Deletion of arrestin-3 does not improve compulsive drug-seeking behavior in a longitudinal paradigm of oral morphine self-administration.

Opioid drugs are potent analgesics that mimic the endogenous opioid peptides, endorphins and enkephalins, by activating the µ-opioid receptor. Opioid use is limited by side effects, including significant risk of opioid use disorder. Improvement of the effect/side effect profile of opioid medications is a key pursuit of opioid research, yet there is no consensus on how to achieve this goal. One hypothesis is that the degree of arrestin-3 recruitment to the µ-opioid receptor impacts therapeutic utility. However, it is not clear whether increased or decreased interaction of the µ-opioid receptor with arrestin-3 would reduce compulsive drug-seeking. To examine this question, we utilized three genotypes of mice with varying abilities to recruit arrestin-3 to the µ-opioid receptor in response to morphine in a novel longitudinal operant self-administration model. We demonstrate that arrestin-3 knockout and wild type mice have highly variable drug-seeking behavior with few genotype differences. In contrast, in mice where the µ-opioid receptor strongly recruits arrestin-3, drug-seeking behavior is much less varied. We created a quantitative method to define compulsivity in drug-seeking and found that mice lacking arrestin-3 were more likely to meet the criteria for compulsivity whereas mice with enhanced arrestin-3 recruitment did not develop a compulsive phenotype. Our data suggest that opioids that engage both G protein and arrestin-3, recapitulating the endogenous signaling pattern, will reduce abuse liability.

Regulation of 20α-Hydroxysteroid Dehydrogenase Expression in Term Pregnant Human Myometrium Ex Vivo.

Metabolic inactivation of progesterone within uterine myocytes by 20α-hydroxysteroid dehydrogenase (20α-HSD) has been postulated as a mechanism contributing to functional progesterone withdrawal at term. In humans, 20α-HSD is encoded by the gene AKR1C1. Myometrial AKR1C1 mRNA abundance has been reported to increase significantly during labor at term. In spontaneous preterm labor, however, we previously found no increase in AKR1C1 mRNA level in the myometrium except for preterm labor associated with clinical chorioamnionitis. This suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. In this study, we have determined the effects of various treatments of therapeutic relevance on AKR1C1 expression in pregnant human myometrium in an ex vivo culture system. AKR1C1 expression increased spontaneously during 48 h culture (p < 0.0001), consistent with the myometrium transitioning to a labor-like phenotype ex vivo, as reported previously. Serum supplementation, prostaglandin F2α, phorbol myristate acetate, and mechanical stretch had no effect on the culture-induced increase, whereas progesterone (p = 0.0058) and cAMP (p = 0.0202) further upregulated AKR1C1 expression. In contrast, culture-induced upregulation of AKR1C1 expression was dose-dependently repressed by three histone/protein deacetylase inhibitors: trichostatin A at 5 (p = 0.0172) and 25 µM (p = 0.0115); suberoylanilide hydroxamic acid at 0.5 (p = 0.0070), 1 (p = 0.0045), 2.5 (p = 0.0181), 5 (p = 0.0066) and 25 µM (p = 0.0014); and suberoyl bis-hydroxamic acid at 5 (p = 0.0480) and 25 µM (p = 0.0238). We propose the inhibition of histone/protein deacetylation helps to maintain the anti-inflammatory, pro-quiescence signaling of progesterone in pregnant human myometrium by blocking its metabolic inactivation. Histone deacetylase inhibitors may represent a class of agents that preserve or restore the progesterone sensitivity of the pregnant uterus.

Eravacycline, the first four years: health outcomes and tolerability data for 19 hospitals in 5 U.S. regions from 2018 to 2022.

IMPORTANCE: The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline's efficacy in addressing the pressing global challenge of MDR bacterial infections.

Multidisciplinary Teams for the Management of Infective Endocarditis: A Systematic Review and Meta-analysis.

Background: The management of infective endocarditis (IE) is complex owing to a high burden of morbidity and mortality. Recent guidelines recommend dedicated multidisciplinary teams (MDTs) for the management of IE. The aim of this systematic review and meta-analysis was to evaluate and summarize the effect of MDT management on patient outcomes. Methods: A systematic review was performed and, where feasible, results were meta-analyzed; otherwise, results were summarized narratively. Data extraction and quality assessment were performed in duplicate. Restricted maximum likelihood random effects models were used to calculate unadjusted risk ratios and 95% CIs. Results: Screening of 2343 studies based on title and abstract yielded 60 full-text reviews; 18 studies were summarized narratively, of which 15 were included in a meta-analysis of short-term mortality. Meta-analysis resulted in a risk ratio of 0.61 (95% CI, .47-.78; I2 = 62%) for mortality in favor of a dedicated MDT as compared with usual care. Length of stay was variable, with 55% (10/18) of studies reporting an increased length of stay. Most studies (16/18, 88.9%) reported a decreased time to surgery and an increased rate of surgery (13/18, 73%). No studies reported on patient-reported outcomes. Conclusions: This is the first systematic review and meta-analysis to assess the impact of MDT management on IE. The sum of evidence demonstrated a significant association between MDTs and improved short-term mortality. Further research is needed to evaluate benefits of virtual MDT care, cost-effectiveness, and the impact on patient-reported outcomes and long-term mortality.

Gaps in the System: Supporting People Living with Dementia.

Persons living with dementia and their caregivers often face challenges in accessing support for their complex needs. This study aims to understand how program administrators, people living with dementia, unpaid caregivers, and decision-makers perceive specific dementia care programs and whether they are adequately meeting the needs of individuals living with dementia. Forty semi-structured interviews were conducted between 2018 and 2020 in five North American jurisdictions. Three main gaps were identified (1) disconnected system infrastructure, (2) lack of comprehensive services to meet diverse needs, and (3) inconsistent understandings of dementia. Despite having programs in place, there remain significant limitations in systems that could be addressed to adequately meet the needs of individuals living with dementia and their caregivers.

Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement.

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence. Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength. Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches. Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions. Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Administration of ß-lactam antibiotics to patients with reported penicillin allergy in the emergency department.

BACKGROUND: ß-lactam antibiotics are amongst the most commonly prescribed medications in the Emergency Department (ED) due to their role in empiric sepsis therapy; however, inferior therapeutic options are often utilized due to a reported allergy; penicillin (PCN) being most frequent. In the United States, 10% of the population endorses an allergic reaction to PCN while <1% experience IgE-mediated reactions. This study aimed to evaluate the frequency and outcome of patients in the ED whose PCN allergies were challenged with ß-lactam antibiotics. METHODS: We conducted a retrospective chart review of patients in the ED at an academic medical center aged ≥18, and who received a ß-lactam despite a reported PCN allergy between January 2015 and December 2019. Patients who did not receive a ß-lactam or did not report a PCN allergy prior to administration were excluded. The primary outcome was the frequency of IgE-mediated reactions in response to ß-lactam administration. A secondary outcome assessed the frequency of continuation of ß-lactams upon admission from the ED. RESULTS: 819 patients were included (66% female) with prior reported PCN reactions: hives (22.5%), rash (15.4%), swelling (6.2%), anaphylaxis (3.5%), other (12.1%), or undocumented on medical electronic record (40.3%). No patients experienced an IgE-mediated reaction to the ß-lactam administered in the ED. Previously reported allergies had no effect on the continuation of ß-lactams when admitted or discharged (OR: 1, 95% CI: 0.7-1.44). Patients who had a history of an IgE-mediated penicillin allergy were frequently continued (77%) on a ß-lactam after leaving the ED via admission or discharge. CONCLUSION: ß-lactam administration in patients with previously reported PCN allergies did not result in any IgE-mediated reactions nor in an increase in adverse reactions. Our data contributes to the body of evidence that supports the administration of ß-lactams to patients with documented PCN allergies.

Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively.

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins. More recently, heterobifunctional small molecules such as Proteolysis Targeting Chimera (PROTACs) have paved the way for protein proximity inducing therapeutic modalities. Here, we describe a proof-of-concept study using novel heterobifunctional small molecules called Regulated Induced Proximity Targeting Chimeras or RIPTACs, which elicit a stable ternary complex between a target protein selectively expressed in cancer tissue and a pan-expressed protein essential for cell survival. The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to cell death selectively in cells expressing the target protein. This approach not only opens new target space by leveraging differentially expressed intracellular proteins but also has the advantage of not requiring the target to be a driver of disease. Thus, RIPTACs can address non-target mechanisms of resistance given that cell killing is driven by inactivation of the essential protein. Using the HaloTag7-FKBP model system as a target protein, we describe RIPTACs that incorporate a covalent or non-covalent target ligand connected via a linker to effector ligands such as JQ1 (BRD4), BI2536 (PLK1), or multi-CDK inhibitors such as TMX3013 or dinaciclib. We show that these RIPTACs exhibit positive co-operativity, accumulate selectively in cells expressing HaloTag7-FKBP, form stable target:RIPTAC:effector trimers in cells, and induce an anti-proliferative response in target-expressing cells. We propose that RIPTACs are a novel heterobifunctional therapeutic modality to treat cancers that are known to selectively express a specific intracellular protein.

Clinical Outcomes of Eravacycline in Patients Treated Predominately for Carbapenem-Resistant Acinetobacter baumannii.

Forty-six patients were treated with eravacycline (ERV) for Acinetobacter baumannii infections, where 69.5% of isolates were carbapenem resistant (CRAB). Infections were primarily pulmonary (58.3%), and most patients received combination therapy (84.4%). The median (IQR) ERV duration was 6.9 days (5.1 to 11.1). Thirty-day mortality was 23.9% in the cohort and 21.9% in CRAB patients. One patient experienced an ERV-possible adverse event. IMPORTANCE Acinetobacter baumannii, particularly when carbapenem resistant (CRAB), is one of the most challenging pathogens in the health care setting. This is complicated by the fact that there is no consensus guideline regarding management of A. baumannii infections. However, the recent Infectious Diseases Society of America guidelines for treatment of resistant Gram-negative infections provided expert recommendations for CRAB management. The panel suggest using minocycline among tetracycline derivatives rather than eravacycline (ERV) until sufficient clinical data are available. Therefore, we present the largest multicenter real-world cohort in patients treated with ERV for A. baumannii, where the majority of isolates were CRAB (69.5%). Our analysis demonstrate that patients treated with ERV-based regimens achieved a 30-day mortality of 23.9% and had a low incidence of ERV-possible adverse events (2.1%). This study is important as it fills the gap in the literature regarding the use of a novel tetracycline (i.e., ERV) in the treatment of this challenging health care infection.

Continuity of care for older adults in a Canadian long-term care setting: a qualitative study.

BACKGROUND: Continuity of care has been shown to improve health outcomes and increase patient satisfaction. Goal-oriented care, a person-centered approach to care, has the potential to positively impact continuity of care. This study sought to examine how a goal-oriented approach impacts continuity of care in a long-term care setting. METHODS: Using a case study approach, we examined what aspects of goal-oriented care facilitate or inhibit continuity of care from the perspectives of administrators, care providers, and residents in a long-term care centre in Ontario, Canada. Data was collected through documentary evidence and semi-structured interviews. RESULTS: We analyzed six internal documents (e.g., strategic plan, client information package, staff presentations, evaluation framework, program logic model), and conducted 13 interviews. The findings indicated that the care provided through the goal-oriented approach program had elements that both facilitated and inhibited continuity of care. These factors are outlined according to the three types of continuity, including aspects of the program that influence informational, relational, and management continuity. CONCLUSIONS: Aspects of the goal-oriented care approach that facilitate continuity can be targeted when designing person-centered care approaches. More research is needed on goal-oriented care approaches that have been implemented in other long-term care settings to determine if the factors identified here as influencing continuity are confirmed.

Policy programs and service delivery models for older adults and their caregivers: Comparing three provinces and two states.

Despite an increase in prevalence of complex chronic conditions and dementia, long-term care services are being continuously pushed out of institutional settings and into the home and community. The majority of people living with dementia in Canada and the United States (U.S.) live at home with support provided by family, friends or other unpaid caregivers. Ten dementia care policy programs and service delivery models across five different North American jurisdictions in Canada and the U.S. are compared deductively using a comparative policy framework originally developed by Richard Rose. One aim of this research was to understand how different jurisdictions have worked to reduce the fragmentation of dementia care. Another aim is to assess, relying on the theory of smart policy layering, the extent to which these policy efforts 'patch' health system structures or add to system redundancies. We find that these programs were introduced in a manner that did not fully consider how to patch current programs and services and thus risk creating further system redundancies. The implementation of these policy programs may have led to policy layers, and potentially to tension among different policies and unintended consequences. One approach to reducing these negative impacts is to implement evaluative efforts that assess 'goodness of fit'. The degree to which these programs have embedded these efforts into an existing policy infrastructure successfully is low, with the possible exception of one program in NY.

Inappropriate Use of Aztreonam.

BACKGROUND: Aztreonam is not a preferred empiric antibiotic because of variable susceptibilities compared with alternative agents. In addition, it has no Gram-positive activity, necessitating coadministration with vancomycin when used empirically, and is more costly when compared with other Gram-negative active agents. Aztreonam is often given to patients with a reported penicillin allergy without further investigation into the reaction or other relevant allergy information. STUDY QUESTION: How frequently is aztreonam being used inappropriately? STUDY DESIGN: We conducted a retrospective chart review at an academic medical center to assess the appropriateness of our aztreonam use. MEASURES AND OUTCOMES: Our primary outcome was frequency of appropriate aztreonam use, based on a true IgE-mediated allergy reported for each patient. We evaluated whether the patients had tolerated a beta-lactam in the past, and what the reported allergic reaction was. RESULTS: We included 165 patients and found that 46.7% of our aztreonam use was inappropriate, based on previous use of a beta-lactam, or no documentation of an IgE-mediated response. Of the patients with a documented beta-lactam allergy, 63 (38.2%) patients had no allergy manifestation listed, and 37 (22.4%) patients had a non-IgE-mediated allergy manifestation. Of the total population, 61 (37%) patients had tolerated a beta-lactam in the past. CONCLUSIONS: Aztreonam should be avoided, except in the case of a true IgE-mediated allergic reaction. Our goal was to reduce the inappropriate use of aztreonam at our institution by one or more of the following: educating providers, reviewing aztreonam orders, requiring answering of order questions, or requiring an indication for use. Penicillin skin testing and desensitization are options as well.

Early Experience With Eravacycline for Complicated Infections.

Eravacycline (ERV) was used in 35 patients for various infections. The most common pathogen was Klebsiella pneumoniae, and 30-day survival was 74%. Absence of 30-day recurrence and resolution of signs and symptoms of infection were 91% and 57%, respectively. ERV was well-tolerated, with adverse events leading to drug discontinuation in one patient.

Modelling the allocation of paediatric intensive care retrieval teams in England and Wales.

BACKGROUND: Following centralisation of UK paediatric intensive care units in 1997, specialist paediatric intensive care retrieval teams (PICRTs) were established to transport critically ill children from district general hospitals (DGHs). The current location and catchment area of PICRTs covering England and Wales are based on historical referral patterns. National quality standards specify that PICRTs should reach the patient bedside within 3 hours of accepting a referral. OBJECTIVE: To determine what proportion of demand for PICRT services in England and Wales can be reached within 3 hours and to explore the potential coverage impact of more stringent 'time to bedside' standards. METHODS: We used mathematical location-allocation methods to: (1) determine the optimal allocation of DGHs to current PICRT locations to minimise road journey time and calculated the proportion of demand reachable within 3 hours, 2 hours, 90 min, 75 min and 1 hour and (2) explore the impact of changing the number and location of PICRTs on demand coverage for the different time thresholds. RESULTS: For current (and optimal) location of 11 PICRTs, 98% (98%) of demand is reachable within 3 hours; 86% (91%) within 2 hours; 59% (69%) within 90 min; 33% (39%) within 75 min; and 20% (20%) within 1 hour. Five hospitals were not reachable within 3 hours. For the 3-hour standard, eight optimally located PICRT locations had similar coverage as the current 11 locations. CONCLUSIONS: If new evidence supports reduction in the time to bedside standard, many more hospitals will not be adequately covered. Location-allocation optimisation is a powerful technique for supporting evidence-based service configuration.

How do patients from South Asian backgrounds experience life on haemodialysis in the UK? A multicentre qualitative study.

OBJECTIVES: End-stage kidney disease disproportionately affects people of South Asian origin. This study aimed to uncover the lived experiences of this group of patients on centre-based haemodialysis (HD), the most prevalent dialysis modality. DESIGN: The study utilised a qualitative focus group methodology. Seven focus groups were conducted across four NHS Trusts in the UK including three in Gujarati and two each in Punjabi and Urdu. This provided an inclusive opportunity for South Asian patients to contribute in their language of origin. A total of 24 patients participated. Focus groups were facilitated by bilingual project workers and data were forward translated and analysed using thematic analysis. RESULTS: Four themes were identified. This included (1) 'treatment imposition', which comprised of the restrictive nature of HD, the effects of treatment and the feeling of being trapped in an endless process. (2) The 'patient-clinician relationship' centred around the impact of a perceived lack of staff time, and inadequacies in the quality of interactions. (3) 'Coping strategies' highlighted the role of cognitive reappraisal, living in the moment and family support networks in facilitating adjustment. (4) 'Pursuit of transplantation' included equating this form of treatment with restoring normality, alongside cultural factors limiting hopefulness for receiving an organ. CONCLUSIONS: In general, the experiences of South Asian patients receiving HD were not unique to this ethnic group. We did find distinct issues in relation to interactions with healthcare professionals, views on access to transplantation and the importance of family support networks. The study provides useful insights which may help enhance culturally tailored renal care.

Medical Management of Endocarditis Caused by Stenotrophomonas maltophilia: A Case Report.

A 44-year-old female was found to be systemically ill at dialysis and admitted to the hospital. Days into the hospitalization, her blood cultures from dialysis were positive with Stenotrophomonas maltophilia bacteremia with a levofloxacin minimum inhibitory concentration (MIC) of 1. She was discharged on ciprofloxacin 500 mg orally (PO) daily on hospital day 2 to complete a 14-day course. Weeks later, she was again found to be bacteremic at dialysis and sent back to the hospital. She was started on empiric antibiotics upon admission until further identification. Blood cultures again revealed S. maltophilia with a levofloxacin MIC of 32. Antibiotics were tailored to trimethoprim/sulfamethoxazole (TMP-SMX) until susceptibilities for additional agents were available. Further workup revealed mitral valve endocarditis. She was subsequently discharged on both minocycline 100 mg PO every 12 hours and TMP-SMX 1 DS PO daily with a planned duration of 6 weeks. Due to ongoing readmissions for hyperkalemia, TMP-SMX was discontinued and her regimen was modified to ceftazidime 1 g intravenously (IV) after HD plus minocycline 100 mg PO every 12 hours. She was deemed clinically and microbiologically cleared based on follow-up assessments. To our knowledge, this is the first case of S. maltophilia endocarditis treated with oral minocycline in combination with another antibiotic.

Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: A Multicenter Study.

BACKGROUND: Multidrug-resistant Pseudomonas aeruginosa infections remain common in hospitals worldwide. We investigated the outcomes associated with the use of ceftolozane-tazobactam for the treatment of these infections. METHODS: Data were collected retrospectively from 20 hospitals across the United States about adults who received ceftolozane-tazobactam for the treatment of multidrug-resistant P aeruginosa infections of any source for at least 24 hours. The primary outcome was a composite of 30-day and inpatient mortality, and secondary outcomes were clinical success and microbiological cure. Multivariable regression analysis was conducted to determine factors associated with outcomes. RESULTS: Two-hundred five patients were included in the study. Severe illness and high degrees of comorbidity were common, with median Acute Physiology and Chronic Health Evaluation (APACHE) II scores of 19 (interquartile range [IQR], 11-24) and median Charlson Comorbidity Indexes of 4 (IQR, 3-6). Delayed initiation of ceftolozane-tazobactam was common with therapy started a median of 9 days after culture collection. Fifty-nine percent of patients had pneumonia. On susceptibility testing, 125 of 139 (89.9%) isolates were susceptible to ceftolozane-tazobactam. Mortality occurred in 39 patients (19%); clinical success and microbiological cure were 151 (73.7%) and 145 (70.7%), respectively. On multivariable regression analysis, starting ceftolozane-tazobactam within 4 days of culture collection was associated with survival (adjusted odds ratio [OR], 5.55; 95% confidence interval [CI], 2.14-14.40), clinical success (adjusted OR, 2.93; 95% CI, 1.40-6.10), and microbiological cure (adjusted OR, 2.59; 95% CI, 1.24-5.38). CONCLUSIONS: Ceftolozane-tazobactam appeared to be effective in the treatment of multidrug-resistant P aeruginosa infections, particularly when initiated early after the onset of infection.

Dynamic Interplay of Pharmacy Learners During a Solid Organ Transplantation Learning Experience.

Institutions with established clinical pharmacy services have the ability to offer focused patient care learning experiences, often led by a clinical specialist, for pharmacy residents and pharmacy students. Since all parties are continually involved in professional development and lifelong learning, the aforementioned groups can all be considered "pharmacy learners." By utilizing the dynamic interplay and collaboration between pharmacy learners through direct and nondirect patient care activities, experiential and educational opportunities may be improved and enhanced for each learner. A tiered learning approach engages individuals in areas such as direct patient care, patient education, presentations, research projects, career development, and the feedback process. We describe our experience during a solid organ transplantation learning experience using a layered learning practice model that included a clinical pharmacy specialist, a postgraduate year 2 specialty pharmacy resident, a postgraduate year 1 pharmacy resident, and a pharmacy student.