European Association of Hospital Pharmacists (EAHP) guidance on the pharmacy handling of in vivo gene therapy medicinal products.

Gene therapy is becoming increasingly prevalent, with new gene therapy medicinal products (GTMPs) being approved for use every year. Hospital pharmacists are expected to prepare and dispense these products, but there is substantial heterogeneity in the availability of up-to-date, practical guidance at a national level in Europe. Many institutions have no or very limited experience in handling GTMPs. As such, there is a need for updated, practical guidance to aid hospital pharmacy teams in developing institutional standard operating procedures (SOPs) for the safe handling of GTMPs across the entire workflow. Here, we present the European Association of Hospital Pharmacists' updated guidance on the handling of GTMPs, developed by a team of recognised experts from around Europe. Each aspect of the GTMP handling process is addressed, including receipt and storage, dispensing and reconstitution, transportation, administration, waste disposal, decontamination of spills and accidental exposure. A series of figures are provided to aid the development of practical workflows. This guidance document is intended as a framework to help develop institutional SOPs and should always be used in conjunction with local regulations.

Ligneous conjunctivitis mimicking preseptal cellulitis in a 3-month-old infant.

BACKGROUND: Ligneous conjunctivitis is a very rare form of pseudomembranous conjunctivitis with few published cases in literature. We aim to describe the ocular findings and treatment in an infant with ligneous conjunctivitis resembling preseptal cellulitis on presentation. MATERIALS AND METHODS: Case report of a 3-month-old girl who was referred to a tertiary centre for ophthalmic assessment due to progressive eyelid oedema with no response to initiated topical and systemic antibiotics. Ethical approval has been achieved from the local ethics committee of the Ghent University Hospital and informed consent has been obtained from the parents of the child. RESULTS: Examination under general anaesthesia showed multiple, wood-like fibrinous pseudomembranes, originating from the conjunctiva, consistent with ligneous conjunctivitis. After careful removal of the coagulated exudate covering the cornea, a central corneal epithelial defect was evident without stromal infiltration. Histopathologic examination confirmed the predominance of fibrin within the pseudomembranes. Plasminogen activity was below the normal range. Genetic analysis did not identify a pathogenic variant in the PLG gene. The corneal epithelium re-epithelialised during the following days and the conjunctival lesions gradually subsided over the ensuing weeks whilst continuing heparin-containing artificial tears. CONCLUSION: A high level of suspicion is warranted in atypical cases of preseptal cellulitis which show no response to antibiotic treatment. Particularly in young children, examination under general anesthesia is warranted to allow diagnosis of rare causes of secondary eyelid oedema. We report an infant with unilateral ligneous conjunctivitis who responded well to topical, commercially-available heparin-containing artificial tears treatment. This approach is an effective and easy first-line treatment option in this condition, particularly in milder phenotypes.

Therapeutic dilemmas with benzodiazepines and Z-drugs: insomnia and anxiety disorders versus increased fall risk: a clinical review.

PURPOSE: The aim of this clinical review was to summarise the existing knowledge on fall risk associated with benzodiazepines (BZDs) and Z-drugs in older people with focus on appropriate prescribing, including deprescribing. METHODS: We conducted a literature search in June 2021 in PubMed and Embase with citation and reference checking. Personal reference libraries and international websites were also used. Keywords for the searches included "benzodiazepines", "Z-drugs", "falls", "deprescribing", "fall-risk-increasing-drugs", "inappropriate prescribing", "older people" and matching synonyms. We discuss use of BZDs and Z-drugs, potential fall-related adverse reactions, alternatives for and deprescribing of BZDs and Z-drugs in older persons. RESULTS: BZDs and Z-drugs differ in fall-related adverse effect profile. They contribute to fall risk through orthostatic hypotension, dizziness and/or imbalance, sedation, muscular weakness, ataxia, etc. Fall incidents contribute significantly to mortality and morbidity. Therefore, there is a need for appropriate prescribing and use of BZDs and Z-drugs in older people. In practice, this means pertaining to a strict indication, strongly consider to non-pharmacological alternatives, limit use to the lowest dose and the shortest duration possible. Judicious deprescribing should be considered and encouraged as well. Practical resources, tools and algorithms are available to guide and assist clinicians in deprescribing BZDs and Z-drugs. CONCLUSIONS: Prescribing BZDs and Z-drugs should be done in a well-considered way in fall-prone older people. A good overview and insight in the fall-related adverse effects of these drugs, as well as the availability of different strategies to increase the appropriate use, including deprescribing initiatives, can assist clinicians in clinical decision-making.

Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward.

OBJECTIVES: Disulfiram is an adjunct in the treatment of alcohol use disorders, but case reports indicate that disulfiram ethanol reactions are not always recognized in the emergency department. Our first aim is to remind of this risk with two case reports of life-threatening reactions not immediately considered by the emergency physician. The second aim is to estimate the probability that a disulfiram reaction goes unrecognized with the use of a retrospective study of patients admitted to the emergency department. METHODS: Clinical files of patients admitted between October 1, 2010 and September 30, 2014 to the emergency department were retrospectively screened for the key words "ethanol use" and "disulfiram". Their diagnoses were then scored by a panel regarding the probability of an interaction. RESULTS: Seventy-nine patients were included, and a disulfiram-ethanol reaction was scored as either 'highly likely', 'likely' or 'possible' in 54.4% and as 'doubtful' or 'certainly not present' in 45.6% of the patients. The interrater agreement was 0.71 (95% CI: 0.64-0.79). The diagnosis was not considered or only after a delay in 44.2% of the patients with a 'possible' to 'highly likely' disulfiram interaction. One patient with a disulfiram overdose died and was considered as a 'possible' interaction. DISCUSSION AND CONCLUSIONS: A disulfiram ethanol interaction can be life threatening and failure to consider the diagnosis in the emergency department seems frequent. Prospective studies with documentation of the intake of disulfiram and evaluation of the value of acetaldehyde as a biomarker are needed to determine the precise incidence. Improving knowledge of disulfiram interactions and adequate history taking of disulfiram intake may improve the care for patients.

Role for neutrophils in host immune responses and genetic factors that modulate resistance to Salmonella enterica serovar typhimurium in the inbred mouse strain SPRET/Ei.

Infection with Salmonella enterica serovar Typhimurium is a complex disease in which the host-bacterium interactions are strongly influenced by genetic factors of the host. We demonstrate that SPRET/Ei, an inbred mouse strain derived from Mus spretus, is resistant to S. Typhimurium infections. The kinetics of bacterial proliferation, as well as histological examinations of tissue sections, suggest that SPRET/Ei mice can control bacterial multiplication and spreading despite significant attenuation of the cytokine response. The resistance of SPRET/Ei mice to S. Typhimurium infection is associated with increased leukocyte counts in the circulation and enhanced neutrophil influx into the peritoneum during the course of infection. A critical role of neutrophils was confirmed by neutrophil depletion: neutropenic SPRET/Ei mice were sensitive to infection with S. Typhimurium and showed much higher bacterial loads. To identify genes that modulate the natural resistance of SPRET/Ei mice to S. Typhimurium infection, we performed a genome-wide study using an interspecific backcross between C3H/HeN and SPRET/Ei mice. The results of this analysis demonstrate that at least two loci, located on chromosomes 6 and 11, affect survival following lethal infection with S. Typhimurium. These two loci contain several interesting candidate genes which may have important implications for the search for genetic factors controlling Salmonella infections in humans and for our understanding of complex host-pathogen interactions in general.

Type I interferon drives tumor necrosis factor-induced lethal shock.

Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-alpha receptor 1 (IFNAR-1) or in IFN-beta are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1(-/-) mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1(-/-) mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element-dependent genes, many of which encode chemokines. In livers of IFNAR-1(-/-) mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.