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1.
Cell ; 183(1): 244-257.e16, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931735

RESUMO

Many bacteria use the flagellum for locomotion and chemotaxis. Its bidirectional rotation is driven by a membrane-embedded motor, which uses energy from the transmembrane ion gradient to generate torque at the interface between stator units and rotor. The structural organization of the stator unit (MotAB), its conformational changes upon ion transport, and how these changes power rotation of the flagellum remain unknown. Here, we present ~3 Å-resolution cryoelectron microscopy reconstructions of the stator unit in different functional states. We show that the stator unit consists of a dimer of MotB surrounded by a pentamer of MotA. Combining structural data with mutagenesis and functional studies, we identify key residues involved in torque generation and present a detailed mechanistic model for motor function and switching of rotational direction.


Assuntos
Proteínas de Bactérias/ultraestrutura , Flagelos/ultraestrutura , Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Microscopia Crioeletrônica/métodos , Flagelos/metabolismo , Conformação Proteica , Torque
2.
Trends Biochem Sci ; 47(2): 160-172, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34294545

RESUMO

The flagellar stator unit is an oligomeric complex of two membrane proteins (MotA5B2) that powers bi-directional rotation of the bacterial flagellum. Harnessing the ion motive force across the cytoplasmic membrane, the stator unit operates as a miniature rotary motor itself to provide torque for rotation of the flagellum. Recent cryo-electron microscopic (cryo-EM) structures of the stator unit provided novel insights into its assembly, function, and subunit stoichiometry, revealing the ion flux pathway and the torque generation mechanism. Furthermore, in situ cryo-electron tomography (cryo-ET) studies revealed unprecedented details of the interactions between stator unit and rotor. In this review, we summarize recent advances in our understanding of the structure and function of the flagellar stator unit, torque generation, and directional switching of the motor.


Assuntos
Proteínas de Bactérias , Flagelos , Bactérias/metabolismo , Proteínas de Bactérias/química , Microscopia Crioeletrônica/métodos , Flagelos/química , Flagelos/metabolismo , Flagelos/ultraestrutura , Torque
3.
Appl Environ Microbiol ; : e0080724, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38940562

RESUMO

Enterotoxigenic Escherichia coli (ETEC) is a diverse and poorly characterized E. coli pathotype that causes diarrhea in humans and animals. Phages have been proposed for the veterinary biocontrol of ETEC, but effective solutions require understanding of porcine ETEC diversity that affects phage infection. Here, we sequenced and analyzed the genomes of the PHAGEBio ETEC collection, gathering 79 diverse ETEC strains isolated from European pigs with post-weaning diarrhea (PWD). We identified the virulence factors characterizing the pathotype and several antibiotic resistance genes on plasmids, while phage resistance genes and other virulence factors were mostly chromosome encoded. We experienced that ETEC strains were highly resistant to Enterobacteriaceae phage infection. It was only by enrichment of numerous diverse samples with different media and conditions, using the 41 ETEC strains of our collection as hosts, that we could isolate two lytic phages that could infect a large part of our diverse ETEC collection: vB_EcoP_ETEP21B and vB_EcoS_ETEP102. Based on genome and host range analyses, we discussed the infection strategies of the two phages and identified components of lipopolysaccharides ( LPS) as receptors for the two phages. Our detailed computational structural analysis highlights several loops and pockets in the tail fibers that may allow recognition and binding of ETEC strains, also in the presence of O-antigens. Despite the importance of receptor recognition, the diversity of the ETEC strains remains a significant challenge for isolating ETEC phages and developing sustainable phage-based products to address ETEC-induced PWD.IMPORTANCEEnterotoxigenic Escherichia coli (ETEC)-induced post-weaning diarrhea is a severe disease in piglets that leads to weight loss and potentially death, with high economic and animal welfare costs worldwide. Phage-based approaches have been proposed, but available data are insufficient to ensure efficacy. Genome analysis of an extensive collection of ETEC strains revealed that phage defense mechanisms were mostly chromosome encoded, suggesting a lower chance of spread and selection by phage exposure. The difficulty in isolating lytic phages and the molecular and structural analyses of two ETEC phages point toward a multifactorial resistance of ETEC to phage infection and the importance of extensive phage screenings specifically against clinically relevant strains. The PHAGEBio ETEC collection and these two phages are valuable tools for the scientific community to expand our knowledge on the most studied, but still enigmatic, bacterial species-E. coli.

4.
J Hum Evol ; 186: 103466, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38134581

RESUMO

Although the Turkana Basin is one of the driest regions of the East African Rift, its Plio-Pleistocene sediments are rich in freshwater vertebrates and invertebrates, providing evidence that freshwater resources were available to hominins in this region during the Plio-Pleistocene (4.2-0.7 Ma). Here we provide an overview of the hydroconnectivity of the Turkana Basin. We then review the period during which freshwater river and lake systems expanded into the western region of the Turkana Basin, where hominin and archeological sites have been discovered in sediments dating back to the Late Pliocene-Pleistocene. Freshwater conditions are reconstructed from river and lake sediments and the flora and micro- and macofauna they contain. Data synthesis suggests that drinking water and freshwater foods prevailed in the western region of the Turkana Basin at 4.20-3.98 Ma, 3.70-3.10 Ma, 2.53-2.22 Ma, then between 2.10 and 1.30 Ma and intermittently from 1.27 to 0.75 Ma. Milestones in hominin evolution occurred in this context, such as the first occurrence of Australopithecus anamensis (4.20-4.10 Ma) and Kenyanthropus platyops (3.50 Ma and 3.30-3.20 Ma), the presence of Paranthropus aethiopicus (2.53-2.45 Ma), early Homo (2.33 Ma), Paranthropus boisei (2.25 Ma and 1.77-1.72 Ma) and Homo ergaster/Homo erectus (1.75 Ma, 1.47-1.42 Ma and 1.10-0.90 Ma). Developments in hominin behavior also occurred during this timeframe, including the first known stone tools (3.30 Ma), the oldest Oldowan sites (2.34 Ma and 2.25 Ma) in the Turkana Basin, the earliest known evidence for the emergence of bifacial shaping in eastern Africa (1.80 Ma), and the first known Acheulean site (1.76 Ma). Our synthesis suggests that, diachronic variation in hydroconnectivity played a role on the amount of drinking water and freshwater foods available in the western region of the Turkana Basin, despite regional aridity.


Assuntos
Água Potável , Hominidae , Animais , Quênia , Fósseis , Água Doce , Evolução Biológica
5.
Gynecol Oncol ; 184: 83-88, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38301310

RESUMO

OBJECTIVE: To determine the utility of sentinel lymph node (SLN) evaluation during hysterectomy for endometrial intraepithelial neoplasia (EIN) in a community hospital setting and identify descriptive trends among pathology reports from those diagnosed with endometrial cancer (EC). METHODS: We reviewed patients who underwent hysterectomy from January 2015 to July 2022 for a pathologically confirmed diagnosis of EIN obtained by endometrial biopsy (EMB) or dilation and curettage. Data was obtained via detailed chart review. Statistical testing was utilized for between-group comparisons and multivariate logistic regression modeling. RESULTS: Of the 177 patients with EIN who underwent hysterectomy during the study period, 105 (59.3%) had a final diagnosis of EC. At least stage IB disease was found in 29 of these patients who then underwent adjuvant therapy. Pathology report descriptors suspicious for cancer and initial specimen type obtained by EMB were independently and significantly associated with increased odds of EC diagnosis (aOR 8.192, p < 0.001;3.746, p < 0.001, respectively). Operative times were not increased by performance of SLN sampling while frozen specimen evaluation added an average of 28 min to procedure length. Short-term surgical outcomes were also similar between groups. CONCLUSION: Patients treated for EIN at community-based institutions might be more likely to upstage preoperative EIN diagnoses and have an increased risk of later stage disease than previous research suggests. Given no surgical time or short-term outcome differences, SLN evaluation should be more strongly considered in this practice setting, especially for patients diagnosed by EMB or with pathology reports indicating suspicion for EC.


Assuntos
Neoplasias do Endométrio , Hospitais Comunitários , Histerectomia , Biópsia de Linfonodo Sentinela , Linfonodo Sentinela , Humanos , Feminino , Pessoa de Meia-Idade , Hospitais Comunitários/estatística & dados numéricos , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/diagnóstico , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo Sentinela/métodos , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Estudos Retrospectivos , Idoso , Adulto , Carcinoma in Situ/patologia , Carcinoma in Situ/cirurgia , Carcinoma in Situ/diagnóstico
6.
Epilepsy Behav ; 150: 109569, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38071829

RESUMO

OBJECTIVE: This overview of systematic reviews aimed to appraise evidence regarding self-management strategies on health-related quality of life, self-efficacy, medication compliance, seizure status and psychosocial outcomes compared to usual care for people with epilepsy. METHODS: Databases were searched until September 2022 using MeSH terms included OVID Medline, Embase and Cochrane. Following application of eligibility criteria, data were extracted and quality of articles was assessed using the AMSTAR2 checklist. A narrative synthesis of evidence included certainty of evidence evaluated using a Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: The 12 selected reviews contained three meta-analyses and 91 unique primary studies. One review considered only epilepsy with intellectual disability and three considered paediatrics. Interventions included technologically-based interventions, small group discussion, or counselling and educational programs. There was high certainty evidence to suggest self-management is associated with improvement in health-related quality of life and moderate certainty evidence to suggest improvement in depression symptoms. There was low certainty evidence to suggest a modest reduction in negative health events and a minimal increase in the satisfaction with life. There was no evidence of benefit favouring self-management on measures of adherence epilepsy self-management, perception of self-efficacy, medication adherence or seizure status. SIGNIFICANCE: Despite high certainty evidence to suggest that self-management strategies for people with epilepsy improve health-related quality of life, benefits have not been demonstrated for outcomes that would be expected to be associated with these improvements, such as seizure status. These results provide support for self-management strategies to supplement usual care for people with epilepsy.


Assuntos
Epilepsia , Autogestão , Humanos , Criança , Qualidade de Vida , Revisões Sistemáticas como Assunto , Epilepsia/tratamento farmacológico , Convulsões
7.
Nature ; 563(7731): 426-430, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30405239

RESUMO

ABCG2 is a transporter protein of the ATP-binding-cassette (ABC) family that is expressed in the plasma membrane in cells of various tissues and tissue barriers, including the blood-brain, blood-testis and maternal-fetal barriers1-4. Powered by ATP, it translocates endogenous substrates, affects the pharmacokinetics of many drugs and protects against a wide array of xenobiotics, including anti-cancer drugs5-12. Previous studies have revealed the architecture of ABCG2 and the structural basis of its inhibition by small molecules and antibodies13,14. However, the mechanisms of substrate recognition and ATP-driven transport are unknown. Here we present high-resolution cryo-electron microscopy (cryo-EM) structures of human ABCG2 in a substrate-bound pre-translocation state and an ATP-bound post-translocation state. For both structures, we used a mutant containing a glutamine replacing the catalytic glutamate (ABCG2EQ), which resulted in reduced ATPase and transport rates and facilitated conformational trapping for structural studies. In the substrate-bound state, a single molecule of estrone-3-sulfate (E1S) is bound in a central, hydrophobic and cytoplasm-facing cavity about halfway across the membrane. Only one molecule of E1S can bind in the observed binding mode. In the ATP-bound state, the substrate-binding cavity has collapsed while an external cavity has opened to the extracellular side of the membrane. The ATP-induced conformational changes include rigid-body shifts of the transmembrane domains, pivoting of the nucleotide-binding domains (NBDs), and a change in the relative orientation of the NBD subdomains. Mutagenesis and in vitro characterization of transport and ATPase activities demonstrate the roles of specific residues in substrate recognition, including a leucine residue that forms a 'plug' between the two cavities. Our results show how ABCG2 harnesses the energy of ATP binding to extrude E1S and other substrates, and suggest that the size and binding affinity of compounds are important for distinguishing substrates from inhibitors.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/ultraestrutura , Trifosfato de Adenosina/metabolismo , Microscopia Crioeletrônica , Proteínas Mutantes/metabolismo , Proteínas Mutantes/ultraestrutura , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/ultraestrutura , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Sítios de Ligação , Humanos , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutação , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Conformação Proteica , Especificidade por Substrato
8.
Arch Sex Behav ; 53(7): 2597-2627, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38724700

RESUMO

Sexual harm within nightlife settings is a pervasive global concern; however, little is known about the nature of available interventions. The current study aims to review the literature on the nature and effectiveness of nightlife-related sexual harm interventions. A systematic literature search of six databases was conducted to identify records that were published between 1970 and June 2023 and reported approaches that aimed to reduce or prevent nightlife-related sexual harm. Records were included if they theorized, discussed, or evaluated an intervention, prevention or response strategy; however, individual safety strategies were excluded. Results were categorized according to intervention type. Thirty-five peer-reviewed journal articles and 16 gray literature records were identified. The most common nightlife-related sexual harm intervention strategies covered by the literature included targeted policies, laws, and regulations, bystander interventions, and awareness-raising campaigns. Literature in the area is increasing, with the majority of the articles (77.1%) being published in the previous six years; however, there are very few interventions that have been critically evaluated (22.9%). Promising areas for intervention include targeted alcohol regulations (e.g., lockout policies), venue-level policies, and environmental interventions. However, an increase in rigorous evaluative practices is urgently required to ensure future interventions are based on sound theoretical work and empirical evidence.


Assuntos
Comportamento Sexual , Humanos , Redução do Dano
9.
Artigo em Inglês | MEDLINE | ID: mdl-38729404

RESUMO

OBJECTIVE: To determine if self-management programs, supported by a health professional, in rehabilitation are cost effective. DATA SOURCES: Six databases were searched until December 2023. STUDY SELECTION: Randomized controlled trials with adults completing a supported self-management program while participating in rehabilitation or receiving health professional input in the hospital or community settings were included. Self-management programs were completed outside the structured, supervised therapy and health professional sessions. Included trials had a cost measure and an effectiveness outcome reported, such as health-related quality of life or function. Grading of Recommendations, Assessment, Development, and Evaluations was used to determine the certainty of evidence across trials included in each meta-analysis. Incremental cost-effectiveness ratios were calculated based on the mean difference from the meta-analyses of contributing health care costs and quality of life. DATA EXTRACTION: After application of the search strategy, two independent reviewers determined eligibility of identified literature, initially by reviewing the title and/or abstract before full-text review. Using a customized form, data were extracted by one reviewer and checked by a second reviewer. DATA SYNTHESIS: Forty-three trials were included, and 27 had data included in meta-analyses. Where self-management was a primary intervention, there was moderate certainty of a meaningful positive difference in quality-of-life utility index of 0.03 units (95% confidence interval, 0.01-0.06). The cost difference between self-management as the primary intervention and usual care (comprising usual intervention/therapy, minimal intervention [including education only], or no intervention) potentially favored the comparison group (mean difference=Australian dollar [AUD]90; 95% confidence interval, -AUD130 to AUD310). The cost per quality-adjusted life year (QALY) gained for self-management programs as a stand-alone intervention was AUD3000, which was below the acceptable willingness-to-pay threshold in Australia per QALY gained (AUD50,000/QALY gained). CONCLUSIONS: Self-management as an intervention is low cost and could improve health-related quality of life.

10.
Child Care Health Dev ; 50(1): e13154, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37487607

RESUMO

BACKGROUND: Waiting lists for community-based paediatric therapy services are common and lead to poorer health outcomes, anxiety and missed opportunities for treatment during crucial developmental stages. The Specific Timely Appointments for Triage (STAT) model has been shown to reduce waiting lists in a range of health settings. AIMS: To determine whether providing training and support in the STAT model to champions within five community health centres using a remote 'hub and spoke' approach could reduce waiting time from referral to first appointment. METHODS: Representatives from five community health centres providing paediatric therapy services (speech therapy, occupational therapy and other allied health services) participated in five online workshops over 6 months. They were guided sequentially through the steps of the STAT model: understanding supply and demand, reducing backlogs, preserving space for new patients based on demand and redesigning models of care to maintain flow. Waiting time was measured in three consecutive years (pre, during and post intervention) and compared using the Kruskal-Wallis test. Employee satisfaction and perception of the model were explored using surveys. RESULTS: Data from 2564 children (mean age 3.2 years, 66% male) showed a 33% reduction in waiting time from the pre-intervention (median 57 days) to the post-intervention period (median 38 days, p < 0.01). The total number of children waiting was observed to reduce from 335 immediately prior to the intervention (mean per centre 67, SD 25.1) to 112 (mean 22, SD 13.6) after implementation (t[8] = 3.56, p < 0.01). There was no impact on employee satisfaction or other aspects of service delivery. CONCLUSION: Waiting lists are a major challenge across the health system. STAT provides a practical, low-cost, data-driven approach to tackling waiting times. This study demonstrates its effectiveness in paediatric therapy services and provides evidence for a 'hub and spoke' approach to facilitate implementation that could be provided at scale.


Assuntos
Terapia Ocupacional , Listas de Espera , Humanos , Masculino , Criança , Pré-Escolar , Feminino , Triagem , Ansiedade , Transtornos de Ansiedade
11.
EMBO J ; 38(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30606715

RESUMO

Contractile injection systems (bacteriophage tails, type VI secretions system, R-type pyocins, etc.) utilize a rigid tube/contractile sheath assembly for breaching the envelope of bacterial and eukaryotic cells. Among contractile injection systems, bacteriophages that infect Gram-positive bacteria represent the least understood members. Here, we describe the structure of Listeria bacteriophage A511 tail in its pre- and post-host attachment states (extended and contracted, respectively) using cryo-electron microscopy, cryo-electron tomography, and X-ray crystallography. We show that the structure of the tube-baseplate complex of A511 is similar to that of phage T4, but the A511 baseplate is decorated with different receptor-binding proteins, which undergo a large structural transformation upon host attachment and switch the symmetry of the baseplate-tail fiber assembly from threefold to sixfold. For the first time under native conditions, we show that contraction of the phage tail sheath assembly starts at the baseplate and propagates through the sheath in a domino-like motion.


Assuntos
Bacteriófagos/fisiologia , Bacteriófagos/ultraestrutura , Listeria/virologia , Conformação Proteica , Proteínas da Cauda Viral/química , Microscopia Crioeletrônica , Cristalografia por Raios X , Infecções , Listeria/crescimento & desenvolvimento , Modelos Moleculares , Proteínas da Cauda Viral/metabolismo
12.
Osteoarthritis Cartilage ; 31(10): 1280-1292, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37394226

RESUMO

OBJECTIVES: Guideline adherence for hip and knee osteoarthritis management is often poor, possibly related to the quality and/or inconsistent recommendations. This systematic review of hip and knee osteoarthritis guidelines aimed to appraise the quality and consistency in recommendations across higher-quality guidelines. METHODS: Eight databases, guideline repositories, and professional associations websites were searched on 27/10/2022. Guideline quality was appraised using the Appraisal of Guidelines for Research and Evaluation II (AGREE II tool) (six domains). Higher quality was defined as scoring ≥60% for domains 3 (rigour of development), 6 (editorial independence), plus one other. Consistency in recommendations across higher-quality guidelines was reported descriptively. This review was registered prospectively (CRD42021216154). RESULTS: Seven higher-quality and 18 lesser-quality guidelines were included. AGREE II domain scores for higher-quality guidelines were > 60% except for applicability (average 46%). Higher-quality guidelines consistently recommended in favour of education, exercise, and weight management and non-steroidal anti-inflammatory drugs (hip and knee), and intra-articular corticosteroid injections (knee). Higher quality guidelines consistently recommended against hyaluronic acid (hip) and stem cell (hip and knee) injections. Other pharmacological recommendations in higher-quality guidelines (e.g., paracetamol, intra-articular corticosteroid (hip), hyaluronic acid (knee)) and adjunctive treatments (e.g., acupuncture) were less consistent. Arthroscopy was consistently recommended against in higher-quality guidelines. No higher-quality guidelines considered arthroplasty. CONCLUSION: Higher-quality guidelines for hip and knee osteoarthritis consistently recommend clinicians implement exercise, education, and weight management, alongside consideration of Non-Steroidal Anti-Inflammatory Drugs and intra-articular corticosteroid injections (knee). Lack of consensus on some pharmacological options and adjunctive treatments creates challenges for guideline adherence. Future guidelines must prioritise providing implementation guidance, considering consistently low applicability scores.


Assuntos
Osteoartrite do Quadril , Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/tratamento farmacológico , Ácido Hialurônico/uso terapêutico , Osteoartrite do Quadril/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Corticosteroides/uso terapêutico
13.
J Vasc Surg ; 78(1): 217-222, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36914077

RESUMO

OBJECTIVES: Peripheral artery disease is a worldwide epidemic that affects millions of patients, especially the elderly. It has a prevalence of 20% in individuals >80 years old. Although peripheral artery disease affects >20% of octogenarians, information about limb salvage rates in this patient population is limited. Therefore, this study aims to understand the impact of bypass surgery on limb salvage in patients aged >80 years with critical limb ischemia. METHODS: We conducted a retrospective analysis by querying the electronic medical records at a single institution from 2016 through 2022 to identify the population of interest and analyzed their outcomes after lower extremity bypass. The primary outcomes were limb salvage and primary patency, with hospital length of stay and 1-year mortality as secondary outcomes. RESULTS: We identified 137 patients who met the inclusion criteria. The lower extremity bypass population was divided into two cohorts: <80 years old (n = 111) with a mean age of 66 or ≥80 years old (n = 26) with a mean age of 84 years. The gender distribution was similar (P = .163). No significant difference was found in the two cohorts when it came to coronary artery disease, chronic kidney disease, or diabetes mellitus. However, when current and former smokers were grouped together, they were significantly more common in the younger cohort when compared with nonsmokers (P = .028). The primary end point of limb salvage was not significantly different between the two cohorts. Hospital length of stay was not significantly different between the two cohorts with 4.13 days vs 4.17 days in the younger vs octogenarian cohorts, respectively (P = .95). The 30-day all-cause readmissions were also not found to be significantly different between the two groups. The primary patency at 1 year was 75% and 77% (P = .16) for the <80-year-old and ≥80-year-old cohorts, respectively. Mortality was low in both cohorts, with two and three for the younger and octogenarian populations, respectively; thus, no analysis was performed. CONCLUSIONS: Our study shows that octogenarians who undergo the same preoperative risk assessment as younger populations have similar outcomes when it comes to primary patency, hospital length of stay, and limb salvage when comorbidities were considered. Further studies need to be done to determine the statistical impact on mortality in this population with a larger cohort.


Assuntos
Isquemia Crônica Crítica de Membro , Doença Arterial Periférica , Idoso de 80 Anos ou mais , Idoso , Humanos , Octogenários , Estudos Retrospectivos , Resultado do Tratamento , Isquemia/diagnóstico por imagem , Isquemia/cirurgia , Fatores de Risco , Grau de Desobstrução Vascular , Extremidade Inferior/irrigação sanguínea , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/cirurgia
14.
Nature ; 546(7659): 504-509, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28554189

RESUMO

ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/ultraestrutura , Microscopia Crioeletrônica , Proteínas de Neoplasias/química , Proteínas de Neoplasias/ultraestrutura , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/química , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/ultraestrutura , Sequência de Aminoácidos , Anticorpos/química , Anticorpos/imunologia , Anticorpos/ultraestrutura , Sítios de Ligação , Transporte Biológico , Colesterol/química , Colesterol/metabolismo , Humanos , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/ultraestrutura , Modelos Moleculares , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Domínios Proteicos
15.
Hum Resour Health ; 21(1): 95, 2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38093376

RESUMO

BACKGROUND: Across the care economy there are major shortages in the health and care workforce, as well as high rates of attrition and ill-defined career pathways. The aim of this study was to evaluate current evidence regarding methods to improve care worker recruitment, retention, safety, and education, for the professional care workforce. METHODS: A rapid review of comparative interventions designed to recruit, retain, educate and care for the professional workforce in the following sectors: disability, aged care, health, mental health, family and youth services, and early childhood education and care was conducted. Embase and MEDLINE databases were searched, and studies published between January 2015 and November 2022 were included. We used the Quality Assessment tool for Quantitative Studies and the PEDro tools to evaluate study quality. RESULTS: 5594 articles were initially screened and after applying the inclusion and exclusion criteria, 30 studies were included in the rapid review. Studies most frequently reported on the professional nursing, medical and allied health workforces. Some studies focused on the single domain of care worker education (n = 11) while most focused on multiple domains that combined education with recruitment strategies, retention strategies or a focus on worker safety. Study quality was comparatively low with a median PEDro score of 5/10, and 77% received a weak rating on the Quality Assessment tool for Quantitative Studies. Four new workforce strategies emerged; early career rural recruitment supports rural retention; workload management is essential for workforce well-being; learning must be contextually relevant; and there is a need to differentiate recruitment, retention, and education strategies for different professional health and care workforce categories as needs vary. CONCLUSIONS: Given the critical importance of recruiting and retaining a strong health and care workforce, there is an immediate need to develop a cohesive strategy to address workforce shortfalls. This paper presents initial evidence on different interventions to address this need, and to inform care workforce recruitment and retention. Rapid Review registration PROSPERO 2022 CRD42022371721 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022371721.


Assuntos
Aprendizagem , Serviços de Saúde Rural , Humanos , Pré-Escolar , Adolescente , Idoso , Recursos Humanos , Pessoal Técnico de Saúde , Carga de Trabalho , Saúde Mental
16.
Clin Rehabil ; 37(1): 47-59, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36163694

RESUMO

OBJECTIVE: To test the feasibility of a walking programme for community-dwelling adults recovering from hip fracture. DESIGN: A randomized controlled trial with embedded qualitative analysis. SETTING: Community. PARTICIPANTS: Aged at least 60 years and living in the community after hip fracture. INTERVENTIONS: In addition to standard care, the experimental group received weekly home-based physiotherapy for 12 weeks to facilitate 100 minutes/week of moderate-intensity walking. MAIN OUTCOME MEASURES: Feasibility domains of demand, acceptability, implementation, practicality and limited efficacy. RESULTS: Of 158 potentially eligible, 38 participated (23 women, mean age 80 years, SD 9). The recruitment rate of 24% indicated low demand. Participants considered the walking programme highly acceptable. The programme was implemented as intended; the experimental group received a mean of 11 (SD 1) consultations and averaged more than 100 min of walking per week. The programme was practical with no serious adverse events and no between-group difference in risk of falling or hospital readmissions. Demonstrating evidence of efficacy, there were moderate standardized mean differences for physical activity favouring the experimental group, who increased daily moderate-intensity physical activity compared to the control group (MD 8 min, 95% CI 2-13). There were no between-group differences in mobility, walking confidence or quality of life. CONCLUSION: A walking programme for community-dwelling older adults after hip fracture was acceptable, could be implemented as intended and was practical and demonstrated preliminary evidence of efficacy in increasing physical activity. However, low demand would threaten the feasibility of such a programme.


Assuntos
Fraturas do Quadril , Qualidade de Vida , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Caminhada , Exercício Físico
17.
BMC Health Serv Res ; 23(1): 933, 2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37653409

RESUMO

BACKGROUND: Delayed access to outpatient care may negatively impact on health outcomes. We aimed to evaluate implementation of the Specific Timely Appointments for Triage (STAT) model of access in an epilepsy clinic to reduce a long waitlist and waiting time. METHODS: This study is an intervention study using pre-post comparison and an interrupted time series analysis to measure the effect of implementation of the STAT model to an epilepsy clinic. Data were collected over 28 months to observe the number of patients on the waitlist and the waiting time over three time periods: 12 months prior to implementation of STAT, ten months during implementation and six months post-intervention. STAT combines one-off backlog reduction with responsive scheduling that protects time for new appointments based on historical data. The primary outcomes were the number of patients on the waitlist and the waiting time across the three time periods. Secondary outcomes evaluated pre- and post-intervention changes in number of appointments offered weekly, non-arrival and discharge rates. RESULTS: A total of 938 patients were offered a first appointment over the study period. The long waitlist was almost eliminated, reducing from 616 during the pre-intervention period to 11 post-intervention (p = 0.002), but the hypothesis that waiting time would decrease was not supported. The interrupted time series analysis indicated a temporary increase in waiting time during the implementation period but no significant change in slope or level in the post- compared to the pre-intervention period. Direct comparison of the cohort of patients seen in the pre- and post-intervention periods suggested an increase in median waiting time following the intervention (34 [IQR 25-86] to 46 [IQR 36-61] days (p = 0.001)), but the interquartile range reduced indicating less variability in days waited and more timely access for the longest waiters. CONCLUSIONS: The STAT model was implemented in a specialist epilepsy outpatient clinic and reduced a large waitlist. Reductions in the waitlist were achieved with little or no increase in waiting time. The STAT model provides a framework for an alternative way to operate outpatient clinics that can help to ensure that all people referred are offered an appointment in a timely manner.


Assuntos
Epilepsia , Pacientes Ambulatoriais , Humanos , Triagem , Instituições de Assistência Ambulatorial , Assistência Ambulatorial , Epilepsia/terapia
18.
Med Teach ; : 1-8, 2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-37992284

RESUMO

INTRODUCTION: Clinical supervision supports patient care and health worker wellbeing. However, access to effective clinical supervision is not equitable. We aimed to explore the access and effectiveness of clinical supervision in allied health workers. METHODS: A cross-sectional survey design using the Manchester Clinical Supervision Scale (MCSS-26), including open-ended survey responses, to collect data on effectiveness. Multivariable regression was conducted to determine how MCSS-26 scores differed across discipline, work location and setting. Open-ended responses were analysed using content analysis. RESULTS: 1113 workers completed the survey, with 319 (28%) reporting they did not receive supervision; this group were more likely to hold management positions, work in a medical imaging discipline and practice in a regional or rural location. For those who received supervision, MCSS-26 scores significantly differed between disciplines and work settings; psychologists and those practising in private practice settings (i.e. fee-for-service) reported the highest levels of effectiveness. Suggested strategies to enhance effectiveness included the use of alternate supervision models, dedicated time for supervision, and training. CONCLUSION: Targeted subgroups for improving access include senior staff, medical imaging professionals, and those working across regional and rural settings. Where supervision was least effective, strategies to address behaviours with organisational support may be required.

19.
Aust J Rural Health ; 31(3): 532-539, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37078513

RESUMO

INTRODUCTION: The Cardiff model is a data sharing approach that aims to reduce the volume of intoxicated patients in emergency departments (EDs). This approach has not been tested in a rural setting. OBJECTIVE: This study assessed whether this approach would reduce the number of alcohol-associated presentations during high-alcohol hours (HAH) in a regional ED. DESIGN: From July 2017, people over the age of 18 attending the ED were asked by the triage nurse (1) whether they had consumed alcohol in the past 12 h, (2) their typical alcohol consumption level, (3) the location where most alcohol was purchased and (4) the location of the last drink. From April 2018, quarterly letters were sent to the top five venues reported within the ED. Deidentified, aggregated data were shared with local police, licensing authorities and local government, identifying the top five venues reported in the ED and providing a summary of alcohol-related attendances to the ED. Interrupted time series analyses were used to estimate the influence of the intervention on monthly injury and alcohol-related ED presentations. FINDINGS: ITS models found that there was a significant gradual decrease in the monthly rate of injury attendances during HAH (Coefficient = -0.004, p = 0.044). No other significant results were found. DISCUSSION: Our study found that sharing last drinks data collected in the ED with a local violence prevention committee was associated with a small, but significant reduction in the rate of injury presentations compared with all ED presentations. CONCLUSION: This intervention continues to have promise for reducing alcohol-related harm.


Assuntos
Transtornos Relacionados ao Uso de Álcool , Humanos , Adulto , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Álcool/prevenção & controle , Austrália , Consumo de Bebidas Alcoólicas/prevenção & controle , Violência/prevenção & controle , Serviço Hospitalar de Emergência
20.
Aust Occup Ther J ; 70(5): 617-626, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37291993

RESUMO

BACKGROUND: Self-directed therapy activities are not currently part of routine care during inpatient rehabilitation. Understanding patient and clinician perspectives on self-directed therapy is key to increasing implementation. The aim of this study was to investigate barriers and facilitators to implementing a self-directed therapy programme ("My Therapy") in adult inpatient rehabilitation settings. METHODS: My Therapy was recommended by physiotherapists and occupational therapists and completed by rehabilitation inpatients independently, outside of supervised therapy sessions. Physiotherapists, occupational therapists, and patients were invited to complete an online questionnaire comprising open-ended questions on barriers and facilitators to prescribing and participating in My Therapy. A directed content analysis of free-text responses was undertaken, with data coded using categories of the Capability, Opportunity, and Motivation Model of Behaviour (COM-B model). RESULTS: Eleven patients and 20 clinicians completed the questionnaire. Patient capability was reported to be facilitated by comprehensive education by clinicians, with mixed attitudes towards the format of the programme booklet. Clinician capability was facilitated by staff collaboration. One benefit was the better use of downtime between the supervised therapy sessions, but opportunities for patients to engage in self-directed therapy were compromised by the lack of space to complete the programme. Clinician opportunity was reported to be provided via organisational support but workload was a reported barrier. Patient motivation to engage in self-directed therapy was reported to be fostered by feeling empowered, engaged, and encouraged to participate. Clinician motivation was associated with belief in the value of the programme. CONCLUSION: Despite some barriers to rehabilitation patients independently practicing therapeutic exercises and activities outside of supervised sessions, both clinicians and patients agreed it should be considered as routine practice. To do this, patient time, ward space, and staff collaboration are required. Further research is needed to scale-up the implementation of the My Therapy programme and evaluate its effectiveness.


Assuntos
Terapia Ocupacional , Fisioterapeutas , Adulto , Humanos , Pacientes Internados , Terapeutas Ocupacionais
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