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Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by deficient activity of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, required to metabolize the amino acids leucine, isoleucine, and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been completely elucidated. We performed a comprehensive multi-omics integration analysis, including genomic, epigenomic, and transcriptomic data from fibroblasts derived from a cohort of MSUD patients and unaffected controls to genetically characterize an MSUD case and to unravel the MSUD pathophysiology. MSUD patients exhibit a defined episignature that reshapes the global DNA methylation landscape, resulting in the stimulation of HOX cluster genes and the restriction of cell cycle gene-related signatures. Subsequent data integration revealed the impact of AP1-related and CEBPB transcription factors on the observed molecular reorganization, with MEIS1 emerging as a potential downstream candidate affected by robust epigenetic repression in MSUD patients. Furthermore, the integration of multi-omics layers facilitated the identification of a strong epigenetic repression in the DBT promoter in a patient wherein no BCKDH pathogenic variants had been detected. A Circular Chromatin Conformation Capture assay indicated a disturbance of the interactions of DBT promoter, thereby unveiling alternative modes of disease inheritance. Integration of multi-omics data unveiled underlying molecular networks rewired in MSUD patients and represents a powerful approach with diagnostic potential for rare genetic disorders with unknown genetic bases., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Liver transplantation (LT) is a curative treatment option. We investigated survival outcomes based on recipient-donor sex constellation (RDSC) following LT., Methods: We performed a European Liver Transplant Registry analysis, including patients from 1988 to December 2022. The cohort was split into four RDSC groups: female donor female recipient (FDFR), female donor male recipient (FDMR), male donor female recipient (MDFR) and male donor male recipient (MDMR). Survival analysis, including death with recurrence, was performed., Results: In 7601 LT for HCC with an overall median follow-up of 22.6 months (5.8, 60.7), death was registered in 25.1% and, as primary cause of death, HCC tumour recurrence in 26.0%. There was no statistically significant difference on crude survival estimates among the different RDSC groups (log-rank p = 0.66) with 10-year overall survival (OS) of 54.5% in FDFR, 54.6% in FDMR, 59.1% in MDFR and 56.9% in MDMR. On multivariable analysis, RDSC showed a significant effect on OS (FDFR as reference): MDFR (aHR 0.72, p = 0.023). No significant difference was found for FDMR (aHR 0.98, p = 0.821) and MDMR (aHR 0.90, p= 0.288). Regarding overall registered causes of death, differences between RDSC groups were found in rejection (p = 0.017) and cardiovascular (p = 0.046) associated deaths., Conclusions: In female recipients undergoing LT for HCC, male donor grafts were associated with a 28% reduction of mortality compared to female donor grafts., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Objectives: To survey practices of iron and recombinant human erythropoietin (rhEpo) administration to infants born preterm across Europe., Study Design: Over a 3-month period, we conducted an online survey in 597 neonatal intensive care units (NICUs) of 18 European countries treating infants born with a gestational age of <32 weeks., Results: We included 343 NICUs (response rate 56.3%) in the survey. Almost all NICUs (97.7%) routinely supplement enteral iron, and 74.3% of respondents to all infants born <32 weeks of gestation. We found that 65.3% of NICUs routinely evaluate erythropoiesis and iron parameters beyond day 28 after birth. Most NICUs initiate iron supplementation at postnatal age of 2 weeks and stop after 6 months (34.3%) or 12 months (34.3%). Routine use of rhEpo was reported in 22.2% of NICUs, and in individual cases in 6.9%. RhEpo was mostly administered subcutaneously (70.1%) and most frequently at a dose of 250 U/kg 3 times a week (44.3%), but the dose varied greatly between centers., Conclusions: This survey highlights wide heterogeneity in evaluating erythropoietic activity and iron deficiency in infants born preterm. Variation in iron supplementation during infancy likely reflects an inadequate evidence base. Current evidence on the efficacy and safety profile of rhEpo is only poorly translated into clinical practice. This survey demonstrates a need for standards to optimize patient blood management in anemia of prematurity., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Medical treatment of acromegaly is currently performed through a trial-and-error approach using first-generation somatostatin receptor ligands (fgSRLs) as first-line drugs, with an effectiveness of about 50%, and subsequent drugs are indicated through clinical judgment. Some biomarkers can predict fgSRLs response., Objective: Here we report the results of the ACROFAST study, a clinical trial in which a protocol based on predictive biomarkers of fgSRLs was evaluated., Methods: This was a prospective trial (21 university hospitals) comparing the effectiveness and time-to-control of 2 treatment protocols during 12 months: (A) a personalized protocol in which the first options were fgSRLs as monotherapy or in combination with pegvisomant, or pegvisomant as monotherapy depending on the short acute octreotide test (sAOT) results, tumor T2 magnetic resonance (MRI) signal or immunostaining for E-cadherin; and (B) a control group with treatment always started by fgSRLs and the other drugs included after demonstrating inadequate control., Results: Eighty-five patients participated; 45 in the personalized and 40 in the control group. More patients in the personalized protocol achieved hormonal control compared to those in the control group (78% vs 53%, P < .05). Survival analysis revealed a hazard ratio for achieving hormonal control adjusted by age and sex of 2.53 (CI, 1.30-4.80). Patients from the personalized arm were controlled in a shorter period of time (P = .01)., Conclusion: Personalized medicine is feasible using a relatively simple protocol, and it allows a higher number of patients to achieve control in a shorter period of time., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background and Objective: Currently, the management for pituitary apoplexy (PA) has been promoted toward a more conservative approach, particularly for patients with low-grade PA scores. Our aim was to investigate trends in PA management and compare clinical presentation, therapeutic approaches, and outcomes before and after 2017, additionally to evaluate long-term outcomes in conservatively treated patients., Methods: Spanish multicenter, retrospective study. Statistical analyses compared clinical presentation and outcomes between periods, adjusting for confounders., Results: A total of 215 patients with PA and nonfunctioning pituitary adenoma were included, with the median age of 62.2 years and 68.4% were male patients. Of which 94 (43.7%) were diagnosed before 2017 and 121 (56.3%) in 2017 or later. Conservative treatment increased from 17% before to 30.6% in the recent period (odd ratio 0.47, 95% CI 0.24-0.90, P 0.02) This trend remained significant after adjusting for hospital, age, and Knosp grade (odd ratio 0.46, 95% CI 0.22-0.89, P = .03). However, surgery remained the most frequently used therapeutic option in both periods. There were no statistically significant differences in outcomes at 3 months between periods. Surgery compared with conservative management was associated with higher permanent arginine vasopressin deficiency in both periods (0 vs 17.9%, P = .07 before 2017; 0 vs 16.7%, P = .01 after). Up to 89.7% of patients treated conservatively, presented more than 25% spontaneous tumor shrinkage, and 74.4% had more than 50% tumor reduction., Conclusion: Although conservative management increased in the last years, surgery remains the predominant option. Patients managed conservatively experience a lower risk of permanent arginine vasopressin deficiency, and a high proportion exhibit clinically significant tumor shrinkage over time., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Clinical phenotypes of COVID-19, associated with mortality risk, have been identified in the general population. The present study assesses their applicability in solid organ transplant recipients (SOTR) hospital-admitted by COVID-19. In a cohort of 488 SOTR, nonvaccinated (n = 394) and vaccinated (n = 94) against SARS-CoV-2, we evaluated 16 demographic, clinical, analytical, and radiological variables to identify the clinical phenotypes A, B, and C. The median age was 61.0 (51-69) years, 330 (67.6%) and 158 (32.4%) were men and women, respectively, 415 (85%) had pneumonia, and 161 (33%) had SpO 2  < 95% at admission. All-cause mortality occurred in 105 (21.5%) cases. It was higher in nonvaccinated versus vaccinated SOTR (23.4% vs 13.8%, P = 0.04). Patients in the entire cohort were classified into phenotypes A (n = 149, 30.5%), B (n = 187, 38.3%), and C (n = 152, 31.1%), with mortality rates of 8.7%, 16.6%, and 40.1%, respectively, which were similar to those of nonvaccinated SOTR (9.5%, 16.7%, and 52.0%) and lower in vaccinated SOTR (4.4%, 15.8%, and 17.3%, respectively), with difference between nonvaccinated and vaccinated in the phenotype C (P < 0.001). In conclusion, COVID-19 clinical phenotypes are useful in SOTR, and all-cause mortality decreases in vaccinated patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Statement: The views expressed in this publication are the sole responsibility of the authors and the Commission is not responsible for any use that may be made of the information it contains., (© 2024. The Author(s).)

Purpose: We aim to describe the characteristics of patients with childhood-onset craniopharyngioma and to analyze factors that impair quality of life (QoL) in this population., Methods: Multicenter national study including patients treated between 2008 and 2022, from 2 to 25 years of age diagnosed with craniopharyngioma. QoL was assessed once during patient's follow-up by age-adapted versions of Pediatric Quality of Life Inventory (PedsQL) questionnaire., Results: Sixty-six patients were included. Median age at diagnosis was 5 years (interquartile range [IQR]: 3-8), while median follow-up was 7.4 years (IQR: 2.8-9.7). Most craniopharyngioma were suprasellar (93.9%), and 59.7% had hypothalamic involvement (HI). All patients underwent surgery, 44.4% received radiotherapy, and 23.6% intracystic therapy. Most frequent long-term complications were visual deficit (72.7%) and endocrine impairment (94.5%). Patients exhibited hypothyroidism requiring hormone replacement (92.4%), hypocortisolism (80.3%), diabetes insipidus (86.4%), and/or growth hormone therapy (50%). When parents evaluated QoL, PedsQL median score was 53.8 points out of 100 (IQR: 41-71.6). Higher scores were noted when patients assessed their own QoL (median score 64.8 [IQR: 57.3-81.8]), observing statistically significant differences (p = .019). QoL was impaired by repeated surgeries (r = -.44; p = .014), HI (median score 51.5 [IQR: 39-63.8] vs. 76.4 [59-84.8]; p = .001), radiotherapy (median score 51.9 [IQR: 38.1-61.3] vs. 63.8 [IQR: 49-82.5]; p = .02) and longer follow-up (r = -.3; p = .01)., Conclusion: In our study, most patients had significant comorbidities and low overall QoL scores, which was mainly affected by repeated surgery, radiation, and hypothalamic involvement. This reflects the need for further research and intensified studies of systemic therapy/alternate strategies to broaden the standard-of-care options, so that treatment-related sequalae can be avoided., (© 2024 Wiley Periodicals LLC.)

Inborn errors of metabolism (IEM) are a large group of single-gene disorders resulting from enzyme defects in biochemical and metabolic pathways [...].

Objective: Management of advanced type 2 diabetes (T2D) typically involves daily insulin therapy alongside frequent blood glucose monitoring, as treatments such as oral antidiabetic agents are therapeutically insufficient. Real-time continuous glucose monitoring (rt-CGM) has been shown to facilitate greater reductions in glycated hemoglobin (HbA1c) levels and improvements in patient satisfaction relative to self-monitoring of blood glucose (SMBG). This study aimed to investigate the cost-utility of rt-CGM versus SMBG in Spanish patients with insulin-treated T2D.., Methods: The analysis was conducted using the IQVIA Core Diabetes Model (CDM V9.5). Baseline characteristics of the simulated patient cohort and treatment efficacy data were sourced from a large-scale, United States-based retrospective cohort study. Costs were obtained from Spanish sources and inflated to 2022 Euros (EUR) where required. A remaining lifetime horizon (maximum 50 years) was used, alongside an annual discount rate of 3% for future costs and health effects. A willingness-to-pay (WTP) threshold of EUR 30,000 per quality-adjusted life year (QALY) was adopted, based on precedent across previous cost-effectiveness studies set in Spain. A Spanish payer perspective was adopted., Results: Over patient lifetimes, rt-CGM yielded 9.933 QALYs, versus 8.997 QALYs with SMBG, corresponding to a 0.937 QALY gain with rt-CGM. Total costs in the rt-CGM arm were EUR 2347 higher with rt-CGM versus SMBG (EUR 125,365 versus EUR 123,017). The base case incremental cost-utility ratio was therefore EUR 2506 per QALY gained, substantially lower than the WTP threshold of EUR 30,000 per QALY. The analysis also projected a reduction in cumulative incidence of ophthalmic, renal, neurological, and cardiovascular events in rt-CGM users, with reductions of 16.03%, 13.07%, 7.34%, and 9.09%, respectively., Conclusion: Compared to SMBG, rt-CGM is highly likely to be a cost-effective intervention for patients living with insulin-treated T2D in Spain., Competing Interests: R.F.P. and W.A. are full-time employees, and R.F.P. is a director and shareholder in, Covalence Research Ltd., which has received consulting fees from Dexcom for this analysis and from Dexcom outside the submitted work. S.I., H.A. and G.J.N. are current employees of Dexcom. H.A. and G.N. hold stock or stock options in Dexcom. J.F.MT received consulting fees from Dexcom. The authors report no other conflicts of interest in this work. Part of this analysis were presented in a poster at ATTD 2024 in Florence, Italy., (© 2024 Merino-Torres et al.)

Background: People with HIV (PWH) in suppressive antiretroviral treatment suffer from chronic inflammation-related comorbidities, mainly cardiovascular diseases. However, given the lack of specific evidence about inflammation in PWH, clinical guidelines do not provide recommendations for the management of this issue. To date, physician awareness of inflammation in PWH remains unclear. We analyzed the knowledge, attitudes, and practices (KAP) related to inflammation, particularly in the clinical management of PWH, of infectious disease specialists (IDS)/internists compared to other specialists treating inflammation directly (rheumatologists) or its cardiovascular consequences (cardiologists)., Methods: A committee of IDS/internists treating PWH, cardiologists, and rheumatologists designed the KAP questionnaire. The survey was completed by 405 participants (135 physicians per specialty) stratified by Spanish geography, hospital size, and number of PWH under care (IDS/internists only)., Results: IDS/internists treating PWH scored higher than cardiologists and rheumatologists on knowledge of inflammation (5.5±1.4 out of 8 points vs. 5.2±1.3 and 4.6±1.4 points, respectively; p<0.05). Nevertheless, rheumatologists showed the most proactive attitude toward inflammation (i.e., biomarkers monitoring, anti-inflammatory drug prescription and cardiologist referral), followed by cardiologists and IDS/internists (13±3 of a total of 16 points vs. 11±3 and 10±3.3 points, respectively; p<0.05), irrespective of hospital size and years of experience. Most IDS/internists (59%) include inflammation in their therapeutic recommendations. However, in IDS/internists treating PWH, we observed a negative correlation between years of experience and concern about the clinical consequences of inflammation., Conclusion: Our findings show that, compared to other specialists, infectious disease specialists/internists have high knowledge about inflammation in HIV infection, but, in the absence of scientific evidence to base their decisions on inflammatory markers, the therapeutic implications are scarce. The results support the need for more evidence on the monitoring and treatment of inflammation in PWH., (Copyright © 2023 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Platelet transfusions are given to preterm infants with severe thrombocytopenia aiming to prevent haemorrhage. The PlaNeT2/MATISSE trial revealed higher rates of mortality and/or major bleeding in preterm infants receiving prophylactic platelet transfusions at a platelet count threshold of 50 × 10 9 /L compared to 25 × 10 9 /L. The extent to which this evidence has been incorporated into clinical practice is unknown, thus we aimed to describe current neonatal platelet transfusion practices in Europe., Methods: We performed a prospective observational study in 64 neonatal intensive care units across 22 European countries between September 2022 and August 2023. Outcome measures included observed transfusion prevalence rates (per country and overall, pooled using a random effects Poisson model), expected rates based on patient-mix (per country, estimated using logistic regression), cumulative incidence of receiving a transfusion by day 28 (with death and discharge considered as competing events), transfusion indications, volumes and infusion rates, platelet count triggers and increment, and adverse effects., Findings: We included 1143 preterm infants, of whom 71 (6.2%, [71/1143]) collectively received 217 transfusions. Overall observed prevalence rate was 0.3 platelet transfusion days per 100 admission days. By day 28, 8.3% (95% CI: 5.5-11.1) of infants received a transfusion. Most transfusions were indicated for threshold (74.2%, [161/217]). Pre-transfusion platelet counts were above 25 × 10 9 /L in 33.1% [53/160] of these transfusions. There was significant variability in volume and duration., Interpretation: The restrictive threshold of 25 × 10 9 /L is being integrated into clinical practice. Research is needed to explore existing variation and generate evidence for various aspects including optimal volumes and infusion rates., Funding: Sanquin, EBA, and ESPR., Competing Interests: CH and TM have received compensation from Sanquin Blood Supply Foundation. JM has received compensation from Sanquin Blood Supply Foundation, research grants from Cooperatio and Personmed, and consulting fees from Danone, Nestlé, Baxter, and Chiesi. All other authors declare no competing interests., (© 2024 The Authors.)

Background and Aims: The landscape in primary biliary cholangitis (PBC) has changed with the advent of second-line treatments. However, the use of obeticholic acid (OCA) and fibrates in PBC-related cirrhosis is challenging. We assessed the impact of receiving a second-line therapy as a risk factor for decompensated cirrhosis in a real-world population with cirrhosis and PBC, and identify the predictive factors for decompensated cirrhosis in these patients., Approach and Results: Multicenter study enrolling 388 patients with PBC-cirrhosis from the Spanish ColHai registry. Biopsy (20%), ultrasound (59%), or transient elastography (21%) defined cirrhosis, and the presence of varices and splenomegaly defined clinically significant portal hypertension (CSPH). Paris-II and PBC OCA international study of efficacy criteria determined the response to ursodeoxycholic acid (UDCA), fibrates (n=93), and OCA (n=104). The incidence of decompensated cirrhosis decreased for UDCA versus OCA or fibrates in the real-world population, but they were similar considering the propensity score-matched cohort (UDCA 3.77 vs. second-line therapy 4.5 100 persons-year, respectively), as patients on second-line therapy exhibited advanced liver disease. Consequently, GGT, albumin, platelets, clinically significant portal hypertension, and UDCA response were associated with a decompensating event. OCA response (achieved in 52% of patients) was associated with bilirubin (OR 0.21 [95% CI: 0.06-0.73]) and AST (OR 0.97 [95% CI: 0.95-0.99]), while fibrate response (achieved in 55% of patients) with AST [OR 0.96 (95% CI: 0.95-0.98]). In patients treated with OCA, drug response (sHR 0.23 [95% CI: 0.08-0.64]), diabetes (sHR 5.62 [95% CI: 2.02-15.68]), albumin (sHR 0.34 [95% CI: 0.13-0.89]), and platelets (sHR 0.99 [95% CI: 0.98-1.00]) were related to decompensation. In patients treated with fibrate, drug response (sHR 0.36 (95% CI: 0.14-0.95]), albumin (sHR 0.36 (95% CI: 0.16-0.81]), and clinically significant portal hypertension (sHR 3.70 (95% CI: 1.17-11.70]) were associated with decompensated cirrhosis., Conclusions: Advanced PBC, rather than OCA and fibrates, was found to be associated with decompensating events. Therefore, biochemical and clinical variables should be considered when making decisions about the management of these drugs. Moreover, a positive response to OCA and fibrates reduced the risk of decompensation., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background and Aim: Determining suitable copper parameters for monitoring Wilson disease remains a topic of ongoing discussion. International recommendations currently rely on the combination of urinary copper excretion and nonspecific liver markers when considering therapy and time elapsed since diagnosis. The emergence of exchangeable copper (CuEX) as a novel measurement reflecting the "free copper pool" held promise as a valuable target to ensure metabolic stability during follow-up, although the validation of target ranges remains unknown. We aimed to evaluate CuEX quantification in repeated samples from 92 real-world patients with Wilson disease during a 2-year period., Approach: Patients were classified as "stable" if a diagnosis had been made more than 1 year before and were compliant with stable anti-copper drug and dose. Otherwise, patients were classified as "nonstable.", Results: Two hundred and thirteen CuEX samples were obtained per clinical practice. Overall, 57% of CuEX measurements fell below the reference "range of normality," whereas only 34% were within and 9% were above normal levels. There was no association of CuEX levels with therapy, elapsed time from diagnosis, or clinical stability, although most of the samples above normality corresponded to nonstable patients. Only 23.4% of the CuEX samples were aligned with data obtained from concomitant urinary copper excretion., Conclusions: Our findings suggest that CuEX is a suboptimal tool for assessing copper homeostasis when used alone and should be used with caution if no additional information is available. Normal reference intervals for Wilson disease-treated patients should be redefined, as most CuEX quantifications fell in the lower range, with no sign of overtreatment in these patients., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Pituitary apoplexy (PA) is the paradigm of endocrine and neurosurgical emergency., Objective: To evaluate the comorbidities, risk factors, clinical presentation, pituitary apoplexy score (PAS) and the outcomes of surgical vs. conservative management of PA in Spain., Methods: Spanish multicenter, observational study of 301 patients with acute PA. Statistical analyses compared risk factors, clinical presentation and outcomes between the surgical and conservative treatment groups, adjusting for potential confounders. The prevalence of cardiovascular risk factors in patients with pituitary apoplexy was compared with the Spanish population and with patients with non-functioning pituitary adenomas., Results: Median age was 59.3 years, 201 (66.8%) were men and non-functioning adenomas (77.9%) were the most common tumor type. The prevalence of diabetes (20.3% vs 13.9%, p<0.01), hypertension (48.8% vs 33.4%, p<0.01) and dyslipidemia (44.2% vs 23.3%, p<0.01), exceeded the Spanish age-adjusted population prevalence. Overall, 209 (69.4%) underwent surgery and 92 (30.6%) received conservative treatment. Surgical patients had larger tumors (26.2 vs 21.0 mm, p<0.01), chiasmal compression more frequently (77.2% vs 53.4%, p<0.01) and higher values of PAS. In the follow-up, while there were no statistically significant differences in anterior pituitary hormonal deficits between treatments, permanent vasopressin deficiency was more frequent after surgery (14.8% vs 3.3%, p<0.01)., Conclusion: There is a high burden of cardiovascular risk factors among patients with PA suggesting that metabolic factors may play a potential role in the development of PA. This underscores the need for comprehensive management of these conditions in addition to treating the apoplexy itself in this population. Surgical management has a relevant place in PA approach mainly in patients with higher PAS. However, it leads permanent vasopressin deficit more frequently than conservative approach., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Purpose: The phase II, multiarm, signal-searching BALTIC study (NCT02937818) assessed novel treatment combinations for platinum-refractory/resistant extensive-stage small cell lung cancer (ES-SCLC)., Patients and Methods: Patients with ES-SCLC with progressive disease during or within 90 days of completing first-line platinum-based chemotherapy received one of three regimens: durvalumab plus tremelimumab followed by durvalumab monotherapy (arm A), adavosertib plus carboplatin (arm B), or ceralasertib plus olaparib (arm C). The primary endpoint was the objective response rate. Prespecified exploratory biomarker analyses were conducted in arms A and C., Results: In arm A (n = 41), arm B (n = 10), and arm C (n = 21), the confirmed objective response rates were 7.3%, 0%, and 4.8%, respectively. Safety profiles in all arms were consistent with those of the individual drugs. In arm A, patients with PD-L1 expression (tumor cells or immune cells) ≥1% seemed to have a greater likelihood of achieving disease control with durvalumab plus tremelimumab than those with PD-L1 (tumor cells and immune cells) <1%, and lower baseline ctDNA and reduction in the on-treatment ctDNA level were both associated with longer overall survival. Among patients treated with ceralasertib plus olaparib in arm C, specific immune response-relevant circulating chemokines and cytokines were identified as early biomarkers of survival and pharmacodynamic biomarkers., Conclusions: In BALTIC, all combination regimens demonstrated tolerable safety profiles, but antitumor activity was limited in refractory/resistant ES-SCLC. Among patients treated with durvalumab plus tremelimumab, an association of on-treatment reduction in ctDNA with longer overall survival suggests the potential use of ctDNA as a surrogate of treatment response, warranting further investigation., (©2024 The Authors; Published by the American Association for Cancer Research.)

Importance: Red blood cell (RBC) transfusions are frequently administered to preterm infants born before 32 weeks of gestation in the neonatal intensive care unit (NICU). Two randomized clinical trials (Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants [ETTNO] and Transfusion of Prematures [TOP]) found that liberal RBC transfusion thresholds are nonsuperior to restrictive thresholds, but the extent to which these results have been integrated into clinical practice since publication in 2020 is unknown., Objective: To describe neonatal RBC transfusion practice in Europe., Design, Setting, and Participants: This international prospective observational cohort study collected data between September 1, 2022, and August 31, 2023, with a 6-week observation period per center, from 64 NICUs in 22 European countries. Participants included 1143 preterm infants born before 32 weeks of gestation., Exposure: Admission to the NICU., Main Outcomes and Measures: Study outcome measures included RBC transfusion prevalence rates, cumulative incidence, indications, pretransfusion hemoglobin (Hb) levels, volumes, and transfusion rates, Hb increment, and adverse effects of RBC transfusion., Results: A total of 1143 preterm infants were included (641 male [56.1%]; median gestational age at birth, 28 weeks plus 2 days [IQR, 26 weeks plus 2 days to 30 weeks plus 2 days]; median birth weight, 1030 [IQR, 780-1350] g), of whom 396 received 1 or more RBC transfusions, totaling 903 transfusions. Overall RBC transfusion prevalence rate during postnatal days 1 to 28 was 3.4 transfusion days per 100 admission days, with considerable variation across countries, only partly explained by patient mix. By day 28, 36.5% (95% CI, 31.6%-41.5%) of infants had received at least 1 transfusion. Most transfusions were given based on a defined Hb threshold (748 [82.8%]). Hemoglobin levels before transfusions indicated for threshold were below the restrictive thresholds set by ETTNO in 324 of 729 transfusions (44.4%) and TOP in 265 of 729 (36.4%). Conversely, they were between restrictive and liberal thresholds in 352 (48.3%) and 409 (56.1%) transfusions, respectively, and above liberal thresholds in 53 (7.3%) and 55 (7.5%) transfusions, respectively. Most transfusions given based on threshold had volumes of 15 mL/kg (470 of 738 [63.7%]) and were administered over 3 hours (400 of 738 [54.2%]), but there was substantial variation in dose and duration., Conclusions and Relevance: In this cohort study of very preterm infants, most transfusions indicated for threshold were given for pretransfusion Hb levels above restrictive transfusion thresholds evaluated in recent trials. These results underline the need to optimize practices and for implementation research to support uptake of evidence.

Background: Subcutaneous [SC] infliximab may provide multiple benefits over intravenous [IV] formulations. However, studies for efficacy and safety in inflammatory bowel disease [IBD] have been constrained by small sizes that limit the interpretation of outcomes, particularly for subgroups potentially at high risk of disease relapse., Methods: We conducted a systematic review and random-effects meta-analysis up to January 2023, to evaluate the change in clinical remission after transitioning from IV to SC infliximab in patients with IBD in clinical remission. The primary outcome was measured using the relative risk for meta-analysis., Results: We identified 15 studies of patients established ≥ 3 months on IV infliximab, consisting of 1371 patients and 840 patient-years of follow-up. There was no loss of clinical remission in the IBD cohort overall, Crohn's disease [CD], or perianal CD [p = 0.55 and p = 0.11 at 9-12 months, and p = 0.50 at 6 months, respectively]. Neither prior IV dose [≤ 10 mg/kg 6-weekly] [p = 0.48] nor IBD disease subtype was associated with an increased clinical relapse rate at 6 months (p = 0.48 and p = 0.45 [UC vs CD], respectively)., Conclusion: Changing patients established on IV infliximab to an SC formulation is associated with a high ongoing clinical remission and a low adverse event rate. Furthermore, there are no signals for adverse outcomes among different IBD disease subtypes, nor in those on escalated IV infliximab dosing schedules up to 10 mg/kg 6-weekly. These data should provide patients and clinicians alike with confidence in SC infliximab use in IBD., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background & Aims: Several hepatocellular carcinoma (HCC) risk-models have been developed to individualise patient surveillance following sustained viral response (SVR) in Hepatitis C Virus patients. Validation of these models in different cohorts is an important step to incorporate a more personalised risk assessment in clinical practice. We aimed at applying these models to stratify the risk in our patients and potentially determine cost-saving associated with individualised HCC risk-stratification screening strategy., Methods: Patients with baseline F3-4 fibrosis treated with new oral direct-acting antivirals who had reached a SVR were regularly followed as part of the HCC surveillance strategy. Six models were applied: Pons, aMAP, Ioannou, HCC risk, Alonso and Semmler. Validation of the models was performed based on sensitivity and the proportion of patients labelled as "high risk"., Results: After excluding 557 with less than 3 fibrosis, 12 without SVR, 18 with a follow up (FU) <1 year, 17 transplant recipients, 16 lost to FU and 31 with HCC at time of antiviral therapy, our cohort consisted of 349 F3-4 SVR patients. Twenty-three patients (6.6%) developed HCC after a median FU of 5.12 years. The sensitivity of the different models varied between 0.17 (Semmler7noalcohol) and 1 (Alonso A and aMAP). The lowest proportion of high-risk patients corresponded to the Semmler-noalcohol model (5%). Sixty-three and 90% of the Alonso A and aMAP patients, respectively were labelled as high risk. The most reliable HCC risk-model applied to our cohort to predict HCC development is the Alonso model (based on fibrosis stage assessed by liver stiffness measurements or Fibrosis-4 index (FIB-4) at baseline and after 1 year, and albumin levels at 1 year) with a-100% sensitivity in detecting HCC among those at high risk and 63% labelled as high risk. The application of the model would have saved the cost of 1290 ultrasound no longer being performed in the 37% low-risk group., Conclusion: In our cohort, the Alonso A model allows the most reliable reduction in HCC screening resulting in safely stopping life-long monitoring in about a third of F3-F4 patients achieving SVR with DAAs., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: This survey aimed to explore the availability and accessibility of echocardiography during noncardiac surgery worldwide., Methods: An internet-based 45-item survey was sent, followed by reminders from August 30, 2021, to August 20, 2022., Results: 1189 responses were received from 62 countries. Nearly seventy-one percent of respondents had intraoperatively used transesophageal or transthoracic echocardiography (TEE and TTE, respectively) for monitoring or examination. The unavailability of echocardiography machines (30.3%), lack of trained personnel (30.2%), and absence of clinical indications (22.6%) were the top 3 reasons for not using intraoperative echocardiography in noncardiac surgery. About 61.5% of participants had access to at least one echocardiography machine. About 41% had access to at least 1 TEE probe, and 62.2% had access to at least 1 TTE probe. Seventy-four percent of centers had a procedure to request intraoperative echocardiography if needed for noncardiac cases. Intraoperative echocardiography service was immediately available in 58% of centers., Conclusions: Echocardiography machines and skilled echocardiographers are still unavailable at many centers worldwide. National societies should aim to train a critical mass of certified TEE/TTE anesthesiologists and provide all anesthesiologists access to perioperative TEE/TTE machines in anesthesiology departments, considering the increasing number of older and sicker surgical patients scheduled for noncardiac surgery., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In 2016, the Spanish Research Group on Bronchopulmonary Dysplasia (BPD) (GEIDIS) established a national registry with participation of 66 hospitals to collect information on clinical characteristics and long-term outcomes of BPD infants into adulthood. The aim of this observational study is to examine forced spirometry data in early childhood and to assess their correlation with the respiratory support required at 36 weeks postmenstrual age (PMA). The study analyzed data from preterm infants with BPD born between January 2016 and December 2017 who underwent forced spirometry at 5-7 years of age. Statistical analyses were conducted to investigate the relationships between spirometry results, perinatal factors, and the required respiratory support at 36 weeks PMA. The study involved 143 patients with a median gestational age (GA) of 27.3 weeks (range 25.7-28.7) and a median weight of 880 g (range 740-1135). Abnormal spirometry results were observed in 39.2% (56) of the patients. Among patients diagnosed with BPD type 3, those requiring over 30% oxygen at 36 weeks PMA exhibited an increased risk of abnormal spirometry results (OR 4.48; 95% CI 1.11-18.13) compared to those requiring positive pressure with less than 30% oxygen. In addition, this subgroup had a higher risk of developing a restrictive-mixed pattern compared to those with BPD type 1 (OR 10.65; 95% CI 2.06-54.98) and BPD type 2 (OR 6.76; 95% CI 1.09-42.06). No significant differences were found in the incidence of an obstructive pattern between BPD types.      Conclusion: The requirement of more than 30% oxygen at 36 weeks PMA serves as a risk indicator for pulmonary function impairment in school-aged children with BPD. These findings suggest persistent airway and parenchymal injury in this specific patient population, and highlight the importance of careful monitoring to evaluate their long-term effects on lung function. What is Known: • Premature patients with bronchopulmonary dysplasia (BPD) may present abnormalities in pulmonary function tests during school age. However, the predictive accuracy of consensus BPD severity classification remains uncertain. What is New: • The requirement of more than 30% oxygen at 36 weeks postmenstrual age (PMA) indicates a potential risk of pulmonary function impairment in school-aged children with BPD. Additionally, a significant correlation has been observed between a restrictive-mixed pattern with exposure to mechanical ventilation and the development of severe forms of BPD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We are creating a synergy among European Health Data Space projects (e.g., IDERHA, EUCAIM, ASCAPE, iHELP, Bigpicture, and HealthData@EU pilot project) via health standards usage thanks to the HSBOOSTER EU Project since they are involved or using standards, and/or designing health ontologies. We compare health-standardized models/ontologies/terminologies such as HL7 FHIR, DICOM, OMOP, ISO TC 215 Health Informatics, W3C DCAT, etc. used in those projects.

Introduction: Obeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in patients with PBC improve with OCA therapy., Methods: Patients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database., Results: In the RCT, the primary endpoint occurred in 28.6% of OCA (n = 168) and 28.9% of placebo patients (n = 166; intent-to-treat analysis hazard ratio [HR] = 1.01, 95% confidence interval = 0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting and as-treated analyses shifted the HR to favor OCA. In the EC (n = 1,051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR = 0.39; 95% confidence interval = 0.22-0.69; P = 0.001). No new safety signals were identified in the RCT., Discussion: Functional unblinding and treatment crossover, particularly in the placebo arm, confounded the intent-to-treat estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Although, in randomized clinical trials, once-weekly subcutaneous semaglutide (OW s.c.) has demonstrated superior efficacy in comparison with placebo and active controls in terms of glycemic control and body weight reduction in patients with type 2 diabetes mellitus (T2DM), these results need to be confirmed in a real-world (RW) setting. An RW ambispective study (6 months retrospective and 6 months prospective) was conducted in 10 tertiary hospitals in Spain. We evaluated changes in HbA1c and body weight in patients with T2DM treated with semaglutide OW s.c. Additionally, we analyzed different subgroups of patients treated with semaglutide OW s.c. as an add-on to glucose-lowering therapy. A total of 752 patients with a mean age of 60.2 years, a mean HbA1c level of 8.5%, a mean body weight of 101.6 kg, and a mean T2DM duration of 10 years were included. At 12 months, compared with baseline, there was a mean difference of -2.1% in HbA1c levels ( p < 0.001) and a mean difference of 9.2 kg in body weight ( p < 0.001). Moreover, there were statistically significant differences ( p < 0.001) between baseline and month 12 in both HbA1c and body weight in the four subgroups receiving semaglutide OW s.c. as an add-on to glucose-lowering therapy. Semaglutide OW s.c. was well tolerated, with gastrointestinal disorders being the most commonly reported side effects. In this RW study, 12 months of treatment with semaglutide OW s.c. in patients with T2DM was associated with significant and clinically relevant improvements in glycemic control and weight loss, regardless of the glucose-lowering therapy received, and the overall safety profile was positive.

Purpose: Annually, over 20 million patients worldwide undergo inguinal hernia repair procedures. Surgery stands as the recommended treatment, however, a consensus on the optimal method is lacking. This study aims to conduct an updated systematic review and meta-analysis to compare the risk of chronic inguinal pain and recurrence between laparo-endoscopic mesh repair (TAPP and TEP) versus Lichtenstein repair for inguinal hernia., Methods: Searches were conducted in Ovid MEDLINE, PubMed, EBSCO, Cochrane, and Google Scholar. Inclusion criteria encompassed randomized controlled trials (RCTs) involving adults, published in English and Spanish, comparing surgical outcomes among the Lichtenstein open technique, TAPP, and/or TEP. Adherence to the PRISMA guidelines was maintained in the methodology, and the CASP tool was employed to assess the quality of the articles. Statistical analysis involved mean [± standard deviation (SD)], Odds Ratio (OR), and Confidence Interval (CI)., Results: Eight RCTs encompassing 1,469 patients randomized to Lichtenstein repair (n = 755) and laparo-endoscopic repair (n = 714) were included. Laparo-endoscopic repair was associated with a lower likelihood of chronic inguinal pain compared to Lichtenstein repair (OR = 0.28, 95% CI [0.30-0.56], p = 0.0001). There were no significant differences in recurrence rates between the laparo-endoscopic and the Lichtenstein group (OR = 1.03, 95% CI [0.57-1.86], p = 0.92)., Conclusions: This systematic review and meta-analysis demonstrate that laparo-endoscopic hernia surgery leads to a lower incidence of chronic inguinal pain compared to Lichtenstein repair, while maintaining similar rates of recurrence., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

This position paper by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Coeliac Disease (SIG-CD) presents an update to the 2016 recommendations concerning early diet and the risk of coeliac disease (CD). This update adheres to the policy that mandates reviewing guidelines every 5 years, particularly when new data emerge. The 2024 statements and recommendations are essentially similar to the 2016 recommendations. Breastfeeding, whether any amount, exclusive, or of any duration, does not reduce the risk of developing CD. Introducing gluten into an infant's diet at any time between completed 4 months (≥17 weeks) and 12 months of age does not affect the cumulative incidence of CD, although earlier introduction may lead to earlier seroconversion and CD. In observational studies involving cohorts with a known risk for CD, consuming a high amount of gluten compared to a low amount during weaning and in the subsequent childhood years-specifically the first 2-3 years, and even up to 5 years in some studies-was associated with an increased risk for CD. However, the specific optimal amounts of gluten consumption remain undetermined due to insufficient evidence on safe thresholds, and the impact of restricting gluten in the diet of healthy children of unknown risk for CD is unknown. Thus, any recommendation on the gluten amount is currently unjustifiable for the general population and infants with known HLA risk types. There is no specific guidance on the type of gluten-containing foods to be introduced at weaning., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

In the context of pancreatic cancer, surgical intervention is typically recommended for localized tumours, whereas chemotherapy is the preferred approach in the advanced and/or metastatic setting. However, pancreatic cancer is closely linked to ageing, with an average diagnosis at 72 years. Paradoxically, despite its increased occurrence among older individuals, this population is often underrepresented in clinical studies, complicating the decision-making process. Age alone should not determine the therapeutic strategy but, given the high comorbidity and mortality of this disease, a comprehensive geriatric assessment (CGA) is necessary to define the best treatment, prevent toxicity, and optimize older patient care. In this review, a group of experts from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica, SEOM), the Spanish Cooperative Group for the Treatment of Digestive Tumours (Grupo Español de Tratamiento de los Tumores Digestivos, TTD), and the Multidisciplinary Spanish Group of Digestive Cancer (Grupo Español Multidisciplinar en Cáncer Digestivo, GEMCAD) have assessed the available scientific evidence and propose a series of recommendations on the management and treatment of the older population with pancreatic cancer., (© 2024. The Author(s).)

Introduction: Serum levels of procalcitonin and C-reactive protein (CRP) have been used to predict anastomotic leakage after colorectal surgery, but information is scarce in advanced ovarian cancer (AOC) surgery with bowel resection. This study aimed to assess the predictive value of procalcitonin and CRP in detecting anastomotic leakage after AOC surgery with bowel resection. The study also aimed to determine the optimal postoperative reference values and the best day for evaluating these markers., Material and Methods: This prospective, observational and multicentric trial included 92 patients with AOC undergoing debulking surgery with bowel resection between 2017 and 2020 in 10 reference hospitals in Spain. Procalcitonin and CRP levels were measured at baseline and on postoperative days 1-6. Receiver operating characteristic analysis was performed to evaluate the predictive value of procalcitonin and CRP at each postoperative day. Sensitivity, specificity, positive and negative predictive values were calculated., Results: Anastomotic leakage was detected in six patients (6.5%). Procalcitonin and CRP values were consistently higher in patients with anastomotic leakage at all postoperative days. The maximum area under the curve (AUC) for procalcitonin was observed at postoperative day 1 (AUC = 0.823) with a cutoff value of 3.8 ng/mL (83.3% sensitivity, 81.3% specificity). For CRP, the maximum AUC was found at postoperative day 3 (AUC = 0.833) with a cutoff level of 30.5 mg/dL (100% sensitivity, 80.4% specificity)., Conclusions: Procalcitonin and C-reactive protein are potential biomarkers for early detection of anastomotic leakage after ovarian cancer surgery with bowel resection. Further prospective studies with a larger sample size are needed to confirm these findings., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: Hypertension and smoking during pregnancy have been linked to various adverse maternal and fetal outcomes. The objective of this work is to study how the smoking influences the development of hypertension, its effects on the pregnant woman, and on the newborn., Materials and Methods: An observational study in two phases was carried out: the descriptive first phase allows characterization of the sample and the analytical second phase is a case-control nested in a retrospective cohort corresponding to pregnancy., Results: A total of 712 women were included in the study. Of the 672 (94.4%) non-hypertensive women, 533 (79.3%) were non-smoking and 139 (20.7%) smoking. For the 40 (5.6%) hypertensive women, 30 (75.0%) were non-smoking and 10 (25.0%) smoking. The prevalence of hypertension was of 5.6%. Women who quit smoking before pregnancy saw a reduced risk of hypertension. For women who smoke during pregnancy, those of younger ages, with a normal body mass index, who are primiparous, employed and with a low-medium level of education have higher risk of hypertension. The risk of hypertension according to the level of physical activity during leisure time follows a "U" shape, with those who perform light physical activity at the lowest risk of hypertension. Hypertensive women have a higher risk of small for gestational age newborns. Smoking does not pose an additional risk for adverse outcomes once hypertension is diagnosed., Conclusions: Future studies should aim to determine the role of smoking habit in the appearance of hypertension in pregnancy in order to establish adequate intervention guidelines that may aid in reducing the prevalence of hypertension., (Copyright © 2023 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.)

Recombinant human relaxin-2 (serelaxin) has been widely proven as a novel drug with myriad effects at different cardiovascular levels, which support its potential therapeutic efficacy in several cardiovascular diseases (CVD). Considering these effects, together with the influence of relaxin-2 on adipocyte physiology and adipokine secretion, and the connection between visceral adipose tissue (VAT) dysfunction and the development of CVD, we could hypothesize that relaxin-2 may regulate VAT metabolism. Our objective was to evaluate the impact of a 2-week serelaxin treatment on the proteome and lipidome of VAT from Sprague-Dawley rats. We found that serelaxin increased 1 polyunsaturated fatty acid and 6 lysophosphatidylcholines and decreased 4 triglycerides in VAT employing ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) based platforms, and that regulates 47 phosphoproteins using SWATH/MS analysis. Through RT-PCR, we found that serelaxin treatment also caused an effect on VAT lipolysis through an increase in the mRNA expression of hormone-sensitive lipase (HSL) and a decrease in the expression of adipose triglyceride lipase (ATGL), together with a reduction in the VAT expression of the fatty acid transporter cluster of differentiation 36 (Cd36). Serelaxin also caused an anti-inflammatory effect in VAT by the decrease in the mRNA expression of tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), chemerin, and its receptor. In conclusion, our results highlight the regulatory role of serelaxin in the VAT proteome and lipidome, lipolytic function, and inflammatory profile, suggesting the implication of several mechanisms supporting the potential benefit of serelaxin for the prevention of obesity and metabolic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Up to 80% of patients under immune checkpoint inhibitors (ICI) face resistance. In this context, stereotactic ablative radiotherapy (SABR) can induce an immune or abscopal response. However, its molecular determinants remain unknown. We present early results of a translational study assessing biomarkers of response to combined ICI and SABR (I-SABR) in liquid biopsy from oligoprogressive patients in a prospective observational multicenter study. Cohort A includes metastatic patients in oligoprogression to ICI maintaining the same ICI due to clinical benefit and who receive concomitant SABR. B is a comparative group of oligometastatic patients receiving only SABR. Blood samples are extracted at baseline (T1), after the first (T2) and last (T3) fraction, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR)-complete and partial responses. We assess peripheral blood mononuclear cells (PBMCs), circulating cell-free DNA (cfDNA) and small RNA from extracellular vesicles. Twenty-seven patients could be analyzed (cohort A: n = 19; B: n = 8). Most were males with non-small cell lung cancer and one progressing lesion. With a median follow-up of 6 months, the last ORR was 63% (26% complete and 37% partial response). A decrease in cfDNA from T2 to T3 correlated with a good response. At T2, CD8+PD1+ and CD8+PDL1+ cells were increased in non-responders and responders, respectively. At T2, 27 microRNAs were differentially expressed. These are potential biomarkers of response to I-SABR in oligoprogressive disease.

Background: In elderly patients with external full-thickness rectal prolapse (EFTRP), the exact differences in postoperative recurrence and functional outcomes between laparoscopic ventral mesh rectopexy (LVMR) and perineal stapler resection (PSR) have not yet been investigated., Methods: We conducted a retrospective multicenter study on 330 elderly patients divided into LVMR group (n = 250) and PSR (n = 80) from April 2012 to April 2019. Patients were evaluated before and after surgery by Wexner incontinence scale, Altomare constipation scale, and patient satisfaction questionnaire. The primary outcomes were incidence and risk factors for EFTRP recurrence. Secondary outcomes were postoperative incontinence, constipation, and patient satisfaction., Results: LVMR was associated with fewer postoperative complications (p < 0.001), lower prolapse recurrence (p < 0.001), lower Wexner incontinence score (p = 0.03), and lower Altomare's score (p = 0.047). Furthermore, LVMR demonstrated a significantly higher surgery-recurrence interval (p < 0.001), incontinence improvement (p = 0.019), and patient satisfaction (p < 0.001) than PSR. Three and 13 patients developed new symptoms in LVMR and PSR, respectively. The predictors for prolapse recurrence were LVMR (associated with 93% risk reduction of recurrence, OR 0.067, 95% CI 0.03-0.347, p = 0.001), symptom duration (prolonged duration was associated with an increased risk of recurrence, OR 1.131, 95% CI 1.036-1.236, p = 0.006), and length of prolapse (increased length was associated with a high recurrence risk (OR = 1.407, 95% CI = 1.197-1.655, p < 0.001)., Conclusions: LVMR is safe for EFTRP treatment in elderly patients with low recurrence, and improved postoperative functional outcomes., Trial Registration: Clinical Trial.gov (NCT05915936), retrospectively registered on June 14, 2023., (© 2024. The Author(s).)

Atopic dermatitis is a cutaneous inflammatory disease characterized by intense pruritus, which is often underestimated despite its direct impact on patients' health-related quality of life and the high burden it poses. The authors' goal was to design a qualitative tool to guide patients and healthcare professionals in their assessment and interpretation of pruritus intensity using a numerical rating scale. The draft of this tool, henceforth "guideline", was developed based on a systematic literature review and focus groups comprising patients and a scientific committee. This draft was validated with an independent group of patients and the final version was designed following their feedback. According to the results of the systematic review, pruritus impacts 6 health-related quality of life domains: sleep quality; emotional status; overall health-related quality of life; physical function; social/sexual activity; productivity, particularly affecting sleep quality and the emotional domain. Patients considered that physical function was the most strongly affected domain, followed by sleep quality and emotional well-being, establishing that a minimum pruritus intensity of 4 and 7 points impacts moderately and severely, respectively, on the different domains of patients' health- related quality of life. The guideline may help patients and healthcare professionals to interpret and assess pruritus intensity using a numerical rating scale and to understand the impact of pruritus on patients' health-related quality of life.

Background and Objective: Coeliac disease is a chronic, immune-mediated disorder for which the only treatment consists of lifelong strict adherence to gluten-free diet (GFD). However, there is a lack of evidence-based guidelines on the GFD dietary management of coeliac disease. This position paper, led by the Special Interest Group in coeliac disease of the European Society of Pediatric, Gastroenterology Hepatology, and Nutrition, supported by the Nutrition Committee and the Allied Health Professionals Committee, aims to present evidence-based recommendations on the GFD as well as how to support dietary adherence., Methods: A wide literature search was performed using the MeSH Terms: "diet, gluten free," "gluten-free diet," "diets, gluten-free," "gluten free diet," and "coeliac disease" in Pubmed until November 8th, 2022., Results: The manuscript provides an overview of the definition of the GFD, regulations as basis to define the term "gluten-free," which foods are naturally gluten-free and gluten-containing. Moreover, it provides recommendations and educational tips and infographics on suitable food substitutes, the importance of reading food labels, risk of gluten cross-contact at home and in public settings, nutritional considerations as well as factors associated to dietary adherence based on available evidence, or otherwise clinical expertise., Conclusions: This position paper provides guidance and recommendations to support children with coeliac disease to safely adhere to a GFD., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Gastric cancer is one of the most frequent and deadly tumours worldwide. However, the evidence that currently exists for the treatment of older adults is limited and is derived mainly from clinical trials in which older patients are poorly represented. In this article, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Group for the Treatment of Digestive Tumours (TTD), and the Spanish Multidisciplinary Group on Digestive Cancer (GEMCAD) reviews the existing scientific evidence for older patients (≥65 years old) with gastric cancer and establishes a series of recommendations that allow optimization of management during all phases of the disease. Geriatric assessment (GA) and a multidisciplinary approach should be fundamental parts of the process. In early stages, endoscopic submucosal resection or laparoscopic gastrectomy is recommended depending on the stage. In locally advanced stage, the tolerability of triplet regimens has been established; however, as in the metastatic stage, platinum- and fluoropyrimidine-based regimens with the possibility of lower dose intensity are recommended resulting in similar efficacy. Likewise, the administration of trastuzumab, ramucirumab and immunotherapy for unresectable metastatic or locally advanced disease is safe. Supportive treatment acquires special importance in a population with different life expectancies than at a younger age. It is essential to consider the general state of the patient and the psychosocial dimension., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Until now, there has been limited evidence, primarily from US cohorts, focusing on frailty as a patient-oriented outcome after liver transplantation (LT). Our study aimed to explore the relationship between pre- and post-LT frailty in a multicenter European cohort of outpatients with cirrhosis undergoing LT., Methods: We conducted a prospective analysis of data from 180 LT recipients recruited between 2018 and 2020 from 5 Spanish centers. Participants underwent objective and subjective frailty assessments using the Liver Frailty Index (LFI) and the Subjective Clinician Assessment (SCA) pretransplant and at 3- and/or 6-mo posttransplant., Results: The median pretransplant LFI was 3.9, showing minimal change at 3 mo (3.8; P  = 0.331) and improvement at 6-mo post-LT (3.6; P  = 0.001). Conversely, the SCA significantly improved early post-LT: at 3 mo, poor SCA decreased from 11% to 1%, and good SCA increased from 54% to 89% ( P  < 0.001), remaining stable between 3- and 6-mo post-LT. Multivariable analysis revealed that each 0.1 increase in pretransplant LFI correlated with a reduced probability of being robust at 3-mo (odds ratio [OR] = 0.75; P  < 0.001) and 6-mo post-LT (OR = 0.74; P  < 0.001). There was poor concordance between SCA and LFI, with SCA underestimating frailty both pre- and post-LT (Kappa < 0.20)., Conclusion: In our European cohort, incomplete improvement of physical frailty was observed, with <20% achieving robust physical condition within 6-mo post-LT. The pretransplant LFI strongly predicted posttransplant frailty. As the SCA tends to overestimate physical function, we recommend using both subjective and objective tools for frailty assessment in LT candidates and recipients., Competing Interests: This research was funded by the Instituto de Salud Carlos III and co-funded by European Regional Development Fund “A Way to Make Europe” (grants number CM17/00006—L.P., PI19/01360—M.B., and INT20/00061—M.B.), by the Generalitat Valenciana (grant AICO/2021/035—M.B.), and by the CIBER-Consorcio Centro de Investigación Biomédica en Red (CB06/04/0065), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea—European Regional Development Fund. No sponsor had a role in the study design, the data collection, the analysis and interpretation of data, the writing of the article, or the decision to submit the article for publication. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Laparoscopy offers numerous advantages over open procedures, minimizing trauma, reducing pain, accelerating recovery, and shortening hospital stays. Despite other technical advancements, pneumoperitoneum insufflation has received little attention, barely evolving since its inception. We explore the impact of pneumoperitoneum on patient outcomes and advocate for a minimally invasive approach that prioritizes peritoneal homeostasis. The nonlinear relationship between intra-abdominal pressure (IAP) and intra-abdominal volume (IAV) is discussed, emphasizing IAP titration to balance physiological effects and surgical workspace. Maintaining IAP below 10 mmHg is generally recommended, but factors such as patient positioning and surgical complexity must be considered. The depth of neuromuscular blockade (NMB) is explored as another variable affecting laparoscopic conditions. While deep NMB appears favorable for surgical stillness, achieving a balance between IAP and NMB depth is crucial. Temperature and humidity management during pneumoperitoneum are crucial for patient safety and optical field quality. Despite the debate over the significance of temperature drop, humidification and the warming of insufflated gas offer benefits in peritoneal homeostasis and visual clarity. In conclusion, there is potential for a paradigm shift in pneumoperitoneum management, with dynamic IAP adjustments and careful control of insufflated gas temperature and humidity to preserve peritoneal homeostasis and improve patient outcomes in minimally invasive surgery.

The Cow's Milk-related Symptom Score (CoMiSS) is an awareness tool for evaluating cow's milk-related symptoms. Previous studies have focused on providing CoMiSS values for healthy and symptomatic infants aged 0-6 months. However, there is a notable gap in the literature concerning CoMiSS values for infants older than 6 months. This cross-sectional study aimed to determine CoMiSS values in presumed healthy infants who have completed 6 months and are up to 12 months old, hereafter referred to as 6 to 12 months old. Physicians from six European countries prospectively determined CoMiSS values in infants attending well-child clinics. Exclusion criteria included preterm delivery, acute or chronic disease, and the consumption of a therapeutic formula, dietary supplements (except vitamins), or medication. The following information was collected: gestational age, gender, age, type of feed (breast milk or infant formula), and complementary feeding. Descriptive statistics were summarized with mean and standard deviation for normally distributed continuous variables, median and IQR for non-normally distributed variables, and differences in CoMiSS values were analyzed with appropriate tests. Data from 609 infants were obtained. The overall median (Q1-Q3) CoMiSS values were 3 (1-5). Significant differences were found across age groups (p < 0.001), but not across groups based on gender (p = 0.551) or feeding type (p = 0.880).   Conclusions: This study provided CoMiSS values in presumed healthy infants aged 6-12 months. Additional studies should be conducted to establish the use of CoMiSS to assess cow's milk-related symptoms in infants 6 months and older. What is Known: • The Cow's Milk-related Symptom Score (CoMiSS) is an awareness tool for evaluating symptoms related to cow's milk. • CoMiSS values for presumed healthy infants aged 0-6 months infants are already available. What is New: • CoMiSS values in European infants aged 6-12 months are provided. • These CoMiSS values differed across various age groups but not across groups based on gender or feeding type., (© 2023. The Author(s).)

A previous guideline on cow's milk allergy (CMA) developed by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) was published in 2012. This position paper provides an update on the diagnosis, treatment, and prevention of CMA with focus on gastrointestinal manifestations. All systematic reviews and meta-analyses regarding prevalence, pathophysiology, symptoms, and diagnosis of CMA published after the previous ESPGHAN document were considered. Medline was searched from inception until May 2022 for topics that were not covered in the previous document. After reaching consensus on the manuscript, statements were formulated and voted on each of them with a score between 0 and 9. A score of ≥6 was arbitrarily considered as agreement. Available evidence on the role of dietary practice in the prevention, diagnosis, and management of CMA was updated and recommendations formulated. CMA in exclusively breastfed infants exists, but is uncommon and suffers from over-diagnosis. CMA is also over-diagnosed in formula and mixed fed infants. Changes in stool characteristics, feeding aversion, or occasional spots of blood in stool are common and in general should not be considered as diagnostic of CMA, irrespective of preceding consumption of cow's milk. Over-diagnosis of CMA occurs much more frequently than under-diagnosis; both have potentially harmful consequences. Therefore, the necessity of a challenge test after a short diagnostic elimination diet of 2-4 weeks is recommended as the cornerstone of the diagnosis. This position paper contains sections on nutrition, growth, cost, and quality of life., (© 2023 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Hernia repair is one of the most frequently performed world-wide surgical procedures in which hernia meshes are becoming increasingly used. Polypropylene (PP) mesh implants reduce the risk of recurrence and post-operative pain, although many other risks are associated with it, such as bacterial infection. In this study we developed PP meshes coated with the well-known antimicrobial compound, benzalkonium chloride (BAK) by dip-coating. Several dilutions (40, 20, 30, 10, 7.5, 5, 2.5, 1, 0.5, 0.1 and 0.05 % v/v ) of commercial BAK solution (BAK diluted in 70 % ethyl alcohol at 0.1 % w/v ) were used to produce antimicrobial meshes with different amounts of BAK. The dip-coating treatment with low concentrations of BAK (1, 0.5, 0.1 and 0.05 % v/v dilutions) was found to have biocompatible results in fibroblast. The use of 0.1 and 0.05 % v/v dilutions (PP meshes with up to ∼2 % w/w of BAK) showed proliferative activity on fibroblast cells, indicating that these novel antimicrobial meshes show great promise for hernia repair due to their ability to prevent infections while inducing fibroblast proliferation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:The findings of this study contributed to patent application AX220202EP to the OEPM Office, Madrid, Spain, with Á.S-A. as inventor. The remaining authors declare no competing interests., (© 2024 The Authors.)

Introduction: The multiparametric nature of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) still leads to uncertainty with its practical management. This study aims to characterize the main posttransplant recurrence patterns of HCC and to explore the therapeutic modalities targeting recurrence., Methods: Consecutive patients who underwent LT for HCC at a single tertiary center were analyzed. The time from first recurrence to death was investigated for each site of presentation. The impact of each recurrence-targeted treatment on survival was studied., Results: Of 660 patients with HCC, any recurrence occurred in 96 (15.4%) patients with a median time to recurrence of 20.0 months (95% CI: 15.6-23.8). Patients recurred across different patters including solitary distant locations (30.8%, n = 28), liver only (24.2%, n = 22), lung (18.7%, n = 17), multi-organ disease (17.6%, n = 16), and bone (8.8%, n = 8). Multi-organ and bone recurrences had the poorest survival, while solitary distant lesions and pulmonary recurrences had the best outcomes. Each treatment modality carried a distinctive survival., Conclusions: Patients recurred across 3 patterns with different prognostic implications. The benefit of each treatment option on distinct recurrence patterns appears to be influenced by the biological behavior inherent in the recurrence pattern itself., (© 2024 S. Karger AG, Basel.)