centers. Results: After a mean venoarterial extracorporeal membrane oxygenation therapy of 6.9 ± 6.2 days, hospital and 1-year mortality were 64.4% and 67.2%, respectively. Hospital mortality after venoarterial extracorporeal membrane oxygenation therapy for more than 7 days was 60.5% (P = .105). Centers that had treated more than 50 patients with postcardiotomy venoarterial extracorporeal membrane oxygenation had a significantly lower hospital mortality than lower-volume centers (60.7% vs 70.7%, adjusted odds ratio, 0.58; 95% confidence interval, 0.41-0.82). The postcardiotomy extracorporeal membrane oxygenation score was derived by assigning a weighted integer to each independent pre–venoarterial extracorporeal membrane oxygenation predictors of hospital mortality as follows: female gender (1 point), advanced age (60-69 years, 2 points; ≥70 years, 4 points), prior cardiac surgery (1 point), arterial lactate 6.0 mmol/L or greater before venoarterial extracorporeal membrane oxygenation (2 points), aortic arch surgery (4 points), and preoperative stroke/unconsciousness (5 points). The hospital mortality rates according to the postcardiotomy extracorporeal membrane oxygenation score was 0 point, 45.6%; 1 point, 40.5%; 2 points, 51.1%; 3 points, 57.8%; 4 points, 70.7%; 5 points, 68.3%; 6 points, 77.5%; and 7 points or more, 89.7% (P < .0001). Conclusions: Age, female gender, prior cardiac surgery, preoperative acute neurologic events, aortic arch surgery, and increased arterial lactate were associated with increased risk of early mortality after postcardiotomy venoarterial extracorporeal membrane oxygenation. Center experience with postcardiotomy venoarterial extracorporeal membrane oxygenation may contribute to improved results.
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| 44. |
- Biancari, Fausto, et al.
(author)
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Postcardiotomy Venoarterial Extracorporeal Membrane Oxygenation in Patients Aged 70 Years or Older
- 2019
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In: Annals of Thoracic Surgery. - : Elsevier BV. - 0003-4975 .- 1552-6259. ; 108:4, s. 1257-1264
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Research review (peer-reviewed)abstract
- Background: There is uncertainty whether venoarterial extracorporeal membrane oxygenation (VA-ECMO) should be used in older patients with cardiopulmonary failure after cardiac surgery. Methods: This was a retrospective multicenter study of 781 patients who required postcardiotomy VA-ECMO for cardiopulmonary failure after adult cardiac surgery from 2010 to 2018 at 19 cardiac surgery centers. A parallel systematic review with meta-analysis of the literature was performed. Results: The hospital mortality in the overall Postcardiotomy Venoarterial Extracorporeal Membrane Oxygenation (PC-ECMO) series was 64.4%. A total of 255 patients were 70 years old or older (32.7%), and their hospital mortality was significantly higher than in younger patients (76.1% vs 58.7%; adjusted odds ratio, 2.199; 95% confidence interval [CI], 1.536 to 3.149). Arterial lactate level greater than 6 mmol/L before starting VA-ECMO was the only predictor of hospital mortality among patients 70 years old or older in univariate analysis (82.6% vs 70.4%; P =.029). Meta-analysis of current and previous studies showed that early mortality after postcardiotomy VA-ECMO was significantly higher in patients aged 70 years or older compared with younger patients (odds ratio, 2.09; 95% CI, 1.59 to 2.75; 5 studies including 1547 patients; I2, 5.9%). The pooled early mortality rate among patients aged 70 years or older was 78.8% (95% CI, 74.1 to 83.5; 6 studies including 617 patients; I2, 41.8%). Two studies reported 1-year mortality (including hospital mortality) of 79.9% and 75.6%, respectively, in patients 70 years old or older. Conclusions: Advanced age should not be considered a contraindication for postcardiotomy VA-ECMO. However, in view of the high risk of early mortality, meaningful scrutiny is needed before using VA-ECMO after cardiac surgery in older patients.
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- Dou, Diana R., et al.
(author)
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Xist ribonucleoproteins promote female sex-biased autoimmunity
- 2024
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In: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 187:3, s. 16-733
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Journal article (peer-reviewed)abstract
- Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
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| 49. |
- Graff, RE, et al.
(author)
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2Pre-diagnostic circulating sex hormone levels and risk of prostate cancer by TMPRSS2:ERG status.
- 2016
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In: JOURNAL OF CLINICAL ONCOLOGY. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 34:2
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Conference paper (other academic/artistic)abstract
- 93 Background: Experimental studies have shown that androgen receptor stimulation can facilitate formation of the TMPRSS2:ERG gene fusion in prostate cell lines. No study has tested whether higher pre-diagnostic circulating sex hormone levels in men increase the risk of developing TMPRSS2:ERG positive prostate cancer specifically. Methods: We conducted a nested case-control study of 200 prostate cancer cases and 1,057 controls from the Physicians’ Health Study and Health Professionals Follow-up Study. We examined associations between pre-diagnostic circulating levels of total testosterone, free testosterone, DHT, androstanediol glucuronide, estradiol, and SHBG and risk of prostate cancer by TMPRSS2:ERG status. TMPRSS2:ERG was assessed by ERG immunohistochemistry. We used multivariable unconditional polytomous logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of fusion-positive (n = 94) and, separately, fusion-negative (n = 106) disease. Results: Free testosterone was significantly associated with the risk of ERG-positive prostate cancer (OR: 1.37, 95% CI: 1.05-1.77), but not ERG-negative prostate cancer (OR: 1.09, 95% CI: 0.86-1.38) (p-diff: 0.17). None of the remaining hormones evaluated showed clear differential associations with ERG-positive versus ERG-negative disease. Conclusions: These findings provide some suggestive evidence that higher pre-diagnostic free testosterone levels are associated with an increased risk of developing TMPRSS2:ERG positive prostate cancer but are not associated with prostate cancer that lacks TMPRSS2:ERG.
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