Reducing unnecessary sedative-hypnotic use among hospitalised older adults.

BACKGROUND: Benzodiazepines and sedative hypnotics (BSH) have numerous adverse effects that can lead to negative outcomes, particularly in vulnerable hospitalised older adults. At our institution, over 15% of hospitalised older adults are prescribed sedative-hypnotics inappropriately. Of these prescriptions, 87% occurred at night to treat insomnia and almost 20% came from standard admission order sets. METHODS: We conducted a time-series study from January 2015 to August 2016 among medical and cardiology inpatients following the implementation in August 2015 of a sedative reduction bundle (education, removal of BSH from available admission order sets and non-pharmacological strategies to improve sleep). Preintervention period was January-July 2015 and postintervention period was August 2015-August 2016. A surgical ward served as control. Primary outcome was the proportion of BSH-naive (not on BSH prior to admission) patients 65 years or older discharged from medical and cardiology wards who were prescribed any new BSH for sleep in hospital. Data were analysed on statistical process control (SPC) p-charts with upper and lower limits set at 3δ using standard rules. Secondary measures included Patient-reported Median Sleep Quality scores and rates of fall and sedating drug prescriptions that may be used for sleep (dimenhydrinate). RESULTS: During the study period, there were 5805 and 1115 discharges from the intervention and control units, respectively. From the mean baseline BSH prescription rate of 15.8%, the postintervention period saw an absolute reduction of 8.0% (95% CI 5.6% to 10.3%; p<0.001). Adjusted for temporal trends, the intervention produced a 5.3% absolute reduction in the proportion of patients newly prescribed BSH (95% CI 5.6% to 10.3%; p=0.002). BSH prescription rates remained stable on the control ward. Patient-reported measure of sleep quality, falls and use of other sedating medications remained unchanged throughout the study duration. CONCLUSION: A comprehensive intervention bundle was associated with a reduction in inappropriate BSH prescriptions among older inpatients.

High Prevalence of Inappropriate Benzodiazepine and Sedative Hypnotic Prescriptions among Hospitalized Older Adults.

BACKGROUND: Benzodiazepines and sedative hypnotics are commonly used to treat insomnia and agitation in older adults despite significant risk. A clear understanding of the extent of the problem and its contributors is required to implement effective interventions. OBJECTIVE: To determine the proportion of hospitalized older adults who are inappropriately prescribed benzodiazepines or sedative hypnotics, and to identify patient and prescriber factors associated with increased prescriptions. DESIGN: Single-center retrospective observational study. SETTING: Urban academic medical center. PARTICIPANTS: Medical-surgical inpatients aged 65 or older who were newly prescribed a benzodiazepine or zopiclone. MEASUREMENTS: Our primary outcome was the proportion of patients who were prescribed a potentially inappropriate benzodiazepine or sedative hypnotic. Potentially inappropriate indications included new prescriptions for insomnia or agitation/anxiety. We used a multivariable random-intercept logistic regression model to identify patient- and prescriber-level variables that were associated with potentially inappropriate prescriptions. RESULTS: Of 1308 patients, 208 (15.9%) received a potentially inappropriate prescription. The majority of prescriptions, 254 (77.4%), were potentially inappropriate. Of these, most were prescribed for insomnia (222; 87.4%) and during overnight hours (159; 62.3%). Admission to a surgical or specialty service was associated with significantly increased odds of potentially inappropriate prescription compared to the general internal medicine service (odds ratio [OR], 6.61; 95% confidence interval [CI], 2.70-16.17). Prescription by an attending physician or fellow was associated with significantly fewer prescriptions compared to first-year trainees (OR, 0.28; 95% CI, 0.08-0.93). Nighttime prescriptions did not reach significance in initial bivariate analyses but were associated with increased odds of potentially inappropriate prescription in our regression model (OR, 4.48; 95% CI, 2.21-9.06). CONCLUSIONS: The majority of newly prescribed benzodiazepines and sedative hypnotics were potentially inappropriate and were primarily prescribed as sleep aids. Future interventions should focus on the development of safe sleep protocols and education targeted at first-year trainees.Journal of Hospital Medicine 2017;12:310-316.

Humanized mice for Salmonella typhi infection: new tools for an old problem.

Salmonella enterica serovar Typhi (S. typhi), is a human restricted pathogen and the causal agent of typhoid fever. Although the use of antimicrobial drugs or vaccines has served as an effective therapeutics strategy against typhoid fever, the recent surge in multidrug resistant strains of S. typhi presents a major health concern worldwide. Progress on typhoid research has been limited in the past due to the lack of a suitable animal model that recapitulates the hallmark immunological features of human typhoid fever. We have recently developed a humanized immune system (HIS) mouse model that after intravenous challenge with S. typhi displayed classical manifestations of human typhoid fever including meningitis, liver pathology and mortality. Concurrent to our studies, two other groups also have developed humanized mouse models of S. typhi infections employing different protocols. All these recently adopted animal models of S. typhi infections provide promise for a new era of S. typhi research that may expedite detailed understanding of the cellular and molecular mechanisms of this bacterial infection and investigations of new antimicrobials and vaccines for effective control.

Humanized mice are susceptible to Salmonella typhi infection.

Salmonella enterica serovar Typhi is a pathogen that only infects humans. Currently, there is no animal model for studying this pathogen. Recently, alymphoid RAG-2(-/-)/γ(c)(-/-) mice engrafted with human leukocytes, known as humanized mice, have been successfully utilized to develop experimental models for several human-specific viral infections, including HIV, human-like dengue fever and hepatitis C virus. Little is known about the usefulness and feasibility of the humanized mouse model for the study of human-specific bacterial pathogens, such as S. typhi. The aim of this study was to determine if Salmonella enterica serovar Typhi could establish productive infection in humanized mice. Here we report that intravenous inoculation of S. typhi into humanized mice, but not controls, established S. typhi infections. High bacterial loads were found in the liver, spleen, blood and bone marrow of mice reconstituted with human leukocytes, but not in the unreconstituted control mice. Importantly, S. typhi-infected humanized mice lost significant body weight, and some of the infected mice displayed neurological symptoms. Our data suggest, for the first time, that humanized mice are susceptible to S. typhi challenge and that this model can be utilized to study the pathogenesis of S. typhi to develop novel therapeutic strategies.

CD4(+) T-cells are important in regulating macrophage polarization in C57BL/6 wild-type mice.

During activation, macrophages undergo physiological changes affecting their surface protein expression and cytokine production and have been subsequently categorized into M1 (classically-activated) and M2 (alternatively-activated) macrophages. It remains unclear which lymphocyte population provides the immune microenvironment to regulate macrophage polarization. In this study, we establish a functional and phenotypic profile of peritoneal macrophages from C57BL/6 wild-type mice. We also showed that Rag1(-/-) and Rag2(-/-)γc(-/-) mice have similar, exaggerated M1 characteristics in comparison to control mice, suggesting that NK and/or NK-T cells may not be essential in this process. By controlling for environmental factors, we determine that lymphocyte-derived cytokines, rather than inherent properties of macrophages themselves, are crucial for their regulation. Lastly, we report that macrophages from CD4(-/-) mice display an M1 profile, suggesting that CD4(+) T-cells play a dominant role over other lymphocyte populations in providing the cytokine environment for regulating macrophages towards an M2 profile under normal wild-type conditions.

Characterization and IL-15 dependence of NK cells in humanized mice.

Natural Killer cells can distinguish between healthy and malignant cells and have the unique ability to lyse tumour cells without prior sensitization. Differences between murine and human NK cells complicate the translation of this knowledge into useful therapeutics. Humanized mouse models that support the development of human leukocytes are a promising avenue of research that aims to address this problem. Here we provide an in-depth phenotypic analysis of human NK cells in Balb/c Rag2(-/-)γ(c)(-/-) mice reconstituted with human hematopoietic stem cells. We have examined the development of NK cells in bone marrow, thymous, spleen, lymph node (LN) and liver. Interestingly, in naive reconstituted mice, NK cells were found in thymus and LN, but not in bone marrow. These NK cells expressed several inhibitory and activating receptors needed for malignant cell detection. Furthermore, we confirm that administration of recombinant human interleukin-15 (rhIL-15) or Ad-vector expressing hIL-15 is able to significantly enhance NK cell development and maturation, particularly in bone marrow and liver, in this model. Our results suggest that human NK cells developed in mice may have phenotypes and tissue distributions similar to those seen in human.