Return of the lysergamides. Part VI: Analytical and behavioural characterization of 1‐cyclopropanoyl‐d‐lysergic acid diethylamide (1CP‐LSD)

Lysergic acid diethylamide (LSD) is a prototypical serotonergic psychedelic drug and the subject of many clinical investigations. In recent years, a range of lysergamides has emerged with the production of some being inspired by the existing scientific literature. Others, for example various 1‐acyl substituted lysergamides, did not exist before their appearance as research chemicals. 1‐Cylopropanoyl‐LSD (1CP‐LSD) has recently emerged as a new addition to the group of lysergamide‐based designer drugs and is believed to be psychoactive in humans. In this investigation, 1CP‐LSD was subjected to detailed analytical characterizations including various mass spectrometry (MS) platforms, gas and liquid chromatography, nuclear magnetic resonance spectroscopy, solid phase and GC condensed phase infrared spectroscopy. Analysis by GC–MS also revealed the detection of artificially induced degradation products. Incubation of 1CP‐LSD with human serum led to the formation of LSD, indicating that it may act as a prodrug for LSD in vivo, similar to other 1‐acyl substituted lysergamides. The analysis of blotters and pellets is also included. 1CP‐LSD also induces the head‐twitch response (HTR) in C57BL/6 J mice, indicating that it produces an LSD‐like behavioural profile. 1CP‐LSD induced the HTR with an ED₅₀ = 430.0 nmol/kg which was comparable to 1P‐LSD (ED₅₀ = 349.6 nmol/kg) investigated previously. Clinical studies are required to determine the potency and profile of the effects produced by 1CP‐LSD in humans.     

Simultaneous analysis of 29 synthetic cannabinoids and metabolites,amphetamines, and cannabinoids in human whole blood by liquid chromatography–tandem mass spectrometry – A New Zealand perspective of use in 2018

We describe the validation of a method for the simultaneous analysis of 29 synthetic cannabinoids (SCs) and metabolites, 4 amphetamines, and 2 cannabinoids in human whole blood. This method enables one analysis to cover what previously required multiple analyses for these classic and novel drugs‐of‐abuse with diverse physicochemical properties. The scope of targeted analytes was based on the most prevalent drugs‐of‐abuse and SCs encountered at the New Zealand border in 2017 and included parent compounds and metabolites belonging to the indole and indazole carboxamide, quinolinyl indole carboxylate, and naphthoylindole classifications. Samples were prepared by supported‐liquid‐extraction (SLE) followed by liquid chromatography?tandem mass spectrometry (LC?MS/MS) analysis with positive electrospray ionization (ESI). The method was validated with respect to selectivity, matrix effects, process efficiency, sensitivity, repeatability, extract stability, and carryover for qualitative confirmation. Linearity as well as accuracy and precision data at target decision concentrations were also evaluated. The limits of detection and confirmation ranged from 0.1 to 6.0 ng/mL and 1.0 to 6.0 ng/mL, respectively. The described method was successfully applied to the analysis of 564 ante‐ and post‐mortem blood samples in 2018. There were 132 cases (23%) with positive findings of at least one SC, with the five most commonly detected SCs being AMB‐FUBINACA and/or acid (61%), 5F‐ADB and/or acid (40%), ADB‐FUBINACA (11%), 5F‐MDMB‐PICA acid (6%), and MDMB‐FUBINACA acid (6%). The results also demonstrate the predominant presence of metabolites at higher levels than the unchanged parent SCs in blood, highlighting the need to maintain forensic screening methods capable of the simultaneous detection of both parent compounds and metabolites.     

Fibrinogen to albumin ratio reflects the activity of antineutrophil cytoplasmic antibody‐associated vasculitis

BackgroundWe investigated whether fibrinogen to albumin ratio (FAR) at diagnosis could reflect the cross‐sectional activity and predict poor outcomes in patients with antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV).MethodsThis cross‐sectional study included 54 immunosuppressant drug‐naïve patients with AAV who had the results of plasma fibrinogen and serum albumin at diagnosis. Clinical and laboratory data at diagnosis were collected, and all‐cause mortality, cerebrovascular accident, cardiovascular disease, end‐stage renal disease occurrences were assessed as poor outcomes. FAR was calculated by the following equation: FAR = plasma fibrinogen (g/dl)/serum albumin (g/dl).ResultsThe median age was 65.5 years, and 59.3% of patients were men (33 MPA, 13 GPA and 8 EGPA). FAR was significantly correlated with Birmingham vasculitis activity score (BVAS; r = 0.271), erythrocyte sedimentation rate (ESR; r = 0.668) and C‐reactive protein (CRP; r = 0.638). High BVAS was defined as BVAS ≥16, and the cut‐off of FAR at diagnosis was set as 0.118. AAV patients with FAR at diagnosis ≥0.118 had a significantly higher risk for the cross‐sectional high BVAS than those without (RR 3.361). In the univariable linear regression analysis, CRP (β = 0.383) and FAR (β = 0.297) were significantly correlated with BVAS at diagnosis. However, in the multivariable analysis, none of them was correlated with the cross‐sectional BVAS. FAR at diagnosis could not predict poor outcomes during follow‐up in AAV patients.ConclusionsFibrinogen to albumin ratio at diagnosis could reflect the cross‐sectional BVAS but could not predict poor outcomes in patients with AAV.     

Joint Trauma System,Defense Committee on Trauma,and Armed Services Blood Program consensus statement on whole blood

Hemorrhage is the most common mechanism of death in battlefield casualties with potentially survivable injuries. There is evidence that early blood product transfusion saves lives among combat casualties. When compared to component therapy, fresh whole blood transfusion improves outcomes in military settings. Cold-stored whole blood also improves outcomes in trauma patients. Whole blood has the advantage of providing red cells, plasma, and platelets together in a single unit, which simplifies and speeds the process of resuscitation, particularly in austere environments. The Joint Trauma System, the Defense Committee on Trauma, and the Armed Services Blood Program endorse the following: (1) whole blood should be used to treat hemorrhagic shock; (2) low-titer group O whole blood is the resuscitation product of choice for the treatment of hemorrhagic shock for all casualties at all roles of care; (3) whole blood should be available within 30 min of casualty wounding, on all medical evacuation platforms, and at all resuscitation and surgical team locations; (4) when whole blood is not available, component therapy should be available within 30 min of casualty wounding; (5) all prehospital medical providers should be trained and logistically supported to screen donors, collect fresh whole blood from designated donors, transfuse blood products, recognize and treat transfusion reactions, and complete the minimum documentation requirements; (6) all deploying military personnel should undergo walking blood bank prescreen laboratory testing for transfusion transmitted disease immediately prior to deployment. Those who are blood group O should undergo anti-A/anti-B antibody titer testing.     

CD4+ follicular regulatory T cells optimize the influenza virus–specific B cell response

CD4⁺ follicular regulatory T (Tfr) cells control B cell responses through the modulation of follicular helper T (Tfh) cells and germinal center development while suppressing autoreactivity; however, their role in the regulation of productive germinal center B cell responses and humoral memory is incompletely defined. We show that Tfr cells promote antigen-specific germinal center B cell responses upon influenza virus infection. Following viral challenge, we found that Tfr cells are necessary for robust generation of virus-specific, long-lived plasma cells, antibody production against both hemagglutinin (HA) and neuraminidase (NA), the two major influenza virus glycoproteins, and appropriate regulation of the BCR repertoire. To further investigate the functional relevance of Tfr cells during viral challenge, we used a sequential immunization model with repeated exposure of antigenically partially conserved strains of influenza viruses, revealing that Tfr cells promote recall antibody responses against the conserved HA stalk region. Thus, Tfr cells promote antigen-specific B cell responses and are essential for the development of long-term humoral memory.     

Extended Use of the Control-IQ Closed-Loop Control System in Children With Type 1 Diabetes

OBJECTIVETo further evaluate the safety and efficacy of the Control-IQ closed-loop control (CLC) system in children with type 1 diabetes.RESEARCH DESIGN AND METHODSAfter a 16-week randomized clinical trial (RCT) comparing CLC with sensor-augmented pump (SAP) therapy in 101 children 6–13 years old with type 1 diabetes, 22 participants in the SAP group initiated use of the CLC system (referred to as SAP-CLC cohort), and 78 participants in the CLC group continued use of CLC (CLC-CLC cohort) for 12 weeks.RESULTSIn the SAP-CLC cohort, mean percentage of time in range 70–180 mg/dL (TIR) increased from 55 ± 13% using SAP during the RCT to 65 ± 10% using CLC (P < 0.001), with 36% of the cohort achieving TIR >70% plus time <54 mg/dL <1% compared with 14% when using SAP (P = 0.03). Substantial improvement in TIR was seen after the 1st day of CLC. Time <70 mg/dL decreased from 1.80% to 1.34% (P < 0.001). In the CLC-CLC cohort, mean TIR increased from 53 ± 17% prerandomization to 67 ± 10% during the RCT and remained reasonably stable at 66 ± 10% through the 12 weeks post-RCT. No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either cohort.CONCLUSIONSThis further evaluation of the Control-IQ CLC system supports the findings of the preceding RCT that use of a closed-loop system can safely improve glycemic control in children 6–13 years old with type 1 diabetes from the 1st day of use and demonstrates that these improvements can be sustained through 28 weeks of use.