Using pharmacokinetics for tailoring prophylaxis in people with hemophilia switching between clotting factor products: A scoping review

Abstract The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hemophilia may require switching of clotting factor concentrates due to a variety of factors, but there have been perceived risks associated with switching, such as inhibitor development or suboptimal protection due to inadequate dosing while titrating treatment. Studies that look at patients switching from one clotting factor concentrate to another are categorized in terms of their primary and/or secondary objectives, notably biosimilarity and comparative pharmacokinetic studies and inhibitor development studies. Research on how best to switch concentrates with respect to dosing regimen are lacking, and currently a trial-and-error approach is used for dosing the new factor concentrate. In the future, studies looking at the predictability of pharmacokinetics (PK) of a new factor concentrate based on individual PK knowledge of the original factor concentrate may offer clinical benefit by providing a safer switching approach and protocol.Peer reviewe

Prevalence of electronic screening for sepsis in National Health Service acute hospitals in England

Sepsis is a worldwide public health problem. Rapid identification is associated with improved patient outcomes—if followed by timely appropriate treatment. Objectives Describe digital sepsis alerts (DSAs) in use in English National Health Service (NHS) acute hospitals. Methods A Freedom of Information request surveyed acute NHS Trusts on their adoption of electronic patient records (EPRs) and DSAs. Results Of the 99 Trusts that responded, 84 had an EPR. Over 20 different EPR system providers were identified as operational in England. The most common providers were Cerner (21%). System C, Dedalus and Allscripts Sunrise were also relatively common (13%, 10% and 7%, respectively). 70% of NHS Trusts with an EPR responded that they had a DSA; most of these use the National Early Warning Score (NEWS2). There was evidence that the EPR provider was related to the DSA algorithm. We found no evidence that Trusts were using EPRs to introduce data driven algorithms or DSAs able to include, for example, pre-existing conditions that may be known to increase risk. Not all Trusts were willing or able to provide details of their EPR or the underlying algorithm. Discussion The majority of NHS Trusts use an EPR of some kind; many use a NEWS2-based DSA in keeping with national guidelines. Conclusion Many English NHS Trusts use DSAs; even those using similar triggers vary and many recreate paper systems. Despite the proliferation of machine learning algorithms being developed to support early detection of sepsis, there is little evidence that these are being used to improve personalised sepsis detection

A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol

Background: Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. Methods: Study design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period. Participants: Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA. Interventions: Rituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. Outcomes: The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3. Discussion: This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. Trial registration: ClinicalTrials.gov NCT03967925. Registered on May 30, 2019

Use of Feedback Data to Reduce Surgical Site Infections and Optimize Antibiotic Use in Surgery: A Systematic Scoping Review.

OBJECTIVE: Surgical site infection (SSI) prevention remains significant, particularly in the era of antimicrobial resistance. Feedback on practices and outcomes is known to be key to reduce SSI rates and optimize antibiotic usage. However, the optimal method, format and frequency of feedback for surgical teams remains unclear. The objective of the study is to understand how data from surveillance and audit are fed back in routine surgical practice. METHODS: A systematic scoping review was conducted, using well-established implementation science frameworks to code the data. Two electronic health-oriented databases (MEDLINE, EMBASE) were searched to September 2019. We included studies that assessed the use of feedback as a strategy either in the prevention and management of SSI and/or in the use of antibiotics perioperatively. RESULTS: We identified 21 studies: 17 focused on SSI rates and outcomes and 10 studies described antimicrobial stewardship for SSI (with some overlap in focus). Several interventions were reported, mostly multimodal with feedback as a component. Feedback was often provided in written format (62%), either individualized (38%) or in group (48%). Only 25% of the studies reported that feedback cascaded down to the frontline perioperative staff. In 65% of the studies, 1 to 5 implementation strategies were used while only 5% of the studies reported to have utilized more than 15 implementation strategies. Among studies reporting antibiotic usage in surgery, most (71%) discussed compliance with surgical antibiotic prophylaxis. CONCLUSIONS: Our findings highlight the need to provide feedback to all levels of perioperative care providers involved in patient care. Future research in this area should report implementation parameters in more detail

Supported exercise TrAining for Men wIth prostate caNcer on Androgen deprivation therapy (STAMINA): study protocol for a randomised controlled trial of the clinical and cost-effectiveness of the STAMINA lifestyle intervention compared with optimised usual care, including internal pilot and parallel process evaluation

Background: UK national clinical guidance recommends that men with prostate cancer on androgen deprivation therapy are offered twice weekly supervised aerobic and resistance exercise to address iatrogenic harm caused by treatment. Very few NHS trusts have established adequate provision of such services. Furthermore, interventions fail to demonstrate sustained behaviour change. The STAMINA lifestyle intervention offers a system-level change to clinical care delivery addressing barriers to long-term behaviour change and implementation of new prostate cancer care pathways. This trial aims to establish whether STAMINA is clinically and cost-effective in improving cancer-specific quality of life and/or reducing fatigue compared to optimised usual care. The process evaluation aims to inform the interpretation of results and, if the intervention is shown to benefit patients, to inform the implementation of the intervention into the NHS. Methods: Men with prostate cancer on androgen deprivation therapy (n = 697) will be identified from a minimum of 12 UK NHS trusts to participate in a multi-centre, two-arm, individually randomised controlled trial. Consenting men will have a ‘safety to exercise’ check and be randomly allocated (5:4) to the STAMINA lifestyle intervention (n = 384) or optimised usual care (n = 313). Outcomes will be collected at baseline, 3-, 6- and 12-month post-randomisation. The two primary outcomes are cancer-specific quality of life and fatigue. The parallel process evaluation will follow a mixed-methods approach to explore recruitment and aspects of the intervention including, reach, fidelity, acceptability, and implementation. An economic evaluation will estimate the cost-effectiveness of the STAMINA lifestyle intervention versus optimised usual care and a discrete choice experiment will explore patient preferences. Discussion: The STAMINA lifestyle intervention has the potential to improve quality of life and reduce fatigue in men on androgen deprivation therapy for prostate cancer. Embedding supervised exercise into prostate cancer care may also support long-term positive behaviour change and reduce adverse events caused by treatment. Findings will inform future clinical care and could provide a blueprint for the integration of supervised exercise and behavioural support into other cancer and/or clinical services. Trial registration: ISRCTN 46385239, registered on 30/07/2020. Cancer Research UK 17002, retrospectively registered on 24/08/2022

A novel clinical score (InterTAK Diagnostic Score) to differentiate takotsubo syndrome from acute coronary syndrome: results from the International Takotsubo Registry

AIMS. Clinical presentation of takotsubo syndrome (TTS) mimics acute coronary syndrome (ACS) and does not allow differentiation. We aimed to develop a clinical score to estimate the probability of TTS and to distinguish TTS from ACS in the acute stage. METHODS AND RESULTS: Patients with TTS were recruited from the International Takotsubo Registry ( www.takotsubo-registry.com) and ACS patients from the leading hospital in Zurich. A multiple logistic regression for the presence of TTS was performed in a derivation cohort (TTS, n = 218; ACS, n = 436). The best model was selected and formed a score (InterTAK Diagnostic Score) with seven variables, and each was assigned a score value: female sex 25, emotional trigger 24, physical trigger 13, absence of ST-segment depression (except in lead aVR) 12, psychiatric disorders 11, neurologic disorders 9, and QTc prolongation 6 points. The area under the curve (AUC) for the resulting score was 0.971 [95% confidence interval (CI) 0.96-0.98] and using a cut-off value of 40 score points, sensitivity was 89% and specificity 91%. When patients with a score of ≥50 were diagnosed as TTS, nearly 95% of TTS patients were correctly diagnosed. When patients with a score ≤31 were diagnosed as ACS, ∼95% of ACS patients were diagnosed correctly. The score was subsequently validated in an independent validation cohort (TTS, n = 173; ACS, n = 226), resulting in a score AUC of 0.901 (95% CI 0.87-0.93). CONCLUSION: The InterTAK Diagnostic Score estimates the probability of the presence of TTS and is able to distinguish TTS from ACS with a high sensitivity and specificity

Investigating infection management and antimicrobial stewardship in surgery: a qualitative study from India and South Africa

Appendix A. Supplementary data: The following is the Supplementary data to this article: Multimedia component 1. Avalable online at https://www.sciencedirect.com/science/article/pii/S1198743X20307734#appsec1 .This work was supported by the Economic and Social Science Research Council (ESRC) and the National Institute for Health Research, UK Department of Health (HPRU-2012-10047) in partnership with Public Health England. This study is part of the ASPIRES project (Antibiotic use across Surgical Pathways—Investigating, Redesigning and Evaluating Systems) (https://www.imperial.ac.uk/arc/aspires/). ASPIRES aims to address antimicrobial resistance and improve clinical outcomes optimizing antibiotic usage along surgical pathways. The support of ESRC as part of the Antimicrobial Cross Council initiative supported by the seven UK research councils, and also the support of the Global Challenges Research Fund, is gratefully acknowledged

Investigating infection management and antimicrobial stewardship in surgery: a qualitative study from India and South Africa

OBJECTIVES: To investigate the drivers for infection management and antimicrobial stewardship (AMS) across high-infection-risk surgical pathways. METHODS: A qualitative study-ethnographic observation of clinical practices, patient case studies, and face-to-face interviews with healthcare professionals (HCPs) and patients-was conducted across cardiovascular and thoracic and gastrointestinal surgical pathways in South Africa (SA) and India. Aided by Nvivo 11 software, data were coded and analysed until saturation was reached. The multiple modes of enquiry enabled cross-validation and triangulation of findings. RESULTS: Between July 2018 and August 2019, data were gathered from 190 hours of non-participant observations (138 India, 72 SA), interviews with HCPs (44 India, 61 SA), patients (six India, eight SA), and case studies (four India, two SA). Across the surgical pathway, multiple barriers impede effective infection management and AMS. The existing implicit roles of HCPs (including nurses and senior surgeons) are overlooked as interventions target junior doctors, bypassing the opportunity for integrating infection-related care across the surgical team. Critically, the ownership of decisions remains with the operating surgeons, and entrenched hierarchies restrict the inclusion of other HCPs in decision-making. The structural foundations to enable staff to change their behaviours and participate in infection-related surgical care are lacking. CONCLUSIONS: Identifying the implicit existing HCP roles in infection management is critical and will facilitate the development of effective and transparent processes across the surgical team for optimized care. Applying a framework approach that includes nurse leadership, empowering pharmacists and engaging surgical leads, is essential for integrated AMS and infection-related care

Final Report for Grant No. DE-FG02-01ER63220 "The Dynamics of Cellular Stress Responses in Deinococcus radiodurans"

Bacteria belonging to the family Deinococcaceae are some of the most ionizing radiation (IR) resistant organisms yet discovered. Deinococcus radiodurans is obligate aerobic, capable of growth under chronic IR (60 Gy/hour) and relatively resistant to many DNA damaging conditions including exposure to desiccation, ultraviolet radiation and hydrogen peroxide. The genes and cellular pathways underlying the survival strategies of D. radiodurans have been under investigation for fifty years. In the last decade, D. radiodurans was subjected to whole-genome sequencing, annotation and comparative analysis, whole-transcriptome and whole-proteome analyses, and numerous DNA repair studies. Collectively, published reports support that the key to survival of D. radiodurans resides in its ability to repair DNA, but the mechanisms responsible remain poorly defined. Unexpectedly, many novel genes implicated in recovery from IR by transcriptome and proteome profiling have had little effect on survival when disrupted, and there is reason to ask if something is missing from classical models of radiation resistance. The prevailing dogma of radiation toxicity has been that the cytotoxic and mutagenic effects of radiation are principally the result of DNA damage that occurs during IR. However, in light of available whole genome sequences, one broad observation that is difficult to reconcile with this view is that many organisms that encode a compliment of DNA repair and protection functions are killed at radiation doses that cause little DNA damage. This indicates that there are cellular targets involved in recovery that are more vulnerable to IR damage than DNA. It has been reported that D. radiodurans and other resistant organisms accumulate very high intracellular concentrations of Mn(II), and restricting the amount of Mn(II) during recovery from IR substantially reduced survival of D. radiodurans. At high intracellular concentrations, Mn(II) is known to act as a true catalyst of the dismutase of superoxde (O2?-), with Mn cycling between the divalent and trivalent states. Superoxide is generated during water radiolysis, particularly in the presence of iron redox-cycling processes, and has been implicated in damaging [4Fe-4S] cluster-containing proteins, with the release of bound Fe(II). Thus, it is possible that Mn(II) accumulation acts as keystone among antioxidant defenses which limits protein damage during both irradiation and recovery, with the result that DNA repair and other enzymic systems involved in recovery function with greater efficiency in D. radiodurans than other organisms