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This study, conducted between 4 October 2013, and 30 November 2018, tested the hypothesis that triple antimicrobial therapy, targeting Mycobacterium avium subspecies paratuberculosis (MAP), long considered a putative cause, would favorably affect Crohn's disease. A double-blind multicenter study of adults with active Crohn's disease, (i.e., Crohn's Disease Activity Index [CDAI] 220-450 plus C-reactive protein ≥ 1.0 mg/dL, fecal calprotectin (FCP) >162.9 µg/g stool, or recent endoscopic or radiographic confirmation of active disease) receiving concomitant standard-of-care Crohn's disease treatment (Clinicaltrials.gov: NCT01951326) were stratified by anti-tumor necrosis factor use and randomized (1:1) to anti-MAP RHB-104 (clarithromycin 95 mg, rifabutin 45 mg, and clofazimine 10 mg per capsule) (n = 166), resulting in clarithromycin 950 mg/day, rifabutin 450 mg/day, and clofazimine 100 mg/day, or placebo (n = 165) for up to 52 weeks. A greater proportion of RHB-104 versus placebo-treated patients met the primary endpoint-remission (i.e., CDAI < 150)-at week 26 (36.7% [61/166] vs. 22.4% [37/165], respectively; 95% CI for difference: 4.6, 24.0, p = 0.0048; chi-square test). Clinical response (reduction of CDAI by ≥100 points from baseline) at week 26 (first secondary endpoint) was also higher among the patients treated with RHB-104 (73/166 [44.0%]) compared with placebo (50/165 [30.3%]; 95% CI for difference: 3.4, 24.0, p = 0.0116), and it remained higher at week 52 among the patients treated with RHB-104 (59/166 [35.5%] vs. (35/165 [21.2%] for placebo; 95% CI for difference: 4.7, 23.9, p = 0.0042). A statistically significantly greater decline in FCP (another prospective efficacy endpoint) was also observed in RHB-104-treated patients, compared with placebo, at weeks 12, 26, and 52. The rates of serious adverse events were similar between groups (RHB-104: 18.7%; placebo: 18.8%). No patient died during the study. Antimicrobial therapy directed against MAP resulted in significantly greater improvement in clinical and laboratory (FCP) measures of active Crohn's disease.
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BACKGROUND: Chronic pain is a debilitating and common health issue. General Practitioners (GPs) often prescribe opioids to treat chronic pain, despite limited evidence of benefit and increasing evidence of harms, including prescription Opioid Use Disorder (pOUD). Australian GPs are worried about the harms of long-term opioids, but few are involved in the treatment of pOUD. There is little research on GPs' experiences diagnosing and managing pOUD in their chronic pain patients. METHODS: This qualitative research used semi-structured interviews and a case study to investigate GPs' experiences through the lens of the Theory of Planned Behaviour (TPB). TPB describes three factors, an individual's perceived beliefs/attitudes, perceived social norms and perceived behavioural controls. Participants were interviewed via an online video conferencing platform. Interviews were transcribed verbatim and thematically analysed. RESULTS: Twenty-four GPs took part. Participants were aware of the complex presentations for chronic pain patients and concerned about long-term opioid use. Their approach was holistic, but they had limited understanding of pOUD diagnosis and suggested that pOUD had only one treatment: Opioid Agonist Treatment (OAT). Participants felt uncomfortable prescribing opioids and were fearful of difficult, conflictual conversations with patients about the possibility of pOUD. This led to avoidance and negative attitudes towards diagnosing pOUD. There were few positive social norms, few colleagues diagnosed or managed pOUD. Participants reported that their colleagues only offered positive support as this would allow them to avoid managing pOUD themselves, while patients and other staff were often unsupportive. Negative behavioural controls were common with low levels of knowledge, skill, professional supports, inadequate time and remuneration described by many participants. They felt OAT was not core general practice and required specialist management. This dichotomous approach was reflected in their views that the health system only supported treatment for chronic pain or pOUD, not both conditions. CONCLUSIONS: Negative beliefs, negative social norms and negative behavioural controls decreased individual behavioural intention for this group of GPs. Diagnosing and managing pOUD in chronic pain patients prescribed opioids was perceived as difficult and unsupported. Interventions to change behaviour must address negative perceptions in order to lead to more positive intentions to engage in the management of pOUD.
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Analgésicos Opioides , Dolor Crónico , Medicina General , Trastornos Relacionados con Opioides , Investigación Cualitativa , Humanos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/psicología , Dolor Crónico/diagnóstico , Analgésicos Opioides/uso terapéutico , Analgésicos Opioides/efectos adversos , Masculino , Femenino , Australia , Trastornos Relacionados con Opioides/diagnóstico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/psicología , Persona de Mediana Edad , Médicos Generales/psicología , Adulto , Pautas de la Práctica en Medicina , Actitud del Personal de Salud , Teoría Psicológica , Entrevistas como Asunto , Teoría del Comportamiento PlanificadoRESUMEN
INTRODUCTION: Pedestrian and bicycling injuries may be less likely to be captured by traffic injury surveillance relying on police reports. Non-collision injuries, including pedestrian falls and single bicycle crashes, may be more likely than motor vehicle collisions to be missed. This study uses healthcare records to expand the ascertainment of active transportation injuries and evaluate their demographic and clinical features. METHODS: We identified pedestrian and bicyclist injuries in records of deaths, hospitalisations and emergency department visits in Ontario, Canada, between 2002 and 2017. We described the most common types of clinical injury codes among these records and assessed overall counts and proportions of injury types captured by each ascertainment definition. We also ascertained relevant fall injuries where the location was indicated as 'street or highway'. RESULTS: Pedestrian falls represented over 50% of all pedestrian injuries and affected all age groups, particularly non-fatal falls. Emergency department records indicating in-traffic bicycle injuries not involving a collision with motor vehicles increased from 14% of all bicycling injury records in 2003 to 34% in 2017. The overall number of injuries indicated by these ascertainment methods was substantially higher than official counts derived from police reports. CONCLUSION: The use of healthcare system records to ascertain bicyclist and pedestrian injuries, particularly to include non-collision falls, can more fully capture the burden of injury associated with these transportation modes.
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BACKGROUND & AIMS: This was a randomized, double-blind, placebo-controlled study to assess the effects of pemvidutide, a glucagon-like peptide-1 (GLP-1)/glucagon dual receptor agonist, on liver fat content (LFC) in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Subjects with a BMI ≥28.0 kg/m2 and LFC ≥10% by magnetic resonance imaging-proton density fat fraction were randomized 1:1:1:1 to pemvidutide at 1.2 mg, 1.8 mg, or 2.4 mg, or placebo administered subcutaneously once weekly for 12 weeks. Participants were stratified according to a diagnosis of type 2 diabetes mellitus (T2DM). The primary efficacy endpoint was relative reduction (%) from baseline in LFC after 12 weeks of treatment. RESULTS: 94 subjects were randomized and dosed. Median baseline BMI and LFC across the study population were 36.2 kg/m2 and 20.6%; 29% of subjects had T2DM. At Week 12, relative reductions in LFC from baseline were (1.2 mg) 46.6% [95% CI -63.7 to -29.6], (1.8 mg) 68.5% [95% CI -84.4 to -52.5], and (2.4 mg) 57.1% [95% CI -76.1 to -38.1] versus 4.4% [95% CI -20.2 to 11.3] in placebo subjects (p <0.001 vs. placebo, all treatment groups), with 94.4% and 72.2% of subjects achieving 30% and 50% reductions in LFC and 55.6% achieving normalization (≤5% LFC) at the 1.8 mg dose. Maximal responses for weight loss (-4.3%; p <0.001), alanine aminotransferase (-13.8 IU/L; p = 0.029), and corrected cT1 (-75.9 ms; p = 0.002) were all observed at the 1.8 mg dose. Pemvidutide was well-tolerated at all doses with no severe or serious adverse events. CONCLUSIONS: In subjects with MASLD, weekly pemvidutide treatment yielded significant reductions in LFC, markers of hepatic inflammation, and body weight compared to placebo. IMPACT AND IMPLICATIONS: MASLD, and MASH, are strongly associated with overweight and obesity and it is believed that the excess liver fat associated with obesity is an important driver of these diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite. Unlike GLP-1R agonists, glucagon receptor (GCGR) agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, potentially providing a more potent mechanism for liver fat content (LFC) reduction than weight loss alone. This study demonstrated the ability of once-weekly treatment with pemvidutide, a dual GLP-1R/GCGR agonist, to significantly reduce LFC, hepatic inflammatory activity, and body weight, suggesting that pemvidutide may be an effective treatment for both MASH and obesity. CLINICAL TRIAL NUMBER: NCT05006885.
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PURPOSE: This study leverages pre-procedural data and machine learning (ML) techniques to predict outcomes at one year following prostate artery embolization (PAE). MATERIALS AND METHODS: This retrospective analysis combines data from the UK-ROPE registry and patients that underwent PAE at our institution between 2012 and 2023. Traditional ML approaches, including linear regression, lasso regression, ridge regression, decision trees and random forests, were used with leave-one-out cross-validation to predict international prostate symptom score (IPSS) at baseline and change at 1 year. Predictors included age, prostate volume, Qmax (maximum urinary flow rate), post-void residual volume, Abrams-Griffiths number (urodynamics score) and baseline IPSS (for change at 1 year). We also independently confirmed our findings using a separate dataset. An interactive digital user interface was developed to facilitate real-time outcome prediction. RESULTS: Complete data were available in 128 patients (66.7 ± 6.9 years). All models predicting IPSS demonstrated reasonable performance, with mean absolute error ranging between 4.9-7.3 for baseline IPSS and 5.2-8.2 for change in IPSS. These numbers represent the differences between the patient-reported and model-predicted IPSS scores. Interestingly, the model error in predicting baseline IPSS (based on objective measures alone) significantly correlated with the change in IPSS at 1-year post-PAE (R2 = 0.2, p < 0.001), forming the basis for our digital user interface. CONCLUSION: This study uses ML methods to predict IPSS improvement at 1 year, integrated into a user-friendly interface for real-time prediction. This tool could be used to counsel patients prior to treatment.
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Embolización Terapéutica , Aprendizaje Automático , Próstata , Hiperplasia Prostática , Humanos , Masculino , Estudios Retrospectivos , Embolización Terapéutica/métodos , Anciano , Próstata/irrigación sanguínea , Próstata/diagnóstico por imagen , Persona de Mediana Edad , Hiperplasia Prostática/terapia , Hiperplasia Prostática/diagnóstico por imagen , Resultado del Tratamiento , Sistema de RegistrosRESUMEN
Viscosity is a fundamental physical property of lava that dictates style and rate of effusive transport. Studies of lava viscosity have predominantly focused on measuring re-melted rocks in the laboratory. While these measurements are well-constrained in temperature, shear rate, and oxygen fugacity, they cannot reproduce the complexities of the natural emplacement environment. Field viscosity measurements of active lava are the only way to fully capture lava's properties, but such measurements are scarce, largely due to a lack of easy-to-use, portable, and accurate measurement devices. Thus, there is a need for developing suitable field instruments to help bolster the understanding of lava. Here, we present a new penetrometer capable of measuring a material's viscosity under the harsh conditions of natural lava emplacement. This device uses a stainless-steel tube with a semi-spherical tip fixed to a load cell that records axial force when pushed into a material, while simultaneously measuring the penetration depth via a free-moving tube that is pushed backward along the penetration tube. The device is portable (1.5 m long, 5.5 kg in weight) and uses a single-board computer for data acquisition. The penetrometer has an operational range from 2.5 × 102 to 2.1 × 105 Pa s and was calibrated for viscosities ranging from 5.0 × 102 to 1.6 × 105 Pa s. It was deployed to the 2023 Litli-Hrútur eruption in Iceland. These field measurements successfully recorded the in situ viscosities of the lava in the range of 1.2 × 104-3.4 × 104 Pa s, showcasing it as an efficient method of measuring natural lava viscosity.
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BACKGROUND: The COVID-19 pandemic policy response dramatically changed local transportation patterns. This project investigated the impact of COVID-19 policies on motor vehicle collision (MVC)-related emergency department (ED) visits and hospitalisations in Ontario. METHODS: Data were collected on MVC-related ED visits and hospitalisations in Ontario between March 2016 and December 2022. Using an interrupted time series design, negative binomial regression models were fitted to the pre-pandemic data, including monthly indicator variables for seasonality and accounting for autocorrelation. Extrapolations simulated expected outcome trajectories during the pandemic, which were compared with actual observed outcome counts using the overall per cent change and mean monthly difference. Data were modelled separately for vehicle occupants, pedestrians and cyclists (MVC and non-MVC injuries). RESULTS: There was a 31.5% decrease in observed ED visits (95% CI -35.4 to -27.3) and a 6.0% decrease in hospitalisations (95% CI -13.2 to 1.6) among vehicle occupants, relative to expected counts during the pandemic. Results were similar for pedestrians. Among cyclist MVCs, there was an increase in ED visits (12.8%, 95% CI -8.2 to 39.4) and hospitalisations (46.0%, 95% CI 11.6 to 93.6). Among non-MVC cyclists, there was also an increase in ED visits (47.0%, 95% CI 12.5 to 86.8) and hospitalisations (50.1%, 95% CI 8.2 to 101.2). CONCLUSIONS: We observed fewer vehicle occupant and pedestrian collision injuries than expected during the pandemic. By contrast, we observed more cycling injuries than expected, especially in cycling injuries not involving motor vehicles. These observations may be attributable to changes in transportation patterns during the pandemic and increased uptake of recreational cycling.
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BACKGROUND: The COVID-19 pandemic altered traffic patterns worldwide, potentially impacting pedestrian and bicyclists safety in urban areas. In Toronto, Canada, work from home policies, bicycle network expansion, and quiet streets were implemented to support walking and cycling. We examined pedestrian and bicyclist injury trends from 2012 to 2022, utilizing police-reported killed or severely injured (KSI), emergency department (ED) visits and hospitalization data. METHODS: We used an interrupted time series design, with injury counts aggregated quarterly. We fit a negative binomial regression using a Bayesian modeling approach to data prior to the pandemic that included a secular time trend, quarterly seasonal indicator variables, and autoregressive terms. The differences between observed and expected injury counts based on pre-pandemic trends with 95% credible intervals (CIs) were computed. RESULTS: There were 38% fewer pedestrian KSI (95%CI: 19%, 52%), 35% fewer ED visits (95%CI: 28%, 42%), and 19% fewer hospitalizations (95%CI: 2%, 32%) since the beginning of the COVID-19 pandemic. A reduction of 35% (95%CI: 7%, 54%) in KSI bicyclist injuries was observed, but However, ED visits and hospitalizations from bicycle-motor vehicle collisions were compatible with pre-pandemic trends. In contrast, for bicycle injuries not involving motor vehicles, large increases were observed for both ED visits, 73% (95% CI: 49%, 103%) and for hospitalization 108% (95% CI: 38%, 208%). CONCLUSION: New road safety interventions during the pandemic may have improved road safety for vulnerable road users with respect to collisions with motor vehicles; however, further investigation into the risk factors for bicycle injuries not involving motor vehicles is required.
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Accidentes de Tránsito , Ciclismo , COVID-19 , Servicio de Urgencia en Hospital , Análisis de Series de Tiempo Interrumpido , Heridas y Lesiones , Humanos , COVID-19/epidemiología , Accidentes de Tránsito/estadística & datos numéricos , Ciclismo/lesiones , Ciclismo/estadística & datos numéricos , Heridas y Lesiones/epidemiología , Adulto , Masculino , Femenino , Ontario/epidemiología , Persona de Mediana Edad , Servicio de Urgencia en Hospital/estadística & datos numéricos , SARS-CoV-2 , Peatones/estadística & datos numéricos , Adolescente , Anciano , Pandemias , Adulto Joven , Niño , Caminata/lesiones , Caminata/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Preescolar , Teorema de Bayes , LactanteRESUMEN
The burden of cancer exerts a disproportionate impact across different regions and population subsets. Disease-specific attributes, coupled with genetic and socioeconomic factors, significantly influence cancer treatment outcomes. Precision oncology promises the development of safe and effective options for specific ethnic phenotypes and clinicodemographic profiles. Currently, clinical trials are concentrated in resource-rich geographies with younger, healthier, white, educated, and empowered populations. Vulnerable and marginalized people are often deprived of opportunities to participate in clinical trials. Despite consistent endeavors by regulators, industry, and other stakeholders, factors including diversity in trial regulations and patient and provider-related cultural, logistic, and operational barriers limit the inclusiveness of clinical trials. Understanding and addressing these constraints by collaborative actions involving regulatory initiatives, industry, patient advocacy groups, community engagement in a culturally sensitive manner, and designing and promoting decentralized clinical trials are vital to establishing a clinical research ecosystem that promotes equity in the representation of population subgroups.
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Ensayos Clínicos como Asunto , Oncología Médica , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/etnología , Selección de Paciente/éticaRESUMEN
INTRODUCTION: Improving sustainable transportation options will help cities tackle growing challenges related to population health, congestion, climate change and inequity. Interventions supporting active transportation face many practical and political hurdles. Implementation science aims to understand how interventions or policies arise, how they can be translated to new contexts or scales and who benefits. Sustainable transportation interventions are complex, and existing implementation science frameworks may not be suitable. To apply and adapt implementation science for healthy cities, we have launched our mixed-methods research programme, CapaCITY/É. We aim to understand how, why and for whom sustainable transportation interventions are successful and when they are not. METHODS AND ANALYSIS: Across nine Canadian municipalities and the State of Victoria (Australia), our research will focus on two types of sustainable transportation interventions: all ages and abilities bicycle networks and motor vehicle speed management interventions. We will (1) document the implementation process and outcomes of both types of sustainable transportation interventions; (2) examine equity, health and mobility impacts of these interventions; (3) advance implementation science by developing a novel sustainable transportation implementation science framework and (4) develop tools for scaling up and scaling out sustainable transportation interventions. Training activities will develop interdisciplinary scholars and practitioners able to work at the nexus of academia and sustainable cities. ETHICS AND DISSEMINATION: This study received approval from the Simon Fraser University Office of Ethics Research (H22-03469). A Knowledge Mobilization Hub will coordinate dissemination of findings via a website; presentations to academic, community organisations and practitioner audiences; and through peer-reviewed articles.
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Creación de Capacidad , Ciencia de la Implementación , Humanos , Ciudades , Canadá , VictoriaRESUMEN
The metabolic engineering of microbes has broad applications, including biomanufacturing, bioprocessing, and environmental remediation. The introduction of a complex, multistep pathway often imposes a substantial metabolic burden on the host cell, restraining the accumulation of productive biomass and limiting pathway efficiency. One strategy to alleviate metabolic burden is the division of labor (DOL) in which different subpopulations carry out different parts of the pathway and work together to convert a substrate into a final product. However, the maintenance of different engineered subpopulations is challenging due to competition and convoluted interstrain population dynamics. Through modeling, we show that dynamic division of labor (DDOL), which we define as the DOL between indiscrete populations capable of dynamic and reversible interchange, can overcome these limitations and enable the robust maintenance of burdensome, multistep pathways. We propose that DDOL can be mediated by horizontal gene transfer (HGT) and use plasmid genomics to uncover evidence that DDOL is a strategy utilized by natural microbial communities. Our work suggests that bioengineers can harness HGT to stabilize synthetic metabolic pathways in microbial communities, enabling the development of robust engineered systems for deployment in a variety of contexts.
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Consorcios Microbianos , Microbiota , Transferencia de Gen Horizontal , Ingeniería Metabólica , GenómicaRESUMEN
INTRODUCTION: Isolated splenic vein thrombosis (iSVT) is a common complication of pancreatic disease. Whilst patients remain asymptomatic, there is a risk of sinistral portal hypertension and subsequent bleeding from gastric varices if recanalisation does not occur. There is wide variation of iSVT treatment, even within single centres. We report outcomes of iSVT from tertiary referral hepatobiliary and pancreatic (HPB) units including the impact of anticoagulation on recanalisation rates and subsequent variceal bleeding risk. METHODS: A retrospective cohort study including all patients diagnosed with iSVT on contrast-enhanced CT scan abdomen and pelvis between 2011 and 2019 from two institutions. Patients with both SVT and portal vein thrombosis at diagnosis and isolated splenic vein thrombosis secondary to malignancy were excluded. The outcomes of anticoagulation, recanalisation rates, risk of bleeding and progression to portal vein thrombosis were examined using CT scan abdomen and pelvis with contrast. RESULTS: Ninety-eight patients with iSVT were included, of which 39 patients received anticoagulation (40%). The most common cause of iSVT was acute pancreatitis n = 88 (90%). The recanalisation rate in the anticoagulation group was 46% vs 15% in patients receiving no anticoagulation (p = 0.0008, OR = 4.7, 95% CI 1.775 to 11.72). Upper abdominal vascular collaterals (demonstrated on CT scan angiography) were significantly less amongst patients who received anticoagulation treatment (p = 0.03, OR = 0.4, 95% CI 0.1736 to 0.9288). The overall rate of upper GI variceal-related bleeding was 3% (n = 3/98) and it was independent of anticoagulation treatment. Two of the patients received therapeutic anticoagulation. CONCLUSION: The current data supports that therapeutic anticoagulation is associated with a statistically significant increase in recanalisation rates of the splenic vein, with a subsequent reduction in radiological left-sided portal hypertension. However, all patients had a very low risk of variceal bleeding regardless of anticoagulation. The findings from this retrospective study should merit further investigation in large-scale randomised clinical trials.
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Várices Esofágicas y Gástricas , Pancreatitis , Trombosis , Humanos , Enfermedad Aguda , Anticoagulantes/efectos adversos , Várices Esofágicas y Gástricas/terapia , Hemorragia Gastrointestinal , Estudios Retrospectivos , Medición de Riesgo , Vena Esplénica/diagnóstico por imagenRESUMEN
INTRODUCTION: Anterior lumbar interbody fusion (ALIF) can treat spondylolisthesis, degenerative disc disease and pseudoarthrosis. This approach facilitates complete discectomy, disc space distraction, indirect decompression of neural foramina and placement of large interbody devices. Several intra- and postoperative complications can be attributed to the anterior approach: vascular/visceral injury, hypogastric plexus injury and urogenital consequences. Spine-specific complications include implant migration, graft failure, pseudoarthrosis and persistent symptomology. METHODS: This retrospective study reviewed patient demographics, medium-term outcomes and complication rates following ALIF surgery performed over a 5-year period. A total of 110 consecutive patients had undergone ALIF surgery at a single tertiary spinal centre. The database was reviewed with a primary outcome of identifying postoperative 90-day complications and whether a revision anterior operation was required after primary ALIF. RESULTS: No patients required revision anterior operation after their primary ALIF surgery by final follow-up. Out of 110 patients, 11 (10%) recorded a complication attributed to the anterior stage of their operation within 90 days. CONCLUSIONS: Our 90-day complication rate of 10% lies within the 2.6% acute complication and 40% overall complications rates described in previous literature. The risk of vascular/visceral injury is significant (3%) and we recommend that ALIF be performed as a dual surgeon procedure with a vascular-trained access surgeon accompanying the spinal surgeon. ALIF is a valid revision surgical option for failed posterior approaches leading to complications such as pseudoarthrosis. In our sample, 89% of patients were managed with posterior fixation to augment the anterior fusion as, biomechanically, this is a proven construct.
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Vértebras Lumbares , Complicaciones Posoperatorias , Fusión Vertebral , Humanos , Fusión Vertebral/métodos , Fusión Vertebral/efectos adversos , Estudios Retrospectivos , Vértebras Lumbares/cirugía , Masculino , Femenino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Anciano , Adulto , Resultado del Tratamiento , Reoperación/estadística & datos numéricos , Centros de Atención Terciaria/estadística & datos numéricos , Anciano de 80 o más Años , Espondilolistesis/cirugía , Degeneración del Disco Intervertebral/cirugíaRESUMEN
The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor-positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib-a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle "paths" that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.
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Neoplasias de la Mama , Piperazinas , Piridinas , Humanos , Femenino , Ciclo Celular , División Celular , Piperazinas/farmacología , Piperazinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Invasive primary Candida surgical site infections (IP-SSIs) are a common complication of liver transplantation, and targeted antifungal prophylaxis is an efficient strategy to limit their occurrence. We performed a retrospective single-center cohort study among adult single liver transplant recipients at Duke University Hospital in the period between 1 January 2015 and 31 December 2020. The study aimed to determine the rate of Candida IP-SSI according to the peri-transplant antifungal prophylaxis received. Of 470 adult single liver transplant recipients, 53 (11.3%) received micafungin prophylaxis, 100 (21.3%) received fluconazole prophylaxis, and 317 (67.4%) did not receive systemic antifungal prophylaxis in the peri-transplant period. Ten Candida IP-SSIs occurred among 5 of 53 (9.4%) micafungin recipients, 1 of 100 (1.0%) fluconazole recipients, and 4 of 317 (1.3%) recipients who did not receive antifungal prophylaxis. Our study highlights the limitations of antifungal prophylaxis in preventing invasive Candida IP-SSI after liver transplant surgery. We hypothesize that pathogen, host, and pharmacokinetic-related factors contributed to the occurrence of Candida IP-SSI despite antifungal prophylaxis. Our study reinforces the need for a risk-based, multi-pronged approach to fungal prevention, including targeted antifungal administration in patients with risks for invasive candidiasis and close monitoring, especially among patients with surgically complex procedures, with timely control of surgical leaks.
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Candidiasis Invasiva , Candidiasis , Trasplante de Hígado , Adulto , Humanos , Antifúngicos/uso terapéutico , Fluconazol/uso terapéutico , Trasplante de Hígado/efectos adversos , Micafungina/uso terapéutico , Estudios Retrospectivos , Estudios de Cohortes , Infección de la Herida Quirúrgica/prevención & control , Infección de la Herida Quirúrgica/tratamiento farmacológico , Candidiasis Invasiva/tratamiento farmacológico , Candidiasis Invasiva/prevención & control , CandidaRESUMEN
OBJECTIVES: Eating disorders (EDs) have a worldwide prevalence of 7.8%, with towering mortality rates and high healthcare costs. The current recommended treatment for EDs principally works by directly targeting ED thoughts and behaviours, but recovery rates are low. A multifaceted link between difficulties with emotions and EDs is now widely established, and newer third-wave therapies that aim to address these underlying emotion difficulties are promising. The current study piloted an online emotion self-help intervention which was co-developed with clinicians and people with lived experienced of EDs. The intervention aimed to specifically address difficulties with emotion identification and regulation, as well as unhelpful beliefs about emotions, which are believed to give rise to and maintain ED thoughts and behaviours. METHOD: We recruited 39 people with self-reported EDs to test this intervention over a one-week period. Our participants were asked to complete a series of questionnaires measuring emotion processes and psychopathology on Day 1 (T1) before being given access to the intervention. Participants were then asked to practice the newly acquired skills for seven days, before taking the same questionnaires on Day 9 (T2). We also asked participants to qualitatively report on their experience of the intervention. RESULTS: We found significant improvements in ED psychopathology (ED-15), depression (PHQ-9), and anxiety (GAD-7) pre- to post-intervention, with medium to large effect sizes. All our emotion variables namely alexithymia (TAS-20), difficulties regulating emotions (DERS-SF), and unhelpful beliefs about emotions (EBQ) also showed significant changes post-intervention with medium to large effect sizes. Most importantly, changes in emotion regulation processes were linked to improved eating psychopathology. The qualitative analysis corroborated this finding, highlighting how the intervention helped them form new beliefs about emotions, which helped them reduce ED behaviours. DISCUSSION: Significant improvements in emotion processing and regulations, as well as psychopathology, along with positive qualitative feedback, suggest that the intervention effectively met its aims of increasing awareness of the link between emotions and eating psychopathology, providing help to identify and regulate emotions, and normalising emotional experiences. While our results are promising, further research is required to assess its effectiveness longer term and in clinical settings.
About one person dies every hour as a direct result of an eating disorder (ED), in part because of poor treatment outcomes. Current recommended treatments have a limited focus around emotion difficulties, such as the ability to identify emotions and regulate them, which are linked to ED thoughts and behaviours. With the help of clinicians and people with lived experience of EDs, we developed an online intervention that works on these emotion difficulties. We recruited 39 people with EDs to test this intervention over a one-week period and evaluated our results using quantitative and qualitative analyses. Comparing scores before and after the intervention, we found that ED psychopathology, depression and anxiety were significantly lower post-intervention. Beliefs about emotions as well as the ability to identify, describe and regulate emotions were also significantly improved post-intervention. Qualitative analysis showed that our intervention helped people feel better equipped to deal with their feelings in a healthier way, which helped reduce ED behaviours. One person even described the intervention as "life-changing". While our results are promising, further research is required to assess our intervention in a clinical setting.
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BACKGROUND: Road traffic injury contributes substantially to morbidity and mortality. Canada stands out among developed countries in not conducting a national household travel survey, leading to a dearth of national transportation mode data and risk calculations that have appropriate denominators. Since traffic injuries are specific to the mode of travel used, these risk calculations should consider travel mode. METHODS: Census data on mode of commute is one of the few sources of these data for persons aged 15 and over. This study leveraged a national data linkage cohort, the Canadian Census Health and Environment Cohorts, that connects census sociodemographic and commute mode data with records of deaths and hospitalizations, enabling assessment of road traffic injury associations by indicators of mode of travel (commuter mode). We examined longitudinal (1996-2019) bicyclist, pedestrian, and motor vehicle occupant injury and fatality risk in the Canadian Census Health and Environment Cohorts by commuter mode and sociodemographic characteristics using Cox proportional hazards models within the working adult population. RESULTS: We estimated positive associations between commute mode and same mode injury and fatality, particularly for bicycle commuters (hazard ratios for bicycling injury was 9.1 and for bicycling fatality was 11). Low-income populations and Indigenous people had increased injury risk across all modes. CONCLUSIONS: This study shows inequities in transportation injury risk in Canada and underscores the importance of adjusting for mode of travel when examining differences between population groups.
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Censos , Caminata , Adulto , Humanos , Canadá/epidemiología , Caminata/lesiones , Transportes , Factores de Riesgo , Ciclismo/lesiones , Accidentes de TránsitoRESUMEN
INTRODUCTION: Pedestrian and cyclist injuries represent a preventable burden to Canadians. Police-reported collision data include information on where such collisions occur but under-report the number of collisions. The primary objective of this study was to compare the number of police-reported collisions with emergency department (ED) visits and hospitalisations in Toronto, Canada. METHODS: Police-reported collisions were provided by Toronto Police Services (TPS). Data included the location of the collision, approximate victim age and whether the pedestrian or cyclist was killed or seriously injured. Health services data included ED visits in the National Ambulatory Care Reporting System and hospitalisations from the Discharge Abstract Database using ICD-10 codes for pedestrian and cycling injuries. Data were compared from 2016 to 2021. RESULTS: Injuries reported in the health service data were higher than those reported in the TPS for cyclists and pedestrians. The discrepancy was the largest for cyclists treated in the ED, with TPS capturing 7.9% of all cycling injuries. Cyclist injuries not involving a motor vehicle have increased since the start of the pandemic (from 3629 in 2019 to 5459 in 2020 for ED visits and from 251 in 2019 to 430 for hospital admissions). IMPLICATIONS: While police-reported data are important, it under-reports the burden. There have been increases in cyclist collisions not involving motor vehicles and decreases in pedestrian injuries since the start of the pandemic. The results suggest that using police data alone when planning for road safety is inadequate, and that linkage with other health service data is essential.
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Pueblos de América del Norte , Peatones , Heridas y Lesiones , Humanos , Accidentes de Tránsito/prevención & control , Canadá/epidemiología , Policia , Ciclismo/lesiones , Heridas y Lesiones/epidemiologíaRESUMEN
The metabolic engineering of microbes has broad applications, including in biomanufacturing, bioprocessing, and environmental remediation. The introduction of a complex, multi-step pathway often imposes a substantial metabolic burden on the host cell, restraining the accumulation of productive biomass and limiting pathway efficiency. One strategy to alleviate metabolic burden is division of labor (DOL), in which different subpopulations carry out different parts of the pathway and work together to convert a substrate into a final product. However, the maintenance of different engineered subpopulations is challenging due to competition and convoluted inter-strain population dynamics. Through modeling, we show that dynamic division of labor (DDOL) mediated by horizontal gene transfer (HGT) can overcome these limitations and enable the robust maintenance of burdensome, multi-step pathways. We also use plasmid genomics to uncover evidence that DDOL is a strategy utilized by natural microbial communities. Our work suggests that bioengineers can harness HGT to stabilize synthetic metabolic pathways in microbial communities, enabling the development of robust engineered systems for deployment in a variety of contexts.
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Mounted on top of furnaces, laboratory viscometers can be used for the rheological characterization of high temperature melts, such as molten rocks (lava). However, there are no instruments capable of measuring the viscosity of large volumes of high temperature melts outside the laboratory at, for example, active lava flows on volcanoes or at industrial sites. In this article, we describe a new instrument designed to be easy to operate, highly mobile, and capable of measuring the viscosity of high temperature liquids and suspensions (<1350 °C). The device consists of a torque sensor mounted in line with a stainless-steel shear vane that is immersed in the melt and driven by a motor that rotates the shear vane. In addition, a thermocouple placed between the blades of the shear vane measures the temperature of the melt at the measurement location. An onboard microcomputer records torque, rotation rate, and temperature simultaneously and in real time, thus enabling the characterization of the rheological flow curve of the material as a function of temperature and strain rate. The instrument is calibrated using viscosity standards at low temperatures (20-60 °C) and over a wide range of stress (30-3870 Pa), strain rate (0.1-27.9 s-1), and viscosity (10-650 Pa s). High temperature tests were performed in large scale experiments within â¼25 l of lava at temperatures between 1000 and 1350 °C to validate the system's performance for future use in natural lava flows. This portable field viscometer was primarily designed to measure the viscosity of geological melts at their relevant temperatures and in their natural state on the flanks of volcanoes, but it could also be used for industrial purposes and beyond.