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Atomically thin semiconductor heterostructures provide a two-dimensional (2D) device platform for creating high densities of cold, controllable excitons. Interlayer excitons (IEs), bound electrons and holes localized to separate 2D quantum well layers, have permanent out-of-plane dipole moments and long lifetimes, allowing their spatial distribution to be tuned on demand. Here, we employ electrostatic gates to trap IEs and control their density. By electrically modulating the IE Stark shift, electron-hole pair concentrations above 2 × 1012 cm-2 can be achieved. At this high IE density, we observe an exponentially increasing linewidth broadening indicative of an IE ionization transition, independent of the trap depth. This runaway threshold remains constant at low temperatures, but increases above 20 K, consistent with the quantum dissociation of a degenerate IE gas. Our demonstration of the IE ionization in a tunable electrostatic trap represents an important step towards the realization of dipolar exciton condensates in solid-state optoelectronic devices.
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Vaccine-mediated protection and susceptibility to Streptococcus pneumoniae (pneumococcus) infections are influenced by biological sex. The incidence of invasive pneumococcal disease remains higher in males compared to females even after the introduction of the pneumococcal conjugate vaccine (PCV). However, sex-based differences in the immune response to this conjugate vaccine remain unexplored. To investigate those differences, we vaccinated adult male and female mice with PCV and assessed cellular and humoral immune responses. Compared to females, male mice displayed lower levels of T follicular helper cells, germinal center B cells and plasmablasts, which are all required for antibody production following vaccination. This was linked to lower IgG and IgM levels against pneumococci and lower isotype switching to IgG3 in vaccinated males. Due to lower antibody levels, sera of vaccinated male mice had lower efficacy in several anti-pneumococcal functions including neutralization of bacterial binding to pulmonary epithelial cells as well as direct cytotoxicity against S. pneumoniae. Importantly, while the vaccine was highly protective in females, vaccinated males succumbed to infection more readily and were more susceptible to both lung-localized infection and systemic spread following S. pneumoniae challenge. These findings identify sex-based differences in immune responses to PCV that can inform future vaccine strategies.
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Methane emissions from the oil and gas sector are a large contributor to climate change. Robust emission quantification and source attribution are needed for mitigating methane emissions, requiring a transparent, comprehensive, and accurate geospatial database of oil and gas infrastructure. Realizing such a database is hindered by data gaps nationally and globally. To fill these gaps, we present a deep learning approach on freely available, high-resolution satellite imagery for automatically mapping well pads and storage tanks. We validate the results in the Permian and Denver-Julesburg basins, two high-producing basins in the United States. Our approach achieves high performance on expert-curated datasets of well pads (Precision = 0.955, Recall = 0.904) and storage tanks (Precision = 0.962, Recall = 0.968). When deployed across the entire basins, the approach captures a majority of well pads in existing datasets (79.5%) and detects a substantial number (>70,000) of well pads not present in those datasets. Furthermore, we detect storage tanks (>169,000) on well pads, which were not mapped in existing datasets. We identify remaining challenges with the approach, which, when solved, should enable a globally scalable and public framework for mapping well pads, storage tanks, and other oil and gas infrastructure.
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BACKGROUND: Chronic pain, defined as pain persisting for more than 3-6 months, has a mean one-year prevalence in the United States of 25.8% and is one of the most frequent reasons adults seek medical care. Treatment options include physical therapy, analgesics, anticonvulsants, exercise, and muscle relaxants. Even with conventional treatment modalities, in a subset of patients, pain may persist. Cooled radiofrequency ablation (c-RFA), a minimally invasive therapy, employs thermal energy generated by electrical currents to disrupt the transmission of pain stimuli along nociceptive pathways. This leads to an attenuation of pain impulses, primarily through nerve tissue necrosis. The potential of c-RFA to alleviate chronic pain for patients who struggle to find relief elsewhere accentuates the importance of rigorously investigating its outcomes. This study investigates whether patients receiving c-RFA for relief of chronic neck pain caused by cervical facet joint arthropathy experience a reduction in pain scores, the length of this reduction in pain scores, and the magnitude of this reduction in pain. METHODS: This study was a retrospective analysis of data extracted from UW-Health Electronic Medical Health records (EMR), encompassing cervical c-RFA procedures performed from 2015 through 2022. Patient data were obtained, including diagnosis, pre-operative pain score, post-operative pain score, duration of relief, patient age, sex, and BMI. A two-tailed paired t-test was used to statistically analyze the pre-operative and post-operative pain scores, in which a p-value ≤0.05 was considered significant. RESULTS: A total of 450 cervical c-RFA procedures were reviewed, 152 were excluded due to absent pre- or post-op pain scores. 298 were included in the analysis, comprising 203 unique patients: 129 females and 74 males with an average age of 56.03 ± 12.76 and a BMI of 28.76 ± 6.05. Improvement of pain symptoms was reported in 85.23% (n = 263), 6% (n = 19) reported complete pain remission, 8.72% (n = 26) reported no change, and 3.02% (n = 9) reported worsening symptoms. Patients reported an average pre-operative pain score of 6.15 (M = 6.15, SD = 1.55) and an average post-operative pain score of 3.64 (M = 3.64, SD = 2.09) this achieved significance (p < 0.0001). Of the 85.23% (n = 263) charts that noted improvement, there is an average of 48.04% ± 26.53 reduction from their pre-operative pain scores. The average duration of relief lasted 6.67 ± 4.84 months. CONCLUSION: This study supports the potential efficacy of c-RFA as a minimally invasive treatment for chronic neck pain secondary to cervical facet joint arthropathy refractory to conventional treatment measures, demonstrating significant relief for a substantial length of time. Due to chronic pain's detrimental effect on one's quality of life, finding effective treatment options is essential, especially for those refractory to conventional treatments.
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BACKGROUND & OBJECTIVES: Screening for pancreatic cancer is recommended for individuals with a strong family history, certain genetic syndromes, or a neoplastic cyst of the pancreas. However, limited data supports a survival benefit attributable to screening these higher-risk individuals. METHODS: All patients enrolled in screening at a High-Risk Pancreatic Cancer Clinic (HRC) from July 2013 to June 2020 were identified from a prospectively maintained institutional database and compared to patients evaluated at a Surgical Oncology Clinic (SOC) at the same institution during the same period. Clinical outcomes of patients selected for surgical resection, particularly clinicopathologic stage and overall survival, were compared. RESULTS: Among 826 HRC patients followed for a median (IQR) of 2.3 (0.8-4.2) years, 128 were selected for surgical resection and compared to 402 SOC patients selected for resection. Overall survival was significantly longer among HRC patients (median survival: not reached vs. 2.6 years, p < 0.001). Among 31 HRC and 217 SOC patients with a diagnosis of pancreatic ductal adenocarcinoma (PDAC), the majority of HRC patients were diagnosed with stage 0 disease (carcinoma in situ), while the majority of SOC patients were diagnosed with stage II disease (p < 0.001). Overall survival after resection of invasive PDAC was also significantly longer among HRC patients compared to SOC patients (median survival 5.5 vs. 1.6 years, p = 0.002). CONCLUSION: Patients at increased risk for PDAC and followed with guideline-based screening exhibited downstaging of disease and improved survival from PDAC in comparison to patients who were not screened.
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Multiple host and microbial factors dictate whether Candida albicans can colonize the mammalian gastrointestinal tract. In this issue of Cell Host & Microbe, Savage et al. demonstrate that restoration of intestinal epithelial hypoxia is sufficient to restore Candida albicans colonization resistance, even when other Candida inhibitory effectors remain depleted.
Subject(s)
Candida albicans , Candidiasis , Gastrointestinal Tract , Candida albicans/growth & development , Candida albicans/physiology , Humans , Gastrointestinal Tract/microbiology , Candidiasis/microbiology , Animals , Hypoxia/metabolism , Intestinal Mucosa/microbiology , Intestinal Mucosa/metabolism , Mice , Host-Pathogen Interactions , Gastrointestinal Microbiome/physiologyABSTRACT
BACKGROUND: The prevalence of super obesity (body mass index [BMI] > 50) continues to rise. However, the adoption of bariatric surgery in this population remains very low. There are limited studies evaluating the utility of endoscopic sleeve gastroplasty (ESG) in super obesity. OBJECTIVES: The purpose of this study is to evaluate the short-term safety profile of ESG in patients with super obesity using data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database. SETTING: United States. METHODS: We retrospectively analyzed patients who underwent ESG and sleeve gastrectomy (SG) from 2016 to 2021. Patients with BMI >50 who underwent ESG were compared to ESG patients with BMI <50 and also SG patients with BMI >50. Primary outcomes included the incidence of severe adverse events (AEs), hospital readmission, reintervention, and reoperation within 30 days of the primary procedure. Secondary outcomes included procedure time, hospital length of stay, and total body weight loss at 30 days. RESULTS: There were no significant differences in AE, reoperations, hospital readmissions, or reinterventions for patients with super obesity undergoing ESG, compared to patients with BMI below 50. Mean total body weight loss was greater in patients with super obesity. There were no significant differences in AEs for patients with super obesity who underwent ESG versus SG, although ESG patients had more hospital readmissions, reinterventions, and reoperations. CONCLUSIONS: ESG may be performed safely, with comparable safety to SG, in patients with BMI as high as 70. However, further studies are needed to validate the feasibility and long-term efficacy prior to clinical implementation.
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BACKGROUND: Limited data exist regarding adverse drug events (ADEs) in the outpatient setting. The objective of this study was to determine the incidence, severity, and preventability of ADEs in the outpatient setting and identify potential prevention strategies. METHODS: We conducted an analysis of ADEs identified in a retrospective electronic health records review of outpatient encounters in 2018 at 13 outpatient sites in Massachusetts that included 13 416 outpatient encounters in 3323 patients. Triggers were identified in the medical record including medications, consultations, laboratory results, and others. If a trigger was detected, a further in-depth review was conducted by nurses and adjudicated by physicians to examine the relevant information in the medical record. Patients were included in the study if they were at least 18 years of age with at least one outpatient encounter with a physician, nurse practitioner or physician's assistant in that calendar year. Patients were excluded from the study if the outpatient encounter occurred in outpatient surgery, psychiatry, rehabilitation, and paediatrics. RESULTS: In all, 5% of patients experienced an ADE over the 1-year period. We identified 198 ADEs among 170 patients, who had a mean age of 60. Most patients experienced one ADE (87%), 10% experienced two ADEs and 3% experienced three or more ADEs. The most frequent drug classes resulting in ADEs were cardiovascular (25%), central nervous system (14%), and anti-infective agents (14%). Severity was ranked as significant in 85%, 14% were serious, 1% were life-threatening, and there were no fatal ADEs. Of the ADEs, 22% were classified as preventable and 78% were not preventable. We identified 246 potential prevention strategies, and 23% of ADEs had more than one prevention strategy possibility. CONCLUSIONS: Despite efforts to prioritise patient safety, medication-related harms are still frequent. These results underscore the need for further patient safety improvement in the outpatient setting.
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INTRODUCTION: A risk factor for a potentially fatal ventricular arrhythmia Torsade de Pointes is a prolongation in the heart rate-corrected QT interval (QTc) ≥ 500 milliseconds (ms) or an increase of ≥ 60 ms from a patient's baseline value, which can cause sudden cardiac death. The Tisdale risk score calculator uses clinical variables to predict which hospitalized patients are at the highest risk for QTc prolongation. OBJECTIVE: To determine the rate of overridden QTc drug-drug interaction (DDI)-related clinical decision support (CDS) alerts per patient admission and the prevalence by Tisdale risk score category of these overridden alerts. Secondary outcome was to determine the rate of drug-induced QTc prolongation (diQTP) associated with overrides. METHODS: Our organization's enterprise data warehouse was used to retrospectively access QTc DDI alerts presented for patients aged ≥ 18 years who were admitted to Brigham and Women's Hospital during 2022. The QTc DDI CDS alerts were included if shown to a physician, fellow, resident, physician assistant, or nurse practitioner when entering the order in inpatient areas for patients with a length of stay of at least 2 days. Variables collected for the Tisdale calculator included age, sex, whether patient was on a loop diuretic, potassium level, admission QTc value, admitting diagnosis of acute myocardial infarction, sepsis, or heart failure, and number of QTc-prolonging drugs given to the patient. RESULTS: A total of 2649 patients with 3033 patient admissions had 18,432 QTc DDI alerts presented that were overridden. An average of 3 unique QTc DDI alerts were presented per patient admission and the alerts were overridden an average of 6 times per patient admission. Overall, 6% of patient admissions were low risk (score ≤ 6), 64% moderate risk (score 7-10), and 30% high risk (score ≥ 11) of QTc prolongation. The most common QTc DDI alerts overridden resulting in an diQTP were quetiapine and propofol (11%) and amiodarone and haloperidol (7%). The diQTP occurred in 883 of patient admissions (29%) and was more frequent in those with higher risk score, with 46% of patient admissions with diQTP in high risk, 23% in moderate risk, and 8% in low risk. CONCLUSION: Use of the Tisdale calculator to assess patient-specific risk of QT prolongation combined with CDS may improve overall alert quality and acceptance rate, which may decrease the diQTP rate.
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Circulating plasma cells (CPCs) are detected in most multiple myeloma (MM) patients, both at diagnosis and on relapse. A small subset, plasma cell leukemia (PCL), represents a different biology and has a poor prognosis. In this retrospective analysis, we evaluated patients with primary (pPCL, n = 35) or secondary (sPCL, n = 49), with ≥5% CPCs and a smaller subset with lower CPCs of 1-4% (n = 20). The median age was 61 years; 45% were men and 54% were Black. High-risk cytogenetics were found in 87% and extramedullary disease in 47%. For the entire cohort, 75% received a proteasome inhibitor, 70% chemotherapy, 54% an immunomodulatory drug, 24% a daratumumab-based regimen and 26% an autologous stem cell transplant (ASCT). The treatments marginally improved the overall survival (OS) for pPCL vs. sPCL (13 vs. 3.5 months p = 0.002). However, the 5-year survival for the whole cohort was dismal at 11%. High-risk cytogenetics, low platelets, extramedullary disease and high LDH were independently associated with poor outcomes. Further research is urgently needed to expand the treatment options and improve the outcomes in PCL.
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BACKGROUND: There is an unmet surgical burden among people living with rheumatic heart disease (RHD) in Uganda. Nevertheless, risk factors associated with time to first intervention and preoperative mortality are poorly understood. METHODS: Individuals with RHD who met indications for valve surgery were identified using the Uganda National RHD Registry (January 2010-August 2022). Kaplan-Meier estimates and multivariable Cox proportional hazard models were used. RESULTS: Of the cohort with clinical RHD, 64% (1452 of 2269) met criteria for an index operation. Of those, 13.5% obtained a surgical intervention, whereas 30.6% died before the operation. The estimated likelihood of first operation was 50% at 9.3 years of follow-up (95% CI, 8.1-upper limit not reached). Intervention was more likely in men vs women (hazard ratio [HR], 1.78; 95% CI, 1.21-2.64), those with postsecondary education vs primary school or less (HR, 3.60; 95% CI, 1.88-6.89), and those with a history of atrial fibrillation (HR, 2.78; 95% CI, 1.63-4.76). Surgical intervention was less likely for adults vs those aged <18 years (HR, 0.49; 95% CI, 0.32-0.77) and those with New York Heart Association Functional Class III/IV vs I/II (HR, 0.51; 95% CI, 0.32-0.83). The median preoperative survival time among those awaiting first operation was 4.6 years (95% CI, 3.9-5.7 years). History of infective endocarditis, right ventricular dysfunction, pericardial effusion, atrial fibrillation, and having surgical indications for multiple valves were associated with increased probability of death. CONCLUSIONS: Our analysis revealed a prolonged time to first surgical intervention and high preintervention death for RHD in Uganda, with factors such as age, sex, and education level remaining barriers to obtaining surgery.
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The metabolic profile of dendritic cells (DCs) shapes their phenotype and functions. Carboxylestrase 1 (CES1) enzyme is highly expressed in mononuclear myeloid cells however its exact role in DCs is elusive. We used a CES1 inhibitor (WWL113) and genetic overexpression to explore the role of CES1 in DCs differentiation in inflammatory models. CES1 expression was analyzed during CD14+ monocytes differentiation to DCs (MoDCs) using quantitative PCR. CES1 Inhibitor (WWL113) was applied during MoDCs differentiation. Surface markers, secreted cytokines, lactic acid production, phagocytic and T cell polarization capacity were analyzed. Transcriptomic and metabolic profile were assessed with RNA-sequencing and mass spectrometry. Cellular respiration was assessed with seahorse respirometry. Transgenic mice were used to assess CES1 overexpression in DCs in inflammatory models. CES1 expression peaks early during MoDCs differentiation. Pharmacological inhibition of CES1 led to higher expression of CD209, CD86 and MHCII. WWL113 treated MoDCs secreted higher quantities of IL6, IL8, TNF and IL10 and demonstrated stronger phagocytic ability and higher capacity to polarize Th17 differentiation in autologous DCs-T cells co-culture model. Transcriptomic profiling revealed enrichment of multiple inflammatory and metabolic pathways. Functional metabolic analysis shows impaired maximal mitochondrial respiration capacity, increased lactate production and decreased intracellular amino acids and TCA intermediates. Transgenic human CES1 overexpression in murine DCs generated less inflammatory phenotype and increased resistance to T cell mediated colitis. In conclusion, CES1 inhibition directs DCs differentiation towards more inflammatory phenotype, that shows stronger phagocytic capacity and supports Th17 skewing. This is associated with disrupted mitochondrial respiration and amino acids depletion.
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Backgrounds/Aims: The guidelines regarding the management of intraductal papillary mucinous neoplasms (IPMNs) all have slightly different surgical indications for high-risk lesions. We aim to retrospectively compare the accuracy of four guidelines in recommending surgery for high-risk IPMNs, and assess the accuracy of elevated CA-19-9 levels and imaging characteristics of IPMNs considered high-risk in predicting malignancy or high-grade dysplasia (HGD). Methods: The final histopathological diagnosis of surgically resected high-risk IPMNs during 2013-2020 were compared to preoperative surgical indications, as enumerated in four guidelines: the 2015 American Gastroenterological Association (AGA), 2017 International Consensus, 2018 European Study Group, and 2018 American College of Gastroenterology (ACG). Surgery was considered "justified" if histopathology of the surgical specimen showed HGD/malignancy, or there was postoperative symptomatic improvement. Results: Surgery was postoperatively justified in 26/65 (40.0%) cases. All IPMNs with HGD/malignancy were detected by the 2018 ACG and the combined (absolute and relative criteria) 2018 European guidelines. The combined ("high-risk stigmata" and "worrisome features") 2017 International guideline missed 1/19 (5.3%) IPMNs with HGD/malignancy. The 2015 AGA guideline missed the most cases (11/19, 57.9%) of IPMNs with HGD/malignancy. We found the features most-associated with HGD/malignancy were pancreatic ductal dilation, and elevated CA-19-9 levels. Conclusions: Following the 2015 AGA guideline results in the highest rate of missed HGD/malignancy, but the lowest rate of operating on IPMNs without these features; meanwhile, the 2018 ACG and the combined (absolute and relative criteria) 2018 European guidelines result in more operations for IPMNs without HGD/malignancy, but the lowest rates of missed HGD/malignancy in IPMNs.
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White-tailed deer, Odocoileus virginianus Zimmermann (Artiodactyla: Cervidae), are the primary wildlife host for adult stages of blacklegged ticks (Acari: Ixodidae: Ixodes scapularis Say) and an important host for lone star ticks (Acari: Ixodidae: Amblyomma americanum Linnaeus), both of which are vectors of numerous tick-borne pathogens. The 4-poster passive deer treatment device is a topical, host-targeted method to control free-living tick populations and has been proven to successfully reduce tick abundance in several states. Aggressive behavior of white-tailed deer at concentrated feeding stations is hypothesized to interfere with the effective use of 4-poster devices and deer contact with acaricide applicators. We analyzed images collected by camera traps at 4-poster feeding stations deployed at 3 sites in Maryland and found a negative relationship between some aggressive interactions and contact with applicators. Our results emphasize the need for further investigation into whether deer social dynamics can impact 4-poster efficacy for tick control. This study serves as a reminder that intraspecific interactions are important to consider when using host-targeted acaricide approaches.
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Deer , Tick Control , Tick Infestations , Animals , Deer/parasitology , Tick Control/methods , Tick Infestations/veterinary , Tick Infestations/prevention & control , Tick Infestations/parasitology , Aggression , Ixodes/physiology , Acaricides , Amblyomma , Maryland , Ixodidae/physiologyABSTRACT
Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.
Subject(s)
Electron Transport Complex I , Mitochondrial Diseases , Mitochondrial Proteins , Humans , Electron Transport Complex I/genetics , Electron Transport Complex I/metabolism , Mitochondrial Diseases/genetics , Mitochondrial Diseases/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Mutation , Mitochondria/metabolism , Mitochondria/geneticsABSTRACT
A Newcastle disease virus (NDV)-vectored vaccine expressing clade 2.3.4.4b H5 Hemagglutinin was developed and assessed for efficacy against H5N1 highly pathogenic avian influenza (HPAI) in specific pathogen-free (SPF) chickens, broilers, and domestic ducks. In SPF chickens, the live recombinant NDV-vectored vaccine, rK148/22-H5, achieved complete survival against HPAI and NDV challenges and significantly reduced viral shedding. Notably, the live rK148/22-H5 vaccine conferred good clinical protection in broilers despite the presence of maternally derived antibodies. Good clinical protection was observed in domestic ducks, with decreased viral shedding. It demonstrated complete survival and reduced cloacal viral shedding when used as an inactivated vaccine from SPF chickens. The rK148/22-H5 vaccine is potentially a viable and supportive option for biosecurity measure, effectively protecting in chickens against the deadly clade 2.3.4.4b H5 HPAI and NDV infections. Furthermore, it aligns with the strategy of Differentiating Infected from Vaccinated Animals (DIVA).
Subject(s)
Antibodies, Viral , Chickens , Ducks , Hemagglutinin Glycoproteins, Influenza Virus , Influenza A Virus, H5N1 Subtype , Influenza in Birds , Newcastle disease virus , Vaccines, Inactivated , Vaccines, Synthetic , Virus Shedding , Animals , Chickens/immunology , Influenza in Birds/prevention & control , Influenza in Birds/immunology , Newcastle disease virus/immunology , Newcastle disease virus/genetics , Influenza A Virus, H5N1 Subtype/immunology , Influenza A Virus, H5N1 Subtype/genetics , Influenza A Virus, H5N1 Subtype/pathogenicity , Ducks/virology , Ducks/immunology , Vaccines, Inactivated/immunology , Vaccines, Inactivated/administration & dosage , Vaccines, Synthetic/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Antibodies, Viral/immunology , Antibodies, Viral/blood , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/genetics , Specific Pathogen-Free Organisms , Vaccines, Attenuated/immunology , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/genetics , Poultry Diseases/prevention & control , Poultry Diseases/virology , Poultry Diseases/immunology , Newcastle Disease/prevention & control , Newcastle Disease/immunology , Viral Vaccines/immunology , Viral Vaccines/administration & dosage , Viral Vaccines/geneticsABSTRACT
Methylene blue (MB) has been shown to reduce mortality and morbidity in vasoplegic patients after cardiac surgery. Though MB is considered to be safe, extravasation of MB leading to cutaneous toxicity has been reported. In this study, we sought to characterize MB-induced cutaneous toxicity and investigate the underlying mechanisms. To induce MB-induced cutaneous toxicity, we injected 64 adult male Sprague-Dawley rates with 200 µL saline (vehicle) or 1%, 0.1%, or 0.01% MB in the plantar hind paws. Paw swelling, skin histologic changes, and heat and mechanical hyperalgesia were measured. Injection of 1%, but not 0.1% or 0.01% MB, produced significant paw swelling compared to saline. Injection of 1% MB produced heat hyperalgesia but not mechanical hyperalgesia. Pain behaviors were unchanged following injections of 0.1% or 0.01% MB. Global transcriptomic analysis by RNAseq identified 117 differentially expressed genes (111 upregulated, 6 downregulated). Ingenuity Pathway Analysis showed an increased quantity of leukocytes, increased lipids, and decreased apoptosis of myeloid cells and phagocytes with activation of IL-1ß and Fos as the two major regulatory hubs. qPCR showed a 16-fold increase in IL-6 mRNA. Thus, using a novel rat model of MB-induced cutaneous toxicity, we show that infiltration of 1% MB into cutaneous tissue causes a dose-dependent pro-inflammatory response, highlighting potential roles of IL-6, IL-1ß, and Fos. Thus, anesthesiologists should administer dilute MB intravenously through peripheral venous catheters. Higher concentrations of MB (1%) should be administered through a central venous catheter to minimize the risk of cutaneous toxicity.
Subject(s)
Disease Models, Animal , Hyperalgesia , Inflammation , Methylene Blue , Rats, Sprague-Dawley , Skin , Animals , Male , Methylene Blue/pharmacology , Methylene Blue/administration & dosage , Hyperalgesia/pathology , Hyperalgesia/chemically induced , Inflammation/pathology , Inflammation/chemically induced , Skin/drug effects , Skin/pathology , Dose-Response Relationship, Drug , Hot Temperature , Rats , Interleukin-1beta/metabolism , Interleukin-1beta/geneticsABSTRACT
BACKGROUND: Primary endpoint measures in clinical trials are typically measures of disease severity, with patient reported outcome measures (PROMs) relegated as secondary endpoints. However validation of some PROMs may be more rigorous than that of disease severity measures, arguing for a primary role for PROMs. OBJECTIVES: This study reports on 24 peer reviewed journal articles that used the Dermatology Life Quality Index (DLQI) as primary outcome, derived from a systematic review of randomised controlled trials (RCTs) utlising DLQI covering all diseases and interventions. MATERIALS AND METHOD: The study protocol was prospectively published on the PROSPERO database, and the study followed PRISMA guidelines. Searches were made with Medline, Cochrane library, EMBASE, Web of Science, SCOPUS, CINAHL(EBSCO) and PsycINFO databases and records combined into an Endnote database. Records were filtered for duplicates and selected by study inclusion/exclusion criteria. Full text articles were sourced and data was extracted by two reviewers into a bespoke REDCap database, with a third reviewer adjudicating differences. The Jadad scoring method was used to determine risk of bias. RESULTS: Of the 3,220 publications retrieved from online searching, 457 articles met eligibility criteria and included 198,587 patients. DLQI scores were primary outcomes in 24 (5.3%) of these studies comprising 15 different diseases and 3,436 patients. Most study interventions (17/24 studies, 68%) were systemic drugs with biologics (liraglutide, alefacept, secukinumab, ustekinumab, adalimumab) accounting for five out of 25 pharmacological interventions (20%). Topical treaments comprised 32% (8 studies) whereas non-pharmacological interventions (8) were 24% of the total interventions (33). Three studies used non-traditional medicines. Eight studies were multicentred (33.3%), with trials conducted in at least 14 different countries, and four (16.7%) were conducted in multiple countries. The Jadad risk of bias scale showed that bias was uncertain or low, as 87.5% of studies had Jadad scores of ≥3. CONCLUSIONS: This study provides evidence for use of the DLQI as primary outcome in clinical trials to inform researchers' and clinicians' decisions for its further use.
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Vitamin D has been proposed as a potential strategy to mitigate age-related cognitive decline and dementia, including Alzheimer's dementia, the predominant type of dementia. Rodent studies have provided insight into the potential mechanisms underlying the role of vitamin D in Alzheimer's disease and dementia. However, inconsistencies with respect to age, sex, and genetic background of the rodent models used poses some limitations regarding scientific rigor and translation. Several human observational studies have evaluated the association of vitamin D status with cognitive decline and dementia, and the results are conflicting. Randomized clinical trials of vitamin D supplementation have included cognitive outcomes. However, most of the available trials have not been designed specifically to test the effect of vitamin D on age-related cognitive decline and dementia, so it remains questionable how much additional vitamin D will improve cognitive performance. Here we evaluate the strengths and limitations of the available evidence regarding the role of vitamin D in AD, cognitive decline, dementia.
Subject(s)
Alzheimer Disease , Dementia , Vitamin D , Humans , Vitamin D/pharmacology , Vitamin D/therapeutic use , Animals , Dietary Supplements , Vitamin D Deficiency/complicationsABSTRACT
INTRODUCTION: Chronic pain is one of the leading causes of reduced quality of life in the USA, with knee pain commonly reported. Multiple therapeutic modalities are traditionally utilized for pain management; however, some patients may have pain refractory to these techniques. Cooled radiofrequency ablation (c-RFA) of the geniculate nerve is a growing and promising therapy offering a potentially long-term solution to chronic knee pain. METHODS: This study assessed the efficacy, average duration of relief, and potential adverse events using a retrospective chart review of 406 procedures. A two-tailed paired t test was used to assess the statistical significance between pre-RFA vs. post-RFA visual analog scale (VAS) pain scores self-reported by patients. An analysis of variance (ANOVA) test was used to evaluate for statistical differences in pre-RFA pain scores and post-RFA pain scores among the categories of age, sex, body mass index (BMI), and diagnosis group. RESULTS: The mean percent in pain improvement calculated was 65.5% with an average duration of relief of 7.20 months. The average pre-RFA pain score on the VAS was 6.26 out of 10 and 2.59 out of 10 post-RFA. The ANOVA post-RFA pain scores demonstrated statistically significant differences among the categories of age and sex. A total of 54 adverse events were reported, including worsening pain, numbness, paresthesia, and knee swelling. CONCLUSION: The study demonstrated that c-RFA can potentially be utilized as an alternative safe therapy for chronic knee pain, providing pain relief with a relatively prolonged duration. Inherent challenges of retrospective studies remain a part of the limitations of this study.