Near-normal aerobic capacity in long-term survivors after lung transplantation

Lung transplant; Survivors; Aerobic capacityTrasplantaments de pulmó; Supervivents; Capacitat aeròbicaTrasplantes de pulmón; Supervivientes; Capacidad aeróbicaThe clinical course of lung transplantation (LT) is diverse: some patients present chronic lung allograft dysfunction (CLAD) and progressive decline in pulmonary function, but others maintain normal spirometric values and active lives. Objectives The aim of this study was to elucidate whether long-term LT survivors with normal spirometry achieve normal exercise capacity, and to identify predictive factors of exercise capacity. Methods This was a cross-sectional multicentre study, where bilateral LT recipients who survived at least 10 years after LT, with normal spirometry, no diagnosis of CLAD and modified Medical Research Council dyspnoea degree ≤2 underwent cardiopulmonary exercise testing (CPET). Results 28 LT recipients were included with a mean±sd age of 48.7±13.6 years. Oxygen uptake (V′O2) had a mean±sd value of 21.49±6.68 mL·kg−1·min−1 (75.24±15.6%) and the anaerobic threshold was reached at 48.6±10.1% of the V′O2max predicted. The mean±sd heart rate reserve at peak exercise was 17.56±13.6%. The oxygen pulse increased during exercise and was within normal values at 90.5±19.4%. The respiratory exchange ratio exceeded 1.19 at maximum exercise. The median (25–75th percentile) EuroQol-5D score was 1 (0.95–1), indicating a good quality of life. The median (25–75th percentile) International Physical Activity Questionnaire score was 5497 (4007–9832) MET-min·week−1 with 89% of patients reporting more than 1500 MET-min·week−1. In the multivariate regression models, age, sex and diffusing capacity of the lung for carbon monoxide remained significantly associated with V′O2max (mL·kg−1·min−1); haemoglobin and forced expiratory volume in 1 s were significantly associated with maximum work rate (watts), after adjusting for confounders. Conclusion We report for the first time near-normal peak V′O2 values during CPET and normal exercise capacity in long-term LT recipients without CLAD.Support statement: This study was financed by Instituto de Salud Carlos III (PI13/01076); the European Regional Development Fund (FEDER), FUCAP, Astellas, Novartis and Chiesi. Funding information for this article has been deposited with the Crossref Funder Registry.Ojanguren is a researcher supported by the “Pla Estratègic de Recerca i Innovació en Salut (PERIS)” 2016–2020 (SLT008/18/00108;G60594009)

Community-curated and standardised metadata of published ancient metagenomic samples with AncientMetagenomeDir

Ancient DNA and RNA are valuable data sources for a wide range of disciplines. Within the field of ancient metagenomics, the number of published genetic datasets has risen dramatically in recent years, and tracking this data for reuse is particularly important for large-scale ecological and evolutionary studies of individual taxa and communities of both microbes and eukaryotes. AncientMetagenomeDir (archived at https://doi.org/10.5281/zenodo.3980833) is a collection of annotated metagenomic sample lists derived from published studies that provide basic, standardised metadata and accession numbers to allow rapid data retrieval from online repositories. These tables are community-curated and span multiple sub-disciplines to ensure adequate breadth and consensus in metadata definitions, as well as longevity of the database. Internal guidelines and automated checks facilitate compatibility with established sequence-read archives and term-ontologies, and ensure consistency and interoperability for future meta-analyses. This collection will also assist in standardising metadata reporting for future ancient metagenomic studies

Early-Stage Breast Cancer Detection in Breast Milk

Breast cancer; Breast milkCáncer de mama; Leche maternaCàncer de mama; Llet maternaBreast cancer occurring during pregnancy (PrBC) and postpartum (PPBC) is usually diagnosed at more advanced stages compared with other breast cancer, worsening its prognosis. PPBC is particularly aggressive, with increased metastatic risk and mortality. Thus, effective screening methods to detect early PrBC and PPBC are needed. We report for the first time that cell-free tumor DNA (ctDNA) is present in breast milk (BM) collected from patients with breast cancer. Analysis of ctDNA from BM detects tumor variants in 87% of the cases by droplet digital PCR, while variants remain undetected in 92% of matched plasma samples. Retrospective next-generation sequencing analysis in BM ctDNA recapitulates tumor variants, with an overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in BM collected 18 and 6 months prior to standard diagnosis. Our results open up the potential use of BM as a new source for liquid biopsy for PPBC detection. Significance: For the first time, we show that BM obtained from patients with breast cancer carries ctDNA, surpassing plasma-based liquid biopsy for detection and molecular profiling of early-stage breast cancer, even prior to diagnosis by image.We thank the patients who participated in the study and donated samples for analysis for their generous contribution, with particular thanks to the first patient, Maite, and her daughter Àneu, who inspired us to initiate this study (oral consent to name the patient and her daughter was provided by the patient, and her legal partner provided written consent after patient's exitus). We are grateful to Javier Carmona for his valuable contributions and support in the manuscript's conceptualization, preparation, and revision. VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment and the CERCA Programme from the Generalitat de Catalunya for their support of this research. The authors from VHIO acknowledge the State Agency for Research (Agencia Estatal de Investigación) for the financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/501100011033). This research is financially supported by the “El paseíco de la mama” Foundation. C. Saura was the recipient of a II FERO-GHD grant from the FERO Foundation (FERO/5086), a Junior Clinical award from the Spanish Association Against Cancer Foundation (FAECC; CLJUN212026ORTI), and a SEOM-Daiichi Sankyo grant for its support on the Breast Cancer Research Projects 2021 (SEOM/FECMA2022) and received funding from the Department of Health (Generalitat de Catalunya SLT008/18/00198) and from the Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER), cofunded by the European Union (PI21/01020). C. Ortiz was the recipient of a Junior Clinician award from the FAECC (CLJUN212026ORTI) and a SEOM-Daiichi Sankyo grant for its support on the Breast Cancer Research Projects 2021 (SEOM/FECMA2022), and received funding from the Department of Health (Generalitat de Catalunya SLT008/18/00198). N. Bayó-Puxan received funding from the Department of Health (Generalitat de Catalunya SLT008/18/00205), MCIN/AEI/10.13039/501100011033 (GPE2022-001029) and MCIN/AEI/10.130.39/501100011033, and the European Union “Next GenerationEU/PRTR” (ECT2020-000827). J.M. Miquel received funding from the Department of Health (Generalitat de Catalunya SLT008/18/00205), MCIN/AEI/10.130.39/501100011033, and the European Union “Next GenerationEU/PRTR” (ECT2020-000827). J. Arribas is funded by the Breast Cancer Research Foundation (BCRF-23-008), Instituto de Salud Carlos III (project reference numbers AC15/00062, CB16/12/00449, and PI22/00001), and the European Commission under the framework of the ERA-NET TRANSCAN-2 initiative cofinanced by FEDER and Asociación Española Contra el Cáncer. A. Vivancos was the recipient of a project award from the FAECC (AVP/18/AECC/3219) and received funding from the Advanced Molecular Diagnostic (DIAMAV) program from the FERO Foundation (8361) and from ISDIN for supporting the development of liquid biopsy applications at the Cancer Genomics Lab (1848). M. Sansó was the recipient of a II FERO-GHD grant from the FERO Foundation (FERO/5086) and an investigator award from the FAECC (INVES19056SANS), and received funding from the Health Research Institute of the Balearic Islands (IdISBa), the RADIX-Janssen program (RADIX/JANSSEN21/01), and the Miguel Servet Program funded by the ISCIII (CP22/00131)

Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when = 50 years and symptomatic for <= 7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with <= 5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Global survival trends for brain tumors, by histology: analysis of individual records for 556,237 adults diagnosed in 59 countries during 2000–2014 (CONCORD-3)

Background: Survival is a key metric of the effectiveness of a health system in managing cancer. We set out to provide a comprehensive examination of worldwide variation and trends in survival from brain tumors in adults, by histology. Methods: We analyzed individual data for adults (15–99 years) diagnosed with a brain tumor (ICD-O-3 topography code C71) during 2000–2014, regardless of tumor behavior. Data underwent a 3-phase quality control as part of CONCORD-3. We estimated net survival for 11 histology groups, using the unbiased nonparametric Pohar Perme estimator. Results: The study included 556,237 adults. In 2010–2014, the global range in age-standardized 5-year net survival for the most common sub-types was broad: in the range 20%–38% for diffuse and anaplastic astrocytoma, from 4% to 17% for glioblastoma, and between 32% and 69% for oligodendroglioma. For patients with glioblastoma, the largest gains in survival occurred between 2000–2004 and 2005–2009. These improvements were more noticeable among adults diagnosed aged 40–70 years than among younger adults. Conclusions: To the best of our knowledge, this study provides the largest account to date of global trends in population-based survival for brain tumors by histology in adults. We have highlighted remarkable gains in 5-year survival from glioblastoma since 2005, providing large-scale empirical evidence on the uptake of chemoradiation at population level. Worldwide, survival improvements have been extensive, but some countries still lag behind. Our findings may help clinicians involved in national and international tumor pathway boards to promote initiatives aimed at more extensive implementation of clinical guidelines