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1.
Artigo em Inglês | MEDLINE | ID: mdl-38958043

RESUMO

Introduction: Hip fractures are the most common serious injury in the elderly, associated with disability, morbidity, and mortality. Surgical site infection (SSI) is a serious post-operative complication. This prospective cohort study outlines how our center made cumulative improvements in SSI incidence rates, reaching a 12-month average of 0.5%. Methods: All patients undergoing hip fracture operation between 2016 and 2021 were included. The primary outcome measure was confirmed SSI, according to the Public Health England definition. Results were compared with the baseline recordings by an independent SSI team in 2013. Demographic data were compared with National Hip Fracture Database records. Peri-operative infection control and wound management tactics introduced between 2014 and 2021 were collated to gain an overview care bundle. Results: Baseline recordings identified a 9.0% SSI rate in a three-month observation period. In our study, 3,138 hip fracture operative cases were completed between October 2016 and December 2021. There were 9 superficial and 32 deep infections identified, yielding an overall infection rate of 1.3%. However, when analyzing the 12-month average, there was consistent decline in SSI from the baseline 9.0% in 2013 to 0.5% in 2021 (p < 0.05). A peri-operative care bundle included pre-operative bleeding risk assessment. Intra-operatively, double preparation and draping is used for arthroplasty. Broad-spectrum antibiotic agents and tranexamic acid are administered. Meticulous hemostasis and watertight wound closure are observed. Anti-coagulated patients received negative pressure dressings. Post-operatively, a dedicated senior lead team provided daily inpatient review of patients, with urgent consultant review of all wound healing concerns. Conclusion: Patients with a hip fracture have numerous risk factors for SSI. A dedicated multi-focal tactic, adopted by a multi-disciplinary department, can yield substantial risk reduction. Each intervention is evidence based and contributes to cumulative improvement. By prioritizing infection prevention, we have minimized the need for complex infection management interventions and achieved an annual saving of £860,000 for our trust.

2.
PLoS Negl Trop Dis ; 18(5): e0012106, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38820564

RESUMO

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that displays considerable genetic diversity. Infections result in a range of pathological outcomes, and different strains can exhibit a wide spectrum of anti-parasitic drug tolerance. The genetic determinants of infectivity, virulence and therapeutic susceptibility remain largely unknown. As experimental tools to address these issues, we have generated a panel of bioluminescent:fluorescent parasite strains that cover the diversity of the T. cruzi species. These reporters allow spatio-temporal infection dynamics in murine models to be monitored in a non-invasive manner by in vivo imaging, provide a capability to detect rare infection foci at single-cell resolution, and represent a valuable resource for investigating virulence and host:parasite interactions at a mechanistic level. Importantly, these parasite reporter strains can also contribute to the Chagas disease drug screening cascade by ensuring that candidate compounds have pan-species in vivo activity prior to being advanced into clinical testing. The parasite strains described in this paper are available on request.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Trypanosoma cruzi/genética , Trypanosoma cruzi/efeitos dos fármacos , Doença de Chagas/parasitologia , Animais , Camundongos , Genótipo , Modelos Animais de Doenças , Variação Genética , Fenótipo , Medições Luminescentes/métodos , Genes Reporter , Humanos , Feminino , Interações Hospedeiro-Parasita
3.
Mol Ther Methods Clin Dev ; 32(2): 101228, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38524756

RESUMO

Manufacturing of adeno-associated viruses (AAV) for gene and cell therapy applications has increased significantly and spurred development of improved mammalian and insect cell-based production systems. We developed a baculovirus-based insect cell production system-the SGMO Helper-with a novel gene architecture and greater flexibility to modulate the expression level and content of individual Rep and Cap proteins. In addition, we incorporated modifications to the AAV6 capsid sequence that improves yield, capsid integrity, and potency. Production of recombinant AAV 6 (rAAV6) using the SGMO Helper had improved yields compared to the Bac-RepCap helper from the Kotin lab. SGMO Helper-derived rAAV6 is resistant to a previously described proteolytic cleavage unique to baculovirus-insect cell production systems and has improved capsid ratios and potency, in vitro and in vivo, compared with rAAV6 produced using Bac-RepCap. Next-generation sequencing sequence analysis demonstrated that the SGMO Helper is stable over six serial passages and rAAV6 capsids contain comparable amounts of non-vector genome DNA as rAAV6 produced using Bac-RepCap. AAV production using the SGMO Helper is scalable using bioreactors and has improved yield, capsid ratio, and in vitro potency. Our studies demonstrate that the SGMO Helper is an improved platform for AAV manufacturing to enable delivery of cutting-edge gene and cell therapies.

4.
Gynecol Oncol ; 168: 114-118, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36434945

RESUMO

BACKGROUND: This study investigated whether there are pharmacogenomic markers predictive of chemotherapy induced peripheral neuropathy (CIPN) as a result of taxane-based chemotherapy. METHODS: Patients were enrolled from August 2020 to November 2020 in a prospective, case-control trial evaluating pharmacogenetic predictors of CIPN. All women were treated with at least 3 cycles of taxane-based chemotherapy for histologically confirmed gynecologic malignancies. Buccal saliva samples were used to test for 32 drug metabolism variations. All testing was performed by ⍺LPHA-GENOMIX laboratories. Fisher's Exact test was used to assess for event differences of categorical variables. RESULTS: Of 102 enrolled patients, 58%, 28%, and 14% had ovarian, endometrial, or cervical cancers, respectively. The median age was 67, 72% were Caucasian and 25% were African American. 16% of patients were treated with 3-4 cycles, 57% received 5-7 cycles, and 27% received 8 or more cycles of chemotherapy that included paclitaxel. Grade 2 CIPN was experienced by 51 patients. There was no difference in age, race, disease site, or number of chemotherapy cycles (p > 0.05) between those who did or did not develop CIPN. CYP2D6 genotype (p = 0.009) and CYP3A5 genotype (p = 0.023) had different frequencies among those with and without CIPN. Patients classified as having poor or intermediate function of CYP2D6 had increased risk of CIPN (OR 1.63, 95% CI 1.04-2.57, p = 0.026). There was no difference in CYP2D6 phenotype by race (p = 0.29). No patients with normal function of CYP3A5 developed CIPN. There were no Caucasians with normal function of CYP3A5, but 28% of African Americans had normal CYP3A5 function (p < 0.001). CONCLUSIONS: Pharmacogenomics appear associated with the development of CIPN and may be able to help personalize treatment decision making.


Assuntos
Antineoplásicos , Neoplasias da Mama , Neoplasias dos Genitais Femininos , Doenças do Sistema Nervoso Periférico , Feminino , Humanos , Antineoplásicos/efeitos adversos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Farmacogenética , Estudos Prospectivos , Taxoides/efeitos adversos , Estudos de Casos e Controles , Idoso
5.
Dev Cell ; 57(12): 1545-1557.e4, 2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35649417

RESUMO

Bardet-Biedl syndrome (BBS) is a genetic disorder that affects primary cilia. BBSome, a protein complex composed of eight BBS proteins, regulates the structure and function of cilia, and its malfunction causes BBS in humans. Here, we report a cilia-independent function of BBSome. To identify genes that regulate the C. elegans photoreceptor protein LITE-1 in ciliated ASH photosensory neurons, we performed a genetic screen and isolated bbs mutants. Functional analysis revealed that BBSome regulates LITE-1 protein stability independently of cilia. Through another round of genetic screening, we found that this cilia-independent function of BBSome is mediated by DLK-MAPK signaling, which acts downstream of BBSome to control LITE-1 stability via Rab5-mediated endocytosis. BBSome exerts its function by regulating the expression of DLK. BBSome also regulates the expression of LZK, a mammalian DLK in human cells. These studies identify a cilia-independent function of BBSome and uncover DLK as an evolutionarily conserved BBSome effector.


Assuntos
Síndrome de Bardet-Biedl , Cílios , Animais , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Cílios/metabolismo , Humanos , Mamíferos/metabolismo , Transporte Proteico/genética , Proteínas/metabolismo
6.
J Appl Clin Med Phys ; 23(2): e13510, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34936205

RESUMO

BACKGROUND: Pencil beam scanning (PBS) proton therapy offers dosimetric advantages for several treatment sites, including head and neck (H&N). However, to achieve the optimal target coverage and robustness, these plans can be complex and time consuming to develop and optimize. Automating the treatment planning process can ensure a high-quality and standardized plan, reduce burden to the planner, and decrease time-to-treatment. We utilized in-house scripting to automate a four-field multi-field optimization (MFO) H&N planning technique. METHODS AND MATERIALS: Ten bilateral H&N patients were planned in RayStation v6 with a four-field modified-X beam configuration using MFO planning. Automation included creation of avoidance structures to control spot placement and development of standardized beams, PBS spot settings, robust optimization objectives, and patient-specific predicted planning constraints. Each patient was planned both with and without automation to evaluate differences in planning time, perceived effort and plan quality, plan robustness, and OAR sparing. RESULTS: On average, scripted plans required 3.2 h, compared to 4.3 h without the script. There was no difference in target coverage or plan robustness with or without automation. Automation significantly reduced mean dose to the oral cavity, parotids, esophagus, trachea, and larynx. Perceived effort was scaled from 1 (minimum effort) to 100 (maximum effort), and automation reduced perceived effort by 42% (p < 0.05). Two non-scripted plans required re-planning due to errors. CONCLUSIONS: Automation of this multi-beam, the MFO proton planning process reduced planning time and improved OAR sparing compared to the same planning process without scripting. Scripting generation of complex structures and planning objectives reduced burden on the planner. With most current treatment planning software, this automation is simple to implement and can standardize quality of care across all treatment planners.


Assuntos
Terapia com Prótons , Radioterapia de Intensidade Modulada , Humanos , Radiometria , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador
7.
J Mark Access Health Policy ; 9(1): 1922163, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34122780

RESUMO

Background: Simulation modeling facilitates the estimation of long-term health and economic outcomes to inform healthcare decision-making. Objective: To develop a framework to simulate progression of Parkinson's disease (PD), capturing motor and non-motor symptoms, clinical outcomes, and associated costs over a lifetime. Methods: A patient-level simulation was implemented accounting for individual variability and interrelated changes in common disease progression scales. Predictive equations were developed to model progression for newly diagnosed patients and were combined with additional sources to inform long-term progression. Analyses compared a hypothetical disease-modifying therapy (DMT) with a standard of care to explore the drivers of cost-effectiveness. Results: The equations captured the dependence between the various measures, leveraging prior values and rates of change to obtain realistic predictions. The simulation was built upon several interrelated equations, validated by comparison with observed values for the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) and UPDRS subscales over time. In a case study, disease progression rates, patient utilities, and direct non-medical costs were drivers of cost-effectiveness. Conclusions: The developed equations supported the simulation of early PD. This model can support conducting simulations to inform internal decision-making, trial design, and strategic planning early in the development of new DMTs entering clinical trials.

8.
J Foot Ankle Surg ; 60(4): 669-675, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33573901

RESUMO

Ankle fractures are common conditions which are associated with significant morbidity when managed incorrectly. With the incidence due to triple by 2030, standards of practice were created by the British Orthopaedic Association and the British Orthopaedic Foot and Ankle Society to ensure optimal treatment. In spite of this, anecdotally there is still a variation in practice and therefore a questionnaire study was designed to explore clinician decision-making around Weber B and Posterior Malleolus ankle fractures. Five scenarios explored management regarding minimally and grossly displaced injuries, as well as the use of further imaging. The questionnaires were distributed via AUGMENT collaborators at their sites and at the British Orthopaedic Foot and Ankle Society congress 2018. About 315 questionnaires were completed and included in analysis. For Weber B injuries, overall there was a consensus across all respondents with minimally displaced and grossly displaced fractures being treated conservatively and operatively respectively. For Posterior Malleolus injuries, there was variation in practice between Foot and Ankle specialists and their non-Foot and Ankle colleagues. Computed tomography (CT) was more likely to be used to assess these injuries by specialists (97.50 vs 69.79%) and these injuries were more likely to be treated operatively across the board. This study identified key variation in practice of the management of Posterior Malleolar ankle fractures, including the use of imaging to further define the anatomy and the decision to operate. Foot and Ankle surgeons were more likely to organize CT scans and to surgically manage these injures.


Assuntos
Fraturas do Tornozelo , Traumatismos do Tornozelo , Consenso , Fixação Interna de Fraturas , Humanos , Inquéritos e Questionários , Reino Unido
9.
Surgeon ; 19(5): e237-e244, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33414043

RESUMO

BACKGROUND: Ankle fractures are one of the most common fractures in adults aged 20-65 years. The British Orthopaedic Association (BOA) and British Orthopaedic Foot and Ankle Society (BOFAS) jointly produced Standards for Trauma (BOAST) BOAST 12, with the aim of reducing morbidity by standardising care of these injuries. The primary aim of the AUGMENT study was to determine the extent and clinical effect of variation from BOAST 12. METHODS: AUGMENT was a multi-centre prospective trainee led audit of consecutive patients presenting with an ankle fracture within a four-week period. Data were collected on patient demographics, comorbidities, management and 12-week outcome. The BOAST 12 standards were divided into four subgroups; documentation, imaging, management and follow-up. Percentage compliance with each subgroup was analysed. A multivariate logistic regression analysis was used to determine impact of overall compliance on likelihood of discharge in follow-up period. FINDINGS: 971 patients were included across 52 sites. The overall rate of BOAST 12 compliance was 41.7%. Variations in practice were observed in clinical documentation, especially of neurovascular status, (40.7%) and VTE assessment (61.5%). Patient management compliance with all 16 of the BOAST 12 standards was associated with a higher rate of discharge during the 12-week follow-up period (p = 0.005). CONCLUSION: AUGMENT has demonstrated that the management of ankle fractures is variable across the UK. Over half of patients had aspects of their care that were not BOAST 12 compliant. When compliance was observed, it was associated with earlier discharge from orthopaedic care.


Assuntos
Fraturas do Tornozelo , Ortopedia , Adulto , Fraturas do Tornozelo/terapia , Fixação Interna de Fraturas , Humanos , Extremidade Inferior , Estudos Prospectivos
10.
Bone Jt Open ; 1(11): 669-675, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33263106

RESUMO

AIMS: Within the UK, around 70,000 patients suffer neck of femur (NOF) fractures annually. Patients presenting with this injury are often frail, leading to increased morbidity and a 30-day mortality rate of 6.1%. COVID-19 infection has a broad spectrum of clinical presentations with the elderly, and those with pre-existing comorbidities are at a higher risk of severe respiratory compromise and death. Further increased risk has been observed in the postoperative period. The aim of this study was to assess the impact of COVID-19 infection on the complication and mortality rates of NOF fracture patients. METHODS: All NOF fracture patients presenting between March 2020 and May 2020 were included. Patients were divided into two subgroup: those with or without clinical and/or laboratory diagnosis of COVID-19. Data were collected on patient demographics, pattern of injury, complications, length of stay, and mortality. RESULTS: Overall, 132 patients were included. Of these, 34.8% (n = 46) were diagnosed with COVID-19. Bacterial pneumonia was observed at a significantly higher rate in those patients with COVID-19 (56.5% vs 15.1%; p =< 0.000). Non respiratory complications such as acute kidney injury (30.4% vs 9.3%; p =0.002) and urinary tract infection (10.9% vs 3.5%; p =0.126) were also more common in those patients with COVID-19. Length of stay was increased by a median of 21.5 days in patients diagnosed with COVID-19 (p < 0.000). 30-day mortality was significantly higher in patients with COVID-19 (37.0%) when compared to those without (10.5%; p <0.000). CONCLUSION: This study has shown that patients with a neck of femur fracture have a high rate of mortality and complications such as bacterial pneumonia and acute kidney injury when diagnosed with COVID-19 within the perioperative period. We have demonstrated the high risk of in hospital transmission of COVID-19 and the association between the infection and an increased length of stay for the patients affected.Cite this article: Bone Joint Open 2020;1-11:669-675.

11.
BMC Psychiatry ; 20(1): 290, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517724

RESUMO

BACKGROUND: Here we describe a unique case of clozapine-associated hypothermia during initial titration of this medication in an acute inpatient psychiatry setting. Only a handful of cases on this topic have been published. We discuss possible pharmacologic mechanisms supporting or refuting the propensity of clozapine to induce hypothermia, as well as risk factors for clozapine-induced hypothermia, and a comparison to clozapine-induced hyperthermia. CASE PRESENTATION: A 70 year-old African American female with treatment-refractory schizoaffective disorder developed hypothermia with a nadir temperature of 89 °F (31.7 °C) after 7 days on clozapine, on a total dose of 50 mg twice daily. Accompanying symptoms included bradycardia, hypotension, QTc prolongation, tachypnea, hypoxemia, and an absence of shivering. The patient was transferred to the ICU, and rewarmed within 10 h with the discontinuation of her clozapine, ziprasidone, and carvedilol. Broad spectrum antibiotics were initiated, but discontinued shortly after, as the patient had no leukocytosis, and blood cultures were negative. DISCUSSION: While hypoglycemia, hypothyroidism, sepsis, and stroke were effectively ruled out, alternative drug-disease (including chronic kidney disease), and drug-drug interactions were considered possible contributing features. Benzodiazepines, valproic acid, ziprasidone, and the numerous antihypertensive agents the patient was taking were considered as either primary or compounding factors for hypothermia. After exclusion or inclusion of these alternative causes, we calculated a score of 4 (possible) for clozapine-induced hypothermia on the Naranjo Scale. CONCLUSIONS: Clozapine-induced hypothermia may occur more commonly than clinicians believe. Practitioners should be cognizant of this potentially fatal phenomenon, and monitor for temperature dysregulations while on clozapine, especially during initial titration, in those with multiple comorbid factors, and on additional medications that may contribute to hypothermia.


Assuntos
Antipsicóticos/efeitos adversos , Regulação da Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Clozapina/administração & dosagem , Clozapina/efeitos adversos , Hipotermia/induzido quimicamente , Idoso , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Feminino , Humanos , Pacientes Internados
12.
J Card Surg ; 35(6): 1314-1321, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32353909

RESUMO

BACKGROUND: The saphenous vein remains the most frequently used conduit for coronary artery bypass grafting, despite reported unsatisfactory long-term patency rates. Understanding the pathophysiology of vein graft failure and attempting to improve its longevity has been a significant area of research for more than three decades. This article aims to review the current understanding of the pathophysiology and potential new intervention strategies. METHODS: A search of three databases: MEDLINE, Web of Science, and Cochrane Library, was undertaken for the terms "pathophysiology," "prevention," and "treatment" plus the term "vein graft failure." RESULTS: Saphenous graft failure is commonly the consequence of four different pathophysiological mechanisms, early acute thrombosis, vascular inflammation, intimal hyperplasia, and late accelerated atherosclerosis. Different methods have been proposed to inhibit or attenuate these pathological processes including modified surgical technique, topical pretreatment, external graft support, and postoperative pharmacological interventions. Once graft failure occurs, the available treatments are either surgical reintervention, angioplasty, or conservative medical management reserved for patients not eligible for either procedure. CONCLUSION: Despite the extensive amount of research performed, the pathophysiology of saphenous vein graft is still not completely understood. Surgical and pharmacological interventions have improved early patency and different strategies for prevention seem to offer some hope in improving long-term patency.


Assuntos
Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/cirurgia , Oclusão de Enxerto Vascular/prevenção & controle , Oclusão de Enxerto Vascular/terapia , Disfunção Primária do Enxerto/prevenção & controle , Disfunção Primária do Enxerto/terapia , Veia Safena/transplante , Enxerto Vascular/métodos , Oclusão de Enxerto Vascular/etiologia , Humanos , Disfunção Primária do Enxerto/etiologia , Resultado do Tratamento , Grau de Desobstrução Vascular
13.
J Foot Ankle Surg ; 59(1): 105-111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882132

RESUMO

Weber C ankle fractures are unstable ankle fractures occurring above the syndesmosis. These fractures are often managed operatively, although a small population of patients are still selected for nonoperative management. This study primarily aimed to summarize the current evidence on functional outcomes for Weber C patients managed operatively and nonoperatively. Evidence on secondary outcomes such as complications and radiographic outcomes were also reviewed. This systematic search was conducted according to PRISMA guidelines. A literature search was conducted using the EMBASE, Medline, and Central databases. A total of 26 studies were included in the final analysis. All papers studied the management of Weber C fractures using open reduction and internal fixation (ORIF). Three main functional outcome scores were identified: American Orthopedic Foot and Ankle Society score, Olerud-Molander Ankle Score, and Foot and Ankle Outcome Score. Only 1 study compared operative and conservative management, which showed similar outcomes for either option (median Olerud-Molander Ankle Score 95 [range 20 to 95] vs 100 [70 to 100], respectively). Complications associated with operative management included infection, wound dehiscence, implant failure, and malunion or nonunion. The mean rate of syndesmosis malreduction was 18.2%. This study showed that operative management, regardless of the method of ORIF used, as well as nonoperative management resulted in good functional outcomes, indicating that patient selection for either method is important. However, there is limited evidence on the complications and radiographic outcomes associated with nonoperative management. We recommend further studies to compare all ORIF methods with conservative management and examine the complications associated with nonoperative management.


Assuntos
Fraturas do Tornozelo/terapia , Fixação de Fratura , Moldes Cirúrgicos , Humanos , Recuperação de Função Fisiológica , Resultado do Tratamento
14.
Foot Ankle Surg ; 26(5): 494-502, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31266676

RESUMO

BACKGROUND: The aim of this systematic review was to compare surgical and non-surgical management of Weber B ankle fractures. METHODS: A systematic computer-based search was conducted using the MEDLINE (via OvidSP), EMBASE (via OvidSP) and Central databases. Data were extracted regarding functional outcome, radiological union, range of motion (RoM), infection rate and quality of life (QoL). RESULTS: There were no significant differences identified between surgical and non-surgical management of Weber B fractures with respect to functional outcome. There is a higher rate of complication following surgical management, including infection, reoperation, thromboembolic events and death. With respect to QoL and ankle RoM, this review identified no differences between surgical and non-surgical management. CONCLUSIONS: There is a need for further published literature evaluating the most efficacious management as there is a poverty of high-level research available. Currently, the available literature does not overwhelmingly favour a particular approach to Weber B ankle fractures.


Assuntos
Fraturas do Tornozelo/cirurgia , Articulação do Tornozelo/cirurgia , Fixação de Fratura/métodos , Fraturas do Tornozelo/diagnóstico , Fraturas do Tornozelo/fisiopatologia , Articulação do Tornozelo/diagnóstico por imagem , Humanos , Qualidade de Vida , Radiografia , Amplitude de Movimento Articular , Resultado do Tratamento
15.
Proc Natl Acad Sci U S A ; 116(32): 16068-16073, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31341080

RESUMO

Our understanding of the mechanisms of neural circuit assembly is far from complete. Identification of wiring molecules with novel mechanisms of action will provide insights into how complex and heterogeneous neural circuits assemble during development. In the Drosophila olfactory system, 50 classes of olfactory receptor neurons (ORNs) make precise synaptic connections with 50 classes of partner projection neurons (PNs). Here, we performed an RNA interference screen for cell surface molecules and identified the leucine-rich repeat-containing transmembrane protein known as Fish-lips (Fili) as a novel wiring molecule in the assembly of the Drosophila olfactory circuit. Fili contributes to the precise axon and dendrite targeting of a small subset of ORN and PN classes, respectively. Cell-type-specific expression and genetic analyses suggest that Fili sends a transsynaptic repulsive signal to neurites of nonpartner classes that prevents their targeting to inappropriate glomeruli in the antennal lobe.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Membrana/metabolismo , Neurônios Receptores Olfatórios/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Animais , Axônios/metabolismo , Dendritos/metabolismo , Proteínas de Repetições Ricas em Leucina , Mutação/genética , Fenótipo , Proteínas/metabolismo
16.
Arch Orthop Trauma Surg ; 139(10): 1351-1360, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30895464

RESUMO

INTRODUCTION: All the surgeries carry risks, which may lead to readmission at a later date. At present, there is limited Trauma and Orthopaedic (T&O) specific data in the literature. As a result, a prospective regional service evaluation aimed to discover the current complication and readmission rates across all T&O procedures and identify any factors associated with these outcomes. METHODS: Data were collected at six sites across Yorkshire and Humber for all T&O procedures during October 2016. Patient demographics and procedure-specific data were collected. Post-operative complications and length of stay were recorded. All the patients were then followed up for 30 days post-discharge to determine if they experienced complications which resulted in readmission and further surgical intervention. RESULTS: 1411 patients having a total of 64 operations were recorded with 1391 completing follow-up (98.5%). Overall in-patient complication rate was 8.4% with the readmission rate being 4.4%. An ASA grade of three or more was found to be associated with readmission. Procedure-related factors such as the use of VTE prophylaxis and prophylactic antibiotics, as well as the elective nature of certain operations were negatively associated with readmission. The largest subgroup of patients was those undergoing total hip (THR) or knee replacements (TKR). For these 234 patients, the readmission rate for TKR and THR being 3.77% and 3.13%, respectively. CONCLUSIONS: This large, multi-centre project describes readmission rates following trauma and orthopaedic surgery. In the presented study, the elective nature of the procedure was associated with a reduced risk of readmission.


Assuntos
Procedimentos Ortopédicos/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/etiologia , Ferimentos e Lesões/cirurgia , Adulto , Idoso , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Procedimentos Cirúrgicos Eletivos/estatística & dados numéricos , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos/efeitos adversos , Estudos Prospectivos , Fatores de Risco
18.
Orphanet J Rare Dis ; 12(1): 38, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-28219443

RESUMO

BACKGROUND: The Disease Severity Scoring System (DS3) is a validated measure for evaluating Gaucher disease type 1 (GD1) severity. We developed a new framework, consisting of health states, transition probabilities between those states, and preferences for those states (utilities) based on the DS3 to predict long-term outcomes of patients starting treatment. We defined nine mutually exclusive (alive) health states based on three DS3 categories: mild (0 ≤ DS3 ≤ 3.5) without symptoms of bone disease; mild with bone pain, mild with severe skeletal complications (SSC) defined as lytic lesions, avascular necrosis, or fracture; moderate (3.5 < DS3 ≤ 6.5) without SSC; moderate with SSC; marked (6.5 < DS3 ≤ 9.5) without SSC; marked with SSC; severe (9.5 < DS3 ≤ 19) without SSC; and severe with SSC. Health-state transition probabilities and utilities were estimated from a longitudinal sample of patients with GD1 who started enzyme replacement therapy (the DS3 Score Study). Age dependent GD1-specific mortality was derived from published data. We used a Markov state-transition model to illustrate how to estimate time spent in each health state. RESULTS: The average predicted utilities for each health state ranged from 0.76 for mild disease with no clinical symptoms of bone disease to 0.52 with severe disease with SSC. Transition probabilities depended on disease severity (DS3 score) at treatment initiation and whether patients had undergone a total splenectomy or had an intact spleen/partial splenectomy prior to starting treatment. Patients who started treatment with intact or residual spleens spent more time in better health states than those who started treatment with total splenectomy. CONCLUSIONS: This new framework, which is based on the DS3, can be used to project the long-term outcomes of GD1 patients starting treatment. The framework could also be used to compare the long-term outcomes of different GD1 treatment options. TRIAL REGISTRATION: NCT01136304 . Registered: May 31, 2010 (retrospectively registered).


Assuntos
Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/patologia , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Terapia de Reposição de Enzimas , Glucosilceramidase/uso terapêutico , Humanos
20.
Cell ; 167(5): 1252-1263.e10, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27863243

RESUMO

Many animal tissues/cells are photosensitive, yet only two types of photoreceptors (i.e., opsins and cryptochromes) have been discovered in metazoans. The question arises as to whether unknown types of photoreceptors exist in the animal kingdom. LITE-1, a seven-transmembrane gustatory receptor (GR) homolog, mediates UV-light-induced avoidance behavior in C. elegans. However, it is not known whether LITE-1 functions as a chemoreceptor or photoreceptor. Here, we show that LITE-1 directly absorbs both UVA and UVB light with an extinction coefficient 10-100 times that of opsins and cryptochromes, indicating that LITE-1 is highly efficient in capturing photons. Unlike typical photoreceptors employing a prosthetic chromophore to capture photons, LITE-1 strictly depends on its protein conformation for photon absorption. We have further identified two tryptophan residues critical for LITE-1 function. Interestingly, unlike GPCRs, LITE-1 adopts a reversed membrane topology. Thus, LITE-1, a taste receptor homolog, represents a distinct type of photoreceptor in the animal kingdom.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Membrana/metabolismo , Animais , Caenorhabditis elegans/efeitos da radiação , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/isolamento & purificação , Proteínas de Membrana/química , Proteínas de Membrana/isolamento & purificação , Fótons , Conformação Proteica , Triptofano/metabolismo , Raios Ultravioleta
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