A Serological Neoepitope Biomarker of Neutrophil Elastase-Degraded Calprotectin, Associated with Neutrophil Activity, Identifies Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease More Effectively Than Total Calprotectin.

Neutrophil activation can release neutrophil extracellular traps (NETs) in acute inflammation. NETs result in the release of human neutrophil elastase (HNE) and calprotectin, where the former can degrade the latter and generate protein fragments associated with neutrophil activity. We investigated this in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) using the novel neoepitope biomarker CPa9-HNE, quantifying a specific HNE-mediated fragment of calprotectin in serum. CPa9-HNE was compared to total calprotectin. Initially, CPa9-HNE was measured in healthy (n = 39), COPD (n = 67), and IPF (n = 16) serum using a neoepitope-specific competitive enzyme-linked immunosorbent assay. Then, a head-to-head comparison of CPa9-HNE and total calprotectin, a non-neoepitope, was conducted in healthy (n = 19), COPD (n = 25), and IPF (n = 19) participants. CPa9-HNE levels were significantly increased in COPD (p < 0.0001) and IPF subjects (p = 0.0001) when compared to healthy participants. Additionally, CPa9-HNE distinguished IPF (p < 0.0001) and COPD (p < 0.0001) from healthy participants more effectively than total calprotectin for IPF (p = 0.0051) and COPD (p = 0.0069). Here, CPa9-HNE also distinguished IPF from COPD (p = 0.045) participants, which was not observed for total calprotectin (p = 0.98). Neutrophil activity was significantly higher, as assessed via serum CPa9-HNE, for COPD and IPF compared to healthy participants. Additionally, CPa9-HNE exceeded the ability of non-neoepitope calprotectin serum measurements to separate healthy from lung disease and even COPD from IPF participants, indicating that neutrophil activity is essential for both COPD and IPF.

Evaluation of a Primary Care-Based Multidisciplinary Transition Clinic for Patients Newly Initiated on Buprenorphine in the Emergency Department.

BACKGROUND: Care transitions represent vulnerable events for patients newly initiating medications for opioid use disorder (MOUD). Multidisciplinary primary care-based transition clinics may improve care linkage and retention in MOUD treatment. Additionally, these interventions may help primary care clinicians (PCPs) overcome barriers to adopting MOUD into practice. In this evaluation, we assessed the impact of a primary care-based transition clinic for patients newly initiating buprenorphine for opioid use disorder (OUD) in the emergency department. METHODS: We conducted a retrospective program evaluation within a single academic health system involving adults who newly initiated buprenorphine for OUD through an emergency department-based program and were referred to follow up in either a dedicated multidisciplinary primary care-based transition clinic (SPARC) vs referral to usual primary care (UPC). We performed descriptive analyses comparing patient demographics, referral volume, linkage to care, treatment retention, and markers of high-quality care between the 2 groups. A log-rank test was used to determine the difference in probabilities of retention between SPARC and UPC over 6 months. RESULTS: Over 12 months, the number of referrals to SPARC was greater than to UPC (N = 64 vs N = 26). About 58% of patients referred to SPARC attended an initial visit vs 38% referred to UPC. Treatment retention was consistently greater in SPARC than UPC (1 m: 90% vs 60%; 3 m: 76% vs 40%; 6 m: 60% vs 30%). Markers of care quality including naloxone provision (100% vs 80%) and infectious screening (81% vs 40%) were greater in SPARC clinic. SPARC was associated with a statistically significant increased probability of retention in treatment as compared to UPC (P < .01). CONCLUSIONS: In this observational evaluation, a primary care-based multidisciplinary transition clinic for patients initiating buprenorphine MOUD was associated with expanded access to longitudinal OUD treatment and superior linkage to care, retention in care, and quality of care compared to referral to usual primary care. Further research using a more rigorous research design is required to further evaluate these findings.

A serologically assessed neo-epitope biomarker of cellular fibronectin degradation is related to pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) remodeling, herein ECM degradation. Fibronectin (FN) is an important component of the ECM that is produced by multiple cell types, including fibroblasts. Extra domain B (EDB) is specific for a cellular FN isoform which is found in the ECM. We sought to develop a non-invasive test to investigate whether matrix metalloproteinase 8 (MMP-8) degradation of EDB in cellular FN results in a specific protein fragment that can be assessed serologically and if levels relate to pulmonary fibrosis. METHOD: Cellular FN was cleaved in vitro by MMP-8 and a protein fragment was identified by mass spectrometry. A monoclonal antibody (mAb) was generated, targeting a neo-epitope originating from EDB in cellular FN. Utilizing this mAb, a neo-epitope specific enzyme-linked immunosorbent assay (FN-EDB) was developed and technically validated. Serum FN-EDB was assessed in an IPF cohort (n = 98), registered at clinicaltrials.gov (NCT02818712), and in healthy controls (n = 35). RESULTS: The FN-EDB assay had high specificity for the MMP-8 degraded neo-epitope and was technically robust. FN-EDB serum levels were not influenced by age, sex, ethnicity, or BMI. Moreover, FN-EDB serum levels were significantly higher in IPF patients (median 31.38 [IQR 25.79-46.84] ng/mL) as compared to healthy controls (median 28.05 [IQR 21.58-33.88] ng/mL, p = 0.023). CONCLUSION: We developed the neo-epitope specific FN-EDB assay, a competitive ELISA, as a tool for serological assessment of MMP-8 mediated degradation of EDB in cellular FN. This study indicates that degradation of EDB in cellular FN is elevated in IPF and warrants further investigation.

Comparing Visual Outcomes of Light Adjustable Intraocular Lenses in Patients With and Without Prior History of Corneal Refractive Surgery.

PURPOSE: To assess visual outcomes of light adjustable intraocular lens (LAL; Calhoun Vision, Inc) implantation after cataract extraction in patients with a history of corneal refractive surgery. METHODS: The records of patients who received LALs with and without a history of corneal refractive surgery were retrospectively reviewed. Data for 51 eyes (30 patients) with a history of corneal refractive surgery and 52 eyes (44 patients) without refractive surgery were analyzed. A total of 36 eyes of patients with and 43 eyes of patients without a history of corneal refractive surgery had 12-month follow-up data available. The primary outcomes evaluated were uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA). RESULTS: At 12 months, 31% of eyes with a history of corneal refractive surgery had a UDVA of 20/20 or better and 97% of eyes were 20/40 or better. In contrast, 63% of patients with no history of corneal refractive surgery had 20/20 UDVA or better at 12 months and 100% were 20/40 or better. Of patients with a history of corneal refractive surgery, 55% and 83% of eyes at 12 months were within ±0.50 and ±1.00 diopters, respectively, of the target refraction compared to 89% and 96% of eyes without a history of corneal refractive surgery. CONCLUSIONS: LALs are a promising platform for achieving excellent visual outcomes following cataract surgery. Patients with a prior history of corneal refractive surgery can achieve excellent visual outcomes with the LAL. However, this study found that patients with a history of corneal refractive surgery demonstrated less predictable visual acuity outcomes when compared to patients without a history of corneal refractive surgery. [J Refract Surg. 2023;39(5):311-318.].

BDNF rs6265 Met carriers with alcohol use disorder show greater age-related decline of N-acetylaspartate in left dorsolateral prefrontal cortex.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is implicated in neuronal and glial cell growth and differentiation, synaptic plasticity, and apoptotic mechanisms. A single-nucleotide polymorphism of the BDNF rs6265 gene may contribute to the pattern and magnitude of brain metabolite abnormalities apparent in those with an Alcohol Use Disorder (AUD). We predicted that methionine (Met) carriers would demonstrate lower magnetic resonance spectroscopy (MRS) measures of N-acetylaspartate level (NAA) and greater age-related decline in NAA than valine (Val) homozygotes. METHODS: Veterans with AUD (n=95; 46±12 years of age, min = 25, max = 71) were recruited from VA Palo Alto residential treatment centers. Single voxel MRS, at 3 Tesla, was used to obtain NAA, choline (Cho) and creatine (Cr) containing compounds from the left dorsolateral prefrontal cortex (DLPFC). Metabolite spectra were fit with LC Model and NAA and Cho were standardized to total Cr level and NAA was also standardized to Cho. RESULTS: Val/Met (n=35) showed markedly greater age-related decline in left DLPFC NAA/Cr level than Val/Val (n=60); no differences in mean metabolite levels were observed between Val/Met and Val/Val. Val/Met demonstrated greater frequency of history of MDD and higher frequency of cannabis use disorder over 12 months prior to study. CONCLUSIONS: The greater age-related decline in left DLPFC NAA/Cr and the higher frequency of MDD history and Cannabis Use disorder in BDNF rs6265 Met carriers with AUD are novel and may have implications for non-invasive brain stimulation targeting the left DLFPC and other psychosocial interventions typically utilized in the treatment of AUD.

Corneal opacities after small-incision lenticule extraction.

A 36-year-old woman was referred to our clinic in October 2021 with suboptimal vision at intermediate and near distances and halos and photophobia after a small-incision lenticule extraction (SMILE) in December 2019. The patient needs to increase font size of her computer to 150% to read text, but images still appear blurred. She indicates that sunglasses seem to improve her contrast. Preoperatively, her refractive error was -2.5 diopters (D) and -2.25 D for right and left eyes. The optical zone size of the SMILE procedure was 6.8 mm. There is no further information available on the peroperative course of the SMILE procedure. Her uncorrected distance visual acuity (UDVA) is 20/20 in both eyes and does not improve with correction. The Schirmer tear test is 14 to 13 mm. Slitlamp biomicroscopy of the right eye and the left eye reveals hyperreflective small opacities in the anterior one-third of the corneal stroma ( Figures 1 and 2JOURNAL/jcrs/04.03/02158034-202209000-00021/figure1/v/2022-08-29T115553Z/r/image-tiffJOURNAL/jcrs/04.03/02158034-202209000-00021/figure2/v/2022-08-29T115553Z/r/image-tiff ). No other abnormalities are seen. The scotopic pupil sizes are 6.41 and 6.73 mm. Straylight measurements are within normal limits. Higher-order aberrations (HOAs) measure for the right eye (6.03 mm pupil) 0.818 µm and for the left eye (6.17 mm pupil) 0.560 µm. The corneal Scheimpflug tomography quad maps for both eyes are shown in Supplemental Figures 1 and 2 ( http://links.lww.com/JRS/A663 , http://links.lww.com/JRS/A664 ). What is your diagnosis or are additional diagnostic methodologies needed to establish a diagnosis? What is your treatment advice for this patient?

Older patients' autonomy when cared for at emergency departments.

BACKGROUND: Older patients in emergency care often have complex needs and may have limited ability to make their voices heard. Hence, there are ethical challenges for healthcare professionals in establishing a trustful relationship to determine the patient's preferences and then decide and act based on these preferences. With this comes further challenges regarding how the patient's autonomy can be protected and promoted. AIM: To describe nurses' experiences of dealing with older patients' autonomy when cared for in emergency departments (EDs). RESEARCH DESIGN: This study adopted reflective lifeworld theory and a phenomenological design. PARTICIPANTS AND RESEARCH CONTEXT: A total of 13 open-ended interviews were performed with nurses working at two EDs in Sweden. ETHICAL CONSIDERATIONS: The study was reviewed by the Ethical Advisory Board in South East Sweden and conducted according to the Declaration of Helsinki. All participants gave consent. FINDINGS: Nurses' experiences of dealing with older patients' autonomy in EDs are characterized by moving in a conflicting uphill struggle, indicating obscure thoughts on how patient autonomy can be protected in an ethically challenging context. The phenomenon is further described with its meaning constituents: 'Being hampered by prioritization under stress', 'Balancing paternalism and patient autonomy', 'Making decisions without consent in the patient's best interests' and 'Being trapped by notions of legitimate care needs'. CONCLUSION: Stressful work conditions and lacking organizational strategies in EDs contribute to nurses maintaining unjustified paternalistic care, regardless of the patient's ability and medical condition, and questioning who has legitimacy for participating in decisions about care. The nurses' protection and promotion of older patients' autonomy is dependent on the opportunity, ability and willingness to create a patient relationship where the patient's voice and preferences are valued as important. Consequently, strategies are needed to improve patient autonomy in EDs based on the idea of 'relational autonomy'.

Improved nonclinical safety profile of a novel, highly selective inhibitor of the immunoproteasome subunit LMP7 (M3258).

M3258 is the first selective inhibitor of the immunoproteasome subunit LMP7 (Large multifunctional protease 7) in early clinical development with the potential to improve therapeutic utility in patients of multiple myeloma (MM) or other hematological malignancies. Safety pharmacology studies with M3258 did not reveal any functional impairments of the cardiovascular system in several in vitro tests employing human cardiomyocytes and cardiac ion channels (including hERG), guinea pig heart refractory period and force contraction, and rat aortic contraction as well as in cardiovascular function tests in dogs. Following single dose M3258 administration to rats, no changes were observed on respiratory function by using whole body plethysmography, nor did it change (neuro)behavioral parameters in a battery of tests. Based on pivotal 4-week toxicity studies with daily oral dosing of M3258, the identified key target organs of toxicity were limited to the lympho-hematopoietic system in rats and dogs, and to the intestine with its local lymphoid tissues in dogs only. Importantly, the stomach, nervous system, heart, lungs, and kidneys, that may be part of clinically relevant toxicities as reported for pan-proteasome inhibitors, were spared with M3258. Therefore, it is anticipated that by targeting highly selective and potent inhibition of LMP7, the resulting favorable safety profile of M3258 together with the maintained potent anti-tumor activity as previously reported in mouse MM xenograft models, may translate into an improved benefit-risk profile in MM patients.

Dimensions of Craving Interact with COMT Genotype to Predict Relapse in Individuals with Alcohol Use Disorder Six Months after Treatment.

(1) Background: Alcohol use disorder (AUD) is associated with poor medical, psychological, and psychosocial outcomes and approximately 60% of individuals with AUD relapse six months after treatment. Craving is a core aspect of AUD and associated with high risk of relapse. One promising avenue to improve outcomes may be in understanding the relationship between COMT genotype, craving, and treatment outcomes. (2) Methods: To this end, we assessed craving, recent drinking history, and impulsivity in 70 individuals with AUD undergoing a standard course of treatment at a regional Veteran Affairs (VA) medical center. Saliva samples were collected to determine COMT genotype. In this prospective observational study, participants were followed for six months to determine who went on to relapse after treatment. (3) Results: Results revealed a significant interaction between craving and catechol-O-methyltransferse (COMT) genotype in predicting relapse. Post hoc exploratory analyses indicated that Met/Met homozygotes reported the highest levels of craving, and craving was associated with recent drinking history. Among Val/Val homozygotes, who had higher rates of relapse, craving was associated with impulsivity. (4) Conclusions: These associations highlight that specific profiles of psychological and biological factors may be important in understanding which individuals are at highest risk of relapse following treatment. Future studies that build on these findings are warranted.

A comparative study of S/MAR prediction tools.

BACKGROUND: S/MARs are regions of the DNA that are attached to the nuclear matrix. These regions are known to affect substantially the expression of genes. The computer prediction of S/MARs is a highly significant task which could contribute to our understanding of chromatin organisation in eukaryotic cells, the number and distribution of boundary elements, and the understanding of gene regulation in eukaryotic cells. However, while a number of S/MAR predictors have been proposed, their accuracy has so far not come under scrutiny. RESULTS: We have selected S/MARs with sufficient experimental evidence and used these to evaluate existing methods of S/MAR prediction. Our main results are: 1.) all existing methods have little predictive power, 2.) a simple rule based on AT-percentage is generally competitive with other methods, 3.) in practice, the different methods will usually identify different sub-sequences as S/MARs, 4.) more research on the H-Rule would be valuable. CONCLUSION: A new insight is needed to design a method which will predict S/MARs well. Our data, including the control data, has been deposited as additional material and this may help later researchers test new predictors.

Increasing feasibility of optimal gene network estimation.

Disentangling networks of regulation of gene expression is a major challenge in the field of computational biology. Harvesting the information contained in microarray data sets is a promising approach towards this challenge. We propose an algorithm for the optimal estimation of Bayesian networks from microarray data, which reduces the CPU time and memory consumption of previous algorithms. We prove that the space complexity can be reduced from O(n(2) x 2(n)) to O(2(n)), and that the expected calculation time can be reduced from O(n(2) x 2(n)) to O(n x 2(n)), where n is the number of genes. We make intrinsic use of a limitation of the maximal number of regulators of each gene, which has biological as well as statistical justifications. The improvements are significant for some applications in research.