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1.
Resuscitation ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34648921

RESUMO

OBJECTIVES: The primary aim of this review was to investigate neurocognitive outcomes following out-of-hospital cardiac arrest (OHCA). Specifically, the focus was on identifying the different neurocognitive domains that are assessed, the measures used, and the level of, and criteria for, impairment. Design and review methods: A systematic review of the literature from 2006 to 2021 was completed using Medline, Cinahl and Psychinfo. Criteria for inclusion were studies with participants over the age of 18, OHCA and at least one neurocognitive function measure. Qualitative and case studies were excluded. Reviewers assessed criteria and risk of bias using a modified version of Downs and Black. RESULTS: Forty-three studies were identified. Most studies had a low risk of bias (n=31) or moderate risk of bias (n=11) and one had a high risk; however, only six reported effect sizes or power analyses. Multiple measures of neurocognitive outcomes were used (>50) and level of impairment criteria varied considerably. Memory impairments were frequently found and were also more likely to be impaired followed by executive function and processing speed. DISCUSSION: This review highlights the heterogeneity of measures and approaches used to assess neurocognitive outcomes following OHCA as well as the need to improve risk of bias concerning generalizability. Improved understanding of the approaches used for assessment and the subsequent findings will facilitate a standardized evaluation of neurocognitive outcomes following OHCA.

2.
Adv Med Sci ; 67(1): 1-9, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34562855

RESUMO

PURPOSE: Antibiotic resistance is widespread throughout the world and represents a serious health concern. There is an urgent need for the development of novel tools for rapidly distinguishing antibiotic resistant bacteria from susceptible strains. Previous work has demonstrated that differences in antimicrobial susceptibility can be reflected in differences in the profile of volatile organic compounds (VOCs) produced by dissimilar strains. The aim of this study was to investigate the effect of the presence of cephalosporin antibiotics on the VOC profile of extended spectrum beta-lactamase (ESBL) and non-ESBL producing strains of Escherichia coli. MATERIAL AND METHODS: In this study, VOCs from strains of Escherichia coli positive and negative for the most commonly encountered ESBL, CTX-M in the presence of cephalosporin antibiotics were assessed using solid-phase microextraction (SPME) coupled with a combined gas chromatography-mass spectrometry/metal oxide sensor (GC-MS/MOS) system. RESULTS: Our proof-of-concept study allowed for distinguishing CTX-M positive and negative bacteria within 2 â€‹h after the addition of antibiotics. One MOS signal (RT: 22.6) showed a statistically significant three-way interaction (p â€‹= â€‹0.033) in addition to significant two-way interactions for culture and additive (p â€‹= â€‹0.046) plus time and additive (p â€‹= â€‹0.020). There were also significant effects observed for time (p â€‹= â€‹0.009), culture (p â€‹= â€‹0.030) and additive (p â€‹= â€‹0.028). No effects were observed in the MS data. CONCLUSIONS: The results of our study showed the potential of VOC analysis using SPME combined with a GC-MS/MOS system for the early detection of CTX-M-producing, antibiotic-resistant E. coli, responsible for urinary tract infections (UTIs).

3.
Artigo em Inglês | MEDLINE | ID: mdl-34519403

RESUMO

The stereoselective introduction of the glycosidic bond remains one of the main challenges in carbohydrate synthesis. Characterizing the reactive intermediates of this reaction is key to develop stereoselective glycosylation reactions. Herein we report the characterization of low-populated, rapidly equilibrating, mannosyl dioxanium ions that arise from participation of a C-3 acyl group using chemical exchange saturation transfer (CEST) NMR spectroscopy. Dioxanium ion structure and equilibration kinetics were measured under relevant glycosylation conditions and highly α -selective couplings were observed suggesting glycosylation took place via this elusive intermediate.

4.
Postgrad Med ; : 1-14, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34551662

RESUMO

Background: This review article discusses the pharmacology of the most commonly used chronic medications in patients undergoing elective surgical procedures. The mechanism of action and adverse side effects of cardiovascular medications (e.g., beta blockers, alpha-2 agonist, calcium channel blockers, ACE inhibitors, diuretics), lipid-lowering drugs, gastrointestinal medications (H2-blockers, proton pump inhibitors), pulmonary medications (inhaled ß-agonists, anticholinergics,), antibiotics (tetracyclines, clindamycin and macrolide, linezolid), opioids and non-opioids analgesics (NSAIDs, COX-2 inhibitors, acetaminophen), gabapentanoids, erectile dysfunction (ED) drugs, and psychotropic drugs (tricyclic antidepressants [TCAs], monoamine oxidase inhibitors [MAOI], selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], and cannabinol-containing drugs) will be reviewed.Materials and Methods: An online search was conducted from January 2000 through February 2021 with the Medline database through PubMed and Google Scholar using the following search terms/keywords: "chronic medications in the perioperative period", and "chronic medications and anesthetic implications." In addition, we searched for anesthetic side effects associated with the major drug groups.Results and Conclusions: An understanding of the pharmacology and pharmacokinetics of most used chronic medications is important to avoid untoward outcomes in the perioperative period. These drug interactions may result in altered efficacy and toxicity of the anesthetic medications administered during surgery. These drug-drug interactions can also effect the morbidity, mortality, and recovery time of surgical patients. Part I of this two-part review article focuses on the mechanisms of action and adverse side effects of the chronic medications most commonly taken by surgical patients in the preoperative period.

5.
Postgrad Med ; : 1-19, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34551658

RESUMO

Background: This review article discusses the pharmacodynamic effects of the most commonly used chronic medications by patients undergoing elective surgical procedures, namely cardiovascular drugs (e.g., beta blockers, alpha-2 agonist, calcium channel blockers, ACE inhibitors, diuretics, etc.), lipid-lowering drugs, gastrointestinal medications (H2-blockers, proton pump inhibitors), pulmonary medications (inhaled ß-agonists, anticholinergics,), antibiotics (tetracyclines, clindamycin and macrolide, linezolid.), opioids and non-opioids analgesics (NSAIDs, COX-2 inhibitors, acetaminophen), gabapentanoids, erectile dysfunction (ED) drugs, psychotropic drugs (tricyclic antidepressants [TCAs], monoamine oxidase inhibitors [MAOI], selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], and cannabinol-containing drugs).  In addition, the potential adverse drug-interactions between these chronic medications and commonly used anesthetic drugs during the perioperative period will be reviewed. Finally, recommendations regarding the management of chronic medications during the preoperative period will be provided.Materials and Methods: An online search was conducted from January 2000 through February 2021 with the Medline database through PubMed and Google Scholar using the following search terms/keywords: "chronic medications in the perioperative period", and "chronic medications and anesthetic implications." In addition, we searched for anesthetic side effects associated with the major drug groups.Results and Conclusions: An understanding of the pharmacodynamic effects of most used chronic medications is important to avoid untoward outcomes in the perioperative period. These drug interactions may result in altered efficacy and toxicity of the anesthetic medications administered during surgery. These drug-drug interactions can also affect the morbidity, mortality, recovery time of surgical patients and acute relapse of chronic illnesses which could lead to last minute cancellation of surgical procedures. Part II of this two-part review article focuses on the reported interactions between most commonly taken chronic medications by surgical patients and anesthetic and analgesic drugs, as well as recommendations regarding the handling these chronic medications during the perioperative period.

6.
Nature ; 597(7877): 571-576, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34497422

RESUMO

The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A1R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A1R co-bound to adenosine, MIPS521 and a Gi2 heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.

7.
J Clin Anesth ; 75: 110500, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34517291
8.
BMJ Open ; 11(8): e054055, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408062

RESUMO

INTRODUCTION: Breast reconstruction (BR) is offered to improve quality of life for women with breast cancer undergoing mastectomy. As most women will be long-term breast cancer survivors, high-quality information regarding the long-term outcomes of different BR procedures is essential to support informed decision-making. As different techniques vary considerably in cost, policymakers also require high-quality cost-effectiveness evidence to inform care. The Brighter study aims to explore the long-term clinical and patient-reported outcomes (PROs) of implant-based and autologous BR and use health economic modelling to compare the long-term cost-effectiveness of different reconstructive techniques. METHODS AND ANALYSIS: Women undergoing mastectomy and/or BR following a diagnosis of breast cancer between 1 January 2008 and 31 March 2009 will be identified from hospital episode statistics (HES). Surviving women will be contacted and invited to complete validated PRO measures including the BREAST-Q, EQ-5D-5L and ICECAP-A, or opt out of having their data included in the HES analysis. Long-term clinical outcomes will be explored using HES data. The primary outcome will be rates of revisional surgery between implant-based and autologous procedures. Secondary outcomes will include rates of secondary reconstruction and reconstruction failure. The long-term PROs of implant-based and autologous reconstruction will be compared using BREAST-Q, EQ-5D-5L and ICECAP-A scores. Multivariable regression will be used to examine the relationship between long-term outcomes, patient comorbidities, sociodemographic and treatment factors. A Markov model will be developed using HES and PRO data and published literature to compare the relative long-term cost-effectiveness of implant-based and autologous BR. ETHICS AND DISSEMINATION: The Brighter study has been approved by the South-West -Central Bristol Research Ethics Committee (20/SW/0020), and the Confidentiality Advisory Group (20/CAG/0021). Results will be published in peer-reviewed journals and presented at national meetings. We will work with the professional associations, charities and patient groups to disseminate the results.


Assuntos
Neoplasias da Mama , Mamoplastia , Neoplasias da Mama/cirurgia , Estudos de Coortes , Análise Custo-Benefício , Feminino , Humanos , Mastectomia , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Qualidade de Vida
9.
Nat Commun ; 12(1): 4174, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234105

RESUMO

The folding of ß-barrel outer membrane proteins (OMPs) in Gram-negative bacteria is catalysed by the ß-barrel assembly machinery (BAM). How lateral opening in the ß-barrel of the major subunit BamA assists in OMP folding, and the contribution of membrane disruption to BAM catalysis remain unresolved. Here, we use an anti-BamA monoclonal antibody fragment (Fab1) and two disulphide-crosslinked BAM variants (lid-locked (LL), and POTRA-5-locked (P5L)) to dissect these roles. Despite being lethal in vivo, we show that all complexes catalyse folding in vitro, albeit less efficiently than wild-type BAM. CryoEM reveals that while Fab1 and BAM-P5L trap an open-barrel state, BAM-LL contains a mixture of closed and contorted, partially-open structures. Finally, all three complexes globally destabilise the lipid bilayer, while BamA does not, revealing that the BAM lipoproteins are required for this function. Together the results provide insights into the role of BAM structure and lipid dynamics in OMP folding.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Escherichia coli/metabolismo , Hidrolases/metabolismo , Lipossomos/metabolismo , Dobramento de Proteína , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/isolamento & purificação , Proteínas da Membrana Bacteriana Externa/ultraestrutura , Microscopia Crioeletrônica , Difusão Dinâmica da Luz , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/isolamento & purificação , Proteínas de Escherichia coli/ultraestrutura , Hidrolases/genética , Hidrolases/isolamento & purificação , Hidrolases/ultraestrutura , Metabolismo dos Lipídeos , Lipossomos/ultraestrutura , Simulação de Dinâmica Molecular , Conformação Proteica em Folha beta , Proteolipídeos/metabolismo , Proteolipídeos/ultraestrutura , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura
10.
Pharmacol Res Perspect ; 9(4): e00836, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34288559

RESUMO

Pharmacology education currently lacks an agreed knowledge curriculum. Evidence from physics and biology education indicates that core concepts are useful and effective structures around which such a curriculum can be designed to facilitate student learning. Building on previous work, we developed a novel, criterion-based method to identify the core concepts of pharmacology education. Five novel criteria were developed, based on a literature search, to separate core concepts in pharmacology from topics and facts. Core concepts were agreed to be big ideas, enduring, difficult, applicable across contexts, and useful to solve problems. An exploratory survey of 33 pharmacology educators from Australia and New Zealand produced 109 terms, which were reduced to a working list of 26 concepts during an online workshop. Next, an expert group of 12 educators refined the working list to 19 concepts, by applying the five criteria and consolidating synonyms, and added three additional concepts that emerged during discussions. A confirmatory survey of a larger group resulted in 17 core concepts of pharmacology education. This list may be useful for educators to evaluate existing curricula, design new curricula, and to inform the development of a concept inventory to test attainment of the core concepts in pharmacology.

11.
Chem Commun (Camb) ; 57(55): 6788-6791, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34137401

RESUMO

Histone lysine methylation and acetylation are important posttranslational modifications that regulate gene expression in humans. Due to the interplay of these two modifications, new chemical methods to study lysine posttranslational modifications are highly desired. Here, we report the use of γ-difluorolysine as a lysine mimic and 19F NMR probe for examinations of histone methylation and acetylation.


Assuntos
Histona Acetiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Lisina/química , Espectroscopia de Ressonância Magnética/métodos , Acetilação , Metilação
12.
Behav Processes ; 189: 104416, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33971249

RESUMO

Collective behaviour, such as shoaling in fish, benefits individuals through a variety of activities such as social information exchange and anti-predator defence. Human driven disturbance (e.g. anthropogenic noise) is known to affect the behaviour and physiology of individual animals, but the disruption of social aggregations of fish remains poorly understood. Anthropogenic noise originates from a variety of activities and differs in acoustic structure, dominant frequencies, and spectral complexity. The response of groups of fish may differ greatly, depending on the type of noise, and how it is perceived (e.g. threatening or attractive). In a controlled laboratory study, high resolution video tracking in combination with fine scale acoustic mapping was used to investigate the response of groups of European minnows (Phoxinus phoxinus) to signals of differing acoustic complexity (sinewave tones vs octave band noise) under low (150 Hz) and high (2200 Hz) frequencies. Fish startled and decreased their mean group swimming speed under all four treatments, with low frequency sinewave tones having the greatest influence on group behaviour. The shoals exhibited spatial avoidance during both low frequency treatments, with more time spent in areas of lower acoustic intensity than expected. This study illustrates how noise can influence the spatial distribution and social dynamics within groups of fish, and owing to the high potential for freshwater aquatic environments to be influenced by anthropogenic activity, wider consequences for populations should be further investigated.


Assuntos
Cyprinidae , Acústica , Animais , Humanos , Ruído , Som , Natação
13.
Eur J Cancer Care (Engl) ; 30(5): e13464, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34028913

RESUMO

OBJECTIVE: Many women choose to have breast reconstruction after mastectomy; however, decision-making can be difficult and expectations are often unmet. The PEGASUS intervention (Patient Expectations and Goals: Assisting Shared Understanding of Surgery) was developed to support shared decision-making by helping women and healthcare professionals to clarify and discuss their individual expectations around surgery. This study aimed to explore patients' and health professionals' experiences of using the intervention and its implementation. METHODS: Forty interviews were conducted with participants in a large scale, multi-site trial of the effectiveness of PEGASUS, from 'intervention' (n=16) and 'usual care' groups (n=11), and healthcare professionals (n=13). Data were analysed using thematic analysis. RESULTS: 'Usual care' participants described feeling overwhelmed in decision-making ('bombarded'), often using their own research to break down information ('process of elimination'). In contrast, intervention group participants described PEGASUS providing focus ('focus amongst the frenetic'), and increased connection with clinicians ('more than a number'). Healthcare professionals described increased focus on patient priorities ('shifting focus'), but stressed the need for whole team buy-in ('collective commitment'). CONCLUSIONS: The PEGASUS intervention offered a qualitatively different experience to individuals considering breast reconstruction, with potential to enhance patients' and healthcare professionals' feelings of shared decision-making and patient-centred care. TRIAL REGISTRATION: ISRCTN 18000391 (https://doi.org/10.1186/ISRCTN18000391) 27/01/2016.


Assuntos
Neoplasias da Mama , Mamoplastia , Neoplasias da Mama/cirurgia , Tomada de Decisões , Feminino , Pessoal de Saúde , Humanos , Mastectomia , Pesquisa Qualitativa
14.
J Trauma Acute Care Surg ; 91(2S Suppl 2): S226-S232, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34039922

RESUMO

INTRODUCTION: Penetrating cervical carotid artery injury is an uncommon but high-stake scenario associated with stroke and death. The objective of this study was to characterize and compare penetrating carotid injury in the military and civilian setting, as well as provide considerations for management. METHODS: Cohorts with penetrating cervical carotid artery injury from the Department of Defense Trauma Registry (2002-2015) and the American Association for the Surgery of Trauma Prospective Observation Vascular Injury Treatment Registry (2012-2018) were analyzed. A least absolute shrinkage and selection operator multivariate analysis using random forest-based imputation was performed to identify risk factors affecting stroke and mortality. RESULTS: There were a total of 157 patients included in the study, of which 56 (35.7%) were military and 101 (64.3%) were civilian. The military cohort was more likely to have been managed with open surgery (87.5% vs. 44.6%, p < 0.001) and to have had any procedure to restore or maintain flow to the brain (71.4% vs. 35.6%, p < 0.001), while the civilian cohort was more likely to undergo nonoperative management (45.5% vs. 12.5%, p < 0.001). Stroke rate was higher within the military cohort (41.1% vs. 13.9%, p < 0.001); however, mortality did not differ between the groups (12.5% vs. 17.8%, p = 0.52). On multivariate analysis, predictors for stroke were presence of a battle injury (log odds, 2.1; p < 0.001) and internal or common carotid artery ligation (log odds 1.5, p = 0.009). For mortality outcome, protective factors included a high Glasgow Coma Scale on admission (log odds, -0.21 per point; p < 0.001). Increased admission Injury Severity Score was a predictor of mortality (log odds, 0.05 per point; p = 0.005). CONCLUSION: The stroke rate was higher in the military cohort, possibly reflecting complexity of injury; however, there was no difference in mortality between military and civilian patients. For significant injuries, concerted efforts should be made at carotid reconstruction to reduce the occurrence of stroke. LEVEL OF EVIDENCE: Retrospective cohort analysis, level III.


Assuntos
Lesões das Artérias Carótidas/epidemiologia , Ferimentos Penetrantes/epidemiologia , Adulto , Lesões das Artérias Carótidas/complicações , Lesões das Artérias Carótidas/mortalidade , Lesões das Artérias Carótidas/cirurgia , Artéria Carótida Primitiva/cirurgia , Artéria Carótida Interna/cirurgia , Feminino , Escala de Coma de Glasgow , Humanos , Escala de Gravidade do Ferimento , Masculino , Militares/estatística & dados numéricos , Sistema de Registros , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Ferimentos Penetrantes/complicações , Ferimentos Penetrantes/mortalidade , Ferimentos Penetrantes/cirurgia
15.
Shock ; 56(4): 493-506, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34014887

RESUMO

ABSTRACT: Resuscitative endovascular balloon occlusion of the aorta (REBOA) allows for effective temporization of exsanguination from non-compressible hemorrhage (NCTH) below the diaphragm. However, the therapeutic window for aortic occlusion is time-limited given the ischemia-reperfusion injury generated. Significant effort has been put into translational research to develop new strategies to alleviate the ischemia-reperfusion injury and extend the application of endoaortic occlusion. Targeted regional optimization (TRO) is a partial REBOA strategy to augment proximal aortic and cerebral blood flow while targeting minimal threshold of distal perfusion beyond the zone of partial aortic occlusion. The objective of TRO is to reduce the degree of ischemia caused by complete aortic occlusion while providing control of distal hemorrhage. This review provides a synopsis of the concept of TRO, pre-clinical, translational experiences with TRO and early clinical outcomes. Early results from TRO strategies are promising; however, further studies are needed prior to large-scale implementation into clinical practice.

17.
Body Image ; 37: 282-290, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33813345

RESUMO

This pilot study evaluated the acceptability and preliminary efficacy of a culturally adapted school-based body image intervention, Dove Confident Me, for use in urban India. Two private schools in New Delhi were randomly assigned at the school level to receive either the five-session intervention facilitated by trained psychologists or lessons-as-usual (control). Participants were Year 7 students (N = 166; Mage = 11.9 years). Students, facilitators, and observing teachers, provided acceptability feedback. Fidelity was assessed. Body image and related measures were completed by students in a classroom setting at pre-intervention, post-intervention, and two-month follow-up. Most students enjoyed (73.7 %) and understood (84.2 %) the intervention. Facilitators (90 %) and observing teachers (70 %) reported that the learning objectives were achieved. Adherence and facilitator competence were rated as very good. Body esteem improved significantly among intervention students at post-intervention and follow-up (Cohen's ds = .45-.46), relative to control students. Positive affect also improved at post-intervention (d = .58). No significant effects on internalisation, life engagement, eating pathology, self-esteem, or negative affect emerged. This study provides evidence for the acceptability and preliminary efficacy of Dove Confident Me in urban India. Intervention refinements to increase acceptability and efficacy are recommended.


Assuntos
Imagem Corporal/psicologia , Serviços de Saúde Escolar , Estudantes/psicologia , População Urbana , Criança , Estudos de Viabilidade , Feminino , Humanos , Índia , Masculino , Projetos Piloto , Instituições Acadêmicas , Estudantes/estatística & dados numéricos , População Urbana/estatística & dados numéricos
18.
BMJ Open ; 11(4): e046622, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863715

RESUMO

INTRODUCTION: Approximately 40% of the 55 000 women diagnosed with breast cancer each year in the UK undergo mastectomy because they are considered unsuitable for standard breast-conserving surgery (BCS) due to tumour size or multiple tumour foci. Mastectomy can significantly impact women's quality of life, and only one in four women currently undergo immediate breast reconstruction (IBR).Level 2 oncoplastic breast-conserving surgery (OPBCS) combines removing the cancer with a range of plastic surgical volume replacement (eg, local perforator flaps) and volume displacement techniques (eg, therapeutic mammaplasty) that can extend the role of BCS and may allow some women not suitable for standard BCS to avoid mastectomy. High-quality research to determine whether OPBCS offers a safe and effective alternative to mastectomy±IBR is currently lacking. Preliminary work is needed to ensure a future large-scale study is feasible and well designed and addresses questions important to patients and the National Health Service. METHODS AND ANALYSIS: Mixed methods will be used to inform feasibility and design of a future large-scale study comparing the clinical effectiveness and cost-effectiveness of OPBCS and mastectomy±IBR. It will have four parts: (1) a National Practice Questionnaire to determine current practice and provision of oncoplastic breast and reconstructive surgery in the UK; (2) a pilot multicentre prospective cohort study to explore the proportion of patients choosing OPBCS versus mastectomy, the proportion in OPBCS is successful and clinical and patient-reported outcomes of different techniques at 3 and 12 months postsurgery; (3) a qualitative interview study to explore patients' attitudes to different procedures, rationale for decision-making and perceptions of outcomes; and (4) design of the future study.All centres offering OPBCS and mastectomy in the UK will be invited to participate. Recruitment is planned to commence winter 2020 and continue for 12 months. ETHICS AND DISSEMINATION: The study has ethical approval from the Wales Research Ethics Committee 6 National Research Ethics Service (REC Ref 20/WA/0225). Results will be presented at national and international meetings and published in peer-reviewed journals. We will work with patients to develop lay summaries and share these through patient groups and breast cancer charities. TRIAL REGISTRATION NUMBER: ISRCTN18238549.


Assuntos
Neoplasias da Mama , Mamoplastia , Neoplasias da Mama/cirurgia , Estudos de Viabilidade , Feminino , Humanos , Mastectomia , Mastectomia Segmentar , Estudos Multicêntricos como Assunto , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Qualidade de Vida , Medicina Estatal , País de Gales
19.
Clin Genitourin Cancer ; 19(4): 325-332, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33727028

RESUMO

INTRODUCTION: Neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle-invasive bladder cancer. However, response rates and survival remain suboptimal. We evaluated the efficacy, safety, and tolerability of cisplatin plus cabazitaxel. METHODS: A phase II single-arm trial was designed to recruit at least 26 evaluable patients. This would give 80% power to detect the primary endpoint, an objective response rate defined as a pathologic complete response plus partial response (pathologic downstaging), measured by pathologic staging at cystectomy (p0 = 0.35 and p1 = 0.60, α = 0.05). RESULTS: Objective response was seen in 15 of 26 evaluable patients (57.7%) and more than one- third of patients achieved a pathologic complete response (9/26; 34.6%). Seventy-eight percent of the patients (21/27) completed all cycles of treatment, with only 6.7% of the reported adverse events being graded 3 or 4. There were 6 treatment-related serious adverse event reported, but no suspected unexpected serious adverse reactions. In the patients who achieved an objective response, the median progression-free survival and overall survival were not reached (median follow-up of 41.5 months). In contrast, the median progression-free survival (7.2 months) and overall survival (16.9 months) were significantly worse (P = .001, log-rank) in patients who did not achieve an objective response. CONCLUSION: Cabazitaxel plus cisplatin for neoadjuvant treatment of muscle-invasive bladder cancer can be considered a well-tolerated and effective regimen before definitive therapy with higher rates (57.7%) of objective response, comparing favorably to that with of cisplatin/gemcitabine (23%-26%). These results warrant further evaluation in a phase III study.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante , Cisplatino/efeitos adversos , Cistectomia , Intervalo Livre de Doença , Humanos , Músculos , Terapia Neoadjuvante , Taxoides , Resultado do Tratamento , Bexiga Urinária , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia
20.
Science ; 371(6531)2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33602829

RESUMO

Transmembrane ß-barrel proteins (TMBs) are of great interest for single-molecule analytical technologies because they can spontaneously fold and insert into membranes and form stable pores, but the range of pore properties that can be achieved by repurposing natural TMBs is limited. We leverage the power of de novo computational design coupled with a "hypothesis, design, and test" approach to determine TMB design principles, notably, the importance of negative design to slow ß-sheet assembly. We design new eight-stranded TMBs, with no homology to known TMBs, that insert and fold reversibly into synthetic lipid membranes and have nuclear magnetic resonance and x-ray crystal structures very similar to the computational models. These advances should enable the custom design of pores for a wide range of applications.


Assuntos
Simulação por Computador , Proteínas de Membrana/química , Modelos Moleculares , Conformação Proteica em Folha beta , Engenharia de Proteínas , Sequência de Aminoácidos , Cristalografia por Raios X , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Bicamadas Lipídicas , Espectroscopia de Ressonância Magnética , Membranas Artificiais , Micelas , Conformação Proteica , Dobramento de Proteína , Estabilidade Proteica
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