Antimicrobial use in UK long-term care facilities: results of a point prevalence survey.

BACKGROUND: The majority of people in long-term care facilities (LTCFs) are aged 65 years and older, and most of their care needs are provided by the LTCF staff. Provision of healthcare services for residents in LTCFs is variable and can result in disjointed care between carers and NHS healthcare professionals. OBJECTIVES: Our aim was to understand the use of antibiotics in LTCFs across the UK and to identify potential gaps in knowledge and support for carers and residents when using antibiotics, in order to determine how community pharmacy teams can provide additional support. METHODS: A point prevalence survey (PPS) was conducted by community pharmacists (n = 57) when they carried out visits to LTCFs across the UK between 13 November and 12 December 2017. Anonymized data were recorded electronically by the individual pharmacists. RESULTS: Data were analysed for 17909 residents in 644 LTCFs across the UK. The mean proportion of residents on antibiotics on the day of the visit was as follows: 6.3% England (536 LTCFs), 7.6% Northern Ireland (35 LTCFs), 8.6% Wales (10 LTCFs) and 9.6% Scotland (63 LTCFs). The percentage of antibiotics prescribed for prophylactic use was 25.3%. Antibiotic-related training was reported as being available for staff in 6.8% of LTCFs and 7.1% of LTCFs reported use of a catheter passport scheme. Pharmacists conducting the PPS intervened during the survey for 9.5% of antibiotic prescription events; 53.4% of interventions were for clinical reasons and 32.2% were for administration reasons. CONCLUSIONS: This survey identified high prophylactic use of antibiotics. There are opportunities for community pharmacy teams to improve antimicrobial stewardship in LTCF settings, including workforce education.

Procedures of recruiting, obtaining informed consent, and compensating research participants in Qatar: findings from a qualitative investigation.

BACKGROUND: Very few researchers have reported on procedures of recruiting, obtaining informed consent, and compensating participants in health research in the Arabian Gulf Region. Empirical research can inform the debate about whether to adjust these procedures for culturally diverse settings. Our objective was to delineate procedures related to recruiting, obtaining informed consent, and compensating health research participants in the extremely high-density multicultural setting of Qatar. METHODS: During a multistage mixed methods project, field observations and qualitative interviews were conducted in a general medicine clinic of a major medical center in Qatar. Participants were chosen based on gender, age, literacy, and preferred language, i.e., Arabic, English, Hindi and Urdu. Qualitative analysis identified themes about recruitment, informed consent, compensation, and other research procedures. RESULTS: A total of 153 individuals were approached and 84 enrolled; the latter showed a diverse age range (18 to 75 years); varied language representation: Arabic (n = 24), English (n = 20), Hindi (n = 20), and Urdu (n = 20); and balanced gender distribution: women (n = 43) and men (n = 41). Primary reasons for 30 declinations included concern about interview length and recording. The study achieved a 74% participation rate. Qualitative analytics revealed key themes about hesitation to participate, decisions about participation with family members as well as discussions with them as "incidental research participants", the informed consent process, privacy and gender rules of the interview environment, reactions to member checking and compensation, and motivation for participating. Vulnerability emerged as a recurring issue throughout the process among a minority of participants. CONCLUSIONS: This study from Qatar is the first to provide empirical data on recruitment, informed consent, compensation and other research procedures in a general adult population in the Middle East and Arabian Gulf. This investigation illustrates how potential research participants perceive research participation. Fundamentally, Western ethical research principles were applicable, but required flexibility and culturally informed adaptations.

Wellness as a worldwide phenomenon?

This article examines the concept of wellness through a comparative political economy and legal framework. It asks whether wellness, an increasingly defined term within US federal and state legislative instruments including, for example, the Patient Protection and Affordable Care Act, is primarily a US-centric phenomenon. Or is wellness, in its various different guises, a worldwide phenomenon? By focusing on three distinctly different jurisdictions - the United States, Germany, and Australia - this article examines wellness through the lens of employers, the health care system, employment and tort law, and the greater political economy. It notes that while improving employee health, well-being, and productivity is common across the three countries and their respective cultures, the focus on wellness as a distinct legal concept is unique to the United States.

An Improved 21st Century Judicial System with Environmental Science Expertise is Needed for Resolving Interstate Water Conflicts.

As stresses on groundwater resources increase due to growing population and climate change, water litigation, such as the recently decided Mississippi (MS) vs Tennessee (TN) lawsuit, will become more common. In the United States, lawsuits between states can be heard only by the Supreme Court of the United States (SCOTUS). These lawsuits are expensive and lengthy, often requiring highly specialized technical expertise. In the MS vs TN case, the Court unanimously held that an interstate aquifer is subject to equitable apportionment. Although this appears to be a sound resolution, a careful examination of the SCOTUS hearing transcript revealed that the Justices had several egregious misconceptions about the groundwater system. These misconceptions arose in part due to the failure of technical experts to communicate groundwater concepts in understandable terms and in part due to the Justices' lack of expertise in groundwater science. To address these issues, we first explore methods for improving scientific communication in courtrooms. Second, we propose ideas for reforming the legal system and provide compelling arguments for using the lower courts to hear such cases. We also explore the possibility of creating specialized federal water courts to resolve water disputes.

Infection and Prophylaxis During Normothermic Liver Perfusion: Audit of Incidence and Pharmacokinetics of Antimicrobial Therapy.

BACKGROUND: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy. METHODS: Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed. RESULTS: Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium . All the Candida -infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus -infected liver was not transplanted. CONCLUSIONS: Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment.

Pharmacodynamics of the antibacterial effect of and emergence of resistance to doripenem in Pseudomonas aeruginosa and Acinetobacter baumannii in an in vitro pharmacokinetic model.

An in vitro dilutional pharmacokinetic model of infection was used to study the pharmacodynamics of doripenem in terms of the ability to kill Pseudomonas aeruginosa or Acinetobacter baumannii and also changes in their population profiles. In dose-ranging studies, the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T(MIC)s) required for doripenem to produce a 24-h bacteriostatic effect and a -2-log-unit reduction in viable count were 25% ± 11% and 35% ± 13%, respectively, for P. aeruginosa (MIC range, 0.24 to 3 mg/liter) and 20% ± 11% and 33% ± 12%, respectively, for Acinetobacter spp. (MIC range, 0.45 to 3.0 mg/liter). A T(MIC) of >40 to 50% produced a maximum response with both species at 24 h or 48 h of exposure. After 24 h of exposure to doripenem at a T(MIC) in the range of 12.5 to 37.5%, P. aeruginosa and A. baumannii population profiles revealed mutants able to grow on 4× MIC-containing medium; such changes were further amplified by 48 h of exposure. Dose-fractionation experiments targeting T(MIC)s of 12.5%, 25%, or 37.5% as six exposures, two exposures, or a single exposure over 48 h with a single strain of P. aeruginosa indicated that changes in population profiles were greatest with multiple exposures at T(MIC) targets of 12.5 or 25%. In contrast, multiple exposures at 37.5% T(MIC) most effectively suppressed total bacterial counts and changes in population profiles. Simulations of human doses of doripenem of 500 mg, 1,000 mg, 2,000 mg, and 3,000 mg every 8 h over 96 h showed marked initial killing up to 6 h but growback thereafter. Changes in population profiles occurred only in the regimen of 500 mg every 8 h against P. aeruginosa but occurred with all dose regimens for A. baumannii strains. A doripenem T(MIC) of ≥40 to 50% is maximally effective in killing P. aeruginosa or A. baumannii and suppressing changes in population profiles in short-term experiments for up to 48 h; however, a T(MIC) of 12.5 to 25% amplifies population changes, especially with exposures every 8 h. In longer-term experiments, up to 96 h, even doripenem doses of 4 to 6 times those used in human studies proved incapable of pathogen eradication and prevention of changes in population profiles. The association of a T(MIC) of 25 to 37.5% with changes in population profiles has implications in terms of future clinical breakpoint setting.

Involvement of the skin during bluetongue virus infection and replication in the ruminant host.

Bluetongue virus (BTV) is a double stranded (ds) RNA virus (genus Orbivirus; family Reoviridae), which is considered capable of infecting all species of domestic and wild ruminants, although clinical signs are seen mostly in sheep. BTV is arthropod-borne ("arbovirus") and able to productively infect and replicate in many different cell types of both insects and mammalian hosts. Although the organ and cellular tropism of BTV in ruminants has been the subject of several studies, many aspects of its pathogenesis are still poorly understood, partly because of inherent problems in distinguishing between "virus replication" and "virus presence".BTV replication and organ tropism were studied in a wide range of infected sheep tissues, by immuno-fluorescence-labeling of non-structural or structural proteins (NS2 or VP7 and core proteins, respectively) using confocal microscopy to distinguish between virus presence and replication. These results are compared to gross and microscopic pathological findings in selected organs from infected sheep. Replication was demonstrated in two major cell types: vascular endothelial cells, and agranular leukocytes which morphologically resemble lymphocytes, monocytes/macrophages and/or dendritic cells. Two organs (the skin and tonsils) were shown to support relatively high levels of BTV replication, although they have not previously been proposed as important replication sites during BTV infection. The high level of BTV replication in the skin is thought to be of major significance for the pathogenesis and transmission of BTV (via biting insects) and a refinement of our current model of BTV pathogenesis is discussed.

Mapping communicable disease control in the European union.

Understanding both the current performance of communicable disease control in Europe and the scale of the differences among systems is crucial to understanding its present performance and possible Europeanization. We attempt to identify the structure of authority in communicable disease control in each European Union (EU) member state. The primary sources of information were the competent bodies list posted on the European Centre for Disease Prevention and Control website and the Health in Transition reports produced by the European Observatory on Health Systems and Policies. Three key patterns emerge to answer the question of who does what. First, the landscape is full and crowded, with many actors involved. Second, the landscape is highly fragmented, with many organizations performing overlapping functions in each country. Third, regional patterns describe which types of organizations are assigned which functions. These full, fragmented, and regionally disparate systems show no signs of constituting a shared model. As a result, if there is an EU model of communicable disease control today, it is at most an aspiration.

Pharmacodynamics of razupenem (PZ601) studied in an in vitro pharmacokinetic model of infection.

Simulations of administration of razupenem at 1 g every 12 h by 1-h intravenous (i.v.) infusion were performed in an in vitro pharmacokinetic model of infection. The antibacterial effect of this razupenem dosing regimen against six strains of Staphylococcus aureus (one methicillin-sensitive S. aureus [MSSA] strain [MIC, 0.015 µg/ml] and five methicillin-resistant S. aureus [MRSA] strains [MIC range, 0.09 to 3 µg/ml]) and five strains of Enterobacteriaceae (three Escherichia coli strains [two containing extended-spectrum ß-lactamases {ESBLs}] and two Enterobacter sp. strains [one with an AmpC enzyme and the other with a raised razupenem MIC; MIC range, 0.09 to 6 µg/ml]) was assessed. Against the MSSA and MRSA strains, razupenem produced a >3.5-log-unit reduction in viable count after 24 h. There were no changes in population profiles. In a second series of experiments, over 5 days there was rapid initial clearance of MRSA from the model followed by regrowth after 48 h. MRSA colonies appeared on 2× MIC recovery medium after 72 h with strain 33820 (MIC, 3.0 µg/ml) and at 120 h with strain 27706 (MIC, 1.5 µg/ml). Against E. coli and Enterobacter spp., razupenem produced a >3.5-log-unit reduction in bacterial counts for all strains except that with an MIC of 6 µg/ml, where razupenem had a notably poorer antibacterial effect. Population profiles were unchanged after 48 h of exposure to razupenem except for Enterobacter strain 34425 (MIC, 6.0 µg/ml), where colonies were recovered from media containing 2×, 4×, and 8× MIC. In dose-ranging studies with MRSA strains, the percentage of the dosing interval that the free drug concentration remained higher than the pathogen MIC (fT>MIC) for a 24-h bacteriostatic effect was 5.0% ± 1.4%, and that for a 1-log-unit reduction in count was 12.5% ± 5.8%. Population profiles indicated growth on 2× MIC recovery medium at fT>MIC values of 1 to 35% but not at a value of >35%. In a similar set of experiments with Enterobacteriaceae, the fT>MIC for a 24-h bacteriostatic effect was 34.2% ± 7.6% and that for a 1-log-unit reduction in count was 42.5% ± 7.8%. Population analysis profiles indicated growth on recovery media with 2×, 4×, and 8× MIC at fT>MICs in the range of 1 to 69% but rarely at values of ≥ 70%. In conclusion, razupenem at simulated human doses of 1 g i.v. every 12 h has a marked antibacterial effect on MSSA and MRSA strains with MICs of ≤ 3.0 µg/ml and Enterobacteriaceae with MICs of ≤ 0.4 µg/ml. fT>MIC targets of ≥ 35% for MRSA and ≥ 70% for Enterobacteriaceae should provide significant antibacterial effects combined with low risks of changing pathogen antibiotic population profiles.

Pharmacodynamics of telavancin studied in an in vitro pharmacokinetic model of infection.

The antibacterial effects of telavancin, vancomycin, and teicoplanin against six Staphylococcus aureus strains (1 methicillin-susceptible S. aureus [MSSA] strain, 4 methicillin-resistant S. aureus [MRSA] strains, and 1 vancomycin-intermediate S. aureus [VISA] strain) and three Enterococcus sp. strains (1 Enterococcus faecalis strain, 1 Enterococcus faecium strain, and 1 vancomycin-resistant E. faecium [VREF] strain) were compared using an in vitro pharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptible S. aureus (VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC(24)) and 48 h (AUBKC(48)) in comparison to vancomycin or teicoplanin (P < 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (P < 0.05). Against the three Enterococcus spp. tested, telavancin was superior to vancomycin in terms of its AUBKC(24), AUBKC(48), and greater early bactericidal effect (P < 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3 Enterococcus strains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for the Enterococcus spp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than with S. aureus, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity against Enterococcus spp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they support a clinical breakpoint of sensitive at ≤1 mg/liter for both S. aureus and Enterococcus spp.

Refining rodent models of spinal cord injury.

This report was produced by an Expert Working Group (EWG) consisting of UK-based researchers, veterinarians and regulators of animal experiments with specialist knowledge of the use of animal models of spinal cord injury (SCI). It aims to facilitate the implementation of the Three Rs (Replacement, Reduction and Refinement), with an emphasis on refinement. Specific animal welfare issues were identified and discussed, and practical measures proposed, with the aim of reducing animal use and suffering, reducing experimental variability, and increasing translatability within this critically important research field.

How paradata can illuminate technical, social and professional role changes between the Poverty in the UK (1967/1968) and Poverty and Social Exclusion in the UK (2012) surveys.

This article brings together analyses of the micro paradata 'by-products' from the 1967/1968 Poverty in the United Kingdom (PinUK) and 2012 Poverty and Social Exclusion in the UK (PSE) surveys to explore changes in the conditions of production over this 45 year period. We highlight technical, social and professional role continuities and changes, shaped by the institutionalisation of survey researchers, the professionalization of the field interviewer, and economisation. While there are similarities between the surveys in that field interviewers were and are at the bottom of the research hierarchy, we demonstrate an increasing segregation between the core research team and field interviewers. In PinUK the field interviewers are visible in the paper survey booklets; through their handwritten notes on codes and in written marginalia they can 'talk' to the central research team. In PSE they are absent from the computer mediated data, and from communication with the central team. We argue that, while there have been other benefits to field interviewers, their relational labour has become less visible in a shift from the exercise of observational judgement to an emphasis on standardisation. Yet, analyses of what field interviewers actually do show that they still need to deploy the same interpersonal skills and resourcefulness to secure and maintain interviews as they did 45 years previously.

Engineered G protein coupled receptors reveal independent regulation of internalization, desensitization and acute signaling.

BACKGROUND: The physiological regulation of G protein-coupled receptors, through desensitization and internalization, modulates the length of the receptor signal and may influence the development of tolerance and dependence in response to chronic drug treatment. To explore the importance of receptor regulation, we engineered a series of Gi-coupled receptors that differ in signal length, degree of agonist-induced internalization, and ability to induce adenylyl cyclase superactivation. All of these receptors, based on the kappa opioid receptor, were modified to be receptors activated solely by synthetic ligands (RASSLs). This modification allows us to compare receptors that have the same ligands and effectors, but differ only in desensitization and internalization. RESULTS: Removal of phosphorylation sites in the C-terminus of the RASSL resulted in a mutant that was resistant to internalization and less prone to desensitization. Replacement of the C-terminus of the RASSL with the corresponding portion of the mu opioid receptor eliminated the induction of AC superactivation, without disrupting agonist-induced desensitization or internalization. Surprisingly, removal of phosphorylation sites from this chimera resulted in a receptor that is constitutively internalized, even in the absence of agonist. However, the receptor still signals and desensitizes in response to agonist, indicating normal G-protein coupling and partial membrane expression. CONCLUSIONS: These studies reveal that internalization, desensitization and adenylyl cyclase superactivation, all processes that decrease chronic Gi-receptor signals, are independently regulated. Furthermore, specific mutations can radically alter superactivation or internalization without affecting the efficacy of acute Gi signaling. These mutant RASSLs will be useful for further elucidating the temporal dynamics of the signaling of G protein-coupled receptors in vitro and in vivo.

A new primate model of focal stroke: endothelin-1-induced middle cerebral artery occlusion and reperfusion in the common marmoset.

The purpose of the present set of studies was to develop a new primate model of focal ischemia with reperfusion for long-term functional assessment in the common marmoset. Initially, the cerebral vascular anatomy of the marmoset was interrogated by Araldite-cast and ink-perfusion methods to determine the feasibility of an intravascular surgical approach. The methods showed that the internal carotid artery was highly tortuous in its passage, precluding the development of an extracranial method of inducing temporary middle cerebral artery occlusion in the marmoset. A pilot dose-response study investigated an intracranial approach of topically applying endothelin-1 (ET-1) to the M2 portion of the middle cerebral artery in a small sample of marmosets for up to 6 hours (n = 2 or 3 per group). Dose-dependent reductions in middle cerebral artery vessel caliber followed by gradual reperfusion were inversely related to increases in corrected lesion volume after ET-1 treatment, relative to vehicle control application. Finally, the functional consequences of ET-1-induced lesions to the M2 vascular territory were assessed up to 24 hours after surgery using the optimal dose established in the pilot study (2.5 nmol/25 microL). ET-1-treated marmosets (n = 4) showed marked contralateral motor deficits in grip strength and retrieval of food rewards and contralateral sensory/motor neglect towards tactile stimulation, relative to their ipsilateral side and vehicle-treated marmosets (n = 4). Strong correlations were shown between contralateral impairments and histopathologic parameters, which revealed unilateral putamen and cortical damage to the middle cerebral artery territory. No deficits were shown on general mobility, and self-care was promptly resumed in ET-1 marmosets after surgery. These results show that this novel model of ischemia with reperfusion in the marmoset has the potential to assess long-term function and to gauge the efficacy of novel therapeutic strategies targeted for clinical stroke.

'Everywhere and nowhere': locating and understanding the 'new' public health.

Public health was recently described as being 'everywhere and nowhere' (Br. Med.J. 319(7213)(1999)839). This image captures the idea that public health is shaped by a range of social, environmental and physiological influences, and that these are mapped across the activities and practices of a range of players. It also suggests it is difficult to capture the spaces of public health. This paper explores how theoretical and methodological developments in the social sciences, in particular ideas around reflexive modernisation, can help us to read the complex terrain of public health policy and practice, and visualise these spaces more clearly.

Challenges and opportunities of US and Arab collaborations in health services research: a case study from Qatar.

Economic globalization and advances in technology have made it more feasible and even necessary to develop international research collaborations in global public health. Historically, collaborations in global research described in the literature have been mostly "North-South" collaborations in which the more developed "North" country works together with a developing "South" country to conduct research in the latter. This type of collaboration has for the most part, represented unequal partnership and rarely left behind a lasting impact. Recently, the opportunity for a new kind of international research partnership has emerged in which the host country has significant financial resources, but relatively limited expertise in research Methodology or techniques and research implementation.  This type of collaboration features a relative equalization of power between the international partners. The purpose of this paper is to describe the process of building a successful research collaboration between a team in the United States and a team in Qatar, a rich Arabic nation in Gulf. We present a case study that provides an overview of our own project focused on the development of a culturally and linguistically adapted health care quality instrument for Qatar, discussing many of the benefits and challenges we encountered during each phase of instrument development. We present recommendations for researchers seeking sustainable and equitable partnerships with the Arab World.

Viraemia and clinical disease in Dorset Poll sheep following vaccination with live attenuated bluetongue virus vaccines serotypes 16 and 4.

The spread of bluetongue virus (BTV) is most successfully controlled by vaccination of susceptible ruminant populations. Currently two different types of BTV vaccines are used for this purpose; inactivated, mostly monovalent vaccine formulations and modified live virus vaccines (MLVs). Clinical signs and viraemia in Dorset Poll sheep vaccinated with BTV-4 and BTV-16 MLVs or inoculated with homogenates of midges (C. sonorensis and C. nubeculosus) previously infected with BTV-4 MLV are presented. All sheep vaccinated with the two MLVs mounted an infectious viraemia lasting for a minimum of 9 up to 23 days post vaccination and developed a range of clinical signs associated with BTV infection. Peak viraemia titres recorded in individual sheep ranged from 3.5 to 6.83 log(10)TCID(50)/ml indicating a high potential for infection of vector insects and onward transmission. The implications of these results are discussed with reference to the current outbreaks of BTV occurring in northern Europe and in relation to the future development of vaccines for this virus.