Threats to external validity in the neuroprediction of substance use treatment outcomes.

Background: Tools predicting individual relapse risk would invaluably inform clinical decision-making (e.g. level-of-care) in substance use treatment. Studies of neuroprediction - use of neuromarkers to predict individual outcomes - have the dual potential to create such tools and inform etiological models leading to new treatments. However, financial limitations, statistical power demands, and related factors encourage restrictive selection criteria, yielding samples that do not fully represent the target population. This problem may be further compounded by a lack of statistical optimism correction in neuroprediction research, resulting in predictive models that are overfit to already-restricted samples.Objectives: This systematic review aims to identify potential threats to external validity related to restrictive selection criteria and underutilization of optimism correction in the existing neuroprediction literature targeting substance use treatment outcomes.Methods: Sixty-seven studies of neuroprediction in substance use treatment were identified and details of sample selection criteria and statistical optimism correction were extracted.Results: Most publications were found to report restrictive selection criteria (e.g. excluding psychiatric (94% of publications) and substance use comorbidities (69% of publications)) that would rule-out a considerable portion of the treatment population. Furthermore, only 21% of publications reported optimism correction.Conclusion: Restrictive selection criteria and underutilization of optimism correction are common in the existing literature and may limit the generalizability of identified neural predictors to the target population whose treatment they would ultimately inform. Greater attention to the inclusivity and generalizability of addiction neuroprediction research, as well as new opportunities provided through open science initiatives, have the potential to address this issue.

Dynamic early warning scores for predicting clinical deterioration in patients with respiratory disease.

BACKGROUND: The National Early Warning Score-2 (NEWS-2) is used to detect patient deterioration in UK hospitals but fails to take account of the detailed granularity or temporal trends in clinical observations. We used data-driven methods to develop dynamic early warning scores (DEWS) to address these deficiencies, and tested their accuracy in patients with respiratory disease for predicting (1) death or intensive care unit admission, occurring within 24 h (D/ICU), and (2) clinically significant deterioration requiring urgent intervention, occurring within 4 h (CSD). METHODS: Clinical observations data were extracted from electronic records for 31,590 respiratory in-patient episodes from April 2015 to December 2020 at a large acute NHS Trust. The timing of D/ICU was extracted for all episodes. 1100 in-patient episodes were annotated manually to record the timing of CSD, defined as a specific event requiring a change in treatment. Time series features were entered into logistic regression models to derive DEWS for each of the clinical outcomes. Area under the receiver operating characteristic curve (AUROC) was the primary measure of model accuracy. RESULTS: AUROC (95% confidence interval) for predicting D/ICU was 0.857 (0.852-0.862) for NEWS-2 and 0.906 (0.899-0.914) for DEWS in the validation data. AUROC for predicting CSD was 0.829 (0.817-0.842) for NEWS-2 and 0.877 (0.862-0.892) for DEWS. NEWS-2 ≥ 5 had sensitivity of 88.2% and specificity of 54.2% for predicting CSD, while DEWS ≥ 0.021 had higher sensitivity of 93.6% and approximately the same specificity of 54.3% for the same outcome. Using these cut-offs, 315 out of 347 (90.8%) CSD events were detected by both NEWS-2 and DEWS, at the time of the event or within the previous 4 h; 12 (3.5%) were detected by DEWS but not by NEWS-2, while 4 (1.2%) were detected by NEWS-2 but not by DEWS; 16 (4.6%) were not detected by either scoring system. CONCLUSION: We have developed DEWS that display greater accuracy than NEWS-2 for predicting clinical deterioration events in patients with respiratory disease. Prospective validation studies are required to assess whether DEWS can be used to reduce missed deteriorations and false alarms in real-life clinical settings.

Classification of acute appendicitis (CAA): treatment directed new classification based on imaging (ultrasound, computed tomography) and pathology.

PURPOSE: Acute appendicitis (AA) is amongst the most common causes of acute abdominal pain. In spite of progress based on risk stratifications, "negative" appendectomies are performed in up to 30% of patients whilst the appendix perforates in others. Preoperative classification of AA based on imaging is therefore recommended. The aim was to classify AA based on imaging (ultrasound/US, computed tomography/CT), surgical pathology, and/or histopathology in order to differentiate between complicated and uncomplicated AA. A new classification of acute appendicitis (CAA) shall be illustrated by typical US and CT images and be employed in a diagnostic and therapeutic algorithm. METHODS: Medline, Embase, and the Cochrane Library were searched. Any study after 1970, which investigated clinical scores, pathology, US, CT, magnetic resonance imaging, and treatment of AA, was included. Typical images were taken from the author's image database. RESULTS: Five main types of AA are defined, normal appendix (type 0), nonvisualised appendix (type X), uncomplicated AA (type 1), complicated AA without perforation (type 2), and complicated AA with perforation (type 3). The imaging modality is indicated by an additional letter, e.g., type p3b for free perforation on pathology. Standardised reporting of the appendix evaluation by US and CT is presented, as well as algorithms for AA management. Imaging features indicating imminent perforation, as well as likely recurrence, were both classified as complicated AA. CONCLUSION: Imaging is mandatory in suspected AA. The CAA clearly separates uncomplicated from complicated forms of AA allowing nonoperative management in selected patients with uncomplicated forms of AA.

Evaluating effects of episodic future thinking on valuation of delayed reward in cocaine use disorder: a pilot study.

Background: Episodic future thinking (EFT; i.e., envisioning oneself in future contexts) has been demonstrated to reduce discounting of future reward in healthy adults. While this approach has the potential to support future-oriented decision-making in substance use recovery, the impact of EFT on discounting behavior in illicit stimulant users has not yet been evaluated.Objectives: This pilot study aimed to (1) assess the feasibility of utilizing EFT methods in individuals with cocaine use disorder (CUD) and (2) conduct preliminary measurement of the EFT effect on discounting behavior in this population.Methods: Eighteen treatment-seeking individuals with CUD (17 males) were interviewed about positive and neutral events expected to occur at a range of future latencies. Future event information identified by participants was subsequently included on a subset of trials in an intertemporal choice task to promote EFT; within-subject differences in discounting between standard and EFT conditions were evaluated.Results: Participants identified relevant events and demonstrated decreased discounting of future reward when event descriptors were included (relative to discounting without event descriptors; p = .039). It was further noted that most events identified by participants were goals, rather than plans or significant dates.Conclusion: While methods previously used to study the effect of EFT on discounting behavior in healthy individuals are also effective in individuals with CUD, methodological factors - including types of events identified - should be carefully considered in future work. These preliminary findings suggest that EFT can reduce impulsive decision-making in cocaine use disorder and may therefore have therapeutic value.

Protein Paucimannosylation Is an Enriched N-Glycosylation Signature of Human Cancers.

While aberrant protein glycosylation is a recognized characteristic of human cancers, advances in glycoanalytics continue to discover new associations between glycoproteins and tumorigenesis. This glycomics-centric study investigates a possible link between protein paucimannosylation, an under-studied class of human N-glycosylation [Man1-3 GlcNAc2 Fuc0-1 ], and cancer. The paucimannosidic glycans (PMGs) of 34 cancer cell lines and 133 tissue samples spanning 11 cancer types and matching non-cancerous specimens are profiled from 467 published and unpublished PGC-LC-MS/MS N-glycome datasets collected over a decade. PMGs, particularly Man2-3 GlcNAc2 Fuc1 , are prominent features of 29 cancer cell lines, but the PMG level varies dramatically across and within the cancer types (1.0-50.2%). Analyses of paired (tumor/non-tumor) and stage-stratified tissues demonstrate that PMGs are significantly enriched in tumor tissues from several cancer types including liver cancer (p = 0.0033) and colorectal cancer (p = 0.0017) and is elevated as a result of prostate cancer and chronic lymphocytic leukaemia progression (p < 0.05). Surface expression of paucimannosidic epitopes is demonstrated on human glioblastoma cells using immunofluorescence while biosynthetic involvement of N-acetyl-ß-hexosaminidase is indicated by quantitative proteomics. This intriguing association between protein paucimannosylation and human cancers warrants further exploration to detail the biosynthesis, cellular location(s), protein carriers, and functions of paucimannosylation in tumorigenesis and metastasis.

Abeta, oxidative stress in Alzheimer disease: evidence based on proteomics studies.

The initiation and progression of Alzheimer disease (AD) is a complex process not yet fully understood. While many hypotheses have been provided as to the cause of the disease, the exact mechanisms remain elusive and difficult to verify. Proteomic applications in disease models of AD have provided valuable insights into the molecular basis of this disorder, demonstrating that on a protein level, disease progression impacts numerous cellular processes such as energy production, cellular structure, signal transduction, synaptic function, mitochondrial function, cell cycle progression, and proteasome function. Each of these cellular functions contributes to the overall health of the cell, and the dysregulation of one or more could contribute to the pathology and clinical presentation in AD. In this review, foci reside primarily on the amyloid ß-peptide (Aß) induced oxidative stress hypothesis and the proteomic studies that have been conducted by our laboratory and others that contribute to the overall understanding of this devastating neurodegenerative disease.

Increased O-GlcNAc levels correlate with decreased O-GlcNAcase levels in Alzheimer disease brain.

The potential role of the posttranslational modification of proteins with O-linked N-acetyl-ß-d-glucosamine (O-GlcNAc) in the pathogenesis of Alzheimer disease (AD) has been studied extensively, yet the exact function of O-GlcNAc in AD remains elusive. O-GlcNAc cycling is facilitated by only two highly conserved enzymes: O-GlcNAc transferase (OGT) catalyzes the addition, while O-GlcNAcase (OGA) catalyzes the removal of GlcNAc from proteins. Studies analyzing global O-GlcNAc levels in AD brain have produced inconsistent results and the reasons for altered O-GlcNAcylation in AD are still poorly understood. In this study, we show a 1.2-fold increase in cytosolic protein O-GlcNAc modification in AD brain when compared to age-matched controls. Interestingly, O-GlcNAc changes seem to be attributable to differential modification of a few individual proteins. While our finding of augmented O-GlcNAcylation concurs with some reports, it is contrary to others demonstrating decreased O-GlcNAc levels in AD brain. These conflicting results emphasize the need for further studies providing conclusive evidence on the subject of O-GlcNAcylation in AD. We further demonstrate that, while OGT protein levels are unaffected in AD, OGA protein levels are significantly decreased to 75% of those in control samples. In addition, augmented protein O-GlcNAc modification correlates to decreased OGA protein levels in AD subjects. While OGA inhibitors are already being tested for AD treatment, our results provide a strong indication that the general subject of O-GlcNAcylation and specifically its regulation by OGA and OGT in AD need further investigation to conclusively elucidate its potential role in AD pathogenesis and treatment.

The validation of a computer-based food record for older adults: the Novel Assessment of Nutrition and Ageing (NANA) method.

Dietary assessment in older adults can be challenging. The Novel Assessment of Nutrition and Ageing (NANA) method is a touch-screen computer-based food record that enables older adults to record their dietary intakes. The objective of the present study was to assess the relative validity of the NANA method for dietary assessment in older adults. For this purpose, three studies were conducted in which a total of ninety-four older adults (aged 65-89 years) used the NANA method of dietary assessment. On a separate occasion, participants completed a 4 d estimated food diary. Blood and 24 h urine samples were also collected from seventy-six of the volunteers for the analysis of biomarkers of nutrient intake. The results from all the three studies were combined, and nutrient intake data collected using the NANA method were compared against the 4 d estimated food diary and biomarkers of nutrient intake. Bland-Altman analysis showed a reasonable agreement between the dietary assessment methods for energy and macronutrient intake; however, there were small, but significant, differences for energy and protein intake, reflecting the tendency for the NANA method to record marginally lower energy intakes. Significant positive correlations were observed between urinary urea and dietary protein intake using both the NANA and the 4 d estimated food diary methods, and between plasma ascorbic acid and dietary vitamin C intake using the NANA method. The results demonstrate the feasibility of computer-based dietary assessment in older adults, and suggest that the NANA method is comparable to the 4 d estimated food diary, and could be used as an alternative to the food diary for the short-term assessment of an individual's dietary intake.

Telehealth-Based Contingency Management Targeting Stimulant Abstinence: A Case Series From the COVID-19 Pandemic.

OBJECTIVE: Contingency management (CM) is the gold standard treatment for stimulant use disorder but typically requires twice- to thrice-weekly in-person treatment visits to objectively verify abstinence and deliver therapeutic incentives. There has been growing interest in telehealth-based delivery of CM to support broad access to this essential intervention--a need that has been emphatically underscored by the COVID-19 pandemic. Herein, we present observations from initial efforts to develop and test a protocol for telehealth-based delivery of prize-based CM treatment incentivizing stimulant abstinence. METHOD: Four participants engaged in hybrid courses of CM, including one or more telehealth-based treatment sessions, involving self-administered oral fluid testing to confirm abstinence. Observations from initial participants informed iterative improvements to telehealth procedures, and a 12-week course of telehealth-based CM was subsequently offered to two additional participants to further evaluate preliminary feasibility and acceptability. RESULTS: In most cases, participants were able to successfully join telehealth treatment sessions, self-administer oral fluid testing, and share oral fluid test results to verify stimulant abstinence. However, further improvements in telehealth-based toxicology testing may be necessary to interpret test results accurately and reliably, especially when colorimetric immunoassay results reflect substance concentrations near the cutoff for point-of-care testing devices. CONCLUSIONS: Preliminary findings suggest that telehealth-based CM is sufficiently feasible and acceptable to support future development, in particular through improved methods for remote interpretation and verification of test results. This is especially important in CM, wherein accurate and reliable detection of both early and sustained abstinence is crucial for appropriate delivery of therapeutic incentives.

Non-invasive Physical Plasma Modulates Macrophage Polarization: A Potential Strategy for Tumor Microenvironment Remodeling.

BACKGROUND/AIM: Non-invasive physical plasma (NIPP) has shown promise in the treatment of cancer. However, conflicting results have been reported regarding the effect of NIPP on macrophage polarization. As tumor-associated macrophages (TAMs) are essential in the regulation of cancer development, this study aimed to determine the role of NIPP treatment in macrophage polarization and tumor-microenvironment (TME) remodeling. MATERIALS AND METHODS: A portable NIPP device, Plasma Care (Terraplasma Medical, Garching, Germany), was employed as the source of NIPP. The human monocytic cell line THP-1 was adopted as the cell model for macrophage differentiation and polarization. The effects of NIPP treatment on temperature, pH value, and oxidative stress induction of the culture medium were examined to validate the feasibility of applying the NIPP device in subsequent cell treatment. The changes in morphology, viability, and proliferation of THP-1 cells after NIPP treatment were determined. The expression of M1/M2 macrophage markers was examined by real-time quantitative polymerase chain reaction. RESULTS: No significant changes were observed in temperature and pH value after NIPP treatment, while the formation of hydrogen peroxide was promoted in a time-dependent manner. Cell morphology, viability, and proliferation were not affected by up to 6 minutes of NIPP treatment. In monocytes, 6 minutes of NIPP treatment significantly increased the expression of M1 markers (TNF-α and IL-6) and suppressed the M2 marker (CD206), findings which were consistent in the monocyte-derived macrophages. Furthermore, NIPP treatment also significantly promoted M1 polarization in the monocyte-derived macrophages induced by phorbol 12-myristate 13-acetate. CONCLUSION: NIPP is a safe and robust oxidative stress inducer and showed potential in TAM regulation by promoting M1 macrophage polarization.

Overcoming donor variability and risks associated with fecal microbiota transplants through bacteriophage-mediated treatments.

BACKGROUND: Fecal microbiota transplantation (FMT) and fecal virome transplantation (FVT, sterile filtrated donor feces) have been effective in treating recurrent Clostridioides difficile infections, possibly through bacteriophage-mediated modulation of the gut microbiome. However, challenges like donor variability, costly screening, coupled with concerns over pathogen transfer (incl. eukaryotic viruses) with FMT or FVT hinder their wider clinical application in treating less acute diseases. METHODS: To overcome these challenges, we developed methods to broaden FVT's clinical application while maintaining efficacy and increasing safety. Specifically, we employed the following approaches: (1) chemostat-fermentation to reproduce the bacteriophage FVT donor component and remove eukaryotic viruses (FVT-ChP), (2) solvent-detergent treatment to inactivate enveloped viruses (FVT-SDT), and (3) pyronin-Y treatment to inhibit RNA virus replication (FVT-PyT). We assessed the efficacy of these processed FVTs in a C. difficile infection mouse model and compared them with untreated FVT (FVT-UnT), FMT, and saline. RESULTS: FVT-SDT, FVT-UnT, and FVT-ChP reduced the incidence of mice reaching the humane endpoint (0/8, 2/7, and 3/8, respectively) compared to FMT, FVT-PyT, and saline (5/8, 7/8, and 5/7, respectively) and significantly reduced the load of colonizing C. difficile cells and associated toxin A/B levels. There was a potential elimination of C. difficile colonization, with seven out of eight mice treated with FVT-SDT testing negative with qPCR. In contrast, all other treatments exhibited the continued presence of C. difficile. Moreover, the results were supported by changes in the gut microbiome profiles, cecal cytokine levels, and histopathological findings. Assessment of viral engraftment following FMT/FVT treatment and host-phage correlations analysis suggested that transfer of phages likely were an important contributing factor associated with treatment efficacy. CONCLUSIONS: This proof-of-concept study shows that specific modifications of FVT hold promise in addressing challenges related to donor variability and infection risks. Two strategies lead to treatments significantly limiting C. difficile colonization in mice, with solvent/detergent treatment and chemostat propagation of donor phages emerging as promising approaches. Video Abstract.

Neuropilin2 in Mesenchymal Stromal Cells as a Potential Novel Therapeutic Target in Myelofibrosis.

Bone marrow fibrosis in myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML) is associated with poor prognosis and early treatment failure. Myelofibrosis (MF) is accompanied by reprogramming of multipotent bone marrow mesenchymal stromal cells (MSC) into osteoid and fiber-producing stromal cells. We demonstrate NRP2 and osteolineage marker NCAM1 (neural cell adhesion molecule 1) expression within the endosteal niche in normal bone marrow and aberrantly in MPN, MDS MPN/MDS overlap syndromes and AML (n = 99), as assessed by immunohistochemistry. Increased and diffuse expression in mesenchymal stromal cells and osteoblasts correlates with high MF grade in MPN (p < 0.05 for NRP2 and NCAM1). Single cell RNA sequencing (scRNAseq) re-analysis demonstrated NRP2 expression in endothelial cells and partial co-expression of NRP2 and NCAM1 in normal MSC and osteoblasts. Potential ligands included transforming growth factor ß1 (TGFB1) from osteoblasts and megakaryocytes. Murine ThPO and JAK2V617F myelofibrosis models showed co-expression of Nrp2 and Ncam1 in osteolineage cells, while fibrosis-promoting MSC only express Nrp2. In vitro experiments with MC3T3-E1 pre-osteoblasts and analysis of Nrp2-/- mouse femurs suggest that Nrp2 is functionally involved in osteogenesis. In summary, NRP2 represents a potential novel druggable target in patients with myelofibrosis.

Secretory expression of biologically active human Herpes virus interleukin-10 analogues in Escherichia coli via a modified Sec-dependent transporter construct.

BACKGROUND: Interleukin-10 homologues encoded by Herpes viruses such as Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) hold interesting structural and biological characteristics compared to human interleukin-10 (hIL-10) that render these proteins promising candidates for therapeutic application in inflammatory bowel disease (IBD). Intestinal delivery of cytokines using bacterial carriers as chassis represents a novel approach for treatment of IBD patients. For proof of concept, a Sec-dependent transporter construct was designed for secretory expression of recombinant viral IL-10 proteins in the periplasm of Escherichia coli laboratory strain BL21 (DE3), which might serve as part of a prospective lysis based delivery and containment system. RESULTS: The signal peptide of E. coli outer membrane protein F fused to the mature form of the viral IL-10 proteins enabled successful transport into the periplasm, a compartment which seems crucial for proper assembly of the dimeric configuration of the cytokines. Cytokine concentrations in different bacterial compartments were determined by ELISA and achieved yields of 67.8 ng/ml ± 24.9 ng/ml for HCMV IL-10 and 1.5 µg/ml ± 841.4 ng/ml for EBV IL-10 in the periplasm. Immunoblot analysis was used to confirm the correct size of the E. coli-derived recombinant cytokines. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) as part of the signal transduction cascade after IL-10 receptor interaction, as well as suppression of tumor necrosis factor α (TNF-α) release of lipopolysaccharide-stimulated mouse macrophages were used as read-out assays for proving in vitro biological activity of the E. coli derived, recombinant viral IL-10 counterparts. CONCLUSIONS: In this study, proof of principle is provided that E. coli cells are a suitable chassis for secretory expression of viral IL-10 cytokines encoded by codon-optimized synthetic genes fused to the E. coli ompF signal sequence. In vitro biological activity evidenced by activation of transcription factor STAT3 and suppression of TNF-α in mammalian cell lines was shown to be strictly dependent on export of viral IL-10 proteins into the periplasmic compartment. E. coli might serve as carrier system for in situ delivery of therapeutic molecules in the gut, thus representing a further step in the development of novel approaches for treatment of IBD.

Patients with cocaine use disorder exhibit reductions in delay discounting with episodic future thinking cues regardless of incarceration history.

Research examining episodic future thinking (EFT; i.e., imagining oneself in future contexts) in community samples has demonstrated reduced discounting of delayed rewards when personalized event cues are included to prompt EFT related to reward latencies. While this EFT effect was recently demonstrated in individuals with substance use disorders, it is not yet known if it manifests similarly in individuals with and without a significant incarceration history-the latter being at elevated risk for negative outcomes including criminal recidivism. Individuals with cocaine use disorder (n = 35) identified personally-relevant future events and participated in a computerized delay discounting task, involving decisions between smaller immediate rewards or larger delayed rewards with and without EFT cues. Individuals with (n = 19) and without (n = 16) a significant history of incarceration were identified using the Addiction Severity Index-Lite. A significant reduction in discounting rates was observed when event cues were included to promote EFT (p = 0.02); however, there was no main effect of incarceration history on discounting behavior, or interaction between episodic future thinking condition and incarceration history. Results suggest personalized cues included to evoke EFT reduce discounting behavior in individuals with cocaine use disorder, regardless of incarceration history. EFT-based interventions may therefore have promise to reduce impulsive decision-making in individuals with cocaine use disorder with and without a significant history of incarceration, potentially supporting improved outcomes with respect to both substance use and future criminality.

Unusual paraneoplastic syndromes in pancreatic cancer: a case report of Lambert-Eaton myasthenic syndrome (LEMS) associated with intraductal papillary mucinous cancer of the pancreas.

Background: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the neuromuscular junction. It can occur as a paraneoplastic disorder associated with various types of carcinomas, usually small cell lung cancer or as an autoimmune disease. LEMS can be misdiagnosed as myasthenia gravis or as an oncological sequela, causing delays in diagnosis. We present a rare case of a male adult with confirmed LEMS occurring with pancreatic carcinoma. Case Description: A 66-year-old man presented with a newly diagnosed pancreatic tumor. He had been experiencing weakness and fatigue in his lower extremities since the summer of 2020. Over time, the weakness progressed to include his proximal upper extremity muscles. Dysphonia, dysarthria, decreased appetite and significant weight loss were also observed. A computed tomography (CT) scan revealed a 3 cm locally resectable cystic tumor in the pancreatic head. Blood tests showed elevated carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) levels. A Whipple procedure was performed, which revealed a poorly differentiated pancreatic adenocarcinoma inside an intraductal pancreatic mucinous neoplasm. Postoperatively, the patient was admitted to the intensive care unit (ICU) because he had no spontaneous breathing and manifested areflexia signs. A train of four (TOF) monitoring of peripheral nerve stimulation was performed and pyridostigmine therapy was initiated, leading to an improvement in symptoms allowing the extubation and transfer to the peripheral ward. Further diagnostic tests revealed a LEMS and an intravenous therapy with cumulative 100 g immunoglobulin (Ig) G was initiated. Upon discharge, 10 days after starting LEMS treatment, the patient showed subjective and objective improvement in strength. Conclusions: Paraneoplastic syndromes are more common than expected, but rare in pancreatic adenocarcinoma. They can appear before abdominal symptoms, facilitating early diagnosis. Successful treatment of cancer may eliminate paraneoplastic symptoms. LEMS may reveal pancreatic cancer. Early recognition of paraneoplastic syndromes is important for pancreatic cancer management. Further investigation is needed to evaluate the diagnostic approach for LEMS in all patients with pancreatic cancer.

Modulation of the Tumor-Associated Immuno-Environment by Non-Invasive Physical Plasma.

Over the past 15 years, investigating the efficacy of non-invasive physical plasma (NIPP) in cancer treatment as a safe oxidative stress inducer has become an active area of research. So far, most studies focused on the NIPP-induced apoptotic death of tumor cells. However, whether NIPP plays a role in the anti-tumor immune responses need to be deciphered in detail. In this review, we summarized the current knowledge of the potential effects of NIPP on immune cells, tumor-immune interactions, and the immunosuppressive tumor microenvironment. In general, relying on their inherent anti-oxidative defense systems, immune cells show a more resistant character than cancer cells in the NIPP-induced apoptosis, which is an important reason why NIPP is considered promising in cancer management. Moreover, NIPP treatment induces immunogenic cell death of cancer cells, leading to maturation of dendritic cells and activation of cytotoxic CD8+ T cells to further eliminate the cancer cells. Some studies also suggest that NIPP treatment may promote anti-tumor immune responses via other mechanisms such as inhibiting tumor angiogenesis and the desmoplasia of tumor stroma. Though more evidence is required, we expect a bright future for applying NIPP in clinical cancer management.

Development and Characterization of a Novel Neuropilin-2 Antibody for Immunohistochemical Staining of Cancer and Sarcoidosis Tissue Samples.

Neuropilin-2 (NRP2) is a cell surface receptor that plays key roles in lymphangiogenesis, but also in pathophysiological conditions such as cancer and inflammation. NRP2 targeting by efzofitimod, a novel immunomodulatory molecule, is currently being tested for the treatment of pulmonary sarcoidosis. To date, no anti-NRP2 antibodies are available for companion diagnostics. Here we describe the development and characterization of a novel NRP2 antibody. Using a variety of research techniques, that is, enzyme-linked immunoassay, Western blot, biolayer interferometry, and immunohistochemistry, we demonstrate that our antibody detects all major NRP2 isoforms and does not cross-react with NRP1. Using this antibody, we show high NRP2 expression in granulomas from sarcoidosis patient skin and lung biopsies. Our novel anti-NRP2 antibody could prove to be a useful clinical tool for sarcoidosis and other indications where NRP2 has been implicated. Clinical Trial Registration: clinicaltrials.gov NCT05415137.

Efzofitimod: a novel anti-inflammatory agent for sarcoidosis.

Efzofitimod is a first-in-class biologic based on a naturally occurring splice variant of histidyl-tRNA synthetase (HARS) that downregulates immune responses via selective modulation of neuropilin-2 (NRP2). Preclinical data found high expression of NRP2 in sarcoidosis granulomas. Treatment with efzofitimod reduced the granulomatous inflammation induced by P. acnes in an animal model of sarcoidosis. A dose escalating trial of efzofitimod in sarcoidosis with chronic symptomatic pulmonary disease found that treatment with efzofitimod was associated with improved quality of life with a trend towards reduced glucocorticoid use and stable to improved pulmonary function. These studies have led to a large Phase 3 trial of efzofitimod in symptomatic pulmonary sarcoidosis.

Effects of mixed dietary supplements on total plasma homocysteine concentrations (tHcy): a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although a number of studies have reported raised total plasma homocysteine (tHcy) concentrations in free-living older people, there are no data on homocysteine response to a mixed nutrient supplement in older patients. A raised plasma homocysteine concentration in older patients is partly a reflection of their co-morbidity, including impaired renal function, and there is uncertainty about the extent to which dietary interventions can improve plasma tHcy. AIM: To determine the plasma tHcy response to dietary supplements during acute illness. METHODS: Two-hundred and thirty-six hospitalized, acutely ill older patients, who were part of a randomized double-blind placebo-controlled trial, were assigned to receive a daily oral nutritional supplement drink containing 1.3 mg of vitamin B2, 1.4 mg of vitamin B6, 1.5 µg of B12, 200 µg of folic acid, or a placebo, for 6 weeks. Outcome measures were plasma tHcy concentration at baseline, 6 weeks, and 6 months. RESULTS: The mean plasma tHcy concentration fell among patients given the supplements (mean difference 4.1 µmol/L [95 % C.I, 0.14 to 8.03), p = 0.043], but tHcy concentration increased between 6 weeks and 6 months, after patients stopped taking the supplements [mean difference -2.0 µmol/L (95 % C.I, -03.9 to -0.18), p = 0.033]. About 46 % of patients in the placebo group and 55 % of patients in the supplement group had hyperhomocysteinemia (>14 µmol/L) at baseline compared with 45 % and 29 % at the end of the treatment period. CONCLUSIONS: A mixed nutrient supplement containing physiological amounts of B vitamins significantly reduced plasma tHcy concentrations in older patients recovering from acute illness.

Effect of implementing the NEWS2 escalation protocol in a large acute NHS trust: a retrospective cohort analysis of mortality, workload and ability of early warning score to predict death within 24 hours.

OBJECTIVES: To describe the inpatient population, establish patterns in admission and mortality over a 4-year period in different cohorts and assess the prognostic ability and workload implications of introducing the National Early Warning Score 2 (NEWS2) and associated escalation protocol. DESIGN: Retrospective cohort analyses of medical and surgical inpatient admissions. SETTING: Large teaching hospital with tertiary inpatient care and a major trauma centre employing an electronic observations platform, initially with a local early warning score, followed by NEWS2 introduction in June 2019. PARTICIPANTS: 332 682 adult patients were admitted between 1 January 2016 and 31 December 2019. OUTCOME MEASURES: Mortality, workload and ability of early warning score to predict death within 24 hours. RESULTS: Admissions rose by 19% from 76 055 in 2016 to 90 587 in 2019. Total bed days rose by 10% from 433 382 to 477 485. Mortality fell from 3.7% to 3.1% and was significantly lower in patients discharged from a surgical specialty, 1.0%-1.2% (p<0.001). Total observations recorded increased by 14% from 1 976 872 in 2016 to 2 249 118 in 2019. 65% of observations were attributable to patients under medical specialties, 34% to patients under surgical specialties. Recorded escalations to the registrar were stable from January 2016 to May 2019 but trebled following the introduction of NEWS2 in June 2019. CONCLUSIONS: There was an increase in hospital inpatient activity between 2016 and 2019, associated with a reduction in mortality and percentage of observations calculated as reaching threshold NEWS2 score of 7 for escalation to the registrar. The introduction of the NEWS2, with a higher sensitivity and lower specificity, when allied to its escalation protocol, was associated with a significant increase in actual recorded escalations to the registrar. This was more marked in the surgical population and would support refining threshold scores based on admission characteristics when developing the next iteration of NEWS.