Implementation frameworks for polypharmacy management within healthcare organisations: a scoping review.

BACKGROUND: Several guidelines support polypharmacy management in individual patients. More organisational-level focus is needed on the use of implementation frameworks. AIM: To characterise the peer reviewed literature on implementation frameworks, focussing on barriers and facilitators to implementation at organisational level in the context of polypharmacy management. METHOD: A scoping review protocol was devised, supporting retrieval of studies published in English, reporting from any sector of practice. Medline, International Pharmaceutical Abstracts, Cumulative Index of Nursing and Allied Health Literature and Business Source Complete were searched to January 2022 using Medical Subject Headings including: 'polypharmacy', 'deprescriptions', 'strategic planning' and 'organizational innovation'. A narrative approach to data synthesis was applied. Searching, data extraction and synthesis were undertaken independently by two reviewers. RESULTS: After screening 797 records eight papers remained. Two were descriptive outlining details of specific initiatives, six used qualitative methods to explore determinants for implementation including barriers and enablers. Organisation level barriers included: poor organisational culture with a lack of sense of urgency and national plans, resource availability and communication issues including patient information and at transitions of care. Organisational facilitators included availability of government funding and regulatory environment promoting patient safety, a national emphasis on quality of care for older adults, co-ordinated national efforts and local evidence. CONCLUSION: Limited literature focusses on the use of implementation frameworks at organisational levels. This review highlights the need for further work on implementation frameworks in this context to help achieve effective organisational change.

Systematic review of topical interventions for the management of odour in patients with chronic or malignant fungating wounds.

Chronic wounds adversely affect the quality of life of individuals and odour is a well-recognised associated factor. Odour can affect sleep, well-being, social interactions, diet and potentially wound healing. This systematic review aims to examine the effectiveness of topical interventions in the management of odour associated with chronic and malignant fungating wounds. A systematic review guided by PRISMA recommendations of randomised controlled trials where odour intensity/odour is the primary outcome was undertaken. Inclusion criteria were adults (18 years and over) with chronic venous, arterial, diabetic or pressure ulcers or with malignant fungating wounds where odour has been managed through topical application of pharmacological/non-pharmacological agents. Searches were conducted in CENTRAL, CINAHL, EMBASE, MEDLINE, Scopus, and Web of Science. Eligibility screening, risk of bias assessment and data extraction was completed by authors working independently. Searches retrieved 171 titles and abstracts (157 post de-duplication). Thirteen studies were retained for full text review of which five (n = 137 individuals) examining the following treatments remained: metronidazole (n = 4), silver (n = 1). Meta-analysis was not possible but individual studies suggest improved outcomes (i.e., reduced odour) using metronidazole. Treatment options to manage wound odour are limited and hampered by lack of clinical trials, small sample sizes, and absence of standardised outcomes and consistent measurement. Whereas metronidazole and silver may have a role in controlling wound odour, robust and well-designed interventions with rigorous procedures and standardised odour outcomes are necessary to evaluate their contribution.

Arrhythmogenic right ventricular cardiomyopathy in dogs.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease seen in dogs, cats, and humans. A common entity in Boxers and the related English bulldog, the disease is characterized by fatty or fibrofatty replacement of the myocardium, ventricular arrhythmias, and the potential for syncope or sudden death. In some individuals, concomitant left ventricular involvement results in systolic dysfunction and a progression to congestive heart failure. The clinical and pathological characteristics of ARVC share many similarities in dogs and humans, and Boxers serve as an important spontaneous model of the disease. Although multiple mechanisms have been implicated in the pathogenesis of ARVC, the disease is ultimately considered to be a disorder of the desmosome. Multiple causal genetic mutations have been identified in people, and over 50% of affected humans have an identifiable mutation in desmosomal proteins. To date, only a single genetic mutation has been associated with ARVC in Boxer dogs. Other as-yet-undiscovered genetic mutations and epigenetic modifiers of the disease are likely. Treatment of ARVC in dogs is focused on controlling ventricular arrhythmias and associated clinical signs. This article will review the pathophysiology, clinical diagnosis, treatment, and prognosis of ARVC in the dog.

The effect of DAFNE education, continuous subcutaneous insulin infusion, or both in a population with type 1 diabetes in Scotland.

AIM: To investigate the effect of DAFNE and continuous subcutaneous insulin infusion in clinical practice. METHODS: Within NHS Lothian, continuous subcutaneous insulin infusion started in 2004 and DAFNE education began in 2006. We extracted anonymized data from the national database for all those aged > 18 years with type 1 diabetes having a Dose Adjustment For Normal Eating course or continuous subcutaneous insulin infusion start date (n = 4617). RESULTS: In total, 956 persons received DAFNE education, and 505 had received an insulin pump, 208 of whom had DAFNE education followed by insulin pump. Mean (SD) HbA1c before DAFNE education was 68 (15) mmol/mol (8.4% [1.4%]) and 66 (13) mmol/mol (8.2% [1.2%]) before continuous subcutaneous insulin infusion. In the year following DAFNE education, the mean fall in within-person HbA1c was 3.8 mmol/mol (95% CI 4.0 to 3.4; 0.3% [0.4% to 0.3%]). Those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]) experienced the largest decline (15.7 mmol/mol [1.4%]). Those in the lowest HbA1c band at initiation (< 53 mmol/mmol [7.0%]) experienced a rise. In the year following continuous subcutaneous insulin infusion initiation there was a mean fall in within-person HbA1c of 6.6 mmol/mol (6.8 to 6.4; 0.6% [0.6% to 0.6%]). In those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]), the mean fall in HbA1c was 22.2 mmol/mol (23 to 21; 2.0% [2.1% to 1.9%]). Continuous subcutaneous insulin infusion effectiveness was not different with or without DAFNE education. The effects of both interventions were sustained over 5 years. CONCLUSIONS: Both DAFNE education and insulin pump therapy had the greatest effect on HbA1c in those with higher baseline values. There was little difference to attained HbA1c when Dose Adjustment For Normal Eating education was introduced before insulin pump therapy.

Qualitative study to identify issues affecting quality of life in adults with craniofacial anomalies.

Our objective was to identify key issues that affect the quality of life (QoL) of adult patients with craniofacial anomalies. This was a qualitative prospective study using in-depth, semi-structured interviews. Ten patients who fulfilled the inclusion criteria were recruited during their attendance at the Adult Craniofacial Clinic at the Eastman Dental Hospital, University College London Hospitals NHS Foundation Trust. Interviews ceased when no new themes arose. A framework method of analysis was used to identify themes that related to QoL. Opinions varied and, although some were positive, the eight main themes that emerged were mainly negative. One of the main themes was that of emotional issues. Within this theme, subthemes included teasing, bullying and abuse, as well as low mood, anxiety, depression, and self-harm. Participants experienced a range of feelings as a result of their craniofacial conditions and expressed the need for further support. Healthcare professionals involved in the treatment of these patients, should be aware of these issues and give advice about how to access further support.

Echocardiographic assessment of right ventricular systolic function in Boxers with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: To determine whether there are differences in measures of longitudinal right ventricular (RV) systolic function among Boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC) compared with healthy control Boxer dogs. To explore relationships between markers of RV systolic function and age, body weight, gender, arrhythmia frequency, and markers of left ventricular (LV) systolic function in Boxer dogs. ANIMALS: The study included 50 client-owned Boxer dogs. METHODS: This is a retrospective echocardiographic study. Tricuspid annular plane systolic excursion (TAPSE) and pulsed wave tissue Doppler imaging-derived systolic myocardial velocity of the lateral tricuspid annulus (S') were measured in healthy control Boxers (n = 18), Boxers with ARVC and normal LV systolic function (n = 19), and Boxers with ARVC and reduced LV systolic function (n = 13). RESULTS: Tricuspid annular plane systolic excursion (p=0.002) and S' (p=0.001) were significantly different between affected and control groups. Significant correlations were found between measures of left heart size and function and both TAPSE and S'. No correlations were found between RV function parameters and age, gender, or body weight in this fairly homogeneous, single-breed population. Receiver operating characteristic curve analysis revealed that both TAPSE and S' had an area under the curve of 0.77 in distinguishing healthy Boxers from those with ARVC. CONCLUSIONS: Tricuspid annular plane systolic excursion and S' are reduced in Boxers with ARVC. In contrast to prior studies evaluating these parameters in dogs of different breeds and body types, no correlation was found between markers of RV function and body weight in this population of Boxer dogs.

Obesity and Associated Comorbidities in People and Companion Animals: A One Health Perspective.

This article reviews the biology, prevalence and risks for obesity in people and companion dogs and cats, and explores the links between obesity and diabetes mellitus and cancer across these species. Obesity is a major healthcare problem in both human and veterinary medicine and there is an increasing prevalence of obesity in people and pets. In people and animals, obesity is a complex disorder involving diet, level of physical activity, behavioural factors, socioeconomic factors, environment exposures, genetics, metabolism and the microbiome. Pets and people share a number of obesity-related comorbidities. Obesity is a major risk factor for type 2 diabetes mellitus in people and in cats, but this association is not recognized in dogs. Obesity is a recognized risk factor for a number of human cancers, but there are fewer data available describing this association with canine neoplastic disease. One approach to addressing the problem of obesity is by taking a 'One Health' perspective. Comparative clinical research examining shared lifestyle and environmental risk factors and the reasons underlying species differences should provide new perspectives on the fundamental biology of obesity. One Health programmes involving human healthcare professionals and veterinarians could help address obesity with simple interventions at the community level.

Evaluation of a real-time PCR assay for rectal screening of OXA-48-producing Enterobacteriaceae in a general intensive care unit of an endemic hospital.

Carbapenemase-producing Enterobacteriaceae are increasing worldwide. Rectal screening for these bacteria can inform the management of infected and colonized patients, especially those admitted to intensive care units (ICUs). A laboratory developed, qualitative duplex real-time polymerase chain reaction assay for rapid detection of OXA-48-like and VIM producing Enterobacteriaceae, performed on rectal swabs, was designed and evaluated in an intensive care unit with endemic presence of OXA-48. During analytical assay validation, no cross-reactivity was observed and 100% sensitivity and specificity were obtained for both blaOXA-48-like and blaVIM in all spiked clinical samples. During the clinical part of the study, the global sensitivity and specificity of the real-time PCR assay for OXA-48 detection were 95.7% and 100% (P=0.1250), respectively, in comparison with culture; no VIM-producing Enterobacteriaceae were detected. Clinical features of patients in the ICU who were colonized or infected with OXA-48 producing Enterobacteriaceae, including outcome, were analyzed. Most had severe underlying conditions, and had risk factors for colonization with carbapenemase-producing Enterobacteriaceae before or during ICU admission, such as receiving previous antimicrobial therapy, prior healthcare exposure (including long-term care), chronic disease, immunosuppression and/or the presence of an intravascular catheter and/or mechanical ventilation device. The described real-time PCR assay is fast (~2-3hours, if DNA extraction is included), simple to perform and results are easy to interpret, features which make it applicable in the routine of clinical microbiology laboratories. Implementation in endemic hospitals could contribute to early detection of patients colonized by OXA-48 producing Enterobacteriaceae and prevention of their spread.

Riparian reforestation: are there changes in soil carbon and soil microbial communities?

Reforestation of pastures in riparian zones has the potential to decrease nutrient runoff into waterways, provide both terrestrial and aquatic habitat, and help mitigate climate change by sequestering carbon (C). Soil microbes can play an important role in the soil C cycle, but are rarely investigated in studies on C sequestration. We surveyed a chronosequence (0-23years) of mixed-species plantings in riparian zones to investigate belowground (chemical and biological) responses to reforestation. For each planting, an adjacent pasture was surveyed to account for differences in soil type and land-use history among plantings. Two remnant woodlands were included in the survey as indicators of future potential of plantings. Both remnant woodlands had significantly higher soil organic C (SOC) content compared with their adjacent pastures. However, there was no clear trend in SOC content among plantings with time since reforestation. The substantial variability in SOC sequestration among plantings was possibly driven by differences in soil moisture among plantings and the inherent variability of SOC content among reference pastures adjacent to plantings. Soil microbial phospholipid fatty acids (PLFA, an indicator of microbial biomass) and activities of decomposition enzymes (ß-glucosidase and polyphenol oxidase) did not show a clear trend with increasing planting age. Despite this, there were positive correlations between total SOC concentration and microbial indicators (total PLFA, fungal PLFA, bacterial PLFA and activities of decomposition enzymes) across all sites. The soil microbial community compositions (explored using PLFA markers) of older plantings were similar to those of remnant woodlands. There was a positive correlation between the soil carbon:nitrogen (C:N) and fungal:bacterial (F:B) ratios. These data indicate that in order to maximise SOC sequestration, we need to take into account not only C inputs, but the microbial processes that regulate SOC cycling as well.

Social anxiety in orthognathic patients.

There is evidence that patients seeking orthognathic treatment may be motivated by social anxiety disorder (SAD). The aim of this study was to investigate SAD in orthognathic patients using the Brief Fear of Negative Evaluation Scale (BFNES) and to compare these findings with those of the general population. This was a cross-sectional, questionnaire study conducted in two parts. Firstly, a national survey was conducted to yield data for the BFNES from a large, random sample of the UK general population. Secondly, orthognathic patients completed the BFNES. The BFNES scores are reported in two formats: the original 12-item scale (O-BFNES) and a shorter eight-item version (S-BFNES). With regards to the national survey, 1196 individuals participated. The mean O-BFNES score was 29.72 (standard deviation (SD) 9.39) and S-BFNES score was 15.59 (SD 7.67). With regards to the orthognathic sample, 61 patients participated. The mean O-BFNES score was 39.56 (SD 10.35) and the mean S-BFNES score was 24.21 (SD 8.41). Orthognathic patients had significantly higher scores than the general UK population (P<0.001), and multiple linear regression revealed that age, gender, and patient status were all independent predictors of BFNES scores. From the results of this study, orthognathic patients experience significantly higher levels of social anxiety than the general population.

Transient suppression of hepatocellular replication in the mouse liver following transduction with recombinant adeno-associated virus.

Recombinant vectors based on adeno-associated virus (AAV) are proving to be powerful tools for genetic manipulation of the liver, for both discovery and therapeutic purposes. The system can be used to deliver transgene cassettes for expression or, alternatively, DNA templates for genome editing via homologous recombination. The replicative state of target cells is known to influence the efficiency of these processes and knowledge of the host-vector interactions involved is required for optimally effective vector deployment. Here we show, for the first time in vivo, that in addition to the known effects of hepatocellular replication on AAV-mediated gene transfer, the vector itself exerts a potent, albeit transient suppressive effect on cell cycle progression that is relieved on a time course that correlates with the known rate of clearance of input single-stranded vector DNA. This finding requires further mechanistic investigation, delineates an excellent model system for such studies and further deepens our insight into the complexity of interactions between AAV vectors and the cell cycle in a clinically promising target tissue.

Orthognathic correction of dento-facial discrepancies.

Orthognathic treatment is a process which involves orthodontics and maxillofacial surgery and is used to treat those dento-facial discrepancies which are outside the scope of conventional orthodontic treatment, for example severe Class II or Class III problems, anterior open bites and facial asymmetries. Patients who present with these severe problems may encounter a wide range of different problems ranging from functional problems (for example, difficulties biting and chewing) to self-consciousness in a wide range of work and social situations. This paper discusses the possible indications for orthognathic treatment and looks at the risks and benefits of treatment. The treatment pathway is also described.

Massive splenomegaly correlates with malignancy: 180 cases of splenic littoral cell tumors in the world literature.

Littoral cell tumors (LCT) are rare primary splenic neoplasms, unique for their morphologic and immunolabeling features resembling the endothelial littoral cells lining the sinusoids of the red pulp. They include the more common and typically benign littoral cell angioma, as well as the less common, potentially malignant, littoral cell hemangioendothelioma (LCHE) and the aggressive littoral cell angiosarcoma (LCAS). The most common presentation of these neoplasms is splenomegaly, and diagnosis is made histologically following biopsy or resection. To better understand these tumors, a comprehensive, international literature search was performed. Patient and tumor data, including presenting symptoms, comorbid cancers, immunosuppressive states, splenic mass and tumor size were analyzed. Massive splenomegaly (≥ 1500 g) following splenic resection, which correlates with a splenic length of 20 cm preoperatively, was found to be significantly associated with the presence of malignancy in the LCT (P<0.05).

Structure-activity relationship models for rat carcinogenesis and assessing the role mutagens play in model predictivity.

We previously demonstrated that fragment based cat-SAR carcinogenesis models consisting solely of mutagenic or non-mutagenic carcinogens varied greatly in terms of their predictive accuracy. This led us to investigate how well the rat cancer cat-SAR model predicted mutagens and non-mutagens in their learning set. Four rat cancer cat-SAR models were developed: Complete Rat, Transgender Rat, Male Rat and Female Rat, with leave-one-out (LOO) validation concordance values of 69%, 74%, 67% and 73%, respectively. The mutagenic carcinogens produced concordance values in the range 69-76% compared with only 47-53% for non-mutagenic carcinogens. As a surrogate for mutagenicity, comparisons between single site and multiple site carcinogen SAR models were analysed. The LOO concordance values for models consisting of 1-site, 2-site and 4+-site carcinogens were 66%, 71% and 79%, respectively. As expected, the proportion of mutagens to non-mutagens also increased, rising from 54% for 1-site to 80% for 4+-site carcinogens. This study demonstrates that mutagenic chemicals, in both SAR learning sets and test sets, are influential in assessing model accuracy. This suggests that SAR models for carcinogens may require a two-step process in which mutagenicity is first determined before carcinogenicity can be accurately predicted.

AAV-encoded OTC activity persisting to adulthood following delivery to newborn spf(ash) mice is insufficient to prevent shRNA-induced hyperammonaemia.

Urea cycle defects presenting in the neonatal period with hyperammonaemia are associated with high morbidity and mortality, and necessitate liver transplantation for long-term management. Gene therapy is therefore an attractive possibility, with vectors based on adeno-associated virus (rAAV) currently showing exciting promise in liver-targeted clinical trials in adults. Successful use of rAAV vectors in infants, however, is more challenging as episomal rAAV genomes will be lost from proliferating hepatocytes during liver growth, leaving stable transgene expression dependent on the subset of vector genomes that undergo genomic integration. To explore this challenge, we exploited the partially ornithine transcarbamylase (OTC)-deficient spf(ash) mouse model and small hairpin RNA-mediated knockdown of residual endogenous OTC enzyme activity in adult mice that had received neonatal treatment with an OTC-encoding rAAV. This leaves mice reliant on vector-encoded OTC activity that has persisted from the newborn period. Despite stable transduction in approximately 8% of hepatocytes and residual vector-encoded OTC activity of up to 33% of wild-type, well above endogenous spf(ash) levels (5-7%), mice were not protected from hyperammonaemia. These data show that the distribution of OTC activity within the liver is critical and that rAAV vector re-delivery after early neonatal treatment is likely to be necessary for stable control of hyperammonaemia into adulthood.

Association of dilated cardiomyopathy with the striatin mutation genotype in boxer dogs.

BACKGROUND: Myocardial disease in the Boxer dog is characterized by 1 of 2 clinical presentations, dilated cardiomyopathy (DCM) characterized by ventricular systolic dysfunction, dilatation and tachyarrhythmias, and arrhythmogenic right ventricular cardiomyopathy (ARVC) characterized by ventricular tachyarrhythmias, syncope, and sudden death. Boxer ARVC has been associated with a deletion in the striatin gene in some families. HYPOTHESIS/OBJECTIVES: We hypothesized that both presentations represent a single disease, and the development of DCM in the Boxer is associated with the striatin deletion. ANIMALS: Thirty-three adult Boxer dogs with DCM, 29 adult Boxer dogs with the striatin deletion and ARVC, and 16 Boxers without cardiac disease. METHODS: DNA samples were evaluated for the striatin deletion. Association of the deletion with the DCM phenotype was tested by a Fisher's exact test. T-tests were used to evaluate potential differences between the positive heterozygous and positive homozygous groups with DCM with regard to age, LVIDD, LVIDS, and FS%. RESULTS: Thirty of 33 dogs with DCM were positive for the striatin deletion. The striatin mutation and the homozygous genotype were strongly associated with the DCM phenotype (P < .001 and P = .005). There was no statistical difference between the heterozygous and homozygous groups with regard to age and echocardiographic measurements. CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrates an association between DCM in the Boxer dog and the striatin mutation, particularly with the homozygous genotype. The observation that 3/33 dogs developed DCM and lacked the striatin mutation suggests that there is at least 1 other cause of DCM in the Boxer dog.

Short-term effects of atorvastatin in normal dogs and dogs with congestive heart failure due to myxomatous mitral valve disease.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may improve heart failure class and survival in people with congestive heart failure (CHF) of various etiologies. HYPOTHESIS/OBJECTIVES: To evaluate the tolerability of atorvastatin in healthy dogs, and the short-term effects of atorvastatin on clinical markers of disease severity, lipid profiles, and markers of systemic inflammation and oxidative stress in dogs with CHF. ANIMALS: Eleven normal dogs and 12 client-owned animals with CHF attributable to myxomatous mitral valve disease. METHODS: Prospective nonblinded observational study. Normal dogs (n = 11) were first treated with atorvastatin and re-evaluated after 14 and 30 days for clinical tolerability and alterations in certain laboratory results. Subsequently, dogs with CHF (n = 12) were treated with atorvastatin at a dosage of 2 mg/kg q24 h for 8 weeks. Echocardiography, blood pressure (BP), quality of life questionnaire, and blood sampling were performed pre and post atorvastatin administration. RESULTS: Atorvastatin was well tolerated and did not result in apparent adverse effects or biochemical abnormalities in healthy dogs and in dogs with CHF. Healthy dogs experienced a decrease in total cholesterol (TC) concentration (P = .03) after atorvastatin administration. Decreases in TC concentration (P = .02), non-HDL cholesterol concentration (P = .02), total white blood cell count (P = .03), neutrophils (P = .01), and systolic BP (P = .01) were noted in the CHF group after 8 weeks of atorvastatin. CONCLUSIONS AND CLINICAL IMPORTANCE: Atorvastatin was well tolerated at clinically relevant doses in healthy dogs and dogs with CHF. Further investigation into the effects of statin treatment in dogs with CHF is warranted.

Comparison of gene transfer to the murine liver following intraperitoneal and intraportal delivery of hepatotropic AAV pseudo-serotypes.

Adeno-associated virus (AAV) vectors are highly efficient for liver-targeted gene delivery in murine models and show promise in early phase human clinical trials. This efficiency is capsid-dependent and was only achieved after discovery that the AAV2 vector genome could be trans-encapsidated into the capsids of other AAV serotypes. This confers novel host-vector biology and target tissue tropism. Optimal exploitation of the growing number of AAV vector pseudo-serotypes, however, requires detailed context-dependent characterisation of transduction performance. In this study, we compared the pattern and efficiency of gene delivery to the adult mouse liver following intraportal and intraperitoneal injection of vectors pseudo-serotyped with known hepatotropic capsids from AAV type 7, 8, 9 and rhesus 10. Vectors pseudo-serotyped with these hepatotropic capsids proved relatively efficient irrespective of administration route, with higher transgene expression in males despite equivalent vector genome delivery in females. Transgene expression was predominantly centrilobular in contrast to the AAV2 capsid, which gave a periportal pattern of expression. Most intriguingly, vector genome performance appeared to be delivery route-dependent, consistent with the possibility of in vivo capsid modification. These data not only inform the experimental use of AAV vectors, but also provide insight into novel aspects of host-vector biology requiring further focused analysis.