UK guideline for the use of HIV post-exposure prophylaxis 2021.

We present the updated British Association for Sexual Health and HIV (BASHH) guidelines for post-exposure prophylaxis (PEP) to HIV following sexual exposures, occupational exposures and other nonoccupational exposures in the community. This serves as an update to the 2015 BASHH guideline on PEP following sexual exposures and the 2008 Expert Advisory Group on AIDS guidelines on HIV PEP. We aim to provide evidence-based guidance on best clinical practice in the provision, monitoring and support of PEP for the prevention of HIV acquisition following sexual, occupational and other nonoccupational exposures in the community. The guideline covers when to prescribe PEP, what antiretroviral agents to use and how to manage PEP. This includes (i) evidence of PEP efficacy; (ii) evidence relating to individual-level efficacy of antiretroviral therapy to prevent the sexual transmission of HIV; (iii) data on the detectable (transmissible) prevalence of HIV in specific populations; (iv) risk of HIV transmission following different types of sexual and occupational exposure; (v) baseline risk assessment; (vi) drug regimens and dosing schedules; (vii) monitoring PEP; (viii) baseline and follow-up blood-borne virus testing; (ix) the role of PEP within broader HIV prevention strategies, for example, HIV pre-exposure prophylaxis (PrEP). The guideline also covers special scenarios such as PEP in pregnancy, breastfeeding and chronic hepatitis B virus infection, and when PEP should be considered in people using HIV PrEP. The guidelines are aimed at clinical professionals directly involved in PEP provision and other stakeholders in the field. A proforma to assist PEP consultations is included. A public consultation process was undertaken prior to finalizing the recommendations.

An improvement model to optimise hospital interdisciplinary learning.

Purpose - Interdisciplinary healthcare education and collaboration facilitates healthcare quality improvement (QI). Education challenges include cost, logistics and defining the optimum staff-engaging method. The purpose of this paper is to determine the optimum QI educational model and measure its impact using plan-do-study-act (PDSA) cycles. Design/methodology/approach - The authors established an on-site interdisciplinary QI learning collaborative: weekly 30-minute learning sessions close to the working environment; a learning materials Twitter repository; and junior doctor-led QI work streams aligned with surgical directorate quality goals supported by a mentorship network. Delivery style (lectures, workshops and QI project reporting) and learning session content was planned weekly using PDSA cycles and modified using participant feedback (score 0-10). All surgical directorate QI work streams were measured before and at nine months. Findings - From May 2014 to February 2015, there were 32 learning sessions with 266 scores (median 12 weekly, range 5-21). Workshop delivery scored the highest (mean score 9.0), followed by live project reports (mean score 8.8). The surgical QI work streams increased threefold from four to 12, including six junior doctor-led projects. Practical implications - By proactively acting upon feedback, the authors centralised QI measurement and tailored learning sessions to staff needs. Building sustainability involves continually refining learning curriculum and QI work streams, and expanding the mentorship network. Originality/value - The collaborative was established at no additional cost. Twitter is used to promote meetings, facilitate conversations and act as a learning repository. The mentorship framework builds QI and coaching expertise.

Systematic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations.

BACKGROUND: Updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30 mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. The objectives of this review were to identify clinical evidence for high-dose amikacin regimens and to determine drug exposures that are related to adverse events and toxicity. METHODS: The literature search was conducted in October 2021 and updated in May 2022 using electronic databases for any study reporting adult participants treated with amikacin at doses ≥20 mg/kg/day. Reference lists of included papers were also screened for potential papers. Data were extracted for pharmacokinetic parameters and clinical outcomes, presented in a summary table and consolidated narratively. Meta-analysis was not possible. Each study was assessed for bias before, during and after the intervention using the ROBINS-I tool. RESULTS: Nine studies (total 501 participants in 10 reports) were identified and included, eight of which were observational studies. Assessment of bias showed substantial flaws. Dosing regimens ranged from 25 to 30 mg/kg/day. Six studies adjusted the dose in obesity when participants had a body mass index of ≥30 kg/m2. Target peak serum concentrations ranged from 60 mg/L to 80 mg/L and 59.6-81.8% of patients achieved these targets, but there was no information on clinical outcomes. Two studies reported the impact of high-dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified. CONCLUSION: All included papers were limited by a significant risk of bias, while methodological and reporting heterogeneity made drawing conclusions challenging. Lack of information on the impact on renal function or ototoxicity means high-dose regimens should be used cautiously in older people. There is a need for a consensus guideline for high-dose amikacin to be written. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42021250022).

Development, implementation and evaluation of high-quality virtual preoperative anaesthetic assessment during COVID-19 and beyond: a quality improvement report.

BACKGROUND: Preoperative risk factor identification and optimisation are widely accepted as the gold standard of care for elective surgery and are essential for reducing morbidity and mortality. COVID-19 public health restrictions required a careful balance between ensuring best medical practices and maintaining safety by minimising patient face-to-face attendance in the hospital. Based on the successful implementation of telemedicine (TM) in other medical specialties and its feasibility in the preoperative context, this study aimed to develop, implement and evaluate a high-quality virtual preoperative anaesthetic assessment process. METHODS: The three-step model for improvement was used. The specific, measurable, actionable, relevant, time aim (step 1) and measures for improvement (step 2) were defined at the onset of the project. The plan-do-study-act tool was used for the structured implementation of improvement interventions (step 3) in three phases. Data relating to virtual and in-person referrals, assessments, did-not-attend (DNA) rate, consultation time, day of surgery delays and cancellations, and service-user and provider experience surveys were recorded prospectively. RESULTS: A total of 2805 patients were assessed in the preoperative anaesthetic assessment clinic between July 2020 and March 2021. The mean rate of virtual preoperative assessments was 50% (SD ±10) (1390/2805). 0.1% (30/2805) were inappropriately referred on the alternative pathway. The DNA rate was 0.4% (8/1398) and 3% (43/1458) for virtual and in-person pathways, respectively. The mean consultation times for virtual and in-person attendance were 19 (SD ±7) and 31 (SD ±13) min, respectively. There were five same-day surgery cancellations and one delay due to medical reasons. When asked about their experience with the virtual assessment, both service users and providers reported high satisfaction, minimal technical difficulties and shared concerns about limited opportunities for physical examination. CONCLUSION: This is one of the first implementational studies to comprehensively outline the feasibility of TM in preoperative anaesthetic assessment during COVID-19.

Synthesis and in vitro activity of N'-cyano-4-(2-phenylacetyl)-N-o-tolylpiperazine-1-carboximidamide P2X7 antagonists.

A novel series of cyanoguanidine-piperazine P2X(7) antagonists was designed based upon the structure of A-740003. Structure-activity relationship (SAR) studies focused on the piperazine moiety and the right hand side substitution. Compounds were assayed for activity at human and rat P2X(7) receptors and compound 29 was found to possess potent activity (IC(50)=30-60 nM) at both species.

Synthesis and activity of N-cyanoguanidine-piperazine P2X7 antagonists.

A novel series of cyanoguanidine-piperazine P2X(7) antagonists were identified and structure-activity relationship (SAR) studies described. Compounds were assayed for activity at human and rat P2X(7) receptors in addition to their ability to inhibit IL-1 beta release from stimulated human whole blood cultures. Compound 27 possesses potent activity (0.12 microM) in this latter assay and demonstrates moderate clearance in-vivo.

UK guideline for the use of HIV Post-Exposure Prophylaxis Following Sexual Exposure, 2015.

We present the updated British Association for Sexual Health and HIV guidelines for HIV post-exposure prophylaxis following sexual exposure (PEPSE). This document includes a review of the current data to support the use of PEPSE, considers how to calculate the risks of infection after a potential exposure, and provides recommendations on when PEPSE should and should not be considered. We also review which medications to use for PEPSE, provide a checklist for initial assessment, and make recommendations for monitoring individuals receiving PEPSE. Special scenarios, cost-effectiveness of PEPSE, and issues relating to service provision are also discussed. Throughout the document, the place of PEPSE within the broader context of other HIV prevention strategies is considered.

Thienopyridine urea inhibitors of KDR kinase.

A series of substituted thienopyridine ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 2, are potent inhibitors of KDR (<10 nM) in both enzymatic and cellular assays. Further characterization of inhibitor 2 indicated that this analog possessed excellent in vivo potency (ED50 2.1 mg/kg) as measured in an estradiol-induced mouse uterine edema model.

1,4-Dihydroindeno[1,2-c]pyrazoles as novel multitargeted receptor tyrosine kinase inhibitors.

A series of 1,4-dihydroindeno[1,2-c]pyrazoles with a 3-thiophene substituent carrying a urea-type side chain were identified as potent multitargeted (VEGFR and PDGFR families) receptor tyrosine kinase inhibitors. A KDR homology model suggested that the urea moiety is able to interact with a recognition motif in the hydrophobic specificity pocket of the enzyme.

Hit-to-lead optimization of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of KDR kinase inhibitors.

A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.

Pyrrolo[2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck.

A series of pyrrolo[2,3-d]pyrimidines was synthesized and evaluated as inhibitors of Lck. Lck accommodates a diverse set of substituents at N-7. Altering the substituent at N-7 provided compound 13, an orally available lck inhibitor which inhibited TCR mediated IL-2 production after oral dosing.

Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck -- a selectivity insight.

A series of para-substituted 3-phenyl pyrazolopyrimidines was synthesized and evaluated as inhibitors of lck. The nature of the substitution affected enzyme selectivity and potency for lck, src, kdr, and tie-2. The para-phenoxyphenyl analogue 2 is an orally active lck inhibitor with a bioavailability of 69% and exhibits an extended duration of action in animal models of T cell inhibition.