A systematic review of national interventions and policies to optimize antibiotic use in healthcare settings in England.

OBJECTIVES: To identify and assess the effectiveness of national antibiotic optimization interventions in primary and secondary care in England (2013-2022). METHODS: A systematic scoping review was conducted. Literature databases (Embase and Medline) were used to identify interventions and evaluations. Reports included the UK AMR Strategy (2013-2018), National Action Plan (2019-2024) and English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) reports (2014-2022). The design, focus and quality of evaluations and the interventions' effectiveness were extracted. FINDINGS: Four hundred and seventy-seven peer-reviewed studies and 13 reports were screened. One hundred and three studies were included for review, identifying 109 interventions in eight categories: policy and commissioning (n = 9); classifications (n = 1); guidance and toolkits (n = 22); monitoring and feedback (n = 17); professional engagement and training (n = 19); prescriber tools (n = 12); public awareness (n = 17); workforce and governance (n = 12).Most interventions lack high-quality effectiveness evidence. Evaluations mainly focused on clinical, microbiological or antibiotic use outcomes, or intervention implementation, often assessing how interventions were perceived to affect behaviour. Only 16 interventions had studies that quantified effects on prescribing, of which six reported reductions. The largest reduction was reported with structural-level interventions and attributed to a policy and commissioning intervention (primary care financial incentives). Behavioural interventions (guidance and toolkits) reported the greatest impact in hospitals. CONCLUSIONS: Many interventions have targeted antibiotic use, each pulling different levers across the health system simultaneously. On the basis of these studies, structural-level interventions may have the greatest impact. Collectively, the combination of interventions may explain England's decline in prescribing but direct evidence of causality is unavailable.

Implementing buprenorphine prolonged-release injection using a health at the margins approach for transactional sex-workers.

Background: Access to prescribed interventions and retention in treatment services are associated with improved health outcomes and reduced premature mortality rates for people living with opioid use disorder (OUD). In Leeds, transactional sex-workers frequently cycled in and out of treatment for OUD such that they never reached a level of engagement that permitted opportunities to meet their healthcare or housing needs. Barriers to accessing care provision include an itinerant lifestyle, difficulties with travel at unpredictable hours, impacting upon adherence to medication regimens including daily supervised consumption. Objectives: To use a co-produced, "health at the margins" approach, to reach the sex-working population in Leeds, and support informed choices about the potential to receive buprenorphine prolonged-release injection (BPRI) as a treatment option for OUD. Methods: BPRI was introduced using a theory of change model and improvements in sex-worker care delivery was reviewed. Strategies included buprenorphine micro-induction, shared decision-making, collaborative multi-agency working and supporting a strengths-based and trauma-informed approach. Results: Benefits of BPRI included removal of the need for daily pharmacy visits, reducing the risk of diversion, improved medication adherence, stability and engagement with treatment and supportive services. Conclusion: BPRI may offer an additional option for pharmacological interventions for people with OUD where there may be increased barriers to accessing treatment for example due to sex-working. Strategies for effective BPRI include micro-induction, shared decision-making, collaborative multi-agency working and supporting a strengths-based approach.

Renal Function Underpins the Cyclooxygenase-2: Asymmetric Dimethylarginine Axis in Mouse and Man.

Introduction: Through the production of prostacyclin, cyclooxygenase (COX)-2 protects the cardiorenal system. Asymmetric dimethylarginine (ADMA), is a biomarker of cardiovascular and renal disease. Here we determined the relationship between COX-2/prostacyclin, ADMA, and renal function in mouse and human models. Methods: We used plasma from COX-2 or prostacyclin synthase knockout mice and from a unique individual lacking COX-derived prostaglandins (PGs) because of a loss of function mutation in cytosolic phospholipase A2 (cPLA2), before and after receiving a cPLA2-replete transplanted donor kidney. ADMA, arginine, and citrulline were measured using ultra-high performance liquid-chromatography tandem mass spectrometry. ADMA and arginine were also measured by enzyme-linked immunosorbent assay (ELISA). Renal function was assessed by measuring cystatin C by ELISA. ADMA and prostacyclin release from organotypic kidney slices were also measured by ELISA. Results: Loss of COX-2 or prostacyclin synthase in mice increased plasma levels of ADMA, citrulline, arginine, and cystatin C. ADMA, citrulline, and arginine positively correlated with cystatin C. Plasma ADMA, citrulline, and cystatin C, but not arginine, were elevated in samples from the patient lacking COX/prostacyclin capacity compared to levels in healthy volunteers. Renal function, ADMA, and citrulline were returned toward normal range when the patient received a genetically normal kidney, capable of COX/prostacyclin activity; and cystatin C positively correlated with ADMA and citrulline. Levels of ADMA and prostacyclin in conditioned media of kidney slices were not altered in tissue from COX-2 knockout mice compared to wildtype controls. Conclusion: In human and mouse models, where renal function is compromised because of loss of COX-2/PGI2 signaling, ADMA levels are increased.

The current landscape of software tools for the climate-sensitive infectious disease modelling community.

Climate-sensitive infectious disease modelling is crucial for public health planning and is underpinned by a complex network of software tools. We identified only 37 tools that incorporated both climate inputs and epidemiological information to produce an output of disease risk in one package, were transparently described and validated, were named (for future searching and versioning), and were accessible (ie, the code was published during the past 10 years or was available on a repository, web platform, or other user interface). We noted disproportionate representation of developers based at North American and European institutions. Most tools (n=30 [81%]) focused on vector-borne diseases, and more than half (n=16 [53%]) of these tools focused on malaria. Few tools (n=4 [11%]) focused on food-borne, respiratory, or water-borne diseases. The under-representation of tools for estimating outbreaks of directly transmitted diseases represents a major knowledge gap. Just over half (n=20 [54%]) of the tools assessed were described as operationalised, with many freely available online.

Associations of Skeletal Muscle Mass and Fat Mass With Incident Cardiovascular Disease and All-Cause Mortality: A Prospective Cohort Study of UK Biobank Participants.

Background There is debate whether body mass index is a good predictor of health outcomes because different tissues, namely skeletal muscle mass (SMM) and fat mass (FM), may be differentially associated with risk. We investigated the association of appendicular SMM (aSMM) and FM with fatal and nonfatal cardiovascular disease (CVD) and all-cause mortality. We compared their prognostic value to that of body mass index. Methods and Results We studied 356 590 UK Biobank participants aged 40 to 69 years with bioimpedance analysis data for whole-body FM and predicted limb muscle mass (to calculate aSMM). Associations between aSMM and FM with CVD and all-cause mortality were examined using multivariable Cox proportional hazards models. Over 3 749 501 person-years of follow-up, there were 27 784 CVD events and 15 844 all-cause deaths. In men, aSMM was positively associated with CVD incidence (hazard ratio [HR] per 1 SD 1.07; 95% CI, 1.06-1.09) and there was a curvilinear association in women. There were stronger positive associations between FM and CVD with HRs per SD of 1.20 (95% CI, 1.19-1.22) and 1.25 (95% CI, 1.23-1.27) in men and women respectively. Within FM tertiles, the associations between aSMM and CVD risk largely persisted. There were J-shaped associations between aSMM and FM with all-cause mortality in both sexes. Body mass index was modestly better at discriminating CVD risk. Conclusions FM showed a strong positive association with CVD risk. The relationship of aSMM with CVD risk differed between sexes, and potential mechanisms need further investigation. Body fat and SMM bioimpedance measurements were not superior to body mass index in predicting population-level CVD incidence or all-cause mortality.

Measuring antibiotic availability and use in 20 low- and middle-income countries.

OBJECTIVE: To assess antibiotic availability and use in health facilities in low- and middle-income countries, using the service provision assessment and service availability and readiness assessment surveys. METHODS: We obtained data on antibiotic availability at 13 561 health facilities in 13 service provision assessment and 8 service availability and readiness assessment surveys. In 10 service provision assessment surveys, child consultations with health-care providers were observed, giving data on antibiotic use in 22 699 children. Antibiotics were classified as access, watch or reserve, according to the World Health Organization's AWaRe categories. The percentage of health-care facilities across countries with specific antibiotics available and the proportion of children receiving antibiotics for key clinical syndromes were estimated. FINDINGS: The surveys assessed the availability of 27 antibiotics (19 access, 7 watch, 1 unclassified). Co-trimoxazole and metronidazole were most widely available, being in stock at 89.5% (interquartile range, IQR: 11.6%) and 87.1% (IQR: 15.9%) of health facilities, respectively. In contrast, 17 other access and watch antibiotics were stocked, by fewer than a median of 50% of facilities. Of the 22 699 children observed, 60.1% (13 638) were prescribed antibiotics (mostly co-trimoxazole or amoxicillin). Children with respiratory conditions were most often prescribed antibiotics (76.1%; 8972/11 796) followed by undifferentiated fever (50.1%; 760/1518), diarrhoea (45.7%; 1293/2832) and malaria (30.3%; 352/1160). CONCLUSION: Routine health facility surveys provided a valuable data source on the availability and use of antibiotics in low- and middle-income countries. Many access antibiotics were unavailable in a majority of most health-care facilities.

Anti-platelet drugs and their necessary interaction with endothelial mediators and platelet cyclic nucleotides for therapeutic efficacy.

For many millions of patients at secondary risk of coronary thrombosis pharmaceutical protection is supplied by dual anti-platelet therapy. Despite substantial therapeutic developments over the last decade recurrent thrombotic events occur, highlighting the need for further optimisation of therapies. Importantly, but often ignored, anti-platelet drugs interact with cyclic nucleotide systems in platelets and these are the same systems that mediate key endogenous pathways of platelet regulation, notably those dependent upon the vascular endothelium. The aim of this review is to highlight interactions between the anti-platelet drugs, aspirin and P2Y12 receptor antagonists and endogenous pathways of platelet regulation at the level of cyclic nucleotides. These considerations are key to concepts such as anti-platelet drug resistance and individualized anti-platelet therapy which cannot be understood by study of platelets in isolation from the circulatory environment. We also explore novel and emerging therapies that focus on preserving haemostasis and how the concepts outlined in this review could be exploited therapeutically to improve anti-thrombotic efficacy whilst reducing bleeding risk.

Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-M.

RATIONALE: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A2, which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A2 are formed after the concerted actions of cPLA2α (cytosolic phospholipase A2) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF1α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2 formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. OBJECTIVE: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA2α knockout, kidney-specific knockin. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2 in the circulation. METHODS AND RESULTS: Metabolites were measured using liquid chromatography-tandem mass spectrometry. Endothelial cells were grown from blood progenitors. Before kidney transplantation, the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-keto-prostaglandin F1α) and thromboxane A2 (measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. After transplantation and the establishment of normal renal function, the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges, whereas endothelial production of prostacyclin and platelet production of thromboxane A2 remained negligible. CONCLUSIONS: These data show that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A2 by platelets in the general circulation. Previous work relying on urinary metabolites of prostacyclin and thromboxane A2 as markers of whole-body endothelial and platelet function now requires reevaluation.

Platelet reactivity influences clot structure as assessed by fractal analysis of viscoelastic properties.

Despite the interwoven nature of platelet activation and the coagulation system in thrombosis, few studies relate both analysis of protein and cellular parts of coagulation in the same population. In the present study, we use matched ex vivo samples to determine the influences of standard antiplatelet therapies on platelet function and use advanced rheological analyses to assess clot formation. Healthy volunteers were recruited following fully informed consent then treated for 7 days with single antiplatelet therapy of aspirin (75 mg) or prasugrel (10 mg) or with dual antiplatelet therapy (DAPT) using aspirin (75 mg) plus prasugrel (10 mg) or aspirin (75 mg) plus ticagrelor (90 mg). Blood samples were taken at day 0 before treatment and at day 7 following treatment. We found that aspirin plus prasugrel or aspirin plus ticagrelor inhibited platelet responses to multiple agonists and reduced P-selectin expression. Significant platelet inhibition was coupled with a reduction in fractal dimension corresponding to reductions in mean relative mass both for aspirin plus prasugrel (-35 ± 16% change, p = 0.04) and for aspirin plus ticagrelor (-45 ± 14% change, p = 0.04). Aspirin alone had no effect upon measures of clot structure, whereas prasugrel reduced fractal dimension and mean relative mass. These data demonstrate that platelets are important determinants of clot structure as assessed by fractal dimension (df) and that effective platelet inhibition is associated with a weaker, more permeable fibrin network. This indicates a strong association between the therapeutic benefits of antiplatelet therapies and their abilities to reduce thrombus density that may be useful in individual patients to determine the functional relationship between platelet reactivity, eventual clot quality, and clinical outcome. df could represent a novel risk stratification biomarker useful in individualizing antiplatelet therapies.

Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies.

OBJECTIVE: Aspirin together with thienopyridine P2Y12 inhibitors, commonly clopidogrel, is a cornerstone of antiplatelet therapy. However, many patients receiving this therapy display high on-treatment platelet reactivity, which is a major therapeutic hurdle to the prevention of recurrent thrombotic events. The emergence of uninhibited platelets after thrombopoiesis has been proposed as a contributing factor to high on-treatment platelet reactivity. Here, we investigate the influences of platelet turnover on platelet aggregation in the face of different dual-antiplatelet therapy strategies. APPROACH AND RESULTS: Traditional light transmission aggregometry, cytometry, advanced flow cytometric imaging, and confocal microscopy were used to follow the interactions of populations of platelets from healthy volunteers and patients with stable cardiovascular disease. Newly formed, reticulated platelets overproportionately contributed to, and clustered at, the core of forming aggregates. This phenomenon was particularly observed in samples from patients treated with aspirin plus a thienopyridine, but was absent in samples taken from patients treated with aspirin plus ticagrelor. CONCLUSIONS: Reticulated platelets are more reactive than older platelets and act as seeds for the formation of platelet aggregates even in the presence of antiplatelet therapy. This is coherent with the emergence of an uninhibited subpopulation of reticulated platelets during treatment with aspirin plus thienopyridine, explained by the short pharmacokinetic half-lives of these drugs. This phenomenon is absent during treatment with ticagrelor, because of its longer half-life and ability to act as a circulating inhibitor. These data highlight the important influences of pharmacokinetics on antiplatelet drug efficacies, especially in diseases associated with increased platelet turnover.

P2Y12 receptor blockade synergizes strongly with nitric oxide and prostacyclin to inhibit platelet activation.

AIMS: In vivo platelet function is a product of intrinsic platelet reactivity, modifiable by dual antiplatelet therapy (DAPT), and the extrinsic inhibitory endothelial mediators, nitric oxide (NO) and prostacyclin (PGI2 ), that are powerfully potentiated by P2Y12 receptor blockade. This implies that for individual patients endothelial mediator production is an important determinant of DAPT effectiveness. Here, we have investigated this idea using platelets taken from healthy volunteers treated with anti-platelet drugs. METHODS: Three groups of male volunteers (n = 8) received either prasugrel (10 mg), aspirin (75 mg) or DAPT (prasugrel + aspirin) once daily for 7 days. Platelet reactivity in the presence of diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NONOate) and PGI2 was studied before and following treatment. RESULTS: Ex vivo, PGI2 and/or DEA/NONOate had little inhibitory effect on TRAP-6-induced platelet reactivity in control conditions. However, in the presence of DAPT, combination of DEA/NONOate + PGI2 reduced platelet aggregation (74 ± 3% to 19 ± 6%, P < 0.05). In vitro studies showed even partial (25%) P2Y12 receptor blockade produced a significant (67 ± 2% to 39 ± 10%, P < 0.05) inhibition when DEA/NONOate + PGI2 was present. CONCLUSIONS: We have demonstrated that PGI2 and NO synergize with P2Y12 receptor antagonists to produce powerful platelet inhibition. Furthermore, even with submaximal P2Y12 blockade the presence of PGI2 and NO greatly enhances platelet inhibition. Our findings highlight the importance of endothelial mediator in vivo modulation of P2Y12 inhibition and introduces the concept of refining ex vivo platelet function testing by incorporating an assessment of endothelial function to predict thrombotic outcomes better and adjust therapy to prevent adverse outcomes in individual patients.

A preliminary investigation into theory of mind and attributional style in adults with grandiose delusions.

INTRODUCTION: A preliminary cognitive model of grandiose delusions has been put forward suggesting that persecutory and grandiose delusions shared distinct, yet overlapping psychological processes. This study aims to test this model and hypothesises that participants experiencing grandiose delusions may demonstrate a theory of mind (ToM) impairment and differences in attributional style compared to a control group. METHODS: A cross-sectional design compared the performance of 18 individuals with grandiose delusions to a control group of 14 participants with depression. ToM was measured using a non-verbal joke appreciation task and a verbal stories task. Attributional style was measured using the internal, personal and situational attributions questionnaire. RESULTS: Participants experiencing grandiose delusions performed significantly worse on both ToM tasks compared to controls. Furthermore, these participants provided significantly more atypical answers when explaining the joke behind the ToM cartoons. No differences for subjective funniness ratings or attributional style were found. CONCLUSIONS: This preliminary study indicated participants experiencing grandiose delusions have ToM impairments which may contribute to the maintenance of this symptom.

Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs.

BACKGROUND: Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified. METHODS AND RESULTS: Transcriptome analysis of wild-type and cyclooxygenase-2(-/-) mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2(-/-) mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage. CONCLUSIONS: We identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction.

Attributional style and theory of mind in people with Alzheimer disease and persecutory delusions.

OBJECTIVE: Between 7% and 40% of people with Alzheimer disease (AD) experience persecutory delusions (PDs) during the course of their dementia. Although attributional style and theory of mind processes have been linked with PDs in people with psychosis, they have not yet been examined in those with AD and PDs. The objective of this study was, hence, to explore the role of these cognitive processes in groups of participants with AD with and without PDs, as well as a nonclinical comparison group. METHOD: Measures of attributional style and theory of mind were administered to three groups: people with AD and PDs (n = 22), people with AD without PDs (n = 22), and a nonclinical group (n = 23). RESULTS: Although no clear differences in attributional style between the three groups were found, the group with AD and PDs were found to perform worse on the first-order (but not second-order) theory of mind task than the other two groups. CONCLUSIONS: Interventions designed to enhance theory of mind skills might be beneficial for individuals with AD and PDs.

More than words? Hypomanic personality traits, visual imagery and verbal thought in young adults.

The use of visual mental imagery has been proposed to be a risk factor for the development of bipolar disorder, due to its potential to amplify affective states. This study examined the relation between visual imagery (both trait usage and intrusive experiences of such imagery), intrusive verbal thought, and hypomania, as assessed by self-report questionnaires, in a sample of young adults (N=219). Regression analyses found (after controlling for anxiety, depression, and positive and negative affect) that levels of intrusive visual imagery predicted levels of hypomania, but that neither trait use of visual imagery nor intrusive verbal thought did. These results were consistent with the proposal that being a 'visualiser', as opposed to a 'verbaliser', is a risk factor for bipolar disorder, with the caveat that it is specifically intrusive experiences of imagery, rather than the tendency to utilize imagery per se, that acts as a risk factor.