Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?

Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups.

Nutrient regulation of the islet epigenome controls adaptive insulin secretion.

Adaptation of the islet ß cell insulin-secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in ß cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. ß Cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

The role of the electroencephalogram (EEG) in determining the aetiology of catatonia: a systematic review and meta-analysis of diagnostic test accuracy.

Background: Catatonia is a psychomotor syndrome that has a wide range of aetiologies. Determining whether catatonia is due to a medical or psychiatric cause is important for directing treatment but is clinically challenging. We aimed to ascertain the performance of the electroencephalogram (EEG) in determining whether catatonia has a medical or psychiatric cause, conventionally defined. Methods: In this systematic review and meta-analysis of diagnostic test accuracy (PROSPERO CRD42021239027), Medline, EMBASE, PsycInfo, and AMED were searched from inception to May 11, 2022 for articles published in peer-reviewed journals that reported EEG findings in catatonia of a medical or psychiatric origin and were reported in English, French, or Italian. Eligible study types were clinical trials, cohort studies, case-control studies, cross-sectional studies, case series, and case reports. The reference standard was the final clinical diagnosis. Data extraction was conducted using individual patient-level data, where available, by two authors. We prespecified two types of studies to overcome the limitations anticipated in the data: larger studies (n ≥ 5), which were suitable for formal meta-analytic methods but generally lacked detailed information about participants, and smaller studies (n < 5), which were unsuitable for formal meta-analytic methods but had detailed individual patient level data, enabling additional sensitivity analyses. Risk of bias and applicability were assessed with the QUADAS-2 tool for larger studies, and with a published tool designed for case reports and series for smaller studies. The primary outcomes were sensitivity and specificity, which were derived using a bivariate mixed-effects regression model. Findings: 355 studies were included, spanning 707 patients. Of the 12 larger studies (5 cohort studies and 7 case series), 308 patients were included with a mean age of 48.2 (SD = 8.9) years. 85 (52.8%) were reported as male and 99 had catatonia due to a general medical condition. In the larger studies, we found that an abnormal EEG predicted a medical cause of catatonia with a sensitivity of 0.82 (95% CI 0.67-0.91) and a specificity of 0.66 (95% CI 0.45-0.82) with an I 2 of 74% (95% CI 42-100%). The area under the summary ROC curve offered excellent discrimination (AUC = 0.83). The positive likelihood ratio was 2.4 (95% CI 1.4-4.1) and the negative likelihood ratio was 0.28 (95% CI 0.15-0.51). Only 5 studies had low concerns in terms of risk of bias and applicability, but a sensitivity analysis limited to these studies was similar to the main analysis. Among the 343 smaller studies, 399 patients were included, resulting in a sensitivity of 0.76 (95% CI 0.71-0.81), specificity of 0.67 (0.57-0.76) and AUC = 0.71 (95% CI 0.67-0.76). In multiple sensitivity analyses, the results were robust to the exclusion of reports of studies and individuals considered at high risk of bias. Features of limbic encephalitis, epileptiform discharges, focal abnormality, or status epilepticus were highly specific to medical catatonia, but features of encephalopathy had only moderate specificity and occurred in 23% of the cases of psychiatric catatonia in smaller studies. Interpretation: In cases of diagnostic uncertainty, the EEG should be used alongside other investigations to ascertain whether the underlying cause of catatonia is medical. The main limitation of this review is the differing thresholds for considering an EEG abnormal between studies. Funding: Wellcome Trust, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust.

Polygenic risk scores: An overview from bench to bedside for personalised medicine.

Since the first polygenic risk score (PRS) in 2007, research in this area has progressed significantly. The increasing number of SNPs that have been identified by large scale GWAS analyses has fuelled the development of a myriad of PRSs for a wide variety of diseases and, more recently, to PRSs that potentially identify differential response to specific drugs. PRSs constitute a composite genomic biomarker and potential applications for PRSs in clinical practice encompass risk prediction and disease screening, early diagnosis, prognostication, and drug stratification to improve efficacy or reduce adverse drug reactions. Nevertheless, to our knowledge, no PRSs have yet been adopted into routine clinical practice. Beyond the technical considerations of PRS development, the major challenges that face PRSs include demonstrating clinical utility and circumnavigating the implementation of novel genomic technologies at scale into stretched healthcare systems. In this review, we discuss progress in developing disease susceptibility PRSs across multiple medical specialties, development of pharmacogenomic PRSs, and future directions for the field.

Pre-operative Considerations in Adult Mucopolysaccharidosis Patients Planned for Cardiac Intervention.

Mucopolysaccharidoses (MPS) are rare lysosomal storage diseases characterized by multiorgan involvement and shortened longevity. Due to advances in therapies such as enzyme replacement therapy and haematopoietic stem cell therapy, life expectancy has increased posing newer challenges to patients and health professionals. One such challenge is cardiovascular manifestations of MPS, which can be life limiting and cause reduction in quality of life. Any cardiovascular intervention mandates comprehensive, multi-systemic work-up by specialist teams to optimize outcome. We highlight the importance of multidisciplinary evaluation of adult MPS patients requiring cardiovascular intervention. Clinical assessments and investigations are discussed, with a focus on the cardiac, anesthetic, airway, respiratory, radiological and psychosocial factors.

Persistent neuropsychiatric symptoms after COVID-19: a systematic review and meta-analysis.

The nature and extent of persistent neuropsychiatric symptoms after COVID-19 are not established. To help inform mental health service planning in the pandemic recovery phase, we systematically determined the prevalence of neuropsychiatric symptoms in survivors of COVID-19. For this pre-registered systematic review and meta-analysis (PROSPERO ID CRD42021239750), we searched MEDLINE, EMBASE, CINAHL and PsycINFO to 20 February 2021, plus our own curated database. We included peer-reviewed studies reporting neuropsychiatric symptoms at post-acute or later time-points after COVID-19 infection and in control groups where available. For each study, a minimum of two authors extracted summary data. For each symptom, we calculated a pooled prevalence using generalized linear mixed models. Heterogeneity was measured with I 2. Subgroup analyses were conducted for COVID-19 hospitalization, severity and duration of follow-up. From 2844 unique titles, we included 51 studies (n = 18 917 patients). The mean duration of follow-up after COVID-19 was 77 days (range 14-182 days). Study quality was most commonly moderate. The most prevalent neuropsychiatric symptom was sleep disturbance [pooled prevalence = 27.4% (95% confidence interval 21.4-34.4%)], followed by fatigue [24.4% (17.5-32.9%)], objective cognitive impairment [20.2% (10.3-35.7%)], anxiety [19.1% (13.3-26.8%)] and post-traumatic stress [15.7% (9.9-24.1%)]. Only two studies reported symptoms in control groups, both reporting higher frequencies in COVID-19 survivors versus controls. Between-study heterogeneity was high (I 2 = 79.6-98.6%). There was little or no evidence of differential symptom prevalence based on hospitalization status, severity or follow-up duration. Neuropsychiatric symptoms are common and persistent after recovery from COVID-19. The literature on longer-term consequences is still maturing but indicates a particularly high prevalence of insomnia, fatigue, cognitive impairment and anxiety disorders in the first 6 months after infection.

Emerging Knowledge of the Neurobiology of COVID-19.

Many patients with COVID-19 will experience acute or longer-term neuropsychiatric complications. The neurobiological mechanisms behind these are beginning to emerge; however, the neurotropic hypothesis is not strongly supported by clinical data. The inflammatory response to SARS-CoV-2 is likely to be responsible for delirium and other common acute neuropsychiatric manifestations. Vascular abnormalities such as endotheliopathies contribute to stroke and cerebral microbleeds, with their attendant neuropsychiatric sequelae. Longer-term neuropsychiatric syndromes fall into 2 broad categories: neuropsychiatric deficits occurring after severe (hospitalized) COVID-19 and "long COVID," which occurs in many patients with a milder acute COVID-19 illness.

Neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives.

There is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations.We searched MEDLINE, Embase, PsycINFO and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence.13 292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% (95% CI 35.2% to 51.3%), n=15 975, 63 studies), weakness (40.0% (95% CI 27.9% to 53.5%), n=221, 3 studies), fatigue (37.8% (95% CI 31.6% to 44.4%), n=21 101, 67 studies), dysgeusia (37.2% (95% CI 29.8% to 45.3%), n=13 686, 52 studies), myalgia (25.1% (95% CI 19.8% to 31.3%), n=66 268, 76 studies), depression (23.0% (95% CI 11.8% to 40.2%), n=43 128, 10 studies), headache (20.7% (95% CI 16.1% to 26.1%), n=64 613, 84 studies), anxiety (15.9% (5.6% to 37.7%), n=42 566, 9 studies) and altered mental status (8.2% (95% CI 4.4% to 14.8%), n=49 326, 19 studies). Heterogeneity for most clinical manifestations was high.Neurological and neuropsychiatric symptoms of COVID-19 in the pandemic's early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.

Prospective studies are needed of the neurology and neuropsychiatry of COVID-19: reply.

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Large slippage and depletion layer at the polyelectrolyte/solid interface.

The slippage of polymer solutions on solid surfaces is often attributed to a depletion layer whose origin, thickness, and interaction with the flow are poorly understood. Using a Dynamic Surface Force Apparatus we report a structural and nanorheological study of the interface between hydrolyzed poly-acrylamide solutions and platinum surfaces. Polyelectrolyte chains adsorb on the surfaces in a thin charged layer, acting as a nonattractive wall for the bulk solution. We investigate the flow of the visco-elastic solution on the adsorbed layer from the nanometer to 10 micrometers, bridging microscopic to macroscopic properties. At distances larger than 200 nanometers, the flow is well described by an apparent slip boundary condition. At smaller distance the apparent slip is found to decrease with the gap. In contrast to the apparent slip model, we show that a 2-fluids model taking into account the finite thickness of depletion layers at the non-attractive wall describes accurately the dynamic forces over 4 spatial decades of confinement. Depletion layers are found to be an equilibrium property of the interface, independent on the flow and on the confinement. Their thickness is phenomenologically described by ξ + 2lD with ξ the correlation length of the semi-dilute solutions and lD the Debye length. We interpret this result in terms of screened repulsion between the charged adsorbed layer and the bulk polyions.

Light-controlled thrombin catalysis and clot formation using a photoswitchable G-quadruplex DNA aptamer.

The reversible photocontrol of an enzyme governing blood coagulation is demonstrated. The thrombin binding aptamer (TBA), was rendered photochromic by modification with two anthracene groups. Light-triggered anthracene photodimerisation distorts its structure, inhibiting binding of the enzyme thrombin, which in turn triggers catalysis and the resulting clotting process.

Glycan recognition at the saliva - oral microbiome interface.

The mouth is a first critical interface where most potentially harmful substances or pathogens contact the host environment. Adaptive and innate immune defense mechanisms are established there to inactivate or eliminate pathogenic microbes that traverse the oral environment on the way to their target organs and tissues. Protein and glycoprotein components of saliva play a particularly important role in modulating the oral microbiota and helping with the clearance of pathogens. It has long been acknowledged that glycobiological and glycoimmunological aspects play a pivotal role in oral host-microbe, microbe-host, and microbe-microbe interactions in the mouth. In this review, we aim to delineate how glycan-mediated host defense mechanisms in the oral cavity support human health. We will describe the role of glycans attached to large molecular size salivary glycoproteins which act as a first line of primordial host defense in the human mouth. We will further discuss how glycan recognition contributes to both colonization and clearance of oral microbes.

A Direct Sensor to Measure Minute Liquid Flow Rates.

Nanofluidics finds its root in the study of fluids and flows at the nanoscale. Flow rate is a quantity that is both central when dealing with flows and notoriously difficult to measure experimentally at the scale of an individual nanopore or nanochannel. We show in this letter that minute flow rate can be directly measured accumulating liquid over time within the compliant membrane of a commercial piezoresistive pressure sensor. Our flow rate sensor is versatile and can be operated independently of the nature of the liquid, flow profile, and type of nanochannel. We demonstrate this method by measuring the pressure-driven flow of silicon oil in a single nanochannel of average radius 200 nm. This approach gives reliable measurement of the flow rate up to 1 pL/min. Unlike other nanoscale flow measurements methods based, for instance, on particle tracking, our sensor delivers a direct voltage output suitable for nanoflow control applications.

Nano-mechanics of ionic liquids at dielectric and metallic interfaces.

Using a dynamic surface force apparatus, we investigate the nano-mechanics and the nano-rheology of an ionic liquid at dielectric and metallic solid surfaces. On smooth dielectric Pyrex surfaces, we find an ordered interfacial phase extending over less than 3 nm away from the top of the layer, with a compression modulus of 15 MPa extracted from the profile of the oscillatory forces. We discuss the boundary flow of the Newtonian bulk phase on this ordered interfacial layer. On metallic platinum surfaces, our hydrodynamic measurements evidence an interfacial soft solid layer extending up to 20 nm away from the top of the layer. The elastic modulus of this interfacial layer, derived from elasto-hydrodynamic measurements, is similar to the one found on Pyrex surfaces. Both on the dielectric and on the metal surfaces, the thickness of the interfacial phases is not found to change upon approach of the opposite surface, and does not exhibit a capillary-freezing transition.

Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model.

BACKGROUND: Dysregulation of the Src pathway has been shown to be important at various stages of cancer. Dasatinib is a potent Src/Abl inhibitor and has demonstrated to have anti-proliferative and anti-invasive activity in many preclinical models. The objective of this study was to determine the anti-tumor activity of dasatinib using in vitro and in vivo preclinical colorectal (CRC) models. METHODS: CRC cell lines and patient-derived tumor explant (PDX) models were used to investigate the efficacy of dasatinib. We treated 50 CRC cell lines with dasatinib for 72 hours and proliferation was assayed by a sulforhodamine B (SRB) assay; an IC50 ≤ 0.08 µmol/L was considered sensitive. We treated 17 patient-derived CRC explants with dasatinib (50 mg/kg/day, administered once-daily) for 28 days to determine in vivo efficacy. Tumor growth inhibition (TGI) ≥ 50% was considered sensitive. RESULTS: We found that 8 out of 50 CRC cell lines reached an IC50 ≤ 0.08 µmol/L with dasatinib treatment. In addition, of 17 CRC explants grown in the xenograft mouse model, 2 showed sensitivity to dasatinib. The anti-tumor effects observed in this study were a result of G1 cell cycle arrest as the dasatinib sensitive CRC cell lines exhibited G1 inhibition. Moreover, those CRC cell lines that were responsive (0.08 µmol/L) to treatment demonstrated a significant baseline increase in Src and FAK gene expression. CONCLUSION: Dasatinib demonstrated significant anti-proliferative activity in a subset of CRC cell lines in vitro, especially in those with increased Src expression at baseline, but only showed modest efficacy in CRC explants. Dasatinib is currently being studied in combination with chemotherapy in patients with advanced CRC, as its use as a single agent appears limited.