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It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVß3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVß3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVß3 shows downregulation of typical effectors involved in apoptosis and necrosis and an upregulation of tumour cell survival factors compared to control sEVs. We also show that the expression of αVß3 in sEVs causes a distinct reposition of EV markers (Alix, CD81, CD9) to a low-density sEV subpopulation. This low-density reposition is independent of extracellular matrix (ECM) protein interactions with sEVs. This sEV subset contains αVß3 and an αVß3 downstream effector, NgR2, a novel marker for NEPrCa. We show that sEVs containing αVß3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVß3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but when injected in vivo intratumorally, they promote tumour growth and induce NED. We show that sEVs expressing NgR2 increase the activation of focal adhesion kinase (FAK), a known promoter of cancer cell proliferation, in recipient cells. We also show that NgR2 mimics the effect of sEVs containing αVß3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe the changes that occur in cargo, density and functions of cancer cell-derived sEVs containing the αVß3 integrin and its effector, NgR2, without affecting the sEV tetraspanin profiles.
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Vesículas Extracelulares , Integrina alfaVbeta3 , Neoplasias de la Próstata , Masculino , Integrina alfaVbeta3/metabolismo , Humanos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Vesículas Extracelulares/metabolismo , Animales , Línea Celular Tumoral , Ratones , Carcinogénesis/metabolismoRESUMEN
ABSTRACT: Cytotoxic T lymphocytes (CTLs) destroy virally infected cells and are critical for the elimination of viral infections such as those caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Delayed and dysfunctional adaptive immune responses to SARS-CoV-2 are associated with poor outcomes. Treatment with allogeneic SARS-CoV-2-specific CTLs may enhance cellular immunity in high-risk patients providing a safe, direct mechanism of treatment. Thirty high-risk ambulatory patients with COVID-19 were enrolled in a phase 1 trial assessing the safety of third party, SARS-CoV-2-specific CTLs. Twelve interventional patients, 6 of whom were immunocompromised, matched the HLA-A∗02:01 restriction of the CTLs and received a single infusion of 1 of 4 escalating doses of a product containing 68.5% SARS-CoV-2-specific CD8+ CTLs/total cells. Symptom improvement and resolution in these patients was compared with an observational group of 18 patients lacking HLA-A∗02:01 who could receive standard of care. No dose-limiting toxicities were observed at any dosing level. Nasal swab polymerase chain reaction testing showed ≥88% and >99% viral elimination from baseline in all patients at 4 and 14 days after infusion, respectively. The CTLs did not interfere with the development of endogenous anti-SARS-CoV-2 humoral or cellular responses. T-cell receptor ß analysis showed persistence of donor-derived SARS-CoV-2-specific CTLs through the end of the 6-month follow-up period. Interventional patients consistently reported symptomatic improvement 2 to 3 days after infusion, whereas improvement was more variable in observational patients. SARS-CoV-2-specific CTLs are a potentially feasible cellular therapy for COVID-19 illness. This trial was registered at www.clinicaltrials.gov as #NCT04765449.
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COVID-19 , SARS-CoV-2 , Linfocitos T Citotóxicos , Humanos , COVID-19/inmunología , COVID-19/terapia , Linfocitos T Citotóxicos/inmunología , Persona de Mediana Edad , Masculino , SARS-CoV-2/inmunología , Femenino , Anciano , Adulto , Estudios de Factibilidad , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Resultado del Tratamiento , Antígeno HLA-A2/inmunologíaRESUMEN
Posttransplant cyclophosphamide (PtCy) has been shown to decrease post-hematopoietic stem cell transplant acute and chronic graft-versus-host disease (GVHD). In this study, PtCy was used in 44 patients along with mycophenolate and tacrolimus with HLA matched (29) and mismatched (15) unrelated donors to determine the impact of graft content on outcome; thus, all patients had flow cytometric analysis of their graft content including the number of B cells, NK cells, and various T cell subsets. Higher γδ T cell dose was associated with the development of acute GVHD (p = .0038). For PtCy, further studies of the cell product along with further graft manipulation, such as selective γδ T cell depletion, could potentially improve outcomes.
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Ciclofosfamida , Enfermedad Injerto contra Huésped , Trasplante de Células Madre de Sangre Periférica , Donante no Emparentado , Humanos , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Masculino , Femenino , Persona de Mediana Edad , Adulto , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Trasplante de Células Madre de Sangre Periférica/métodos , Estudios Prospectivos , Inmunosupresores/uso terapéutico , Linfocitos T/inmunología , Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Anciano , Adulto Joven , Resultado del Tratamiento , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Adolescente , Acondicionamiento Pretrasplante/métodosRESUMEN
OBJECTIVE: The impact of pancreaticoduodenectomy on absorption of drugs in the duodenum remains largely unknown. We aim to characterize the pharmacokinetics of apixaban in patients who had previously undergone pancreaticoduodenectomy. MATERIALS AND METHODS: A single 10-mg dose of apixaban was administered to 4 volunteers who underwent pancreaticoduodenectomy at least 6 months prior. The maximum plasma apixaban concentration (Cmax) and area under the plasma concentration time-curve (AUC0-24, AUC0-inf) were compared against healthy historical control subjects (N = 12). Geometric mean ratios (GMR) with 90% confidence interval (CI) were calculated for determination of comparative bioequivalence. RESULTS: In pancreaticoduodenectomy patients, AUC0-24 and AUC0-inf were 1,861 and 2,080 ng×h/mL, respectively. The GMRs of AUC0-24 and AUC0-inf between study subjects and healthy controls were 1.27 (90% CI 0.88 - 1.83) and 1.18 (90% CI 0.82 - 1.72). The mean Cmax of apixaban was 201 ng/mL (SD 15.6) occurring at a median tmax of 3.25 hours (range 2.5 - 4 hours). The GMR of Cmax between study subjects and healthy controls was 1.12 (90% CI 0.77 - 1.63). CONCLUSION: The pharmacokinetic characteristics of apixaban in subjects who had undergone pancreaticoduodenectomy are not significantly different from those of healthy controls. Though the sample size of this study is small, results suggest that no change to apixaban dose regimen is needed in patients who have had a pancreaticoduodenectomy.
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Área Bajo la Curva , Inhibidores del Factor Xa , Pancreaticoduodenectomía , Pirazoles , Piridonas , Humanos , Piridonas/farmacocinética , Piridonas/administración & dosificación , Pancreaticoduodenectomía/efectos adversos , Pirazoles/farmacocinética , Pirazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Inhibidores del Factor Xa/farmacocinética , Inhibidores del Factor Xa/administración & dosificación , Anciano , Adulto , Equivalencia TerapéuticaRESUMEN
PURPOSE: A novel form of lung function imaging has been developed that uses 4-dimensional computed tomography (4DCT) data to generate lung ventilation images (4DCT-ventilation). Functional avoidance uses 4DCT-ventilation to reduce doses to functional lung with the aim of reducing pulmonary side effects. A phase 2, multicenter 4DCT-ventilation functional avoidance clinical trial was completed. The purpose of this work was to quantify changes in patient-reported outcomes (PROs) for patients treated with functional avoidance and determine which metrics are predictive of PRO changes. MATERIALS AND METHODS: Patients with locally advanced lung cancer receiving curative-intent radiation therapy were accrued. Each patient had a 4DCT-ventilation image generated using 4DCT data and image processing. PRO instruments included the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire administered pretreatment; at the end of treatment; and at 3, 6, and 12 months posttreatment. Using the FACT-Trial Outcome Index and the FACT-Lung Cancer Subscale results, the percentage of clinically meaningful declines (CMDs) were determined. A linear mixed-effects model was used to determine which patient, clinical, dose, and dose-function metrics were predictive of PRO decline. RESULTS: Of the 59 patients who completed baseline PRO surveys. 83% had non-small cell lung cancer, with 75% having stage 3 disease. The median dose was 60 Gy in 30 fractions. CMD FACT-Trial Outcome Index decline was 46.3%, 38.5%, and 26.8%, at 3, 6, and 12 months, respectively. CMD FACT-Lung Cancer Subscale decline was 33.3%, 33.3%, and 29.3%, at 3, 6, and 12 months, respectively. Although an increase in most dose and dose-function parameters was associated with a modest decline in PROs, none of the results were significant (all P > .053). CONCLUSIONS: The current work presents an innovative combination of use of functional avoidance and PRO assessment and is the first report of PROs for patients treated with prospective 4DCT-ventilation functional avoidance. Approximately 30% of patients had clinically significant decline in PROs at 12 months posttreatment. The study provides additional data on outcomes with 4DCT-ventilation functional avoidance.
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OBJECTIVES: Recovery from traumatic brain injury (TBI) is extremely difficult to predict, with TBI severity usually demonstrating weak predictive validity for functional or other outcomes. A possible explanation may lie in the statistical phenomenon called suppression, according to which a third variable masks the true association between predictor and outcome, making it appear weaker than it actually is. Age at injury is a strong candidate as a suppressor because of its well-established main and moderating effects on TBI outcomes. We tested age at injury as a possible suppressor in the predictive chain of effects between TBI severity and functional disability, up to 10 years post-TBI. SETTING: Follow-up interviews were conducted during telephone interviews. PARTICIPANTS: We used data from the 2020 NDILRR Model Systems National Dataset for 4 successive follow-up interviews: year 1 (n = 10,734), year 2 (n = 9174), year 5 (n = 6,201), and year 10 (n = 3027). DESIGN: Successive cross-sectional multiple regression analyses. MAIN MEASURES: Injury severity was operationalized using a categorical variable representing duration of posttrauma amnesia. The Glasgow Outcomes Scale-Extended (GOS-E) operationally defined functioning. Sociodemographic characteristics having significant bivariate correlations with GOS-E were included. RESULTS: Entry of age at injury into the regression models significantly increases the association between TBI severity and functioning up to 10 years post-TBI. CONCLUSIONS: Age at injury is a suppressor variable, masking the true effect of injury severity on functional outcomes. Identifying the mediators of this suppression effect is an important direction for TBI rehabilitation research.
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Background and objective: Radiation therapy has increasingly been used in the management of pelvic malignancies. However, the use of radiation continues to pose a risk of a secondary malignancy to its recipients. This study investigates the risk of secondary malignancy development following radiation for primary pelvic malignancies. Methods: A retrospective cohort review of the Surveillance, Epidemiology, and End Results database from 1975 to 2016 was performed. Primary pelvic malignancies were subdivided based on the receipt of radiation, and secondary malignancies were stratified as pelvic or nonpelvic to investigate the local effect of radiation. Key findings and limitations: A total of 2 102 192 patients were analyzed (1 189 108 with prostate, 315 026 with bladder, 88 809 with cervical, 249 535 with uterine, and 259 714 with rectal/anal cancer). The incidence rate (defined as cases per 1000 person years) of any secondary malignancies (including but not limited to secondary pelvic malignancies) was higher in radiation patients than in nonradiation patients (incidence rate ratio [IRR] 1.04, confidence interval [CI] 1.03-1.05), with significantly greater rates noted in radiation patients with prostate (IRR 1.22, CI 1.21-1.24), uterine (IRR 1.34), and cervical (IRR 1.80, CI 1.72-1.88) cancer. While the overall incidence rate of any secondary pelvic malignancy was lower in radiation patients (IRR 0.79, CI 0.78-0.81), a greater incidence was still noted in the same cohorts including radiation patients with prostate (IRR 1.42, CI 1.39-1.45), uterine (IRR 1.15, CI 1.08-1.21), and cervical (IRR 1.72, CI 1.59-1.86) cancer. Conclusions and clinical implications: Except for localized cervical cancer, when put in the context of median overall survival, the impact of radiation likely does not carry enough weight to change practice patterns. Radiation for pelvic malignancies increases the risk for several secondary malignancies, and more specifically, secondary pelvic malignancies, but with a relatively low absolute risk of secondary malignancies, the benefits of radiation warrant continued use for most pelvic malignancies. Practice changes should be considered for radiation utilization in malignancies with excellent cancer-specific survival such as cervical cancer. Patient summary: The use of radiation for the management of pelvic malignancies induces a risk of secondary malignancies to its recipients. However, the absolute risk being low, the benefits of radiation warrant its continued use, and a change in practice patterns is unlikely.
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Background: Focal chondral defects are often treated with cartilage restoration procedures. Malalignment often accompanies chondral defects. High tibial osteotomy (HTO), classically utilized to treat uni-compartmental knee osteoarthritis, corrects malalignment. HTO combined with cartilage restoration procedures can treat uni-compartmental osteoarthritis and focal chondral defects. Purpose: To assess outcomes of combined HTO and cartilage restoration procedures and review prognostic factors that may assist in preoperative planning and patient counseling. Study design: Systematic Review of published literature. Methods: A systematic review of PubMed and Scopus was performed following PRISMA guidelines. Thirty-four papers were included in qualitative considerations. Results: Thirty-four papers that reported the combined outcome of HTO and cartilage repair were included. Twenty of the 34 included papers reported prognostic factors that affected the success or failure of combined HTO and cartilage repair surgery for focal articular defect and uni-compartmental knee osteoarthritis. Cartilage repair techniques that were combined with HTO and included in this review are bone marrow stimulation, allograft transplantation, osteochondral autograft transplantation, autologous chondrocyte implantation, and mesenchymal stem cell implantation. Conclusions: HTO with adjunctive cartilage repair procedures improve clinical outcome scores and restore alignment in patients with medial compartment osteoarthritis and isolated focal chondral defects. HTO with adjunctive cartilage procedures produces optimal results in younger, non-obese patients with focal chondral defects and varus malalignment, without significant lateral compartment and patellofemoral involvement.
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The great majority of spinal cord injury (SCI) patients have debilitating chronic pain. Despite decades of research, these pain pathways of neuropathic pain (NP) are unknown. SCI patients have been shown to have abnormal brain pain pathways. We hypothesize that SCI NP patients' pain matrix is altered compared to SCI patients without NP. This study examines the functional connectivity (FC) in SCI patients with moderate-severe chronic NP compared to SCI patients with mild-no NP. These groups were compared to control subjects. The Neuropathic Pain Questionnaire and neurological evaluation based on the International Standard Neurological Classification of SCI were utilized to define the severity and level of injury. Of the 10 SCI patients, 7 (48.6 ± 17.02 years old, 6 male and 1 female) indicated that they had NP and 3 did not have NP (39.33 ± 8.08 years old, 2 male and 1 female). Ten uninjured neurologically intact participants were used as controls (24.8 ± 4.61 years old, 5 male and 5 female). FC metrics were obtained from the comparisons of resting-state functional magnetic resonance imaging among our various groups (controls, SCI with NP, and SCI without NP). For each comparison, a region-of-interest (ROI)-to-ROI connectivity analysis was pursued, encompassing a total of 175 ROIs based on a customized atlas derived from the AAL3 atlas. The analysis accounted for covariates such as age and sex. To correct for multiple comparisons, a strict Bonferroni correction was applied with a significance level of p < 0.05/NROIs. When comparing SCI patients with moderate-to-severe pain to those with mild-to-no pain, specific thalamic nuclei had altered connections. These nuclei included: medial pulvinar; lateral pulvinar; medial geniculate nucleus; lateral geniculate nucleus; and mediodorsal magnocellular nucleus. There was increased FC between the lateral geniculate nucleus and the anteroventral nucleus in NP post-SCI. Our analysis additionally highlights the relationships between the frontal lobe and temporal lobe with pain. This study successfully identifies thalamic neuroplastic changes that occur in patients with SCI who develop NP. It additionally underscores the pain matrix and involvement of the frontal and temporal lobes as well. Our findings complement that the development of NP post-SCI involves cognitive, emotional, and behavioral influences.
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BACKGROUND: Anemia is a worldwide problem with iron deficiency being the most common cause. When anemia occurs in pregnancy, it increases the risk of adverse maternal, fetal, and postnatal outcomes. It induces preterm births and low birth weight (LBW) deliveries, long-term neurodevelopmental sequelae, and an increased risk of earlier onset of postnatal iron deficiency. Anemia rates are among the highest in South Asia, and India's National Family Health Survey (NFHS-5) for 2019-2021 indicated that over half of pregnant women, and more than 65% of children, in the country are classified as anemic (Sciences IIfP, National Family Health Survey-5, 2019-21, India Fact Sheet). In 2021, the parent RAPIDIRON Trial (Derman et al., Trials 22:649, 2021) was initiated in two states in India, with the goal of assessing whether a dose of intravenous (IV) iron given to anemic women during early pregnancy results in a greater proportion of participants with normal hemoglobin concentrations in the third trimester and a lower proportion of participants with LBW deliveries compared to oral iron. As a follow-up to the RAPIDIRON Trial, the RAPIDIRON-KIDS Study will follow the offspring of previously randomized mothers to assess, neurobehavioral, hematological, and health outcomes. METHODS: This prospective observational cohort study will follow a subset of participants previously randomized as part of the RAPIDIRON Trial and their newborns. Study visits occur at birth, 6 weeks, 4 months, 12 months, 24 months, and 36 months and include blood sample collection with both maternal and infant participants and specific neurobehavioral assessments conducted with the infants (depending on the study visit). The primary outcomes of interest are (1) infant iron status as indicated by both hemoglobin and ferritin (a) at birth and (b) at 4 months of age and (2) the developmental quotient (DQ) for the cognitive domain of the Bayley Scales of Infant Development Version IV (BSID-IV) at 24 months of age. DISCUSSION: This RAPIDIRON-KIDS Study builds upon its parent RAPIDIRON Trial by following a subset of the previously randomized participants and their offspring through the first 3 years of life to assess neurodevelopmental and neurobehavioral (infants, children), hematological, and health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05504863 , Registered on 17 August 2022. Clinical Trials Registry - India CTRI/2022/05/042933 . Registered on 31 May 2022.
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Anemia , Deficiencias de Hierro , Femenino , Humanos , Lactante , Recién Nacido , Embarazo , Anemia/complicaciones , Estudios de Seguimiento , Hemoglobinas , Hierro , Estudios Observacionales como Asunto , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , PreescolarRESUMEN
Objective: The prevalence of diabetes is higher in Black than in White individuals, and Blacks seek emergency department (ED) care for diabetes more often than Whites. This randomized controlled trial compared the efficacy of a novel intervention called the Diabetes Interprofessional Team to Enhance Adherence to Medical Care (DM I-TEAM) to usual medical care (UMC) to prevent return diabetes-related ED visits and hospitalizations over 12 months in 200 Black individuals with diabetes after an ED visit. The trial also identified baseline variables associated with return ED visits and hospitalizations. Methods: The DM I-TEAM provided diabetes education and behavioral activation services delivered by race-concordant research assistants, telehealth visits with a diabetes care and education specialist and primary care physicians, and clinical pharmacist recommendations. Results: Participants had a mean age of 64.9 years, and 73.0% were women. There was no treatment group difference in return diabetes-related ED visits or hospitalizations over 12 months (DM I-TEAM n = 39 [45.3%] vs. UMC n = 37 [38.5%], χ2 = 0.864, P = 0.353). Baseline variables that were associated with return diabetes-related ED visits or hospitalizations were longer duration of diabetes, higher number of chronic health conditions, higher number of previous ED visits or hospitalizations, greater anticholinergic medication burden, lower satisfaction with primary care physicians, and lower trust in physicians (all P ≤0.05). Conclusion: Among Black individuals with diabetes, the DM I-TEAM interprofessional intervention was no better than UMC at preventing return diabetes-related ED visits or hospitalizations. High medical morbidity, greater anticholinergic medication burden, low satisfaction with primary care physicians, and physician mistrust were associated with diabetes-related ED visits or hospitalizations independent of treatment. Before clinical interventions such as the DM I-TEAM can be effective, reducing system-level barriers to health, improving physician-patient relationships and medication prescribing, and building community health care capacity will be necessary.
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Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVß3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVß3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVß3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVß3 ligands. Moreover, we describe for the first time co-fractionation of αVß3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients' plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. The monocytes incubated with small extracellular vesicles do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as "adhesion competent". Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Antagonistas de Andrógenos , Transducción de Señal , Anticuerpos Monoclonales , Integrinas , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Línea Celular TumoralRESUMEN
BACKGROUND: Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates. METHODS AND ANALYSIS: In a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will be continued to a reach a maximum of 20 mg/kg orally for 3 days, if the previous two dosages (5 mg/kg and 10 mg/kg) were tolerated. Dose-limiting toxicity grade≥3 is used as the primary endpoint. The pharmacokinetic and pharmacodynamic (PK/PD) profile of PP and bioavailability in humans will be used as the secondary objective. Each participant will be monitored weekly for a total of 30 days from the final dose of PP for any side effects. The purpose of this clinical trial is to examine whether PP is safe and tolerable in patients with pancreatic cancer, as well as assess the drug's PK/PD profile in plasma and fatty tissue. Potential implications include the utilisation of PP in a synergistic manner with chemotherapeutics for the treatment of pancreatic cancer. ETHICS AND DISSEMINATION: This study was approved by the Thomas Jefferson Institutional Review Board. The protocol number for this study is 20F.041 (Version 3.1 as of 27 October 2021). The data collected and analysed from this study will be used to present at local and national conferences, as well as, written into peer-reviewed manuscript publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05055323.
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Adenocarcinoma , Antihelmínticos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Reposicionamiento de Medicamentos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/cirugía , Adenocarcinoma/cirugía , Antihelmínticos/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Neoplasias PancreáticasRESUMEN
OBJECTIVES: Internal medicine clerkship grades are important for residency selection, but inconsistencies between evaluator ratings threaten their ability to accurately represent student performance and perceived fairness. Clerkship grading committees are recommended as best practice, but the mechanisms by which they promote accuracy and fairness are not certain. The ability of a committee to reliably assess and account for grading stringency of individual evaluators has not been previously studied. METHODS: This is a retrospective analysis of evaluations completed by faculty considered to be stringent, lenient, or neutral graders by members of a grading committee of a single medical college. Faculty evaluations were assessed for differences in ratings on individual skills and recommendations for final grade between perceived stringency categories. Logistic regression was used to determine if actual assigned ratings varied based on perceived faculty's grading stringency category. RESULTS: "Easy graders" consistently had the highest probability of awarding an above-average rating, and "hard graders" consistently had the lowest probability of awarding an above-average rating, though this finding only reached statistical significance only for 2 of 8 questions on the evaluation form (P = .033 and P = .001). Odds ratios of assigning a higher final suggested grade followed the expected pattern (higher for "easy" and "neutral" compared to "hard," higher for "easy" compared to "neutral") but did not reach statistical significance. CONCLUSIONS: Perceived differences in faculty grading stringency have basis in reality for clerkship evaluation elements. However, final grades recommended by faculty perceived as "stringent" or "lenient" did not differ. Perceptions of "hawks" and "doves" are not just lore but may not have implications for students' final grades. Continued research to describe the "hawk and dove effect" will be crucial to enable assessment of local grading variation and empower local educational leadership to correct, but not overcorrect, for this effect to maintain fairness in student evaluations.
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BACKGROUND: To determine if low-frequency repetitive transcranial magnetic stimulation targeting the primary motor cortex contralateral (M1CL) to the affected corticospinal tract in patients with hemiparetic stroke augments intensive training-related clinical improvement; an extension of the NICHE trial (Navigated Inhibitory rTMS to Contralesional Hemisphere Trial) using an alternative sham coil. METHODS: The present E-FIT trial (Electric Field Navigated 1Hz rTMS for Post-stroke Motor Recovery Trial) included 5 of 12 NICHE trial outpatient US rehabilitation centers. The stimulation protocol remained identical (1 Hz repetitive transcranial magnetic stimulation, M1CL, preceding 60-minute therapy, 18 sessions/6 wks; parallel arm randomized clinical trial). The sham coil appearance mimicked the active coil but without the weak electric field in the NICHE trial sham coil. Outcomes measured 1 week, and 1, 3, and 6 months after the end of treatment included the following: upper extremity Fugl-Meyer (primary, 6 months after end of treatment), Action Research Arm Test, National Institutes of Health Stroke Scale, quality of life (EQ-5D), and safety. RESULTS: Of 60 participants randomized, 58 completed treatment and were included for analysis. Bayesian analysis of combined data from the E-FIT and the NICHE trials indicated that active treatment was not superior to sham at the primary end point (posterior mean odds ratio of 1.94 [96% credible interval of 0.61-4.80]). For the E-FIT intent-to-treat population, upper extremity Fugl-Meyer improvement ≥5 pts occurred in 60% (18/30) active group and 50% (14/28) sham group. Participants enrolled 3 to 6 months following stroke had a 67% (31%-91% CI) response rate in the active group at the 6-month end point versus 50% in the sham group (21.5%-78.5% CI). There were significant improvements from baseline to 6 months for both active and sham groups in upper extremity Fugl-Meyer, Action Research Arm Test, and EQ-5D (P<0.05). Improvement in National Institutes of Health Stroke Scale was observed only in the active group (P=0.004). Ten serious unrelated adverse events occurred (4 active group, 6 sham group, P=0.72). CONCLUSIONS: Intensive motor rehabilitation 3 to 12 months after stroke improved clinical impairment, function, and quality of life; however, 1 Hz-repetitive transcranial magnetic stimulation was not an effective treatment adjuvant in the present sample population with mixed lesion location and extent. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03010462.
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Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Humanos , Rehabilitación de Accidente Cerebrovascular/métodos , Calidad de Vida , Teorema de Bayes , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Estimulación Magnética Transcraneal/métodos , Resultado del Tratamiento , Extremidad Superior , Recuperación de la FunciónRESUMEN
PURPOSE: Functional avoidance radiotherapy uses functional imaging to reduce pulmonary toxicity by designing radiotherapy plans that reduce doses to functional regions of the lung. A phase-II, multi-center, prospective study of 4DCT-ventilation functional avoidance was completed. Pre and post-treatment pulmonary function tests (PFTs) were acquired and assessed pulmonary function change. This study aims to evaluate which clinical, dose and dose-function factors predict PFT changes for patients treated with 4DCT-ventilation functional avoidance radiotherapy. MATERIALS AND METHODS: 56 patients with locally advanced lung cancer receiving radiotherapy were accrued. PFTs were obtained at baseline and three months following radiotherapy and included forced expiratory volume in 1-second (FEV1), forced vital capacity (FVC), and FEV1/FVC. The ability of patient, clinical, dose (lung and heart), and dose-function metrics (metrics that combine dose and 4DCT-ventilation-based function) to predict PFT changes were evaluated using univariate and multivariate linear regression. RESULTS: Univariate analysis showed that only dose-function metrics and the presence of chronic obstructive pulmonary disease (COPD) were significant (p<0.05) in predicting FEV1 decline. Multivariate analysis identified a combination of clinical (immunotherapy status, presence of thoracic comorbidities, smoking status, and age), along with lung dose, heart dose, and dose-function metrics in predicting FEV1 and FEV1/FVC changes. CONCLUSION: The current work evaluated factors predicting PFT changes for patients treated in a prospective functional avoidance radiotherapy study. The data revealed that lung dose- function metrics could predict PFT changes, validating the significance of reducing the dose to the functional lung to mitigate the decline in pulmonary function and providing guidance for future clinical trials.
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Neoplasias Pulmonares , Pulmón , Humanos , Neoplasias Pulmonares/radioterapia , Estudios Prospectivos , Respiración , Pruebas de Función RespiratoriaRESUMEN
BACKGROUND AND PURPOSE: To determine the incidence of acute neuroimaging (NI) findings and comorbidities in the coronavirus disease of 2019 (COVID-19)-infected subjects in seven U.S. and four European hospitals. METHODS: This is a retrospective study of COVID-19-positive subjects with the following inclusion criteria: age >18, lab-confirmed COVID-19 infection, and acute NI findings (NI+) attributed to COVID-19 on CT or MRI brain. NI+ and comorbidities in total hospitalized COVID-19-positive (TN) subjects were assessed. RESULTS: A total of 37,950 COVID-19-positive subjects were reviewed and 4342 underwent NI. NI+ incidence in subjects with NI was 10.1% (442/4342) including 7.9% (294/3701) in the United States and 22.8% (148/647) in Europe. NI+ incidence in TN was 1.16% (442/37,950). In NI (4342), incidence of ischemic stroke was 6.4% followed by intracranial hemorrhage (ICH) (3.8%), encephalitis (0.5%), sinus venous thrombosis (0.2%), and acute disseminated encephalomyelitis (ADEM) (0.2%). White matter involvement was seen in 57% of NI+. Hypertension was the most common comorbidity (54%) before cardiac disease (28.8%) and diabetes mellitus (27.7%). Cardiac disease (p < .025), diabetes (p < .014), and chronic kidney disease (p < .012) were more common in the United States. CONCLUSION: This multicenter, multinational study investigated the incidence and spectrum of NI+ in 37,950 hospitalized adult COVID-19 subjects including regional differences in incidences of NI+, associated comorbidities, and other demographics. NI+ incidence in TN was 1.16% including 0.95% in the United States and 2.09% in Europe. ICH, encephalitis, and ADEM were common in Europe, while ischemic strokes were more common in the United States. In this cohort, incidence and distribution of NI+ helped characterize the neurological complications of COVID-19.
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COVID-19 , Encefalitis , Encefalomielitis Aguda Diseminada , Cardiopatías , Accidente Cerebrovascular Isquémico , Adulto , Humanos , Estados Unidos/epidemiología , COVID-19/diagnóstico por imagen , COVID-19/epidemiología , Estudios Retrospectivos , Neuroimagen/métodos , Hemorragias Intracraneales , Europa (Continente)/epidemiologíaRESUMEN
PURPOSE: Modern wearable devices provide objective and continuous activity data that could be leveraged to enhance cancer care. We prospectively studied the feasibility of monitoring physical activity using a commercial wearable device and collecting electronic patient-reported outcomes (ePROs) during radiotherapy (RT) for head and neck cancer (HNC). METHODS: Patients planned for a course of external beam RT with curative intent for HNC were instructed to use a commercial fitness tracker throughout the RT course. During weekly clinic visits, physician-scored adverse events were recorded during using Common Terminology Criteria for Adverse Events version 4.0, and patients completed ePRO surveys using a clinic tablet or computer. Feasibility of activity monitoring was defined as collection of step data for at least 80% of the RT course for at least 80% of patients. Exploratory analyses described associations between step counts, ePROs, and clinical events. RESULTS: Twenty-nine patients with HNC were enrolled and had analyzable data. Overall, step data were recorded on 70% of the days during patients' RT courses, and there were only 11 patients (38%) for whom step data were collected on at least 80% of days during RT. Mixed effects linear regression models demonstrated declines in daily step counts and worsening of most PROs during RT. Cox proportional hazards models revealed a potential association between high daily step counts and both reduced risk of feeding tube placement (hazard ratio [HR], 0.87 per 1,000 steps, P < .001) and reduced risk of hospitalization (HR, 0.60 per 1,000 steps, P < .001). CONCLUSION: We did not achieve our feasibility end point, suggesting that rigorous workflows are required to achieve continuous activity monitoring during RT. Although limited by a modest sample size, our findings are consistent with previous reports indicating that wearable device data can help identify patients who are at risk for unplanned hospitalization.
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Monitores de Ejercicio , Neoplasias de Cabeza y Cuello , Humanos , Proyectos Piloto , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/radioterapia , Medición de Resultados Informados por el Paciente , ElectrónicaRESUMEN
The data on the safety and feasibility of performing concomitant or staged transcatheter edge-to-edge repair (TEER) of the mitral valve with transcatheter aortic valve implantation (TAVI) remains limited. The Nationwide Readmission Database was used to identify TEER and TAVI procedures from October 1, 2015 to December 31, 2019, using the International Classification of Diseases, Tenth Revision, Clinical Modification administrative data. A total of 627 weighted cases of TEER and TAVI procedures were included in the analysis. Of those cases, 453 underwent staged TEER after TAVI, whereas 174 had concomitant TAVI and TEER during the same admission. Patients who underwent staged procedures were mostly men (64.8%, p = 0.02) and had a higher median age of 85 years (interquartile range 79 to 88) versus 82 years (interquartile range 72 to 86) in the concomitant procedure group. The adjusted propensity-matched mortality rate was similar for staged versus same-admission procedures (6.1% vs 7.0%, p = 0.79). In-hospital complication rates, including acute kidney injury, vascular complications, need for percutaneous coronary intervention, mechanical support, and pacemaker implantation, were higher for the same-admission TEER and TAVI group than TEER performed as a staged procedure. Nonhome facility discharges and length of hospital stay (15 vs 4 days) were also significantly higher for the concomitant same-admission TEER and TAVI groups. In conclusion, there was no difference in in-hospital mortality rate between patients who underwent concomitant or staged TEER and TAVI procedures, whereas complication rates were significantly higher in the concomitant group.
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Estenosis de la Válvula Aórtica , Implantación de Prótesis de Válvulas Cardíacas , Reemplazo de la Válvula Aórtica Transcatéter , Masculino , Humanos , Anciano , Anciano de 80 o más Años , Femenino , Reemplazo de la Válvula Aórtica Transcatéter/métodos , Estenosis de la Válvula Aórtica/cirugía , Válvula Mitral , Estudios de Factibilidad , Complicaciones Posoperatorias , Válvula Aórtica/cirugía , Resultado del Tratamiento , Implantación de Prótesis de Válvulas Cardíacas/métodosRESUMEN
Black individuals with diabetes have high rates of emergency department (ED) use. This randomized controlled trial compared the efficacy of Diabetes Interprofessional Team to Enhance Adherence to Medical Care (DM I-TEAM) versus Usual Medical Care (UMC) to reduce number of return ED visits/hospitalizations over 12 months in 200 Black individuals with diabetes after an ED visit. DM I-TEAM consisted of community health worker-delivered diabetes education and behavior activation, telehealth visits with a diabetes nurse educator and primary care physicians, and clinical pharmacist recommendations to reduce potentially inappropriate medications (PIMs). Secondary outcomes included glycemic control, PIMs use, diabetes self-management, diabetes self-efficacy, depression, and medical trust. Participants had a mean age of 64.9 years and 73.0% were women. The 2 treatment groups were similar in baseline characteristics. Sixty-eight (69.4%) DM I-TEAM participants and 69 (67.6%) UMC participants had at least 1 incident ED visit/hospitalization over 12 months. The adjusted incidence rate ratio for DM I-TEAM versus UMC was 1.11 (95% confidence interval 0.79-1.56; P = 0.54). DM I-TEAM participants attained significantly better diabetes self-management, diabetes self-efficacy, and institutional trust than UMC participants. There were no treatment group differences in hemoglobin A1c level nor PIMs use. Among Black individuals with diabetes, a novel culturally relevant intervention was no better than usual care at preventing return ED visits/hospitalizations over 1 year. Before reasonable clinical interventions such as DM I-TEAM can be effective, reducing system-level barriers to health, building community health care capacity, and designing interventions that better align with the everyday realities of patients' lives are necessary. clinicaltrials.gov NCT03393338.