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1.
J Surg Oncol ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499741

RESUMO

BACKGROUND AND OBJECTIVES: Pancreatic neuroendocrine tumors (PNETs) represent a rare form of pancreatic cancer. Racial/ethnic disparities have been documented in pancreatic ductal adenocarcinoma, but health disparities have not been well described in patients with PNETs. METHODS: A retrospective review of patients with PNETs in the National Cancer Database was performed for 2004-2014. Approximately 16 605 patients with PNETs and available vital status were identified. Survival was compared by race/ethnicity and socioeconomic status using Kaplan-Meier methods and Cox regression. RESULTS: There were no significant differences in survival between Non-Hispanic, White; Hispanic, White; or Non-Hispanic, Black patients on univariate analysis. Kaplan-Meier analysis showed that patients from communities with lower median household income and education level had worse survival (p < 0.001). Patients age less than 65 without insurance, similarly, had worse survival (p < 0.001). Multivariable modeling found no association between race/ethnicity and risk of mortality (p = 0.37). Lower median household income and lower education level were associated with increased mortality (p < 0.001). CONCLUSIONS: Unlike most other malignancies, race/ethnicity is not associated with survival differences in patients with PNETs. Patients with lower socioeconomic status had worse survival. The presence of identifiable health disparities in patients with PNETs represents a target for intervention and opportunity to improve survival in patients with this malignancy.

2.
Clin J Pain ; 37(11): 803-811, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34475340

RESUMO

OBJECTIVE: Acute postoperative pain intensity is associated with persistent postsurgical pain (PPP) risk. However, it remains unclear whether acute postoperative pain intensity mediates the relationship between clinical factors and persistent pain. MATERIALS AND METHODS: Participants from a mixed surgical population completed the Brief Pain Inventory and Pain Catastrophizing Scale before surgery, and the Brief Pain Inventory daily after surgery for 7 days and at 30 and 90 days after surgery. We considered mediation models using the mean of the worst pain intensities collected daily on each of postoperative days (PODs) 1 to 7 against outcomes of worst pain intensity at the surgical site endpoints reflecting PPP (POD 90) and subacute pain (POD 30). RESULTS: The analyzed cohort included 284 participants for the POD 90 outcome. For every unit increase of maximum acute postoperative pain intensity through PODs 1 to 7, there was a statistically significant increase of mean POD 90 pain intensity by 0.287 after controlling for confounding effects. The effects of female versus male sex (m=0.212, P=0.034), pancreatic/biliary versus colorectal surgery (m=0.459, P=0.012), thoracic cardiovascular versus colorectal surgery (m=0.31, P=0.038), every minute increase of anesthesia time (m=0.001, P=0.038), every unit increase of preoperative average pain score (m=0.012, P=0.015), and every unit increase of catastrophizing (m=0.044, P=0.042) on POD 90 pain intensity were mediated through acute PODs 1 to 7 postoperative pain intensity. DISCUSSION: Our results suggest the mediating relationship of acute postoperative pain on PPP may be predicated on select patient and surgical factors.

3.
FASEB J ; 35(9): e21802, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383984

RESUMO

Mutations in transcription factors often exhibit pleiotropic effects related to their complex expression patterns and multiple regulatory targets. One such mutation in the zinc finger homeobox 3 (ZFHX3) transcription factor, short circuit (Sci, Zfhx3Sci/+ ), is associated with significant circadian deficits in mice. However, given evidence of its retinal expression, we set out to establish the effects of the mutation on retinal function using molecular, cellular, behavioral and electrophysiological measures. Immunohistochemistry confirms the expression of ZFHX3 in multiple retinal cell types, including GABAergic amacrine cells and retinal ganglion cells including intrinsically photosensitive retinal ganglion cells (ipRGCs). Zfhx3Sci/+ mutants display reduced light responsiveness in locomotor activity and circadian entrainment, relatively normal electroretinogram and optomotor responses but exhibit an unexpected pupillary reflex phenotype with markedly increased sensitivity. Furthermore, multiple electrode array recordings of Zfhx3Sci/+ retina show an increased sensitivity of ipRGC light responses.


Assuntos
Ritmo Circadiano/fisiologia , Proteínas de Homeodomínio/metabolismo , Retina/metabolismo , Células Amácrinas/metabolismo , Animais , Luz , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Luminosa/métodos , Células Ganglionares da Retina/metabolismo , Visão Ocular/fisiologia
4.
Surgery ; 2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34433515

RESUMO

BACKGROUND: Intraperitoneal drain placement decreases morbidity and mortality in patients who develop a clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). It is unknown whether multiple drains mitigate CR-POPF better than a single drain. We hypothesize that multiple drains decrease the complication burden more than a single drain in cases at greater risk for CR-POPF. METHODS: The Fistula Risk Score (FRS), mitigation strategies (including number of drains placed), and clinical outcomes were obtained from a multi-institutional database of PDs performed from 2003 to 2020. Outcomes were compared between cases utilizing 0, 1, or 2 intraperitoneal drains. Multivariable regression analysis was used to evaluate the optimal drainage approach. RESULTS: A total of 4,292 PDs used 0 (7.3%), 1 (45.2%), or 2 (47.5%) drains with an observed CR-POPF rate of 9.6%, which was higher in intermediate/high FRS zone cases compared with negligible/low FRS zone cases (13% vs 2.4%, P < .001). The number of drains placed also correlated with FRS zone (median of 2 in intermediate/high vs 1 in negligible/low risk cases). In intermediate/high risk cases, the use of 2 drains instead of 1 was not associated with a reduced rate of CR-POPF, average complication burden attributed to a CR-POPF, reoperations, or mortality. Obviation of drains was associated with significant increases in complication burden and mortality - regardless of the FRS zone. CONCLUSION: In intermediate/high risk zone cases, placement of a single drain or multiple drains appears to mitigate the complication burden while use of no drains is associated with inferior outcomes.

5.
Oncologist ; 26(10): 825-e1674, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34101295

RESUMO

LESSONS LEARNED: Preclinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the antitumor effects of oxaliplatin. In this phase II, single-arm study, FOLFOX with dasatinib in previously untreated patients with mPC only showed only modest clinical activity, with a progressive-free survival of 4 months and overall survival of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-fluorouracil and oxaliplatin in a subset of exceptional responders. BACKGROUND: Src tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance antitumor effects of FOLFOX regimen (FOLFOX-D). METHODS: In this single-arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1-14, oxaliplatin 85 mg/m2 intravenous (IV) on day 1 every 14 days, leucovorin (LV) 400 mg/m2 IV on day 1 every 14 days, 5-fluorouracil (5-FU) bolus 400 mg/m2 on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m2 on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with preplanned comparison to historical controls. RESULTS: Forty-four patients enrolled with an estimated median PFS of 4.0 (95% confidence interval [CI], 2.3-8.5) months and overall survival (OS) of 10.6 (95% CI, 6.9-12.7) months. Overall response rate (ORR) was 22.7% (n = 10): one patient (2.3%) with complete response (CR) and nine patients (20.5%) with partial response (PR). Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%). CONCLUSION: The addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated patients with mPC.

6.
J Exp Biol ; 224(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34151984

RESUMO

Human opsin-based photopigments have great potential as light-sensitisers, but their requirement for phototransduction cascade-specific second messenger proteins may restrict their functionality in non-native cell types. In this study, eight chimeric human opsins were generated consisting of a backbone of either a rhodopsin (RHO) or long-wavelength-sensitive (LWS) opsin and intracellular domains from Gq/11-coupled human melanopsin. Rhodopsin/melanopsin chimeric opsins coupled to both Gi and Gq/11 pathways. Greater substitution of the intracellular surface with corresponding melanopsin domains generally showed greater Gq/11 activity with a decrease in Gi activation. Unlike melanopsin, rhodopsin and rhodopsin/melanopsin chimeras were dependent upon exogenous chromophore to function. By contrast, wild-type LWS opsin and LWS opsin/melanopsin chimeras showed only weak Gi activation in response to light, whilst Gq/11 pathway activation was not detected. Immunocytochemistry (ICC) demonstrated that chimeric opsins with more intracellular domains of melanopsin were less likely to be trafficked to the plasma membrane. This study demonstrates the importance of Gα coupling efficiency to the speed of cellular responses and created human opsins with a unique combination of properties to expand the range of customised optogenetic biotools for basic research and translational therapies.


Assuntos
Opsinas , Optogenética , Quimera , Humanos , Luz , Transdução de Sinal Luminoso , Opsinas/genética , Rodopsina/genética , Opsinas de Bastonetes/genética
8.
Surgery ; 170(4): 1195-1204, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33931208

RESUMO

BACKGROUND: The association between intraoperative estimated blood loss and outcomes after pancreatoduodenectomy has, thus far, been rarely explored. METHODS: In total, 7,706 pancreatoduodenectomies performed at 18 international institutions composing the Pancreas Fistula Study Group were examined (2003-2020). High estimated blood loss (>700 mL) was defined as twice the median. Propensity score matching (1:1 exact-match) was employed to adjust for variables associated with high estimated blood loss and clinically relevant pancreatic fistula occurrence. The study was powered to detect a 33% clinically relevant pancreatic fistula increase in the high estimated blood loss group, with α = 0.05 and ß = 0.2. RESULTS: The propensity score model included 966 patients with high estimated blood loss and 966 patients with lower estimated blood loss; all covariate imbalantces were solved. Patients with high estimated blood loss patients experienced higher clinically relevant pancreatic fistula rates (19.4 vs 12.6%, odds ratio 1.66; P < .001), as well as higher severe complication rates (27.8 vs 15.6%), transfusions (50.1 vs 14.3%), reoperations (9.2 vs 4.0%), intensive care unit transfers (9.9 vs 4.8%) and 90-day mortality (4.7 vs 2.0%, all P < .001). High estimated blood loss was an independent predictor for clinically relevant pancreatic fistula (odds ratio 1.78, 95% confidence interval 1.37-2.32), as were prophylactic Octreotide administration (odds ratio 1.95, 95% confidence interval 1.46-2.61) and soft pancreatic texture (odds ratio 5.32, 95% confidence interval 3.74-5.57; all P < .001). Moreover, a second model including 1,126 pancreatoduodenectomies was derived including vascular resections as additional confounder (14.0% vascular resections performed in each group). On multivariable regression, high estimated blood loss was confirmed an independent predictor for clinically relevant pancreatic fistula reduction (odds ratio 1.80, 95% confidence interval 1.32-2.44; P < .001), whereas vascular resection was not (odds ratio 0.64, 95% confidence interval 0.34-1.88; P = .156). CONCLUSION: This study better establishes the relationship between estimated blood loss and outcomes after pancreatoduodenectomy. Despite inherent contributions to blood loss, its minimization is an actionable opportunity for clinically relevant pancreatic fistula reduction and performance optimization in pancreatoduodenectomy. Accordingly, practical insights are offered to achieve this goal.

9.
JAMA Surg ; 156(8): 748-756, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33950242

RESUMO

Importance: Diversity in academic surgery is lacking, particularly among positions of leadership. Objective: To evaluate trends among racial/ethnical minority groups stratified by gender along the surgical pipeline, as well as in surgical leadership. Design, Setting, and Participants: This cross-sectional and longitudinal analysis assessed US surgical faculty census data obtained from the Association of American Medical Colleges faculty roster in the Faculty Administrative Management Online User System database. Surgical faculty members captured in census data from December 31, 2013, to December 31, 2019, were included in the analysis. Faculty were identified from the surgery category of the faculty roster, which includes general surgeons and subspecialists, neurosurgeons, and urologists. Main Outcomes and Measures: Gender and race/ethnicity were obtained for surgical faculty stratified by rank. Descriptive statistics with annual percentage of change in representation are reported based on faculty rank. Results: A total of 15 653 US surgical faculty, including 3876 women (24.8%), were included in the data set for 2019. Female faculty from racial/ethnic minority groups experienced an increase in representation at instructor and assistant and associate professorship appointments, with a more favorable trajectory than male faculty from racial/ethnic minority groups across nearly all ranks. White faculty maintain most leadership positions as full professors (3105 of 3997 [77.7%]) and chairs (294 of 380 [77.4%]). The greatest magnitude of underrepresentation along the surgical pipeline has been among Black (106 of 3997 [2.7%]) and Hispanic/Latinx (176 of 3997 [4.4%]) full professors. Among full professors, although Black and Hispanic/Latinx male representation increased modestly (annual change, 0.07% and 0.10%, respectively), Black female representation remained constant (annual change, 0.00004%) and Hispanic/Latinx female representation decreased (annual change, -0.16%). Overall Hispanic/Latinx (20 of 380 [5.3%]) and Black (13 of 380 [3.4%]) representation as chairs has not changed, with only 1 Black and 1 Hispanic/Latinx woman ascending to chair from 2013 to 2019. Conclusions and Relevance: A disproportionately small number of faculty from minority groups obtain leadership positions in academic surgery. Intersectionality may leave female members of racial/ethnic minority groups more disadvantaged than their male colleagues in achieving leadership positions. These findings highlight the urgency to diversify surgical leadership.

10.
Exp Eye Res ; 207: 108553, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33811915

RESUMO

PURPOSE: Retinal bipolar cells survive even in the later stages of inherited retinal degenerations (IRDs) and so are attractive targets for optogenetic approaches to vision restoration. However, it is not known to what extent the remodelling that these cells undergo during degeneration affects their function. Specifically, it is unclear if they are free from metabolic stress, receptive to adeno-associated viral vectors, suitable for opsin-based optogenetic tools and able to propagate signals by releasing neurotransmitter. METHODS: Fluorescence activated cell sorting (FACS) was performed to isolate labelled bipolar cells from dissociated retinae of litter-mates with or without the IRD mutation Pde6brd1/rd1 selectively expressing an enhanced yellow fluorescent protein (EYFP) as a marker in ON-bipolar cells. Subsequent mRNA extraction allowed Illumina® microarray comparison of gene expression in bipolar cells from degenerate to those of wild type retinae. Changes in four candidate genes were further investigated at the protein level using retinal immunohistochemistry over the course of degeneration. RESULTS: A total of sixty differentially expressed transcripts reached statistical significance: these did not include any genes directly associated with native primary bipolar cell signalling, nor changes consistent with metabolic stress. Four significantly altered genes (Srm2, Slf2, Anxa7 & Cntn1), implicated in synaptic remodelling, neurotransmitter release and viral vector entry had immunohistochemical staining colocalising with ON-bipolar cell markers and varying over the course of degeneration. CONCLUSION: Our findings suggest relatively few gene expression changes in the context of degeneration: that despite remodelling, bipolar cells are likely to remain viable targets for optogenetic vision restoration. In addition, several genes where changes were seen could provide a basis for investigations to enhance the efficacy of optogenetic therapies.


Assuntos
Anexina A7/genética , Contactina 1/genética , Regulação da Expressão Gênica/fisiologia , Células Bipolares da Retina/metabolismo , Degeneração Retiniana/genética , Espermidina Sintase/genética , Sulfatases/genética , Animais , Dependovirus/genética , Feminino , Citometria de Fluxo , Vetores Genéticos , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Optogenética , Reação em Cadeia da Polimerase em Tempo Real
11.
Anesth Analg ; 132(5): 1465-1474, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33591118

RESUMO

BACKGROUND: Evidence suggests that increased early postoperative pain (POP) intensities are associated with increased pain in the weeks following surgery. However, it remains unclear which temporal aspects of this early POP relate to later pain experience. In this prospective cohort study, we used wavelet analysis of clinically captured POP intensity data on postoperative days 1 and 2 to characterize slow/fast dynamics of POP intensities and predict pain outcomes on postoperative day 30. METHODS: The study used clinical POP time series from the first 48 hours following surgery from 218 patients to predict their mean POP on postoperative day 30. We first used wavelet analysis to approximate the POP series and to represent the series at different time scales to characterize the early temporal profile of acute POP in the first 2 postoperative days. We then used the wavelet coefficients alongside demographic parameters as inputs to a neural network to predict the risk of severe pain 30 days after surgery. RESULTS: Slow dynamic approximation components, but not fast dynamic detailed components, were linked to pain intensity on postoperative day 30. Despite imbalanced outcome rates, using wavelet decomposition along with a neural network for classification, the model achieved an F score of 0.79 and area under the receiver operating characteristic curve of 0.74 on test-set data for classifying pain intensities on postoperative day 30. The wavelet-based approach outperformed logistic regression (F score of 0.31) and neural network (F score of 0.22) classifiers that were restricted to sociodemographic variables and linear trajectories of pain intensities. CONCLUSIONS: These findings identify latent mechanistic information within the temporal domain of clinically documented acute POP intensity ratings, which are accessible via wavelet analysis, and demonstrate that such temporal patterns inform pain outcomes at postoperative day 30.


Assuntos
Medição da Dor , Percepção da Dor , Limiar da Dor , Dor Pós-Operatória/diagnóstico , Análise de Ondaletas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/fisiopatologia , Dor Pós-Operatória/psicologia , Valor Preditivo dos Testes , Estudos Prospectivos , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de Tempo
12.
Anesthesiology ; 134(3): 421-434, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33449996

RESUMO

BACKGROUND: The primary goal of this study was to evaluate patterns in acute postoperative pain in a mixed surgical patient cohort with the hypothesis that there would be heterogeneity in these patterns. METHODS: This study included 360 patients from a mixed surgical cohort whose pain was measured across postoperative days 1 through 7. Pain was characterized using the Brief Pain Inventory. Primary analysis used group-based trajectory modeling to estimate trajectories/patterns of postoperative pain. Secondary analysis examined associations between sociodemographic, clinical, and behavioral patient factors and pain trajectories. RESULTS: Five distinct postoperative pain trajectories were identified. Many patients (167 of 360, 46%) were in the moderate-to-high pain group, followed by the moderate-to-low (88 of 360, 24%), high (58 of 360, 17%), low (25 of 360, 7%), and decreasing (21 of 360, 6%) pain groups. Lower age (odds ratio, 0.94; 95% CI, 0.91 to 0.99), female sex (odds ratio, 6.5; 95% CI, 1.49 to 15.6), higher anxiety (odds ratio, 1.08; 95% CI, 1.01 to 1.14), and more pain behaviors (odds ratio, 1.10; 95% CI, 1.02 to 1.18) were related to increased likelihood of being in the high pain trajectory in multivariable analysis. Preoperative and intraoperative opioids were not associated with postoperative pain trajectories. Pain trajectory group was, however, associated with postoperative opioid use (P < 0.001), with the high pain group (249.5 oral morphine milligram equivalents) requiring four times more opioids than the low pain group (60.0 oral morphine milligram equivalents). CONCLUSIONS: There are multiple distinct acute postoperative pain intensity trajectories, with 63% of patients reporting stable and sustained high or moderate-to-high pain over the first 7 days after surgery. These postoperative pain trajectories were predominantly defined by patient factors and not surgical factors.


Assuntos
Analgésicos Opioides/uso terapêutico , Morfina/uso terapêutico , Dor Pós-Operatória/fisiopatologia , Fatores Etários , Estudos de Coortes , Feminino , Florida , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores Sexuais
13.
HPB (Oxford) ; 23(8): 1196-1200, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33388244

RESUMO

BACKGROUND: Neoadjuvant therapy prior to resection of adenocarcinoma of the pancreatic head increases time to surgery and thus the possibility of biliary complications. We hypothesized that biliary complications during neoadjuvant therapy negatively impact clinical outcomes. METHODS: We completed a retrospective study of a cohort of borderline resectable patients consistently treated with neoadjuvant therapy from May 2014 through March 2019. Biliary complications were defined as new-onset biliary obstruction, existing stent failure, cholecystitis, and cholangitis. RESULTS: Of 59 patients that met inclusion criteria, 34 (57.6%) went on to resection. Biliary complications affected 16 patients (27%); 8 (50%) of these patients went on to surgical resection. Of those 43 patients who did not have a biliary intervention, 26 went on to surgical resection (60.4%). There was no significant effect of a biliary complication on total number of chemotherapy cycles (p = 0.12), proceeding to surgical resection (p = 0.56) or on median survival (p = 0.23). Among patients who did proceed to surgery, there was a notable difference in median survival for patients who required a biliary intervention (17.9 vs 31.0 months) that did not reach significance (p = 0.35). CONCLUSION: The need for further biliary interventions during neoadjuvant therapy for pancreatic adenocarcinoma is common, but does not appear to have a significant effect on number of cycles of neoadjuvant therapy or proceeding to surgical resection. Larger studies are necessary to determine if these events compromise overall survival.

14.
Surgery ; 169(4): 708-720, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33386129

RESUMO

BACKGROUND: Pancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood. METHODS: The fistula risk score was applied to identify high-risk patients (fistula risk score 7-10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003-2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models. RESULTS: Eight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (-49.7%) and career length (-41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (≥400 pancreatoduodenectomies performed or ≥21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35-0.76) and was more often associated with pancreatojejunostomy reconstruction and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experience. Moreover, minimizing blood loss (≤400 mL) significantly contributed to clinically relevant pancreatic fistula prevention (odds ratio 0.40, 95% confidence interval 0.22-0.74). CONCLUSION: Surgeon experience is a key contributor to achieve better outcomes after high-risk pancreatoduodenectomy. Surgeons can improve their performance in these challenging situations by employing pancreatojejunostomy reconstruction, omitting prophylactic octreotide, and minimizing blood loss.


Assuntos
Fístula Pancreática/epidemiologia , Fístula Pancreática/etiologia , Pancreaticoduodenectomia/efeitos adversos , Melhoria de Qualidade , Qualidade da Assistência à Saúde/estatística & dados numéricos , Cirurgiões , Idoso , Competência Clínica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Fístula Pancreática/diagnóstico , Pancreaticoduodenectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Medição de Risco , Fatores de Risco
15.
Cell Mol Life Sci ; 78(4): 1597-1613, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32728765

RESUMO

Optogenetic strategies to restore vision in patients blind from end-stage retinal degenerations aim to render remaining retinal neurons light-sensitive. We present an innovative combination of multi-electrode array recordings together with a complex pattern-generating light source as a toolset to determine the extent to which neural retinal responses to complex light stimuli can be restored following viral delivery of red-shifted channelrhodopsin in the retinally degenerated mouse. Our data indicate that retinal output level spatiotemporal response characteristics achieved by optogenetic gene therapy closely parallel those observed for normal mice but equally reveal important limitations, some of which could be mitigated using bipolar-cell targeted gene-delivery approaches. As clinical trials are commencing, these data provide important new information on the capacity and limitations of channelrhodopsin-based gene therapies. The toolset we established enables comparing optogenetic constructs and stem-cell-based techniques, thereby providing an efficient and sensitive starting point to identify future approaches for vision restoration.


Assuntos
Terapia Genética , Neurônios/metabolismo , Retina/metabolismo , Degeneração Retiniana/terapia , Animais , Channelrhodopsins/genética , Channelrhodopsins/uso terapêutico , Ensaios Clínicos como Assunto , Técnicas de Transferência de Genes/tendências , Vetores Genéticos/uso terapêutico , Humanos , Luz , Camundongos , Neurônios/patologia , Optogenética , Retina/patologia , Degeneração Retiniana/genética , Degeneração Retiniana/patologia
16.
Eur J Pain ; 25(3): 624-636, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33171546

RESUMO

BACKGROUND: Increased acute postoperative pain intensity has been associated with the development of persistent postsurgical pain (PPP) in mechanistic and clinical investigations, but it remains unclear which aspects of acute pain explain this linkage. METHODS: We analysed clinical postoperative pain intensity assessments using symbolic aggregate approximations (SAX), a graphical way of representing changes between pain states from one patient evaluation to the next, to visualize and understand how pain intensity changes across sequential assessments are associated with the intensity of postoperative pain at 1 (M1) and 6 (M6) months after surgery. SAX-based acute pain transition patterns were compared using cosine similarity, which indicates the degree to which patterns mirror each other. RESULTS: This single-centre prospective cohort study included 364 subjects. Patterns of acute postoperative pain sequential transitions differed between the 'None' and 'Severe' outcomes at M1 (cosine similarity 0.44) and M6 (cosine similarity 0.49). Stratifications of M6 outcomes by preoperative pain intensity, sex, age group, surgery type and catastrophising showed significant heterogeneity of pain transition patterns within and across strata. Severe-to-severe acute pain transitions were common, but not exclusive, in patients with moderate or severe pain intensity at M6. CONCLUSIONS: Clinically, these results suggest that individual pain-state transitions, even within patient or procedural strata associated with PPP, may not alone offer good predictive information regarding PPP. Longitudinal observation in the immediate postoperative period and consideration of patient- and surgery-specific factors may help indicate which patients are at increased risk of PPP. SIGNIFICANCE: Symbolic aggregate approximations of clinically obtained, acute postoperative pain intraday time series identify different motifs in patients suffering moderate to severe pain 6 months after surgery.


Assuntos
Dor Aguda , Dor Crônica , Humanos , Dor Pós-Operatória/epidemiologia , Período Pós-Operatório , Estudos Prospectivos
17.
Phys Ther Sport ; 48: 20-25, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33341518

RESUMO

OBJECTIVES: To assess whether ankle tape applied by a Sport and Exercise Physiotherapist (SEP) or self-applied by the athlete results in a change in proprioception and whether it is maintained during a netball session. DESIGN: Randomised controlled trial. SETTING: Australian Institute of Sport. PARTICIPANTS: 53 pre-elite netball athletes. MAIN OUTCOME MEASURES: Athlete proprioception was assessed using the Active Movement Extent Discrimination Apparatus (AMEDA) on four occasions for each taping condition: 1) pre-tape, 2) post-tape, 3) post-netball & 4) post-netball no-tape. RESULTS: Mixed effect linear models were used for analysis. A significant increase in proprioception was observed when self-tape: 0.022 (95% CI: [-0.000 - 0.044], p = 0.05), and SEP tape: 0.034 (95% CI: [0.012-0.055], p < 0.01), were initially applied. These improvements were maintained during a netball session for both, self-taping: 0.01 (95% CI: [-0.01 - 0.02], p = 0.45) and SEP-taping: <0.01 (95% CI: [-0.02 - 0.01], p = 0.56). Results also indicate there was no significant difference between taping conditions (ß = -0.001, 95% CI: [-0.02 - 0.02], p = 0.90). CONCLUSIONS: Proprioception improves and is maintained during a netball session with either SEP or self-applied taping.


Assuntos
Tornozelo , Atletas , Fita Atlética , Basquetebol , Propriocepção , Adolescente , Traumatismos do Tornozelo/epidemiologia , Traumatismos do Tornozelo/prevenção & controle , Articulação do Tornozelo , Austrália , Feminino , Humanos , Modelos Lineares , Movimento , Adulto Jovem
18.
Ann Surg ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33201132

RESUMO

OBJECTIVE: To investigate the role of intraoperative EBL on development of CR-POPF after pancreatoduodenectomy (PD). BACKGROUND: Minimizing EBL has been shown to decrease transfusions and provide better perioperative outcomes in PD. EBL is also felt to be influential on CR-POPF development. METHODS: This study consists of 5534 PDs from a 17-institution collaborative (2003-2018). EBL was progressively categorized (≤150 mL; 151-400 mL; 401-1,000 mL; >1,000 mL). Impact of additive EBL was assessed using 20 3-factor fistula risk score (FRS) scenarios reflective of endogenous CR-POPF risk. RESULTS: CR-POPF developed in 13.6% of patients (N = 753) and median EBL was 400 mL (interquartile range 250-600 mL). CR-POPF and Grade C POPF were associated with elevated EBL (median 350 vs 400 mL, P = 0.002; 372 vs 500 mL, P < 0.001, respectively). Progressive EBL cohorts displayed incremental CR-POPF rates (8.5%, 13.4%, 15.2%, 16.9%; P < 0.001). EBL >400 mL was associated with increased CR-POPF occurrence in 13/20 endogenous risk scenarios. Moreover, 8 of 10 scenarios predicated on a soft gland demonstrated increased CR-POPF incidence. Hypothetical projections demonstrate significant reductions in CR-POPF can be obtained with 1-, 2-, and 3-point decreases in FRS points attributed to EBL risk (12.2%, 17.4%, and 20.0%; P < 0.001). This is especially pronounced in high-risk (FRS7-10) patients, who demonstrate up to a 31% reduction (P < 0.001). Surgeons in the lowest-quartile of median EBL demonstrated CR-POPF rates less than half those in the upper-quartile (7.9% vs 18.8%; P < 0.001). CONCLUSION: EBL independently contributes significant biological risk to CR-POPF. Substantial reductions in CR-POPF occurrence are projected and obtainable by minimizing EBL. Decreased individual surgeon EBL is associated with improvements in CR-POPF.

19.
Sci Rep ; 10(1): 15017, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929143

RESUMO

The initial processes for successful biological invasions are transport, introduction, and establishment. These can be directly influenced or completely avoided through activities that reduce the number and frequency of entering nonnative propagules. Economic and environmental benefits through preventative monitoring programs at early stages of invasion far outweigh the long-term costs associated with mitigating ecological and economic impacts once nonnative species establish and spread. In this study, we identified 30 taxa of hitchhiking plant propagules on the air-intake grilles of refrigerated shipping containers arriving into a United States seaport from a port on the Pacific coast of South America. The four monocotyledonous taxa with the highest number of seeds collected were analyzed; we estimated propagule pressure, germination, and survivorship of these taxa, and we used the estimates to determine likelihood of establishment. At the levels of propagule pressure estimated here, non-zero germination and survival rates resulted in high establishment probabilities even when escape rates from shipping containers were modelled to be exceedingly low. Our results suggest high invasion risk for nonnative taxa including Saccharum spontaneum L., a listed Federal Noxious Weed. Currently, not all shipping containers arriving at USA ports are thoroughly inspected due to limited personnel and funding for biological invasion prevention. Our results indicate that there is a significant risk from only a few propagules escaping into the environment from this source, and we propose possible solutions for reducing this risk.


Assuntos
Espécies Introduzidas , Saccharum/fisiologia , Dispersão de Sementes , Transportes , Estados Unidos
20.
Biology (Basel) ; 9(7)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708259

RESUMO

Light around twilight provides the primary entrainment signal for circadian rhythms. Here we review the mechanisms and responses of the mouse and human circadian systems to light. Both utilize a network of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4). In both species action spectra and functional expression of OPN4 in vitro show that melanopsin has a λmax close to 480 nm. Anatomical findings demonstrate that there are multiple pRGC sub-types, with some evidence in mice, but little in humans, regarding their roles in regulating physiology and behavior. Studies in mice, non-human primates and humans, show that rods and cones project to and can modulate the light responses of pRGCs. Such an integration of signals enables the rods to detect dim light, the cones to detect higher light intensities and the integration of intermittent light exposure, whilst melanopsin measures bright light over extended periods of time. Although photoreceptor mechanisms are similar, sensitivity thresholds differ markedly between mice and humans. Mice can entrain to light at approximately 1 lux for a few minutes, whilst humans require light at high irradiance (>100's lux) and of a long duration (>30 min). The basis for this difference remains unclear. As our retinal light exposure is highly dynamic, and because photoreceptor interactions are complex and difficult to model, attempts to develop evidence-based lighting to enhance human circadian entrainment are very challenging. A way forward will be to define human circadian responses to artificial and natural light in the "real world" where light intensity, duration, spectral quality, time of day, light history and age can each be assessed.

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