Idiosyncratic drug reactions (IDRs) are poorly understood, unpredictable, and not detected in preclinical studies. Although the cause of these reactions is likely multi-factorial, one hypothesis is ...that an underlying inflammatory state lowers the tolerance to a xenobiotic. Previously used in an inflammation IDR model, bacterial lipopolysaccharide (LPS) is heterogeneous in nature, making development of standardized testing protocols difficult. Here, the use of rat tumor necrosis factor-α (TNFα) to replace LPS as an inflammatory stimulus was investigated. Sprague-Dawley rats were treated with separate preparations of LPS or TNFα, and hepatic transcriptomic effects were compared. TNFα showed enhanced consistency at the transcriptomic level compared to LPS. TNFα and LPS regulated similar biochemical pathways, although LPS was associated with more robust inflammatory signaling than TNFα. Rats were then codosed with TNFα and trovafloxacin (TVX), an IDR-associated drug, and evaluated by liver histopathology, clinical chemistry, and gene expression analysis. TNFα/TVX induced unique gene expression changes that clustered separately from TNFα/levofloxacin, a drug not associated with IDRs. TNFα/TVX cotreatment led to autoinduction of TNFα resulting in potentiation of underlying gene expression stress signals. Comparison of TNFα/TVX and LPS/TVX gene expression profiles revealed similarities in the regulation of biochemical pathways. In conclusion, TNFα could be used in lieu of LPS as an inflammatory stimulus in this model of IDRs.
There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH ...(MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions.
This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported.
We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%.
Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.
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Compound profiling technologies that enable an early assessment of cellular effects related to toxicology and pharmacology can contribute to a reduction of late stage failures in drug ...development. However, the implementation of ‐omic profiling strategies has been hampered by challenges in analysis and interpretation of these information‐rich data sets. To address this issue, we have rationally combined analytical methods that report compound‐protein interactions (Inhibitor Affinity Capture/IAC; protein arrays) with technologies that monitor down‐stream cellular effects on protein signaling (Protein‐fragment Complementation Assays) and gene expression. IAC is a mass spectrometry‐based technique that discriminates tight from weaker binding proteins using a label‐free affinity binning process. Using these orthogonal approaches and pathway analysis tools, we have: 1) provided additional comprehension of mechanisms driving relevant cellular endpoints for marketed oncology drugs; 2) revealed off‐target profiles for several experimental kinase inhibitors; 3) further elucidated mechanisms of toxicity using a series of fluoroquinolone antibiotics. The multiple lines of evidence generated from this integrated technology scheme provide higher confidence decision‐making and improves the quality of compounds that are progressed towards the clinic.
Background: Visual perception has hindered the development of blinded, placebo‐controlled ultraviolet light exposure conditions in humans. New acrylic thermoplastics that block or transmit ...ultraviolet light have visual properties that may provide a solution.
Methods: In a series of triangle taste tests, 60 subjects were tested for the ability to visually perceive ultraviolet light transmission by two of four types of acrylic thermoplastics.
Results: Forty‐six of sixty (67%) subjects were unable to visually detect ultraviolet light transmitting acrylics among ultraviolet blocking acrylics in both an ambient light background condition and an ambient light background condition with ultraviolet A light supplementation.
Conclusion: Acrylic thermoplastics allow for the production of blinded, placebo‐controlled ultraviolet light exposure conditions by eliminating visual discrimination differences between active and control groups.
In 2016, individual training programs in regional anesthesiology and acute pain medicine (RA/APM) became eligible for accreditation by the Accreditation Council for Graduate Medical Education ...(ACGME), thereby culminating a process that began 15 years earlier. Herein, we review the origins of regional anesthesia training in the USA, the events leading up to accreditation and the current state of the fellowship.
We reviewed pertinent literature on the historical aspects of RA/APM in the USA, related subspecialty training and the formation and current state of RA/APM fellowship training programs. Additionally, a survey was distributed to the directors of the 74 RA/APM fellowships that existed as of 1 January 2017 to gather up-to-date, program-specific information.
The survey yielded a 76% response rate. Mayo Clinic Rochester and Virginia Mason Medical Center likely had the first structured RA/APM fellowships with formalized curriculums and stated objectives, both starting in 1982. Most programs (86%), including ACGME and non-ACGME fellowships, came into existence after the year 2000. Six responding programs have or previously had RA/APM comingled with another subspecialty. Eight current programs originally offered unofficial or part-time fellowships in RA/APM, with fellows also practicing as attending physicians.
The history of RA/APM training in the USA is a tortuous one. It began with short 'apprenticeships' under the tutelage of the early proponents of regional anesthesia and continues today with 84 official RA/APM programs and a robust fellowship directors' group. RA/APM programs teach skills essential to the practice and improvement of anesthesiology as a specialty.
The characterization of diverse subtypes of diabetes is a dynamic field of clinical research and an active area of discussion. The objective of this study was to identify new antigenic determinants ...in the neuroendocrine autoantigen IA-2 (ICA512) and assess whether circulating autoantibodies directed to new IA-2 epitopes identify autoimmune diabetes in young and adult populations with diabetes.
Clinically diagnosed patients with type 2 diabetes (
= 258; diabetes duration: 0.01-31 years) were evaluated using a new biomarker detecting autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2 (IA-2ec). The proportion of IA-2ec autoantibodies was also evaluated in newly diagnosed patients with type 1 diabetes (
= 150; diabetes duration: 0.04-0.49 years). In addition, IA-2 (intracellular domain), GAD65, and zinc transporter 8 autoantibodies were assayed.
IA-2ec autoantibodies were detected in patients with type 1 diabetes and, surprisingly, in 5% of patients with type 2 diabetes without serologic responses to other IA-2 antigenic epitopes or other islet autoantigens. We also assessed the ability of IA-2ec-derived peptides to elicit CD4
T-cell responses by stimulating peripheral blood mononuclear cells from patients with type 1 diabetes (
= 18) and HLA-matched healthy subjects (
= 13) with peptides and staining with the peptide/DQ8-specific tetramers, observing disease-associated responses to previously unreported epitopes within IA-2ec.
We developed a new antibody biomarker identifying novel antigenic determinants within the N terminus of IA-2. IA-2ec autoantibodies can be detected in patients with type 1 diabetes and in a subgroup of adult autoimmune patients with type 2 diabetes phenotype negative for conventional islet autoantibody testing. These observations suggest that islet autoimmunity may be more common in clinically diagnosed type 2 diabetes than previously observed.
Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically ...dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.
Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated ...dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.
Abstract Study Objective To assess anesthesiologists’ familiarity with the American Society of Anesthesiologists (ASA) and American College of Surgeons (ACS) guidelines on Advance Directives in the ...perioperative setting. Design Single-center, 4-question anonymous survey. Setting Urban academic medical center. Subjects Up to 34 subjects responded to each question. Measurements and Main Results Familiarity with the ASA and ACS guidelines on Advance Directives in the perioperative setting ranged from 45% to 100%. Conclusions There was inadequate familiarity with components of the ASA and ACS guidelines on advance directives in the perioperative setting. Larger studies are required to assess anesthesiologists' familiarity with national society guidelines that directly affect patient care. Future work should investigate best practices for guideline implementation, and consequences of poor adherence to national guidelines.
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