A Narrative Review of the Association between Post-Traumatic Stress Disorder and Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) and post-traumatic stress disorder (PTSD) are often co-morbid with implications for disease severity and treatment outcomes. OSA prevalence is higher in PTSD sufferers than in the general population, with a likely bidirectional effect of the two illnesses. There is substantial evidence to support the role that disturbed sleep may play in the pathophysiology of PTSD. Sleep disturbance associated with OSA may interfere with normal rapid eye movement (REM) functioning and thus worsen nightmares and sleep-related movements. Conversely, hyperarousal and hypervigilance symptoms of PTSD may lower the arousal threshold and thus increase the frequency of sleep fragmentation related to obstructive events. Treating OSA not only improves OSA symptoms, but also nightmares and daytime symptoms of PTSD. Evidence suggests that positive airway pressure (PAP) therapy reduces PTSD symptoms in a dose-dependent fashion, but also presents challenges to tolerance in the PTSD population. Alternative OSA treatments may be better tolerated and effective for improving both OSA and PTSD. Further research avenues will be introduced as we seek a better understanding of this complex relationship.

Opinion article: the acute radiation syndrome – need for updated medical guidelines

The major immediate and severe medical consequences in man following exposure to high doses of ionizing radiation can be summarized within the concept of the acute radiation syndrome (ARS). In a dose-dependent fashion, a multitude of organ systems can be affected by such irradiation, presenting considerable medical challenges to treating physicians. Accidents or malevolent events leading to ARS can provoke devastating effects, but they occur at a low frequency and in a highly varying manner and magnitude. Thus, it is difficult to make precise medical predictions and planning, or to draw conclusive evidence from occurred events. Therefore, knowledge from on-going continuous developments within related medical areas needs to be acknowledged and incorporated into the ARS setting, enabling the creation of evidence-based guidelines. In 2011 the WHO published a first global consensus on the medical management of ARS among patients subjected to nontherapeutic radiation. During the recent decade the understanding of and capability to counteract organ damage related to radiation and other agents have improved considerably. Furthermore, legal and logistic hurdles in the process of formally approving appropriate medical countermeasures have been reduced. We believe the time is now ripe for developing an update of internationally consented medical guidelines on ARS.

Cephalic arch stenosis in the arteriovenous fistula: A retrospective analysis of predisposing factors

Background: Cephalic Arch Stenosis (CAS) is a frequently observed complication in brachiocephalic and radiocephalic arteriovenous fistulae (AVF) associated with high morbidity and healthcare expenditure. The predisposing factors and preventative strategies for CAS remain unclear. Our aim was to examine predisposing factors for CAS development in the AVF. Methods: A retrospective case-control study was performed at Gold University Coast Hospital on patients with AVFs created from 2009 to 2018 with ⩾18 months follow-up. CAS was defined as a >50% narrowing on angiographic assessment with clinically significant symptoms (dialysis dysfunction, arm swelling, prolonged bleeding after access). Results: About 187 patients with AVF were included in the analysis (36 brachiocephalic, 151 radiocephalic). CAS developed in 22 of 36 (61%) of brachiocephalic AVF and 9 of 151 (6%) of radiocephalic AVFs. Brachiocephalic AVF were ⩾12 times more likely to develop CAS than radiocephalic AVF (Hazard Ratio (HR) 12.7, 95% CI [5.6–28.3], p < 0.001). Each 1 mL/min increase in flow rate through the AVF, correlated with a 0.07% increase in the probability of development of CAS (HR 1.0007, 95% CI [1.0001–1.0012], p = 0.011). Brachiocephalic AVFs with CAS were associated with a higher number of interventional procedures per access-year compared with their non-CAS counterparts (Median [Interquartile range]: 1.76 [0.74, 3.97] vs 0.41 [0.27, 0.67], p = 0.003). Conclusion: Brachiocephalic AVF with higher access flow rates are more likely to develop CAS and earlier than radiocephalic AVF, and in a dose dependent fashion. AVF flow rate is a major factor in CAS development within brachiocephalic AVF and has potential utility in surveillance thresholds for prophylactic blood flow reduction procedures. AVFs with CAS are associated with a greater number of interventional procedures per access-year, heralding higher patient morbidity and healthcare expenditure. Further prospective studies will help define an AVF access flow rate threshold in the implementation of prophylactic strategies for CAS.

PIAS Factors from Rainbow Trout Control NF-κB- and STAT-Dependent Gene Expression

Four ‘protein inhibitors of activated STAT’ (PIAS) control STAT-dependent and NF-κB-dependent immune signalling in humans. The genome of rainbow trout (Oncorhynchus mykiss) contains eight pias genes, which encode at least 14 different pias transcripts that are differentially expressed in a tissue- and cell-specific manner. Pias1a2 was the most strongly expressed variant among the analysed pias genes in most tissues, while pias4a2 was commonly low or absent. Since the knock-out of Pias factors in salmonid CHSE cells using CRISPR/Cas9 technology failed, three structurally different Pias protein variants were selected for overexpression studies in CHSE-214 cells. All three factors quenched the basal activity of an NF-κB promoter in a dose-dependent fashion, while the activity of an Mx promoter remained unaffected. Nevertheless, all three overexpressed Pias variants from trout strongly reduced the transcript level of the antiviral Stat-dependent mx gene in ifnγ-expressing CHSE-214 cells. Unlike mx, the overexpressed Pias factors modulated the transcript levels of NF-κB-dependent immune genes (mainly il6, il10, ifna3, and stat4) in ifnγ-expressing CHSE-214 cells in different ways. This dissimilar modulation of expression may result from the physical cooperation of the Pias proteins from trout with differential sets of interacting factors bound to distinct nuclear structures, as reflected by the differential nuclear localisation of trout Pias factors. In conclusion, this study provides evidence for the multiplication of pias genes and their sub-functionalisation during salmonid evolution.

487 NC410, a fusion protein of LAIR-2 (Leukocyte Associated Immunoglobulin-like Receptor) with human IgG1 Fc, is safe & tolerable with evidence of immune modulation in subjects with advanced solid tumors

BackgroundCollagen and C1q in the extracellular matrix (ECM), are the predominant ligands for LAIR-1, an inhibitory receptor expressed on the cell surface of several immune cell subsets that inhibits immune activation and migration. LAIR-2, a soluble homolog of LAIR-1, competes for binding to collagen and C1q and serves as a natural decoy to promote immune function under normal conditions. Dysregulation of the ECM and increased expression of collagen and C1q within the tumor microenvironment (TME) plays a critical role in promoting tumor progression. NC410 was engineered to overcome this highly immunosuppressive environment by blocking LAIR-1 function, reversing immune suppression, and inducing ECM remodeling to promote immune cell infiltration within the TME.MethodsThis is a first in human, phase 1/2, open-label, single-armed dose-escalation study to determine the safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, preliminary efficacy and to explore pharmacodynamic biomarkers of NC410 (figure 1). Key eligibility criteria include subjects with advanced or metastatic solid tumors with measurable disease based on RECIST v1.1.ResultsAs of 07/22/2021, a total of 16 patients have been enrolled, treated, and completed the DLT period. NC410 (up to 60 mg), was well tolerated, with no safety concerns, infusion-related toxicities, or DLT reported. No anti-drug antibody (ADA) was detected post-NC410 up to 60 mg treatment. As expected, the C1Q level decreased immediately after the NC410 infusion and was replenished after two hours. Evaluation from samples to date available up to cycle 5 suggests that there was no reduction in the baseline C1Q level with subsequent dosing (figure 2). LAIR-2 levels continued to increase in a dose-dependent fashion post-NC410 dosing and marginal increase pre-dose (figure 3). Interestingly, we observed an increase in soluble LAIR-1 over time in a similar pattern to LAIR-2 (figure 4). Furthermore, immunophenotyping of patient whole blood suggests a trend towards an increase in CD4+ and CD8+ T cells including LAIR-1+ T cells in cohort 4, although overall expression levels of LAIR-1 did not appear to increase (ongoing analysis). Cytokines, chemokines, and collagen degradation products (CDP) will be evaluated as potential pharmacodynamic biomarkers as we continue through higher dose cohorts.Abstract 487 Figure 1NC410: study schemaAbstract 487 Figure 2C1Q levels show immediate reduction after NC410 dosing with no accumulated depletionAbstract 487 Figure 3LAIR-2 levels show an increase in dose-dependent fashion after NC410 dosing with marginal increase pre-doseAbstract 487 Figure 4Soluble LAIR-1 levels show a similar pattern to LAIR-2 levelsConclusionsPreliminary evaluation of NC410 in subjects with advanced or metastatic solid tumors appears to be safe and well-tolerated with evidence of immune modulation consistent with predictive PK/PD modeling in a Phase 1/2 open-label study. Further evaluation will be done with increasing doses to confirm these initial findings.Trial RegistrationNCT04408599Ethics ApprovalThis study has been approved by the IRB of all the participating institutions, and all participants have given informed consent before taking part in the study.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Multiple distinct domains of human XIST are required to coordinate gene silencing and subsequent heterochromatin formation

Background Mammalian dosage compensation is achieved by the inactivation of one X chromosome in XX individuals. In eutheria this process is initiated early in development by the long non-coding RNA XIST. Studies of the initiation of silencing by XIST have focussed on mouse models, so the domains of XIST required to induce silencing in humans, and their relationship with domains required to establish heterochromatin remain to be determined. Methods We have previously established an inducible XIST cDNA in somatic cells and shown it can induce silencing and recruit heterochromatic features. We now assess a series of deletions across the construct for the ability to induce silencing and integrate these results with time-course and chromatin remodelling inhibitor treatments to follow the steps of XIST-induced silencing and heterochromatinization. Discussion We find that in addition to the previously reported necessity of the 5’ A repeat region for XIST-induced silencing, the F repeat region and a non-repetitive region at the 3’ end of the RNA are also required to silence genes. Silencing of genes up to 17Mb from the XIST integration occurs within two days, while formation of a Cot-1 depleted domain is slower, and more dependent on repeat F. The role of Repeat F in both the silencing of actively transcribed genes, the spread of H3K27me3 and the formation of a transcriptionally inert domain suggests a role in a pathway crucial for the spread of XIST across the chromatin to target distal regions of inactivation. Histone deacetylation requires only the A repeat region, with HDAC3 inhibition showing limited effect on silencing, but an impact on H3K27me3 recruitment, and as a result the recruitment of MacroH2A. Global HDAC inhibition impacted silencing in both a distance and dose-dependent fashion. The E repeat region was required for CIZ1 and H4K20me1 recruitment as well as H3K27me3; however, these appeared to act relatively independently. The H3K27me3 mark established by PRC2 integrated silencing and many of the heterochromatic features, while the PRC1 mark ubH2A appeared to be downstream of silencing in these human somatic cells.

Impact of Diuretics on Metabolic Activity of Urogenital Tract Microbiota in Women

Limited knowledge exists about the effects of commonly used diuretic medications on the human normal flora. Thus, we investigated potential stimulatory effects of diuretic drug furosemide on urogenital tract microbiota in women. Three strains of E. coli and C. albicans with different biofilm forming capacities were obtained from female patients diagnosed with urinary tract infections. All tested strains were treated with two different concentrations of furosemide drug, in comparison to non-treated strains as the negative control. At specific time intervals, samples were obtained from growing culture and analyzed for their proliferation rate, aspartyl proteinase excretion and biofilm formation ability. E. coli and C. albicans strains significantly increased their aspartyl proteinase excretion under furosemide treatment. This effect was frequently observed after 16 hours of incubation at 37oC. This drug has also increased the biofilm forming capacities of E. coli and C. albicans strains. Interestingly, both E. coli and C. albicans non-biofilm former strains, gained the capacity of biofilm formation when treated with furosemide at certain concentrations. E. coli control became a weak biofilm former after 48 hours of incubation, while non-biofilm former C. albicans strain became a weak biofilm former in dose-dependent fashion, after 48 hours incubation with furosemide in concentration of 0.1 mg/mL, and after 16 hours of incubation with furosemide in concentration of 0.5 mg/mL. Loop diuretic drug furosemide is able to increase the microbial virulence and turn commensal microbes into opportunistic pathogens. Additionally, the results suggest that enzyme aspartyl proteinase might act as a signal molecule for the biofilm formation, leading to the increased microbial pathogenicity.

Brain functional connectome defines a transdiagnostic dimension associated with cognition and psychopathology in youth

The search for psychiatric biomarkers has remained elusive, in part, due to high comorbidity, low specificity, and poor concordance between neurobiological abnormalities and existing diagnostic categories. Developmental shifts in symptom expression and brain function across the lifespan further complicate biomarker identification. Recent studies suggest that focusing on cognition may be a pathway forward: Cognitive dysfunction is a common feature across psychiatric disorders. Individual differences in cognition may reflect variability in the connectivity of underlying neurocognitive brain networks, and predict psychopathology at different developmental periods. In the present study we identified brain-based dimensions of general cognitive capacity and psychopathology using sparse canonical correlation analysis (sCCA) in a sample of 7,383 preadolescents from the Adolescent Brian Cognitive Development (ABCD) study. This analysis revealed correlated patterns of functional connectivity with cognitive control capacity and psychopathology. Specifically, the results identified a single connectome-based latent brain variate that was positively correlated with performance on cognitive measures across domains and negatively correlated with parent-reported psychopathology across diagnoses and domains. Functional connectivity loadings for the brain variate were across distributed cortical and subcortical brain networks and a dose-dependent relationship with psychopathology based upon the cumulative number of psychiatric diagnoses was observed. These findings provide preliminary evidence for a connectome-based biomarker that indexes individual differences in cognitive control and predicts transdiagnostic psychopathology in a dose-dependent fashion.

Mega-dose 90Y-Ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCL), though outcomes are worse in aggressive disease and most patients will still experience relapse. Radioimmunotherapy (RIT) using 90Y-Ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that mega-doses of 90Y-Ibritumomab tiuxetan with reduced-intensity conditioning (RIC) could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-Ibritumomab tiuxetan (1.5mCi/kg, maximum 120mCi), fludarabine, then 2Gy total body irradiation (TBI) prior to HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y activity of 113.6 mCi (range 71.2-129.2) was administered delivering a median of 552cGy to liver (range 499-2411cGy). The estimated 1 and 5-year PFS was 55% (95% CI, 31-73%) and 50% (95% CI, 27-69%) with a median PFS of 1.57 years. The estimated 1- and 5-year overall survival (OS) was 80% (95% CI, 54-92%) and 63% (95% CI, 38-81%) with a median OS of 6.45 years. Sixteen patients (80%) experienced grade ≥3 toxicities, although nonrelapse mortality was 10% at 1-year. No patients developed secondary AML/MDS. Mega-dose 90Y-Ibritumomab tiuxetan, fludarabine, and low-dose TBI followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified endpoint while producing nonhematologic toxicities comparable to standard RIC regimens. (Registered at ClinicalTrials.gov as NCT01434472).

Exploring Neurobehaviour in Zebrafish Embryos as a Screening Model for Addictiveness of Substances

Tobacco use is the leading cause of preventable death worldwide and is highly addictive. Nicotine is the main addictive compound in tobacco, but less is known about other components and additives that may contribute to tobacco addiction. The zebrafish embryo (ZFE) has been shown to be a good model to study the toxic effects of chemicals on the neurological system and thus may be a promising model to study behavioral markers of nicotine effects, which may be predictive for addictiveness. We aimed to develop a testing protocol to study nicotine tolerance in ZFE using a locomotion test with light-dark transitions as behavioral trigger. Behavioral experiments were conducted using three exposure paradigms: (1) Acute exposure to determine nicotine’s effect and potency. (2) Pre-treatment with nicotine dose range followed by a single dose of nicotine, to determine which pre-treatment dose is sufficient to affect the potency of acute nicotine. (3) Pre-treatment with a single dose combined with acute exposure to a dose range to confirm the hypothesized decreased potency of the acute nicotine exposure. These exposure paradigms showed that (1) acute nicotine exposure decreased ZFE activity in response to dark conditions in a dose-dependent fashion; (2) pre-treatment with increasing concentrations dose-dependently reversed the effect of acute nicotine exposure; and (3) a fixed pre-treatment dose of nicotine induced a decreased potency of the acute nicotine exposure. This effect supported the induction of tolerance to nicotine by the pre-treatment, likely through neuroadaptation. The interpretation of these effects, particularly in view of prediction of dependence and addictiveness, and suitability of the ZFE model to test for such effects of other compounds than nicotine, are discussed.