67 research outputs found
An Integrated Immunopeptidomics and Proteogenomics Framework to Discover Non-Canonical Targets for Cancer Immunotherapy
Un Ă©lĂ©ment essentiel de lâimmunothĂ©rapie appliquĂ©e au cancer est lâidentification de peptides liant les antigĂšnes des leucocytes humains (HLA) et capables dâinduire une puissante rĂ©ponse T anti-tumorale. La spectromĂ©trie de masse (MS) constitue actuellement la seule mĂ©thode non-biaisĂ©e permettant une analyse dĂ©taillĂ©e du panel dâantigĂšnes susceptibles dâĂȘtre prĂ©sentĂ©s aux lymphocytes T in vivo. Lâutilisation de cette mĂ©thode en clinique requiert toutefois des amĂ©liorations significatives de la mĂ©thodologie utilisĂ©e lors de lâidentification des peptides HLA.
Un consortium multidisciplinaire de chercheurs a rĂ©cemment mis en lumiĂšre les problĂšmes actuellement liĂ©s Ă lâutilisation de la MS en immunopeptidomique, soulignant le besoin de dĂ©velopper de nouvelles mĂ©thodes et mettant en Ă©vidence le dĂ©fi que reprĂ©sente la standardisation de lâimmuno-purification des molĂ©cules HLA. La premiĂšre partie de cette thĂšse vise Ă optimiser les mĂ©thodes expĂ©rimentales permettant lâextraction des peptides apprĂȘtĂ©s aux HLA. Lâoptimisation de la mĂ©thodologie de base a permis des amĂ©liorations notables en terme de dĂ©bit, de reproductibilitĂ©, de sensibilitĂ© et a permis une purification sĂ©quentielle des molĂ©cules de HLA de classe I de classe II ainsi que de leurs peptides, Ă partir de lignĂ©es cellulaires ou de tissus. En comparaison avec les mĂ©thodes existantes, ce protocole comprend moins dâĂ©tapes et permet de limiter la manipulation des Ă©chantillons ainsi que le temps de purification. Cette mĂ©thode, pour les peptides HLA extraits, a permis dâobtenir des taux de reproductibilitĂ© et de sensibilitĂ© sans prĂ©cĂ©dents (corrĂ©lations de Pearson jusqu'Ă 0,98 et 0,97 pour les HLA de classe I et de classe II, respectivement). De plus, la faisabilitĂ© dâĂ©tudes comparatives robustes a Ă©tĂ© dĂ©montrĂ©e Ă partir dâune lignĂ©e cellulaire de cancer de lâovaire, traitĂ©e Ă l'interfĂ©ron gamma. En effet, cette nouvelle mĂ©thode a mis en Ă©vidence des changements quantitatifs et qualitatifs du catalogue de peptides prĂ©sentĂ©s aux HLA. Les rĂ©sultats obtenus ont mis en avant une augmentation de la prĂ©sentation de longs ligands chymotryptiques de classe I. Ce phĂ©nomĂšne est probablement liĂ© Ă la modulation de la machinerie de traitement et de prĂ©sentation des antigĂšnes. Dans cette premiĂšre partie de thĂšse, nous avons dĂ©veloppĂ© une mĂ©thodologie robuste et rationalisĂ©e, facilitant la purification des HLA et pouvant ĂȘtre appliquĂ©e en recherche fondamentale et translationnelle.
Bien que les nĂ©oantigĂšnes reprĂ©sentent une cible attractive, des Ă©tudes rĂ©centes ont mis en Ă©vidence lâexistence des antigĂšnes non canoniques. Ces antigĂšnes tumoraux, bien que non mutĂ©s, sont aussi spĂ©cifiques aux cellules cancĂ©reuses et semblent jouer un rĂŽle important dans lâimmunitĂ© anti-tumorale. La seconde partie de cette thĂšse a pour objectif le dĂ©veloppement dâune mĂ©thodologie dâanalyse permettant lâidentification ainsi que la validation de ces antigĂšnes particuliers. Les antigĂšnes non canoniques sont d'origine prĂ©sumĂ©e non codante et ne sont, par consĂ©quent, que rarement inclus dans les bases de donnĂ©es des sĂ©quences de protĂ©ines de rĂ©fĂ©rence. De ce fait, ils ne sont gĂ©nĂ©ralement pas pris en compte lors des recherches de MS utilisant de telles bases de donnĂ©es. Afin de palier ce problĂšme et de permettre leur identification par MS, le sĂ©quençage de l'exome entier, le sĂ©quençage de l'ARN sur une population de cellules et sur des cellules uniques, ainsi que le profilage des ribosomes ont Ă©tĂ© intĂ©grĂ©s aux donnĂ©es dâimmunopeptidomique. Ainsi, NewAnce, un programme informatique permettant de combiner les donnĂ©es de deux outils de recherche MS en tandem, a Ă©tĂ© dĂ©veloppĂ© afin de calculer le taux dâantigĂšnes non canoniques identifiĂ©s comme faux positifs. Lâutilisation de NewAnce sur des lignĂ©es cellulaires provenant de patients atteints de mĂ©lanomes ainsi que sur des biopsies de cancer du poumon a permis lâidentification prĂ©cise de centaines de peptides HLA non classiques, spĂ©cifiques aux cellules tumorales et communs Ă plusieurs patients. Le niveau de confirmation des peptides non canoniques a ensuite Ă©tĂ© testĂ© Ă lâaide dâune approche de MS ciblĂ©e. Les peptides rĂ©sultant de ces analyses ont Ă©tĂ© minutieusement validĂ©s pour un des Ă©chantillons de mĂ©lanome disponibles. De plus, le profilage des ribosomes a rĂ©vĂ©lĂ© que les nouveaux cadres de lecture ouverts, desquels rĂ©sultent certains de ces peptides non classiques, sont activement traduits. LâĂ©valuation de lâimmunogenicitĂ© de ces peptides a Ă©tĂ© Ă©valuĂ©e avec des cellules immunitaires autologues et a rĂ©vĂ©lĂ© un Ă©pitope immunogĂšne non canonique, provenant d'un cadre de lecture ouvert alternatif du gĂšne ABCB5, un marqueur des cellules souches du mĂ©lanome.
De maniĂšre globale, les rĂ©sultats obtenus au cours de cette thĂšse soulignent la possibilitĂ© dâinclure ce type dâanalyse de proteogĂ©nomique dans un protocole dâidentification de nĂ©oantigĂšnes existant. Cela permettrait dâinclure et prioriser des antigĂšnes tumoraux non classiques et de proposer aux patients en impasse thĂ©rapeutique des immunothĂ©rapies anti-tumorales personnalisĂ©es.
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A central factor to the development of cancer immunotherapy is the identification of clinically relevant human leukocyte antigen (HLA)-bound peptides that elicit potent anti-tumor T cell responses. Mass spectrometry (MS) is the only unbiased technique that captures the in vivo presented HLA repertoire. However, significant improvements in MS-based HLA peptide discovery methodologies are necessary to enable the smooth transition to the clinic.
Recently, a consortium of multidisciplinary researchers presented current issues in clinical MS-based immunopeptidomics, highlighting method development and standardization challenges in HLA immunoaffinity purification. The first part of this thesis addresses improvements to the experimental method for HLA peptide extraction. The approach was optimized with several new developments, facilitating high-throughput, reproducible, scalable, and sensitive sequential immunoaffinity purification of HLA class I and class II peptides from cell lines and tissue samples. The method showed increased speed, and reduced sample handling when compared to previous methods. Unprecedented depth and high reproducibility were achieved for the obtained HLA peptides (Pearson correlations up to 0.98 and 0.97 for HLA class I and HLA class II, respectively). Additionally, the feasibility of performing robust comparative studies was demonstrated on an ovarian cancer cell line treated with interferon gamma. Both quantitative and qualitative changes were detected in the cancer HLA repertoire upon treatment. Specifically, a yet unreported and interesting phenomenon was the upregulated presentation of longer and chymotryptic-like HLA class I ligands, likely related to the modulation of the antigen processing and presentation machinery. Taken together, a robust and streamlined framework was built that facilitates peptide purification and its application in basic and translational research.
Furthermore, recent studies have shed light that, along with the highly attractive mutated neoantigens, other non-mutated, yet tumor-specific, non-canonical antigens may also play an important role in anti-tumor immunity. Non-canonical antigens are of presumed non-coding origin and not commonly included in protein reference databases, and are therefore typically disregarded in database-dependent MS searches. The second part of this thesis develops an analytical workflow enabling the confident identification and validation of non- canonical tumor antigens. For this purpose, whole exome sequencing, bulk and single-cell RNA sequencing and ribosome profiling were integrated with MS-based immunopeptidomics for personalized non-canonical HLA peptide discovery. A computational module called NewAnce was designed, which combines the results of two tandem MS search tools and implements group-specific false discovery rate calculations to control the error specifically for the non-canonical peptide group. When applied to patient-derived melanoma cell lines and paired lung cancer and normal tissues, NewAnce resulted in the accurate identification of hundreds of shared and tumor-specific non-canonical HLA peptides. Next, the level of non-canonical peptide confirmation was tested in a targeted MS-based approach, and selected non-canonical peptides were extensively validated for one melanoma sample. Furthermore, the novel open reading frames that generate a selection of these non- canonical peptides were found to be actively translated by ribosome profiling. Importantly, these peptides were assessed with autologous immune cells and a non-canonical immunogenic epitope was discovered from an alternative open reading frame of melanoma stem cell marker gene ABCB5.
This thesis concludes by highlighting the possibility of incorporating the proteogenomics pipeline into existing neoantigen discovery engines in order to prioritize tumor-specific non-canonical peptides for cancer immunotherapy.
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Maladie trĂšs hĂ©tĂ©rogĂšne et multifactorielle, le cancer reprĂ©sente Ă ce jour la seconde cause de dĂ©cĂšs dans le monde. Bien que le systĂšme immunitaire soit capable de reconnaĂźtre puis dâĂ©liminer les cellules cancĂ©reuses, ces derniĂšres peuvent Ă leur tour sâadapter et accumuler des mutations leur permettant dâĂ©chapper Ă cette reconnaissance.
LâimmunothĂ©rapie anti-tumorale dĂ©montre le rĂŽle clĂ© de lâimmunitĂ© dans lâĂ©radication des tumeurs. Cependant, ces thĂ©rapies prometteuses ne sont efficaces que chez une petite proportion des patients traitĂ©s. Une Ă©tape majeure dans lâĂ©tablissement dâune rĂ©ponse immunitaire anti-tumorale est la reconnaissance dâantigĂšnes associĂ©s aux tumeurs. Des Ă©tudes rĂ©centes ont montrĂ© que les antigĂšnes tumoraux issus de rĂ©gions non-codantes du gĂ©nome (antigĂšnes non-canoniques) peuvent jouer un rĂŽle clĂ© dans lâinduction de rĂ©ponses immunitaires. Ainsi, lâidentification de ces antigĂšnes tumoraux particuliers permettrait de guider le dĂ©veloppement dâimmunothĂ©rapies anti-cancĂ©reuses personnalisĂ©es telles que la vaccination ou encore le transfert adoptif de lymphocytes T reconnaissant ces cibles. La spectromĂ©trie de masse (MS) est une technique non biaisĂ©e permettant lâidentification et lâanalyse du rĂ©pertoire des antigĂšnes prĂ©sentĂ©s in vivo. Cependant, cette technique nĂ©cessite dâĂȘtre optimisĂ©e et standardisĂ©e afin dâĂȘtre utilisĂ©e en clinique.
Ainsi, la premiĂšre partie de ces travaux de thĂšse a Ă©tĂ© dĂ©diĂ©e Ă lâoptimisation expĂ©rimentale de cette mĂ©thode Ă partir dâĂ©chantillons de tissus et de lignĂ©es cellulaires. En comparaison avec les protocoles standards, cette technique permet une couverture plus complĂšte, rapide et reproductible du rĂ©pertoire de peptides apprĂȘtĂ©s aux HLA.
La seconde partie de cette thĂšse a Ă©tĂ© consacrĂ©e au dĂ©veloppement dâune mĂ©thode permettant lâidentification dâantigĂšnes tumoraux non-canoniques via le sĂ©quençage dâARN cellulaire, ribosomique et lâutilisation de notre mĂ©thode dâimmunopeptidomique optimisĂ©e. Afin de contrĂŽler lâidentification de faux positifs, nous avons Ă©laborĂ© un nouveau module computationnel. Ce module a permis lâidentification de plusieurs centaines de peptides-HLA non-canoniques, partagĂ©s et spĂ©cifiques au mĂ©lanome et au cancer du poumon. Le sĂ©quençage des ARN ribosomiques a mis en Ă©vidence la traduction de nouveaux cadre ouverts de lecture desquels sont traduits de nouveaux peptides non-canoniques. Cette technique nous a permis de mettre en Ă©vidence un Ă©pitope immunogĂšne issu du gĂšne ABCB5, un marqueur de cellules souches cancĂ©reuses prĂ©alablement identifiĂ© dans le mĂ©lanome.
De maniĂšre globale, ces travaux de thĂšse, alliant immunopeptidomique et protĂ©ogĂ©nomique, ont permis la mise au point dâune mĂ©thode expĂ©rimentale permettant une meilleure identification dâantigĂšnes tumoraux. Nous espĂ©rons que ces rĂ©sultats amĂ©lioreront lâidentification et la priorisation de cibles pertinentes pour lâimmunothĂ©rapie anti-cancĂ©reuse en clinique
A novel approach to increasing community capacity for weight management a volunteer-delivered programme (ActWELL) initiated within breast screening clinics:a randomised controlled trial
Background:
It is estimated that around 30% of breast cancers in post-menopausal women are related to lifestyle. The breast cancer-pooling project demonstrated that sustained weight loss of 2 to 4.5âkg is associated with an 18% lower risk of breast cancer, highlighting the importance of small changes in body weight. Our study aimed to assess the effectiveness a volunteer-delivered, community based, weight management programme (ActWELL) for women with a BMI >â25âkg/m2 attending NHS Scotland Breast Screening clinics.
Methods:
A multicentre, 1:1 parallel group, randomised controlled trial was undertaken in 560 women aged 50 to 70âyears with BMI >â25âkg/m2. On completion of baseline measures, all participants received a breast cancer prevention leaflet. Intervention group participants received the ActWELL intervention which focussed on personalised diet advice and pedometer walking plans. The programme was delivered in leisure centres by (the charity) Breast Cancer Now volunteer coaches.
Primary outcomes were changes between groups at 12âmonths in body weight (kg) and physical activity (accelerometer measured step count).
Results:
Two hundred seventy-nine women were allocated to the intervention group and 281 to the comparison group. Twelve-month data were available from 240 (81%) intervention and 227 (85%) comparison group participants. Coaches delivered 523 coaching sessions and 1915 support calls to 279 intervention participants. Mean weight change was ââ2.5âkg (95% CI ââ3.1 to ââ1.9) in the intervention group andâââ1.2âkg (ââ1.8 to 0.6) in the comparison group. The adjusted mean difference was ââ1.3âkg (95% CI ââ2.2 to ââ0.4, Pâ=â0.003). The odds ratio for losing 5% weight was 2.20 (95% CI 1.4 to 3.4, pâ=â0.0005) in favour of the intervention. The adjusted mean difference in step counts between groups was 483 steps/day (95% CI ââ635 to 1602) (NS).
Conclusions:
A community weight management intervention initiated at breast screening clinics and delivered by volunteer coaches doubled the likelihood of clinically significant weight loss at 12âmonths (compared with usual care) offering significant potential to decrease breast cancer risk
Correction to:A novel approach to increasing community capacity for weight management a volunteer-delivered programme (ActWELL) initiated within breast screening clinics: a randomised controlled trial
Acknowledgements Our thanks to Elizabeth Banks who advised and assisted with many aspects of the study and also to the many women who commented on the development and design of this study including those on our Public Advisory Team (Pamela Deponio, Maggie Taylor and Mary Wotherspoon). Funding This work was supported by The Scottish Government, grant number BC/Screening/17/01. The funders provided independent referee reports which guided the final study design. The funders have read this manuscript. In-kind support was given by Breast Cancer Now for facilitating this study.Peer reviewedPublisher PD
CowN Sustains Nitrogenase Turnover in the Presence of the Inhibitor Carbon Monoxide
Nitrogenase is the only enzyme capable of catalyzing nitrogen fixation, the reduction of dinitrogen gas (N2) to ammonia (NH3). Nitrogenase is tightly inhibited by the environmental gas carbon monoxide (CO). Nitrogen-fixing bacteria rely on the protein CowN to grow in the presence of CO. However, the mechanism by which CowN operates is unknown. Here, we present the biochemical characterization of CowN and examine how CowN protects nitrogenase from CO. We determine that CowN interacts directly with nitrogenase and that CowN protection observes hyperbolic kinetics with respect to CowN concentration. At a CO concentration of 0.001 atm, CowN restores nearly full nitrogenase activity. Our results further indicate that CowNâs protection mechanism involves decreasing the binding affinity of CO to nitrogenaseâs active site approximately tenfold without interrupting substrate turnover. Taken together, our work suggests CowN is an important auxiliary protein in nitrogen fixation that engenders CO tolerance to nitrogenase
Painting the Nation:Examining the Intersection Between Politics and the Visual Arts Market in Emerging Economies
Politics and art have throughout history, intersected in diverse and complex ways. Ideologies and political systems have used the arts to create a certain image and, depending on the form of government this has varied from clear-cut state propaganda, to patronage, to more indirect arms-length funding procedures. Therefore, artists working within the macro-level socio-political context cannot help but be influenced, inspired and sometimes restricted by these policies and political influences. This article examines the contemporary art markets of two emerging, Socialist economies to investigate the relationship between state pol-itics and the contemporary visual arts market. We argue that the respective governments and art worlds are trying to construct a brand narrative for their nations, but that these discourses are often at cross-purposes. In doing so, we illustrate that it is impos-sible to separate a consideration of the artwork from the macro-level context in which it is produced, distributed, and consumed
Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis
BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London
The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study
Background:
Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy.
Methods:
Consecutive women undergoing mastectomyâ±âIBR for breast cancer JulyâDecember, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomyâ±âIBR were compared and risk factors associated with delays explored.
Results:
A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [nâ=â675, 26.6%]; pedicled flaps [nâ=â105,4.1%] and free-flaps [nâ=â228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays.
Conclusions:
IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients
Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study
Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world.
Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231.
Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05â2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001).
Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication
Functional materials discovery using energyâstructureâfunction maps
Molecular crystals cannot be designed in the same manner as macroscopic objects, because they do not assemble according to simple, intuitive rules. Their structures result from the balance of many weak interactions, rather than from the strong and predictable bonding patterns found in metalâorganic frameworks and covalent organic frameworks. Hence, design strategies that assume a topology or other structural blueprint will often fail. Here we combine computational crystal structure prediction and property prediction to build energyâstructureâfunction maps that describe the possible structures and properties that are available to a candidate molecule. Using these maps, we identify a highly porous solid, which has the lowest density reported for a molecular crystal so far. Both the structure of the crystal and its physical properties, such as methane storage capacity and guest-molecule selectivity, are predicted using the molecular structure as the only input. More generally, energyâstructureâfunction maps could be used to guide the experimental discovery of materials with any target function that can be calculated from predicted crystal structures, such as electronic structure or mechanical properties
Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK âAlert Level 4â phase of the B-MaP-C study
Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated âstandardâ or âCOVID-alteredâ, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had âCOVID-alteredâ management. âBridgingâ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2â9%) using âNHS Predictâ. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of âCOVID-alteredâ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown
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