Partial Splenic Embolization in Paediatric Sickle Cell Disease Patients with Hypersplenism.

PURPOSE: To assess the safety and efficacy of partial splenic embolization (PSE) to reduce the need of transfusions and improve hematologic parameters in patients with hypersplenism and sickle cell disease (SCD). MATERIAL AND METHODS: This prospective study includes 35 homozygous hemoglobin S patients with SCD and hypersplenism who underwent PSE from 2015 until 2021 in Kinshasa. Patients were evaluated, before and after PSE (1, 3 and 6 months), using clinical, laboratory and ultrasonographic methods. PSE was performed with the administration of gelatin sponge particles embolizing 60-70% of the splenic parenchyma. RESULTS: The mean age was 10 (± 4) years and (21/35, 60%) were male. After PSE Leucocytes decreased at 3 months (16 692.94 vs 13 582.86, p = 0.02) and at six months Erythrocytes increased 2 004 000 vs. 2 804 142 (p < 0.001), Platelets increased (168 147 vs. 308 445, p < 0.001) and Hemoglobin increased (5.05 g/dL vs. 6.31 g/dL, p < 0.001) There was a significant dicrease in the need of transfusions from 6 (2-20) before PSE to 0.06 (0-1) after PSE (p < 0.001). The most frequent complication was splenic rupture (4/35, 11.4%), seen only and in all patients with hypoechogenic nodules at baseline. CONCLUSION: PSE is a safe procedure in patients with SCD and hypersplenism, that do not have hypoechogenic nodules in the spleen. PSE improves the hematological parameters and reduces the frequency of blood transfusions.

Sex bias in celiac disease: XWAS and monocyte eQTLs in women identify TMEM187 as a functional candidate gene.

BACKGROUND: Celiac disease (CeD) is an immune-mediated disorder that develops in genetically predisposed individuals upon gluten consumption. HLA risk alleles explain 40% of the genetic component of CeD, so there have been continuing efforts to uncover non-HLA loci that can explain the remaining heritability. As in most autoimmune disorders, the prevalence of CeD is significantly higher in women. Here, we investigated the possible involvement of the X chromosome on the sex bias of CeD. METHODS: We performed a X chromosome-wide association study (XWAS) and a gene-based association study in women from the CeD Immunochip (7062 cases, 5446 controls). We also constructed a database of X chromosome cis-expression quantitative trait loci (eQTLs) in monocytes from unstimulated (n = 226) and lipopolysaccharide (LPS)-stimulated (n = 130) female donors and performed a Summary-data-based MR (SMR) analysis to integrate XWAS and eQTL information. We interrogated the expression of the potentially causal gene (TMEM187) in peripheral blood mononuclear cells (PBMCs) from celiac patients at onset, on a gluten-free diet, potential celiac patients and non-celiac controls. RESULTS: The XWAS and gene-based analyses identified 13 SNPs and 25 genes, respectively, 22 of which had not been previously associated with CeD. The X chromosome cis-eQTL analysis found 18 genes with at least one cis-eQTL in naïve female monocytes and 8 genes in LPS-stimulated female monocytes, 2 of which were common to both situations and 6 were unique to LPS stimulation. SMR identified a potentially causal association of TMEM187 expression in naïve monocytes with CeD in women, regulated by CeD-associated, eQTL-SNPs rs7350355 and rs5945386. The CeD-risk alleles were correlated with lower TMEM187 expression. These results were replicated using eQTLs from LPS-stimulated monocytes. We observed higher levels of TMEM187 expression in PBMCs from female CeD patients at onset compared to female non-celiac controls, but not in male CeD individuals. CONCLUSION: Using X chromosome genotypes and gene expression data from female monocytes, SMR has identified TMEM187 as a potentially causal candidate in CeD. Further studies are needed to understand the implication of the X chromosome in the higher prevalence of CeD in women.

Celiac disease (CeD) is an immune-related condition triggered by gluten consumption in genetically susceptible individuals. Women present higher prevalence of CeD than men, but the biological explanation of such difference has not been elucidated. In this study, we investigated whether specific genetic variations on the X chromosome were associated with CeD in each sex. Surprisingly, we found 13 genetic variants and 25 genes significantly linked to CeD in women, but not in men. Additionally, we identified genetic variants on the X chromosome associated with gene expression of monocytes, a type of immune cells that is activated in CeD after gluten intake. Integrating these data with our previous findings, we found that lower expression of a gene termed TMEM187 might be associated with a potential increase in CeD risk in women. Finally, validation experiments confirmed higher TMEM187 levels in blood cells from female CeD patients compared to non-celiac women, while no such difference was seen in males. In summary, our study suggests that the X-chromosome gene TMEM187 may play a key role in CeD development, providing insights into the higher prevalence of CeD in females.

Identifying weak signals to prepare for uncertainty in the energy sector.

This study aims to prepare the energy sector for uncertainty using a foresight tool known as weak signals. Weak signals (subtle signs of emerging issues with significant impact potential) are often overlooked during strategic planning due to their inherent predictive uncertainty. However, the value does not lie in precise forecasting but in broadening the consideration of future possibilities. By proactively monitoring and addressing these otherwise neglected developments, stakeholders can gain early awareness of threats and opportunities and enhance their resilience, adaptability, and innovation. A panel of technology experts identified eight weak signals in this study: 1) growing mistrust and local grid security measures, 2) consumer reactions to overly prescriptive policies, 3) long-term forecasting errors for thin-margin projects, 4) emergence of variable power industries, and 5) establishment of intercontinental transmission precedence; including three potential 'wild cards' requiring proactive mitigation: 6) escalating electrical generation dependence on continued imports, 7) a new threat surpassing climate change, and 8) mass deployment of low-emissions technology triggering a runaway loss of social license. Political factors were the predominant source of uncertainty, as decisions can suddenly transform the energy landscape. Economic, technological, and social factors followed closely behind, generally through the emergence of new industries and behavioural responses. While environmental and legal factors were less frequent, stakeholders should still adopt a holistic approach, as the signals were found to be highly interconnected. Organisations should also assess their local context when applying these findings and continuously update and respond to their own list of weak signals.

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

Summary-data based Mendelian randomization identifies gene expression regulatory polymorphisms associated with bovine paratuberculosis by modulation of the nuclear factor Kappa ß (NF-κß)-mediated inflammatory response.

Genome-wide association studies (GWAS) have identified host genetic variants associated with paratuberculosis (PTB) susceptibility. Most of the GWAS-identified SNPs are in non-coding regions. Connecting these non-coding variants and downstream affected genes is a challenge and, up to date, only a few functional mutations or expression quantitative loci (cis-eQTLs) associated with PTB susceptibility have been identified. In the current study, the associations between imputed whole-genome sequence genotypes and whole RNA-Sequencing data from peripheral blood (PB) and ileocecal valve (ICV) samples of Spanish Holstein cows (N = 16) were analyzed with TensorQTL. This approach allowed the identification of 88 and 37 cis-eQTLs regulating the expression levels of 90 and 37 genes in PB and ICV samples, respectively (False discorey rate, FDR ≤ 0.05). Next, we applied summary-based data Mendelian randomization (SMR) to integrate the cis-eQTL dataset with GWAS data obtained from a cohort of 813 culled cattle that were classified according to the presence or absence of PTB-associated histopathological lesions in gut tissues. After multiple testing corrections (FDR ≤ 0.05), we identified two novel cis-eQTLs affecting the expression of the early growth response factor 4 (EGR4) and the bovine neuroblastoma breakpoint family member 6-like protein isoform 2 (MGC134040) that showed pleiotropic associations with the presence of multifocal and diffuse lesions in gut tissues; P = 0.002 and P = 0.017, respectively. While EGR4 acts as a brake on T-cell proliferation and cytokine production through interaction with the nuclear factor Kappa ß (NF-κß), MGC134040 is a target gene of NF-κß. Our findings provide a better understanding of the genetic factors influencing PTB outcomes, confirm that the multifocal lesions are localized/confined lesions that have different underlying host genetics than the diffuse lesions, and highlight regulatory SNPs and regulated-gene targets to design future functional studies.

Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk.

Background: Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.5/DQ2.2 heterozygous. Both the HLA-DQ2-positive high genetic risk individuals and those that have developed the disease have altered intestinal microbiota, but it remains unclear whether these alterations are a cause or a consequence of CeD. Objective: To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals. Materials and Methods: We performed a bidirectional Two-Sample Mendelian Randomization (2SMR) test using summary statistics from the largest publicly available Genome-Wide Association Study (GWAS) of GM and the summary statistics of the Immunochip CeD study of those individuals with the HLA-DQ2 high-risk haplotype. To test whether changes in GM composition were causally linked to CeD, GM data were used as exposure and CeD data as outcome; to test for reverse causation, the exposure and outcome datasets were inverted. Results: We identified several bacteria from Ruminococcaceae and Lachnospiraceae families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of Veillonellaceae family might be causal in the development of CeD, while alterations in Pasteurellaceae family might be a consequence of the disease itself. Conclusion: Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.

Epidemiological study of vaccination against SARS-CoV-2 and its impact on COVID-19 progression in a cohort of patients in gran Canaria.

Objectives. We analyzed the impact of age, sex, vaccination against COVID-19, immunosuppressive treatment, and comorbidities on patients' risk of requiring hospital admission or of death. Methods. Population-based observational retrospective study conducted on a cohort of 19,850 patients aged 12 years or more, who were diagnosed with COVID-19 between June 1st and December 31st, 2021, in the island of Gran Canaria. Results. Hypertension (18.5%), asthma (12.8%) and diabetes (7.2%) were the most frequent comorbidities; 147 patients died (0.7%). The combination of advanced age, male sex, cancer, coronary heart disease, immunosuppressive treatment, hospital admission, admission to the intensive care unit, mechanical ventilation and lack of complete COVID-19 vaccination or booster dose was strongly predictive of mortality (p < 0.05); 831 patients required hospital admission and it was more frequent in men, older age groups, and patients with cancer, diabetes, arterial hypertension, chronic obstructive pulmonary disease, congestive heart failure or immunosuppressive treatment. The COVID-19 vaccine booster dose was associated with a lower risk of death ([OR] 0.11, 95% CI 0.06-0.21, p < 0.05) or hospital admission ([OR] 0.36, 95% CI 0.29-0.46, p < 0.05). Conclusions. Cancer, coronary heart disease, and immunosuppressive treatment were associated with increased COVID-19 mortality. More complete vaccination was associated with lower risk of hospital admission or death. Three doses of the SARS-CoV-2 vaccine were highly associated with the prevention of death and hospital admission in all age groups. These findings suggest that COVID-19 vaccination can help bring the pandemic under control.

Objetivos. Analizamos el impacto de la edad, el sexo, la vacunación frente a la COVID-19, el tratamiento inmunosupresor y las comorbilidades en el riesgo de los pacientes de precisar ingreso hospitalario o de fallecer.Métodos. Estudio retrospectivo observacional de base poblacional realizado sobre una cohorte de 19.850 pacientes de 12 años o más, que fueron diagnosticados de COVID-19 entre el 1 de junio y el 31 de diciembre de 2021, en la isla de Gran Canaria.Resultados. La hipertensión arterial (18,5%), el asma (12,8%) y la diabetes (7,2%) fueron las comorbilidades más frecuentes; Fallecieron 147 pacientes (0,7%). La combinación de edad avanzada, sexo masculino, cáncer, cardiopatía coronaria, tratamiento inmunosupresor, ingreso hospitalario, ingreso en unidad de cuidados intensivos, ventilación mecánica y la falta de vacunación completa contra el COVID-19 o dosis de refuerzo fue fuertemente predictiva de mortalidad (p < 0,05); 831 pacientes requirieron ingreso hospitalario y fue más frecuente en hombres, grupos de mayor edad y pacientes con cáncer, diabetes, hipertensión arterial, enfermedad pulmonar obstructiva crónica, insuficiencia cardiaca congestiva o tratamiento inmunosupresor. La dosis de refuerzo contra la vacuna del COVID-19 se asoció con un menor riesgo de muerte ([OR] 0.11, IC 95% 0.06­0.21, p < 0,05) o ingreso hospitalario ([OR] 0.36, IC 95% 0.29­0.46; p < 0,05).Conclusiones. El cáncer, la enfermedad coronaria y el tratamiento inmunosupresor se asociaron con una mayor mortalidad por COVID-19. Una vacunación más completa se asoció con un menor riesgo de hospitalización o muerte. Tres dosis de la vacuna contra el SARS-CoV-2 se asociaron a una mayor prevención de la muerte y el ingreso hospitalario relacionados con la COVID-19 en todos los grupos de edad. Estos hallazgos sugieren que la vacunación contra el COVID-19 puede ayudar a controlar la pandemia.

Estudio epidemiológico sobre el impacto de la vacunación antigripal en la evolución clínica de pacientes con COVID-19 y la coinfección por ambos virus en Gran Canaria, España / Epidemiological study on the impact of influenza vaccination on the clinical course of patients with COVID-19 and co-infection by both viruses in Gran Canaria, Spain

Objetivo: Analizar la frecuencia de coinfecciones entre los virus gripales y el SARS-CoV-2, además de las diferencias en la evolución (riesgo de mortalidad, ingreso hospitalario o en intensivos) de los pacientes infectados por el virus del SARS-CoV-2 según vacunación o no vacunación de la gripe en la temporada 2021-2022. Método: Estudio retrospectivo observacional de base poblacional en una cohorte de 19.850 pacientes diagnosticados de COVID-19 entre el 1 de junio de 2021 y 28 de febrero de 2022 en la isla de Gran Canaria. Resultados. Fueron vacunados de la gripe 1.789 personas, el 9% del total de pacientes diagnosticados de COVID-19. 13.676 personas (68,9%) contaban con pauta completa de vacunación del COVID-19. En el periodo comprendido entre el 1 de junio de 2021 y 28 de febrero de 2022 se registraron 8 casos de coinfección gripe y COVID-19. Hipertensión (18,5%), asma (12,8%) y diabetes (7,2%) fueron las comorbilidades más frecuentes. Hubo 147 defunciones (0,7%). Las personas de mayor edad ([OR] 1,11 IC 95% 1,09-1,13) y con cáncer ([OR] 4,21 IC 95% 2,58-6,89) tuvieron mayor riesgo de fallecer por COVID-19 (p<0,05). El sexo femenino fue considerado un factor protector ([OR] 0,61 IC 95% 0,40-0,92). Conclusiones: La edad avanzada, el sexo masculino y el cáncer fueron factores pronósticos independientes de mortalidad. Tres dosis de la vacuna del SARS-CoV-2 y la vacuna de la gripe fueron altamente efectivas para prevenir muertes e ingresos relacionados con COVID-19. Estos hallazgos sugieren que la vacunación contra la gripe puede ayudar a controlar la pandemia. (AU)

Objectives: To analyze the frequency of influenza and SARS-CoV-2 co-infections, as well as the differences in the course of disease (risk of mortality, hospital and intensive care admissions) in patients infected with the SARS-CoV-2 virus in relation to flu vaccination status in the 2021-2022 season.Methodology. Population-based observational retrospective study in a cohort of 19,850 patients diagnosed with COVID-19 between June 1, 2021 and February 28, 2022 on the island of Gran Canaria. Results: A total of 1,789 patients (9%) diagnosed with COVID-19 had received flu vaccinations. 13,676 people (68.9%) had a full course of COVID-19 vaccinations. In the period between June 1, 2021 and February 28, 2022, 8 cases of flu and COVID-19 coinfection were recorded. Hypertension (18.5%), asthma (12.8%) and diabetes (7.2%) were the most frequent comorbidities. There were 147 deaths (0.7%). Older patients ([OR] 1.11 95% CI 1.09-1.13) and people with cancer ([OR] 4.21 95% CI 2.58-6.89) had a higher risk of dying from COVID-19 (p<0.05). Female sex was noted as a protective factor ([OR] 0.61 95% CI 0.40-0.92). Conclusions: Old age, male sex and cancer were independent prognostic factors for mortality. Three doses of SARS-CoV-2 vaccines and influenza vaccines were highly effective in preventing COVID-19-related deaths and hospital admissions. These findings suggest that flu vaccination can help control the pandemic. (AU)

Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders.

Increasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placental cis-mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type- and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placental cis-mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type-imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.

Predictive Factors for Adverse Event Outcomes After Transarterial Radioembolization with Yttrium-90 Resin Microspheres in Europe: Results from the Prospective Observational CIRT Study.

BACKGROUND: Using data collected in the prospective observational study CIRSE Registry for SIR-Spheres Therapy, the present study aimed at identifying predictors of adverse events (AEs) following transarterial radioembolization (TARE) with Yttrium-90 resin microspheres for liver tumours. METHODS: We analysed 1027 patients enrolled between January 2015 and December 2017 and followed up for 24 months. Four hundred and twenty-two patients with hepatocellular carcinoma (HCC), 120 with intrahepatic carcinoma (ICC), 237 with colorectal liver metastases and 248 with liver metastases from other primaries were included. Prognostic factors were calculated with a univariable analysis by using the overall AEs burden score (AEBS). RESULTS: All-cause AEs were reported in 401/1027 (39.1%) patients, with AEs associated with TARE, such as abdominal pain (16.6%), fatigue (17%), and nausea (11.7%) reported most frequently. Grade 3 or higher AEs were reported in 92/1027 (9%) patients. Reports on grade ≥ 3 gastrointestinal ulcerations (0.4%), gastritis (0.3%), radiation cholecystitis (0.2%) or radioembolization-induced liver disease (0.5%) were uncommon. Univariable analysis showed that in HCC, AEBS increased for Eastern Cooperative Oncology Group (ECOG) 0 (p = 0.0045), 1 tumour nodule (0.0081), > 1 TARE treatment (p = 0.0224), no prophylactic embolization (p = 0.0211), partition model dosimetry (p = 0.0007) and unilobar treatment target (0.0032). For ICC, > 1 TARE treatment was associated with an increase in AEBS (p = 0.0224), and for colorectal liver metastases, ECOG 0 (p = 0.0188), > 2 prior systemic treatments (p = 0.0127), and 1 tumour nodule (p = 0.0155) were associated with an increased AEBS. CONCLUSION: Our study confirms that TARE is a safe treatment with low toxicity and a minimal impact on quality of life.

Liver Resection and Transplantation Following Yttrium-90 Radioembolization for Primary Malignant Liver Tumors: A 15-Year Single-Center Experience.

Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. METHODS: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005-2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. RESULTS: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien-Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. CONCLUSION: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival.

Defining textbook outcome for selective internal radiation therapy of hepatocellular carcinoma: an international expert study.

BACKGROUND: A textbook outcome (TO) is a composite indicator covering the entire intervention process in order to reflect the "ideal" intervention and be a surrogate for patient important outcomes. Selective internal radiation therapy (SIRT) is a complex multidisciplinary and multistep intervention facing the challenge of standardization. This expert opinion-based study aimed to define a TO for SIRT of hepatocellular carcinoma. METHODS: This study involved two steps: (1) the steering committee (4 interventional radiologists) first developed an extensive list of possible relevant items reflecting an optimal SIRT intervention based on a literature review and (2) then conducted an international and multidisciplinary survey which resulted in the final TO. This survey was online, from February to July 2021, and consisted three consecutive rounds with predefined settings. Experts were identified by contacting senior authors of randomized trials, large observational studies, or studies on quality improvement in SIRT. This study was strictly academic. RESULTS: A total of 50 items were included in the first round of the survey. A total of 29/40 experts (73%) responded, including 23 interventional radiologists (79%), three nuclear medicine physicians (10%), two hepatologists, and one oncologist, from 11 countries spanning three continents. The final TO consisted 11 parameters across six domains ("pre-intervention workup," "tumor targeting and dosimetry," "intervention," "post-90Y imaging," "length of hospital stay," and "complications"). Of these, all but one were applied in the institutions of > 80% of experts. CONCLUSIONS: This multidimensional indicator is a comprehensive standardization tool, suitable for routine care, clinical round, and research.

Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study.

PURPOSE: To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization. PATIENTS AND METHODS: NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naïve to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS). RESULTS: 42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1). CONCLUSIONS: The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT. TRIAL REGISTRATION NUMBER: NCT03380130.

A meta-analysis of pre-pregnancy maternal body mass index and placental DNA methylation identifies 27 CpG sites with implications for mother-child health.

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenome-wide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings.

Assessment of SARS-CoV-2 Infection According to Previous Metabolic Status and Its Association with Mortality and Post-Acute COVID-19.

Background. SARS-CoV-2 infection was analyzed according to previous metabolic status and its association with mortality and post-acute COVID-19. Methods. A population-based observational retrospective study was conducted on a cohort of 110,726 patients aged 12 years or more who were diagnosed with COVID-19 infection between June 1st, 2021, and 28 February 2022 on the island of Gran Canaria, Spain. Results. In the 347 patients who died, the combination of advanced age, male sex, cancer, immunosuppressive therapy, coronary heart disease, elevated total cholesterol and reduced high-density lipoprotein cholesterol (HDL-C) was strongly predictive of mortality (p < 0.05). In the 555 patients who developed post-acute COVID-19, the persistence of symptoms was most frequent in women, older subjects and patients with obstructive sleep apnea syndrome, asthma, elevated fasting glucose levels or elevated total cholesterol (p < 0.05). A complete vaccination schedule was associated with lower mortality (incidence rate ratio (IRR) 0.5, 95%CI 0.39−0.64; p < 0.05) and post-acute COVID-19 (IRR 0.37, 95%CI 0.31−0.44; p < 0.05). Conclusions. Elevated HDL-C and elevated total cholesterol were significantly associated with COVID-19 mortality. Elevated fasting glucose levels and elevated total cholesterol were risk factors for the development of post-acute COVID-19.

Pure laparoscopic major liver resection after yttrium90 radioembolization: a case-matched series analysis of feasibility and outcomes.

BACKGROUND: Liver surgery after radioembolization (RE) entails highly demanding and challenging procedures due to the frequent combination of large tumors, severe RE-related adhesions, and the necessity of conducting major hepatectomies. Laparoscopic liver resection (LLR) and its associated advantages could provide benefits, as yet unreported, to these patients. The current study evaluated feasibility, morbidity, mortality, and survival outcomes for major laparoscopic liver resection after radioembolization. MATERIAL AND METHODS: In this retrospective, single-center study patients diagnosed with hepatocellular carcinoma, intrahepatic cholangiocarcinoma or metastases from colorectal cancer undergoing major laparoscopic hepatectomy after RE were identified from institutional databases. They were matched (1:2) on several pre-operative characteristics to a group of patients that underwent major LLR for the same malignancies during the same period but without previous RE. RESULTS: From March 2011 to November 2020, 9 patients underwent a major LLR after RE. No differences were observed in intraoperative blood loss (50 vs. 150 ml; p = 0.621), operative time (478 vs. 407 min; p = 0.135) or pedicle clamping time (90.5 vs 74 min; p = 0.133) between the post-RE LLR and the matched group. Similarly, no differences were observed on hospital stay (median 3 vs. 4 days; p = 0.300), Clavien-Dindo ≥ III complications (2 vs. 1 cases; p = 0.250), specific liver morbidity (1 vs. 1 case p = 1.000), or 90 day mortality (0 vs. 0; p = 1.000). CONCLUSION: The laparoscopic approach for post radioembolization patients may be a feasible and safe procedure with excellent surgical and oncological outcomes and meets the current standards for laparoscopic liver resections. Further studies with larger series are needed to confirm the results herein presented.

A new animal model of atrophy-hypertrophy complex and liver damage following Yttrium-90 lobar selective internal radiation therapy in rabbits.

Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy-hypertrophy complex after SIRT. Three groups of 5-8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with different activities (0.3, 0.6 and 1.2 GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2 GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6 GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced significant toxicity. Cranial SIRT with 0.3 GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2 GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3 GBq groups developed moderate damage with inflammation and portal fibrosis at 15 days, partially recovering at 30 days. There was no difference in the expression of hepatocyte function and differentiation genes between 0.3 GBq and control groups. Cranial SIRT with 0.3 GBq of 90Y resin microspheres in rabbits is a reliable animal model to analyse the atrophy-hypertrophy complex and liver damage without toxicity.