Resolution of Historically Discordant Ames Test Negative / Rodent Carcinogenicity Positive N-nitrosamines using a Sensitive, OECD-aligned Design.

The in vitro Bacterial Reverse Mutation (Ames) Test is crucial for evaluating the mutagenicity of pharmaceutical impurities. For N-nitrosamines (NAs) historical data indicated that for certain members of this chemical class the outcomes of the Ames Test did not correlate with their associated rodent carcinogenicity outcomes. This has resulted in negative outcomes in an OECD aligned Ames Test alone (standard or enhanced) no longer being considered sufficient by regulatory authorities to assess potential carcinogenic risk of NAs if present as impurities in drug products.

N-Nitrosamine drug substance related impurities (NDSRIs) - A proposal for the addition of subcategories to carcinogenic potency categorization approach categories 1 and 2 for NDSRIs with a molecular weight > 200 Da.

The carcinogenicity potency categorization approach (CPCA) derived and harmonized by Health Authorities was a significant milestone, as it defined molecular properties that allowed for the rapid evaluation of the chemical structures of N-nitrosamine drug substance related impurities (NDSRIs) and the assignment of associated lifetime Acceptable Intake (AI) limits to inform on appropriate impurity control strategies in certain drug products. Nonetheless, it is important to continue to refine and improve on the CPCA based upon data-derived evidence. Herein, we focus on the default CPCA AI for NDSRIs, which is largely based on the small molecule N-nitrosamines (NAs).

Thiol-responsive lyotropic liquid crystals exhibit triggered phase re-arrangement and hydrogen sulfide (HS) release.

Hydrogen sulfide (HS) is an important signalling molecule with potential pharmaceutical applications. In pursuit of a suitable delivery system for HS, herein we apply an amphiphilic trisulfide to concomitantly alter the mesophase behaviour of dispersed lipid particles and enable triggered HS release. Amperometric release studies indicate the trisulfide acts as a sustained HS donor, with inclusion into the mesophase attenuating release vs neat dispersed trisulfide.

Disinformed social movements: A large-scale mapping of conspiracy narratives as online harms during the COVID-19 pandemic.

The COVID-19 pandemic caused high uncertainty regarding appropriate treatments and public policy reactions. This uncertainty provided a perfect breeding ground for spreading conspiratorial anti-science narratives based on disinformation. Disinformation on public health may alter the population's hesitance to vaccinations, counted among the ten most severe threats to global public health by the United Nations.

Oxygenation Strategies in Critically Ill Patients With COVID-19.

Background: Severe acute respiratory syndrome coronavirus 2 is the virus that causes coronavirus disease 2019 (COVID-19). COVID-19 is a disease characterized by a range of clinical syndromes including variable degrees of respiratory symptoms from mild respiratory illness and severe interstitial pneumonia to acute respiratory distress syndrome, septic shock, coagulopathies, and multiorgan dysfunction. This virus carries the potential to manifest in a wide range of pulmonary findings and hypoxemias, from mild respiratory symptoms to more severe syndromes, such as acute respiratory distress syndrome.

Trisulfide linked cholesteryl PEG conjugate attenuates intracellular ROS and collagen-1 production in a breast cancer co-culture model.

The progression of cancer has been closely-linked with augmentation of cellular reactive oxygen species (ROS) levels and ROS-associated changes in the tumour microenvironment (TME), including alterations to the extracellular matrix and associated low drug uptake. Herein we report the application of a co-culture model to simulate the ROS based cell-cell interactions in the TME using fibroblasts and breast cancer cells, and describe how novel reactive polymers can be used to modulate those interactions. Under the co-culture conditions, both cell types exhibited modifications in behaviour, including significant overproduction of ROS in the cancer cells, and elevation of the collagen-1 secretion and stained actin filament intensity in the fibroblasts.

Polymers with Dithiobenzoate End Groups Constitutively Release Hydrogen Sulfide upon Exposure to Cysteine and Homocysteine.

Dithioesters are well-established as efficient reversible addition-fragmentation chain transfer (RAFT) agents. More recently, certain small molecule dithioesters have been reported to release the biological signaling molecule hydrogen sulfide (HS) upon exposure to cysteine. Herein, we examine the propensity of polymers synthesized using RAFT with a dithioester chain transfer agent to release HS via reaction of cysteine with constitutive dithioester end-groups.

Expedient synthesis of highly substituted 3,4-dihydro-1,2-oxathiine 2,2-dioxides and 1,2-oxathiine 2,2-dioxides: revisiting sulfene additions to enaminoketones.

Diversely substituted 1,2-oxathiine 2,2-dioxides, including 3,5,6-triaryl-, 3,6-diaryl-, 3,5-diaryl-, 5,6-diaryl- and selected fused heterocyclic analogues, have been efficiently obtained by the application of a mild Cope elimination of a 4-amino moiety from the requisite 4-amino-3,4-dihydro-1,2-oxathiine 2,2-dioxides, which themselves were readily obtained by the addition of sulfenes to enaminoketones.

Noradrenergic depletion causes sex specific alterations in the endocannabinoid system in the Murine prefrontal cortex.

Brain endocannabinoids (eCB), acting primarily via the cannabinoid type 1 receptor (CB1r), are involved in the regulation of many physiological processes, including behavioral responses to stress. A significant neural target of eCB action is the stress-responsive norepinephrine (NE) system, whose dysregulation is implicated in myriad psychiatric and neurodegenerative disorders. Using Western blot analysis, the protein expression levels of a key enzyme in the biosynthesis of the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol lipase-α (DGL-α), and two eCB degrading enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) were examined in a mouse model that lacks the NE-synthesizing enzyme, dopamine β-hydroxylase (DβH-knockout, KO) and in rats treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4).

Managing emerging mutagenicity risks: Late stage mutagenic impurity control within the atovaquone second generation synthesis.

The mutagenic-impurity control strategy for a second generation manufacturing route to the non-mutagenic antipneumocystic agent atovaquone (2-((1R,4R)-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. Preliminary assessment highlighted multiple materials of concern which were largely discharged either through returning a negative bacterial mutagenicity assay or through confidence that the impurity would be purged during the downstream processing from when it was first introduced. Additional genotoxicity testing highlighted two materials of concern where initial assessment suggested that testing for these impurities at trace levels within the drug substance would be required.

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies.

The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions.

Using lean methodology to decrease wasted RN time in seeking supplies in emergency departments.

Background: Timely stocking of essential supplies in an emergency department (ED) is crucial to efficient and effective patient care.

Objective: The objective of this study was to decrease wasted nursing time in obtaining needed supplies in an ED through the use of Lean process controls.

Methods: As part of a Lean project, the team conducted a "before and after" prospective observation study of ED nurses seeking supplies.

I can't move my face! a case of bilateral facial palsy.

The authors present a case of bilateral facial palsy in a 52-year-old man. The patient presented to an emergency department in Pennsylvania, describing left-sided neck pain and headache from "sleeping wrong," symptoms which eventually progressed to facial diplegia by his fourth visit in 2 weeks. His admitting diagnosis was Bell palsy; he was ultimately tested for and found to have Lyme disease.

Small and Wide Angle X-ray Scattering studies of biological macromolecules in solution.

In this paper, Small and Wide Angle X-ray Scattering (SWAXS) analysis of macromolecules is demonstrated through experimentation. SWAXS is a technique where X-rays are elastically scattered by an inhomogeneous sample in the nm-range at small angles (typically 0.1 - 5°) and wide angles (typically > 5°).

Carbon monoxide poisoning secondary to hookah smoking.

Hookah smoking, at one time confined to North Africa, the eastern Mediterranean region, the Arabian peninsula, and Southeast Asia, has begun to spread throughout the world. As some practices of eastern and Arab cultures reach the United States, the number of people using hookah on an experimental or regular basis has increased. Carbon monoxide poisoning can be a common adverse effect, possibly undetected by physicians, in hookah smokers.

Accidental decannulation following placement of a tracheostomy tube.

Background: Accidental decannulation is a cause of substantial morbidity and mortality in patients in long-term acute care hospitals who require a tracheostomy tube.

Objective: To analyze features of accidental decannulation (AD) following placement of a tracheostomy tube, and to implement strategies to reduce the problem.

Methods: An analysis of data collected prospectively for quality management in a long-term acute care hospital was performed.

Does the outcome of colonic flexure cancers differ from the other colonic sites?

Background: Anecdotally, colonic flexure cancers (FC) appear to have a poorer prognosis compared to other colonic cancers (OCC). The aim of this study was to determine the outcome of colonic flexure cancers compared to the cancers of the rest of the colon.

Methods: Patients with a diagnosis of colonic cancer over a 5-year period (2002-2006) were retrieved from a prospective database.

Psychological impact of colostomy pouch change and disposal.

This article presents some of the findings from a multicentre cross-sectional correlational study to evaluate the relationship between colostomy pouch change and disposal practices and the patient's psychological wellbeing. Five questionnaires were used in a one-off interview with 86 patients. Patients were assessed at between one and four months postoperatively.

Meniscus allograft transplantation using posterior peripheral suture technique: a preliminary follow-up study.

The aim of this study was to describe the indication, planning, technique, rehabilitation, and clinical results after cryopreserved allograft meniscus transplantation. Forty consecutive patients, 33 men and 7 women (mean, 37.3 years of age), were evaluated at 1-year follow-up post surgery.

Minimal shortening in a high-frequency muscle.

Reducing the cost of high-frequency muscle contractions can be accomplished by minimizing cross-bridge cycling or by recycling elastic strain energy. Energy saving by contractile minimization has very different implications for muscle strain and activation patterns than by elastic recoil. Minimal cross-bridge cycling will be reflected in minimal contractile strains and highly reduced force, work and power output, whereas elastic energy storage requires a period of active lengthening that increases mechanical output.

Luteal phase progesterone excretion in ovulatory women with polycystic ovaries.

Background: Various studies have reported a prevalence of polycystic ovaries (PCO) of approximately 20% in the 'normal' population. Our aim was to investigate the frequency of ovulation and pattern of luteal phase progesterone secretion in a group of women with PCO who reported regular cycles and in whom ovulation had been established on the basis of previous investigations.

Methods: Subjects collected early morning urine samples for pregnanediol-3-glucuronide measurement from day 10 of the cycle to day 1 of their next menses.

Photochemistry of benzotriazole: an unprecedented tautomer-selective intermolecular [2+2] photocycloaddition.

[reaction: see text]. Irradiation of benzotriazole with a variety of maleimide derivatives leads to the stereo- and regioselective formation of aryl [2 + 2] photocycloaddition products. Further studies with 2-alkyl benzotriazole derivatives indicates that in the case of the parent benzotriazole this cycloaddition proceeds selectively via the 2H-tautomer.

Chronic eccentric exercise: improvements in muscle strength can occur with little demand for oxygen.

Eccentric contractions, the lengthening of muscle while producing force, are a common part of our everyday movements. This study presents a challenge to the accepted notion that eccentric work causes obligatory muscle injury while demonstrating that an increase in muscle strength, via eccentric work, can occur with little demand for oxygen. Nine healthy subjects, ages 18-34, were randomly placed in either an eccentric or a concentric training group.

Shoulder immobilization devices.

Currently a myriad of devices are available for immobilization of the injured or postsurgical upper extremity. Some of these devices are straightforward and easily used, but some are more complicated and require more familiarity for their successful application. However, even simple devices have the potential for misapplication and thus prevent their benefit to the patient.