ABSTRACT
PURPOSE: This study assessed the clinical classification performance of an R2*-based MRI technique for LIC quantification relative to FerriScan, with intra-patient FerriScan LIC uncertainty taken into account. The variabilities of R2* and FerriScan LIC were also assessed. MATERIALS AND METHODS: This was an ethics approved retrospective study, performed on patients undergoing chelation treatment for iron overload. 126 patients (69 women, 57 men), with an age of 42 +/- 16 years (range 19-86 years) were included. FerriScan and R2* MRI at 1.5 T were performed as part of a routine liver iron assessment protocol. For R2* MRI, a commercially available pulse sequence and reconstruction implementation was used, together with a previously derived calibration curve to convert R2* to LIC. Clinical classifications arising from R2*-derived LIC estimates were compared to those based on FerriScan. The accuracy and precision of the R2* technique was calculated. The variabilities of FerriScan- and R2*-derived estimates of LIC were compared with a Wilcoxon Signed Rank test. Significance was set at the 95% confidence level. RESULTS: The precision of R2* ranged from 0.59 to 0.92, with an overall accuracy of 72%. When intra-patient FerriScan LIC uncertainty was considered, precision and accuracy increased to >94% and 97% respectively. The R2*-LIC variability (=17%) was significantly lower than the FerriScan-LIC variability (34%) at the 95% confidence level (p < 10-3). CONCLUSION: MRI R2*-based LIC estimates provided a similar clinical classification as FerriScan. The intra-patient uncertainty of R2*-based LIC estimates was significantly lower than FerriScan.
ABSTRACT
Lipid nanoparticles (LNPs) are widely used for mRNA delivery, with cationic lipids greatly affecting biodistribution, cellular uptake, endosomal escape and transfection efficiency. However, the laborious synthesis of cationic lipids limits the discovery of efficacious candidates and slows down scale-up manufacturing. Here we develop a one-pot, tandem multi-component reaction based on the rationally designed amine-thiol-acrylate conjugation, which enables fast (1 h) and facile room-temperature synthesis of amidine-incorporated degradable (AID) lipids. Structure-activity relationship analysis of a combinatorial library of 100 chemically diverse AID-lipids leads to the identification of a tail-like amine-ring-alkyl aniline that generally affords efficacious lipids. Experimental and theoretical studies show that the embedded bulky benzene ring can enhance endosomal escape and mRNA delivery by enabling the lipid to adopt a more conical shape. The lead AID-lipid can not only mediate local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics, but can also alter the tropism of liver-tropic LNPs to selectively deliver gene editors to the lung and mRNA vaccines to the spleen.
ABSTRACT
DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.
Subject(s)
5-Methylcytosine , Aging , Cerebellum , DNA Methylation , Liver , Animals , Aging/genetics , Aging/metabolism , 5-Methylcytosine/metabolism , 5-Methylcytosine/analogs & derivatives , Liver/metabolism , Mice , Humans , Cerebellum/metabolism , Mice, Inbred C57BL , Longevity/genetics , Male , Alternative Splicing , Transcription, Genetic , Female , Gene Expression RegulationABSTRACT
OBJECTIVE: Adherence to combinatorial treatments are important predictors of improved long-term outcomes for patients with glioblastoma (GB); however, factors associated with refusal of surgery, chemotherapy, or radiotherapy (RT) by patients with GB have not been studied. METHODS: The National Cancer Database was queried from 2004 to 2018 to identify patients with a primary diagnosis of GB who underwent surgical resection alone or followed by either RT or chemotherapy. Adult patients who voluntarily rejected a physician's recommendations for 1 or more treatment were selected. Multivariable regression was used to identify factors associated with rejection of surgical resection, chemotherapy, and RT. Patients receiving treatment were 3:1 propensity score matched to those rejecting treatment and median overall survival (OS) was compared. RESULTS: 58,788 patients were included in the analysis. Factors associated with voluntary refusal of GB treatment included: old age, nonprivate insurance, female sex, Black race, comorbidities, treatment at a nonacademic facility, and living 55+ miles away from a treatment facility (P < 0.05). On propensity matched analysis, refusal of surgery conferred a 4 month decrease in OS (P < 0.001), RT an 8 month decrease in OS (P < 0.001), and chemotherapy a 7 month decrease in OS (P < 0.001). CONCLUSIONS: In patients with GB, age, sex, race, nonprivate insurance, medical comorbidities, distance from treatment facility, and geographic location were associated with refusal of surgery, postsurgical RT, and chemotherapy. In addition, treatment refusal had a significant impact on OS length.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Esophagectomy , Humans , Esophageal Neoplasms/surgery , Esophageal Neoplasms/pathology , Esophagectomy/methods , Adenocarcinoma/surgery , Adenocarcinoma/pathology , Propensity Score , Treatment Outcome , Postoperative Complications/epidemiology , Postoperative Complications/etiologyABSTRACT
The full potential of ionizable lipid nanoparticles (LNPs) as an in vivo nucleic acid delivery platform has not yet been realized given that LNPs primarily accumulate in the liver following systemic administration, limiting their success to liver-centric conditions. The engineering of LNPs with antibody targeting moieties can enable extrahepatic tropism by facilitating site-specific LNP tethering and driving preferential LNP uptake into receptor-expressing cell types via receptor-mediated endocytosis. Obstetric conditions stemming from placental dysfunction, such as preeclampsia, are characterized by overexpression of cellular receptors, including the epidermal growth factor receptor (EGFR), making targeted LNP platforms an exciting potential treatment strategy for placental dysfunction during pregnancy. Herein, an EGFR antibody-conjugated LNP (aEGFR-LNP) platform was developed by engineering LNPs with increasing densities of antibody functionalization. aEGFR-LNPs were screened in vitro in immortalized placental trophoblasts and in vivo in non-pregnant and pregnant mice and compared to non-targeted formulations for extrahepatic, antibody-targeted mRNA LNP delivery to the placenta. Our top performing LNP with an intermediate density of antibody functionalization (1:5 aEGFR-LNP) mediated a â¼twofold increase in mRNA delivery in murine placentas and a â¼twofold increase in LNP uptake in EGFR-expressing trophoblasts compared to non-targeted counterparts. These results demonstrate the potential of antibody-conjugated LNPs for achieving extrahepatic tropism, and the ability of aEGFR-LNPs in promoting mRNA delivery to EGFR-expressing cell types in the placenta.
Subject(s)
ErbB Receptors , Lipids , Nanoparticles , Placenta , RNA, Messenger , Female , Animals , ErbB Receptors/metabolism , Pregnancy , Placenta/metabolism , Nanoparticles/chemistry , RNA, Messenger/administration & dosage , Lipids/chemistry , Humans , Mice , Trophoblasts/metabolism , LiposomesABSTRACT
BACKGROUND: Intensive care units are complex settings that require effective communication and collaboration among professionals in many disciplines. Rounding checklists are frequently used during interprofessional rounds and have been shown to positively affect patient outcomes. OBJECTIVE: To identify and summarize the evidence related to the following practice question: In an adult intensive care unit, does the use of a rounding checklist during interprofessional rounds affect the perceived level of staff collaboration or communication? METHODS: An integrative review was performed to address the practice question. No parameters were set for publication year or specific study design. Studies were included if they were set in adult intensive care units, involved the use of a structured rounding checklist, and had measured outcomes that included staff collaboration, communication, or both. RESULTS: Seven studies with various designs were included in the review. Of the 7 studies, 6 showed that use of rounding checklists improved staff collaboration, communication, or both. These results have a variety of practice implications, including the potential for better patient outcomes and staff retention. CONCLUSIONS: Given the complexity of the critical care setting, optimizing teamwork is essential. The evidence from this review indicates that the use of a relatively simple rounding checklist tool during interprofessional rounds can improve perceived collaboration and communication in adult intensive care units.
Subject(s)
Checklist , Teaching Rounds , Adult , Humans , Intensive Care Units , Critical Care , Communication , Patient Care TeamABSTRACT
RNA-based therapeutics have gained traction for the prevention and treatment of a variety of diseases. However, their fragility and immunogenicity necessitate a drug carrier. Lipid nanoparticles (LNPs) have emerged as the predominant delivery vehicle for RNA therapeutics. An important component of LNPs is the ionizable lipid (IL), which is protonated in the acidic environment of the endosome, prompting cargo release into the cytosol. Currently, there is growing evidence that the structure of IL lipid tails significantly impacts the efficacy of LNP-mediated mRNA translation. Here, we optimized IL tail length for LNP-mediated delivery of three different mRNA cargos. Using C12-200, a gold standard IL, as a model, we designed a library of ILs with varying tail lengths and evaluated their potency in vivo. We demonstrated that small changes in lipophilicity can drastically increase or decrease mRNA translation. We identified that LNPs formulated with firefly luciferase mRNA (1929 base pairs) and C10-200, an IL with shorter tail lengths than C12-200, enhance liver transfection by over 10-fold. Furthermore, different IL tail lengths were found to be ideal for transfection of LNPs encapsulating mRNA cargos of varying sizes. LNPs formulated with erythropoietin (EPO), responsible for stimulating red blood cell production, mRNA (858 base pairs), and the C13-200 IL led to EPO translation at levels similar to the C12-200 LNP. The LNPs formulated with Cas9 mRNA (4521 base pairs) and the C9-200 IL induced over three times the quantity of indels compared with the C12-200 LNP. Our findings suggest that shorter IL tails may lead to higher transfection of LNPs encapsulating larger mRNAs, and that longer IL tails may be more efficacious for delivering smaller mRNA cargos. We envision that the results of this project can be utilized as future design criteria for the next generation of LNP delivery systems for RNA therapeutics.
Subject(s)
Lipids , Nanoparticles , RNA, Messenger , RNA, Messenger/genetics , RNA, Messenger/metabolism , Nanoparticles/chemistry , Animals , Lipids/chemistry , Mice , Humans , Transfection , LiposomesABSTRACT
BACKGROUND: Esophagectomy in locally advanced esophageal adenocarcinoma is challenging and carries risk. The value of esophagectomy in locally advanced esophageal adenocarcinoma is not well-defined. STUDY DESIGN: The National Cancer Database was used to identify patients with cT4 esophageal adenocarcinoma from 2004 to 2020. Multivariable regression was used to identify factors associated with use of esophagectomy. Cox modeling was used to identify factors associated with all-cause mortality. Patients undergoing esophagectomy were 1:1 propensity score-matched to patients treated nonsurgically. Kaplan-Meier analysis was used to compare 5-year overall survival (OS). RESULTS: A total of 3,703 patients met inclusion criteria. Of those, 541 (15%) underwent esophagectomy, and 3,162 (85%) did not. Age 65 years or less (adjusted odds ratio [aOR] 1.69, 95% CI 1.33 to 2.14), White race (aOR 2.98, 95% CI 2.24 to 3.96), treatment in academic centers (aOR 1.64, 95% CI 1.33 to 2.02), private insurance (aOR 1.88, 95% CI 1.50 to 2.36), and tumors less than 6 cm (aOR 1.86, 95% CI 1.44 to 2.40) were associated with use of esophagectomy. Government of lack of insurance (hazard ratio [HR] 1.23, 95% CI 1.12 to 1.35), income <$46,000 (HR 1.11, 95% CI 1.03 to 1.20), treatment in nonacademic centers (HR 1.16, 95% CI 1.07 to 1.25), Charlson-Deyo Comorbidity Index 1 or more (HR 1.22, 95% CI 1.12 to 1.32), and tumors 6 cm or more (HR 1.20, 95% CI 1.09 to 1.32) were associated with risk of all-cause mortality. Esophagectomy (HR 0.50, 95% CI 0.44 to 0.56) and systemic therapy (HR 0.40, 95% CI 0.37 to 0.43) were associated with decreased risk of all-cause mortality. Patients undergoing esophagectomy had higher rates of 5-year OS (27.4% vs 13.2%, p < 0.0001) and longer median OS (24.71 vs 10.09 months, p < 0.0001). Among cT4b patients, those who underwent esophagectomy had higher rates of 5-year OS (24.5% vs 12.3%, p < 0.0001) and longer median OS (25.53 vs 11.01 months, p < 0.0001). CONCLUSIONS: In cT4 esophageal adenocarcinoma, esophagectomy is associated with improved rates of 5-year OS compared with nonsurgical treatment.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Esophagectomy , Humans , Esophageal Neoplasms/mortality , Esophageal Neoplasms/surgery , Esophageal Neoplasms/pathology , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Adenocarcinoma/pathology , Male , Female , Aged , Middle Aged , Survival Rate , United States/epidemiology , Propensity Score , Retrospective Studies , Neoplasm StagingABSTRACT
BACKGROUND: The value of palliative surgery in pancreatic cancer is not well-defined. METHODS: We queried the National Cancer Database for patients undergoing curative-intent resection, palliative surgery or medical palliation for clinical stage cT4N0-2M0 pancreatic cancer. Cohorts were 1:1:1 propensity-score-matched for comorbidities and stage. Kaplan-Meier method was used to compare overall survival for matched cohorts. RESULTS: 9,107 patients met inclusion criteria: 3,567 (39 â%) underwent curative intent surgery, 1608 (18 â%) surgical palliation, 3932 (43 â%) medical palliation. Patients undergoing resection and surgical palliation had significant hospitalizations (11.0 â± â0.4 vs. 10.0 â± â0.3 days; p â= â0.821) and rates of readmission (8.1 â% vs. 2.0 â%; p â< â0.001). Patients undergoing surgical palliation demonstrated marginal increases in survival relative to those undergoing medical palliation (8.54 vs. 7.36 months; p â< â0.0001). CONCLUSION: In patients undergoing care for locally advanced pancreatic cancer, palliative surgery is associated with marginal improvement in survival but significant lengths of hospitalization and risk of readmission.
Subject(s)
Pancreas , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/surgery , Palliative Care/methods , Retrospective StudiesABSTRACT
BACKGROUND: While in the intensive care unit, critically ill patients experience a myriad of distressing symptoms and stimuli leading to discomfort, a negative emotional and/ or physical state that arises in response to noxious stimuli. Appropriate management of these symptoms requires a distinct assessment of discomfort-causing experiences. OBJECTIVES: To assess patient-reported discomfort among critically ill patients with the English-language version of the Inconforts des Patients de REAnimation questionnaire, and to explore relationships between demographic and clinical characteristics and overall discomfort score on this instrument. METHODS: This study had a cross-sectional, descriptive, single-cohort design. The convenience sample consisted of alert and oriented patients aged 18 years or older who had been admitted to intensive care units at a Midwestern tertiary referral hospital and were invited to participate. An 18-item questionnaire on physiological and psychological stimuli inducing discomfort was administered once. Each item was scored from 0 to 10, with the total possible discomfort score ranging from 0 to 100. Descriptive statistics were used to analyze participants' demographic and clinical characteristics and questionnaire responses. RESULTS: A total of 180 patients were enrolled. The mean (SD) overall discomfort score was 32.9 (23.6). The greatest sources of discomfort were sleep deprivation (mean [SD] score, 4.0 [3.4]), presence of perfusion catheters and tubing (3.4 [2.9]), thirst (3.0 [3.3]), and pain (3.0 [3.0]). CONCLUSIONS: Intensive care unit patients in this study reported mild to moderate discomfort. Additional research is needed to design and test interventions based on assessment of specific discomfort-promoting stimuli to provide effective symptom management.
Subject(s)
Critical Care , Critical Illness , Adult , Humans , Cross-Sectional Studies , Critical Care/psychology , Intensive Care Units , Surveys and QuestionnairesABSTRACT
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable clinical success in the treatment of hematological malignancies. However, producing these bespoke cancer-killing cells is a complicated ex vivo process involving leukapheresis, artificial T cell activation, and CAR construct introduction. The activation step requires the engagement of CD3/TCR and CD28 and is vital for T cell transfection and differentiation. Though antigen-presenting cells (APCs) facilitate activation in vivo, ex vivo activation relies on antibodies against CD3 and CD28 conjugated to magnetic beads. While effective, this artificial activation adds to the complexity of CAR T cell production as the beads must be removed prior to clinical implementation. To overcome this challenge, this work develops activating lipid nanoparticles (aLNPs) that mimic APCs to combine the activation of magnetic beads and the transfection capabilities of LNPs. It is shown that aLNPs enable one-step activation and transfection of primary human T cells with the resulting mRNA CAR T cells reducing tumor burden in a murine xenograft model, validating aLNPs as a promising platform for the rapid production of mRNA CAR T cells.
Subject(s)
Antigen-Presenting Cells , Immunotherapy, Adoptive , Nanoparticles , RNA, Messenger , Receptors, Chimeric Antigen , T-Lymphocytes , Humans , Nanoparticles/chemistry , Animals , Mice , Antigen-Presenting Cells/immunology , Immunotherapy, Adoptive/methods , T-Lymphocytes/immunology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Neoplasms/therapy , Neoplasms/immunology , Immunotherapy/methods , Cell Line, Tumor , Lipids/chemistry , Transfection/methods , LiposomesABSTRACT
Lipid nanoparticle (LNP)-mediated nucleic acid therapies, including mRNA protein replacement and gene editing therapies, hold great potential in treating neurological disorders including neurodegeneration, brain cancer, and stroke. However, delivering LNPs across the blood-brain barrier (BBB) after systemic administration remains underexplored. In this work, we engineered a high-throughput screening transwell platform for the BBB (HTS-BBB), specifically optimized for screening mRNA LNPs. Unlike most transwell assays, which only assess transport across an endothelial monolayer, HTS-BBB simultaneously measures LNP transport and mRNA transfection of the endothelial cells themselves. We then use HTS-BBB to screen a library of 14 LNPs made with structurally diverse ionizable lipids and demonstrate it is predictive of in vivo performance by validating lead candidates for mRNA delivery to the mouse brain after intravenous injection. Going forward, this platform could be used to screen large libraries of brain-targeted LNPs for a range of protein replacement and gene editing applications.
Subject(s)
Blood-Brain Barrier , Liposomes , Nanoparticles , Animals , Mice , Blood-Brain Barrier/metabolism , Endothelial Cells/metabolism , RNA, Messenger/genetics , Lipids , Transfection , RNA, Small Interfering/geneticsABSTRACT
Generalized pustular psoriasis (GPP) is a rare, chronic, neutrophilic inflammatory skin disease characterized by episodes of widespread eruption of sterile, macroscopic pustules that can be accompanied by systemic inflammation and symptoms. A systematic literature review and narrative synthesis were conducted to determine the impact of GPP on patients' health-related quality of life (HRQoL) and patient-reported severity of symptoms and to compare its impact to patients with plaque psoriasis (plaque PsO). Searches were undertaken in Embase, MEDLINE and the Cochrane Library from 1 January 2002 to 15 September 2022. Screening was carried out by two reviewers independently. Outcome measures included generic (e.g. EQ-5D, SF-36) and dermatology-specific (e.g. DLQI) clinical outcome assessments, and other relevant patient-reported outcome measures (PROMs) (e.g. severity of pain measured by a numerical rating scale). Overall, 20 studies were found to be eligible for inclusion, of which seven also had data for plaque PsO. The DLQI was the most frequently reported outcome measure (16 out of 20 studies). When reported, mean DLQI (SD) scores varied from 5.7 (1.2) to 15.8 (9.6) across the studies, indicating a moderate to very large effect on HRQoL; the wide range of scores and large SDs were explained by the small population sizes (n ≤ 12 for all studies except two). Similar ranges and large SDs were also observed for other measures within individual studies. However, in general, people with GPP reported a greater impact of their skin condition on HRQoL, when compared to people with plaque PsO (i.e. higher DLQI scores) and higher severity for itch, pain and fatigue. This systematic review highlighted the need for studies with a larger population size, a better understanding of the impact of cutaneous and extracutaneous symptoms and comorbidities on HRQoL during and between GPP flares, and outcome measures specifically tailored to the unique symptoms and the natural course/history of GPP.
Subject(s)
Dermatitis , Psoriasis , Skin Diseases, Vesiculobullous , Humans , Quality of Life , Psoriasis/diagnosis , Skin , Chronic Disease , PainABSTRACT
BACKGROUND: Pretreatment clinical staging is used to decide the course of treatment in early-stage esophageal cancer. Few studies assess the effect of inaccurate clinical staging on oncologic outcomes. METHODS: We queried the National Cancer Database to identify patients undergoing esophagectomy for clinical stage cT1bN0 esophageal carcinoma between 2010 and 2019. Patients were categorized as being upstaged if, on final pathology, they had histopathologic disease that would have warranted treatment with neoadjuvant therapy. The textbook oncologic outcome was defined as margin-negative resection, 15 lymph nodes examined, a hospital stay of <21 days, no unplanned 30-day readmission or mortality, and stage-appropriate use of neoadjuvant therapy. RESULTS: In total, 916 patients met inclusion criteria; 378 (41.2%) had a pathologic stage that differed from their pretreatment clinical stage. By multivariable regression, factors associated upstaging included: presentation between 2015 and 2019 (odds ratio 1.92 95% confidence interval [1.19, 3.13]), delay to esophagectomy of >30 days (odds ratio 2.38 95% confidence interval [1.13, 5.57]), larger tumor size (>2 cm relative to <2 cm, odds ratio 2.73 95% confidence interval [1.72, 4.39]), and poorly differentiated histology (odds ratio 2.79 95% confidence interval [1.75, 4.49]). The rate of textbook oncologic outcome assuming reliable clinical staging was 43.8%; accounting for upstaging, the rate of textbook oncologic outcome was 22.5% (P < .001). CONCLUSION: In patients with cT1bN0 esophageal cancer, tumor size and histology are associated with the risk of inaccurate pretreatment clinical staging. Inaccuracies in clinical staging impact the rate at which providers achieve optimal oncologic outcomes.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Humans , Neoplasm Staging , Esophageal Neoplasms/surgery , Lymph Nodes/pathology , Adenocarcinoma/surgery , Adenocarcinoma/pathology , Neoadjuvant Therapy , Esophagectomy , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Prior studies of fragmentation of care in pancreatic cancer have not adjusted for indicators of hospital quality such as Commission on Cancer accreditation. The effect of fragmentation of care has not been well defined. METHODS: We queried the National Cancer Database to identify patients undergoing pancreaticoduodenectomy and distal pancreatectomy with perioperative systemic therapy for clinical stages I-III pancreatic cancer between 2006 and 2019. Patients who received systemic therapy at a center different than the center performing surgery were categorized as having fragmentation of care. Patients having fragmentation of care were further categorized on the basis of whether (fragmentation of care Commission on Cancer) or not (fragmentation of care non-Commission on Cancer) systemic therapy was administered at a facility accredited by the Commission on Cancer. RESULTS: A total of 11,732 patients met inclusion criteria; 5,668 (48.3%) underwent fragmentation of care, and 3,426 (29.2%) fragmentation of care non-Commission on Cancer. Patients undergoing fragmentation of care non-Commission on Cancer were less likely to receive neoadjuvant systemic therapy than those undergoing fragmentation of care Commission on Cancer or non-fragmented care (27.7% vs 40.1% vs 36.8%, P < .001). On Cox analysis, advanced age, comorbid disease, node-positive disease, and facility type were associated with risk of overall survival. Fragmentation of care was not (adjusted hazard ratio = 0.99, 95% confidence interval [0.94-1.06], P = .8). On Kaplan-Meier analysis, there were no significant differences in 5-year overall survival between treatment cohorts. CONCLUSION: In patients undergoing fragmentation of care for localized pancreatic cancer, those treated with systemic therapy in Commission on Cancer accredited facilities are more likely to be given neoadjuvant therapy but demonstrate no significant improvement in survival relative to those undergoing non-fragmented care or those undergoing fragmentation of care but receiving systemic therapy in nonaccredited facilities.
Subject(s)
Pancreatic Neoplasms , Humans , Retrospective Studies , Pancreatic Neoplasms/surgery , Pancreatectomy , Proportional Hazards Models , Neoadjuvant Therapy , AccreditationABSTRACT
OBJECTIVE: Conventional single-echo spin-echo T2 mapping used for liver iron quantification is too long for breath-holding. This study investigated a short TR (~100 ms) single-echo spin-echo T2 mapping technique wherein each image (corresponding to a single TE) could be acquired in ~17 s-short enough for a breath-hold. TE images were combined for T2 fitting. To avoid T1 bias, each TE acquisition incremented TR to maintain a constant TR-TE. MATERIALS AND METHODS: Experiments at 1.5T validated the technique's accuracy in phantoms, 9 healthy volunteers, and 5 iron overload patients. In phantoms and healthy volunteers, the technique was compared to the conventional approach of constant TR for all TEs. Iron overload results were compared to FerriScan. RESULTS: In phantoms, the constant TR-TE technique provided unbiased estimates of T2, while the conventional constant TR approach underestimated it. In healthy volunteers, there was no significant discrepancy at the 95% confidence level between constant TR-TE and reference T2 values, whereas there was for constant TR scans. In iron overload patients, there was a high correlation between constant TR-TE and FerriScan T2 values (r2 = 0.95), with a discrepancy of 0.6+/- 1.4 ms. DISCUSSION: The short-TR single-echo breath-hold spin-echo technique provided unbiased estimates of T2 in phantoms and livers.
Subject(s)
Iron Overload , Liver , Humans , Liver/diagnostic imaging , Magnetic Resonance Imaging/methods , Breath Holding , Iron , Iron Overload/diagnostic imagingABSTRACT
In this study, an oil-in-water (o/w) nanoemulsion is used to deliver siRNA targeting Twist1, a protein that contributes to tumor metastasis in a variety of cancers. The FDA-approved oil, medium chain triglycerides (MCT), is used as the hydrophobic phase for the nanoemulsion. The siRNA is paired with dioleoyl-3-trimethylammonium-propane (DOTAP) to form a hydrophobic salt that is soluble at high concentrations in MCT. The resulting MCT/siRNA-DOTAP solution is formulated into a nanoemulsion with an average particle size of 140 nm. The nanoemulsion displays long term stability over the course of 195 days. In an in vivo murine tumor model, the nanoemulsion facilitates a 46% decrease in Twist1 mRNA after 48 h.
Subject(s)
Fatty Acids, Monounsaturated , Neoplasms , Quaternary Ammonium Compounds , Mice , Animals , Emulsions/chemistry , RNA, Small Interfering , Triglycerides/chemistryABSTRACT
BACKGROUND: We seek to determine the association between COVID-19 diagnosis and postoperative outcomes following bariatric surgery. METHODS: Using the Metabolic and Bariatric Surgery Accreditation Quality Improvement Project (MBSAQIP) database, patients undergoing sleeve gastrectomy and gastric bypass without a COVID-19 diagnosis were 2:1 propensity-score matched to those with COVID-19 infection pre or postoperatively. RESULTS: 1369 (0.74 â%) and 1331 (0.72 â%) patients had a COVID-19 diagnosis within 14 days prior to or 30 days after their operation, respectively. Patients with preoperative COVID-19 infection had equivalent outcomes to COVID-19 negative patients (all p â> â0.05). Postoperative COVID-19 diagnosis was associated with worse outcomes including increased risk of anastomotic/staple line leak (1.1 â% vs 0.1 â%, p â< â0.001), postoperative pneumonia (2.9 â% vs 0.1 â%, p â< â0.001), and 30-day reoperation (2.1 â% vs 0.9 â%, p â= â0.002). CONCLUSIONS: Postoperative diagnosis of COVID-19 after bariatric surgery is associated with worse outcomes; however, it is safe to perform these procedures on patients recently convalesced from COVID-19 infection.
Subject(s)
Bariatric Surgery , COVID-19 , Gastric Bypass , Laparoscopy , Obesity, Morbid , Humans , Gastric Bypass/adverse effects , Gastric Bypass/methods , Obesity, Morbid/complications , Obesity, Morbid/diagnosis , Obesity, Morbid/surgery , Cohort Studies , COVID-19 Testing , Treatment Outcome , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/complications , Bariatric Surgery/adverse effects , Anastomotic Leak/diagnosis , Anastomotic Leak/epidemiology , Anastomotic Leak/etiology , Retrospective Studies , Gastrectomy/methods , Laparoscopy/methods , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Postoperative Complications/etiologyABSTRACT
BACKGROUND: Studies of fragmented care (FC) in rectal cancer have not adjusted for indicators of hospital quality and may misrepresent the effects of FC. METHODS: We queried the National Cancer Database to identify patients undergoing care for clinical stage II and III rectal adenocarcinoma between 2006 and 2019. Those undergoing FC were sub-categorized based on whether (FC CoC) or not (FC non-CoC) they received systemic therapy at CoC accredited facilities. RESULTS: 44,339 patients met inclusion criteria; 23,921 (54 â%) underwent FC, 16,929 (71 â%) FC non-CoC. Differences in utilization of neoadjuvant therapy (92.3 â% vs 89.7 â% vs 89.5 â%, p â< â0.01) and 5-year overall survival (76.1 vs 75.5 vs 74.1 %, p â< â0.01) between treatment cohorts were marginal. CONCLUSION: In patients undergoing multimodality therapy for rectal cancer, care fragmentation is not associated with long-term clinical outcome. Decisions regarding where these patients go for systemic therapy may be safely made on the basis of ease of access.