Is barbotage in central neuraxial blockade a ritual habit or an evidence-based technique?

Barbotage refers to the repeated aspiration and re-injection of CSF following injection of local anaesthetic into the intrathecal space, and its practice varies among anaesthetists. This article reviews the evidence for and against this practice to alter block dynamics following intrathecal injection reserved for spinal anaesthesia.

A systematic review to evaluate the efficacy of azelaic acid in the management of acne, rosacea, melasma and skin aging.

BACKGROUND: Topical azelaic acid (AA) is indicated for acne and rosacea, but there is some evidence for its use for other dermatological conditions. AIMS: To assess the effectiveness and safety of topical AA for acne vulgaris, rosacea, hyperpigmentation/melasma, and skin aging. METHODS: RCTs of at least 6 weeks' treatment duration were eligible for inclusion. Databases including MEDLINE, Embase, CINAHL, and ClinicalTrials.gov were searched up to December 2022. Two reviewers were involved in all stages of the systematic review process. RESULTS: Forty-three RCTs met the inclusion criteria. Meta-analyses within 20 rosacea studies demonstrated that erythema severity, inflammatory lesion counts, overall improvement, and treatment success (achieving skin clarity) were significantly improved with AA compared with vehicle after 12 weeks. AA was more effective than metronidazole 0.75% for improved erythema severity, overall improvement, and inflammatory lesion counts. Sixteen acne studies suggest that AA is more effective than vehicle for improving global assessments and reducing acne severity. AA 20% also significantly reduced more lesions than erythromycin gel. Within seven melasma studies, AA 20% was significantly better than vehicle for both severity and global improvement. AA 20% demonstrated significantly better results compared with hydroquinone 2% for global improvement. Very few significant differences between AA and comparators were observed for commonly reported adverse events. No eligible RCTs were found that evaluated skin aging. CONCLUSIONS: AA is more effective than vehicle for rosacea, acne and melasma. Comparisons between AA and other treatments were often equivalent. Where there is equivalence, AA may be a good option for some clinical situations. RCT evidence is needed to evaluate the effectiveness of AA on skin aging.

A Review of Economic Models Submitted to NICE's Technology Appraisal Programme, for Treatments of T1DM & T2DM.

Background: In the UK, 4.7 million people are currently living with diabetes. This is projected to increase to 5 million by 2025. The direct and indirect costs of T1DM and T2DM are rising, and direct costs already account for approximately 10% of the National Health Service (NHS) budget. Objective: The aim of this review is to assess the economic models used in the context of NICE's Technology Appraisals (TA) Programme of T1DM and T2DM treatments, as well as to examine their compliance with the American Diabetes Association's (ADA) guidelines on computer modelling. Methods: A review of the economic models used in NICE's TA programme of T1DM and T2DM treatments was undertaken. Relevant TAs were identified through searching the NICE website for published appraisals completed up to April 2021. The review also examined the associated Evidence Review Group (ERG) reports and Final Appraisal Documents (FAD), which are publicly accessible. ERG reports were scrutinised to identify major issues pertaining to the economic modelling. The FAD documents were then examined to assess how these issues reflected on NICE recommendations. Results: Overall, 10 TAs pertaining to treatments of T1DM and T2DM were identified. Two TAs were excluded as they did not use economic models. Seven of the 8 included TAs related to a novel class of oral antidiabetic drugs (OADs), gliflozins, and one to continuous subcutaneous insulin infusion (CSII) devices. There is a lack of recent, robust data informing risk equations to enable the derivation of transition probabilities. Despite uncertainty surrounding its clinical relevance, bodyweight/BMI is a key driver in many T2DM-models. HbA1c's reliability as a predictor of hard outcomes is uncertain, chiefly for macrovascular complications. The external validity of T1DM is even less clear. There is an inevitable trade-off between the sophistication of models' design, their transparency and practicality. Conclusion: Economic models are essential tools to support decision-making in relation to market access and ascertain diabetes technologies' cost effectiveness. However, key structural and methodological issues exist. Models' shortcomings should be acknowledged and contextualised within the framework of technology appraisals. Diabetes medications and other technologies should also be subject to regular and consistent re-appraisal to inform disinvestment decisions. Artificial intelligence could potentially enhance models' transparency and practicality.

Challenges of aciclovir-resistant HSV infection in allogeneic bone marrow transplant recipients.

INTRODUCTION: The emergence of herpes simplex virus (HSV) resistance to aciclovir (ACV) has increasingly been reported among hematopoietic stem cell transplant (HSCT) recipients and often associated with extended ACV prophylaxis. METHODS: Between June 2011 and June 2019, medical records of 532 HSCT recipients with suspected HSV infection were retrospectively analyzed. HSV-1 and HSV-2 positive samples were identified in 47 and 16 patients respectively. Analysis of HSV resistance to antivirals was performed at the Public Health England reference laboratory in London using phenotypic and/or genotypic resistance assays. RESULTS: The prevalence of ACV-resistant HSV accounted for 17% (8/48) of infected HSV-1 cases. All 8 patients received T-cell depleted allogeneic HSCT for hematological malignancies. Half of these patients were male with a median age was 57.5 years (range; 26-63). Chronic Graft versus Host disease (cGVHD) affected 7 patients before HSV-1 diagnosis. HSV-1 infection developed while receiving either intravenous ACV (n = 2) or oral ACV (n = 6 patients) prophylaxis at a median of 373 [range,18-2183] days post-HSCT. ACV resistance was clinically suspected at a median of 25 [range,16-109] days after initial HSV diagnosis and subsequently laboratory confirmed at a median of 25 (range,10-59) days. All patients presented with hemorrhagic oral mucositis refractory to treatment dose ACV. Foscarnet (FOS) treatment was initiated in all 8 patients (pending laboratory confirmation of ACV resistance) with some effect but associated with significant toxicity burden. Four patients presented again with recurrent HSV infection or no resolution. Three with recurrent HSV died from other causes while suffering from persistent oral HSV lesions. CONCLUSION: A prolonged immunosuppressed state following T-deplete HSCTs alongside extended use of ACV, early onset systemic HSV infection, presence of cGVHD, and treatment toxicities pose a significant challenge to the management of ACV resistant HSV infections and alternative effective antiviral options remains an unmet need in this clinical setting.

Diabetes as a disease of endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress is an integral part of life for all professional secretory cells, but it has been studied to greatest depth in the pancreatic ß-cell. This reflects both the crucial role played by ER stress in the pathogenesis of diabetes and also the exquisite vulnerability of these cells to ER dysfunction. The adaptive cellular response to ER stress, the unfolded protein response, comprises mechanisms to both regulate new protein translation and a transcriptional program to allow adaptation to the stress. The core of this response is a triad of stress-sensing proteins: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6. All three regulate portions of the transcriptional unfolded protein response, while PERK also attenuates protein synthesis during ER stress and IRE1 interacts directly with the c-Jun amino-terminal kinase stress kinase pathway. In this review we shall discuss these processes in detail, with emphasis given to their impact on diabetes and how recent findings indicate that ER stress may be responsible for the loss of ß-cell mass in the disease.

Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response.

The integrated stress response (ISR) protects cells from numerous forms of stress and is involved in the growth of solid tumours; however, it is unclear how the ISR acts on cellular proliferation. We have developed a model of ISR signalling with which to study its effects on tissue growth. Overexpression of the ISR kinase PERK resulted in a striking atrophic eye phenotype in Drosophila melanogaster that could be rescued by co-expressing the eIF2alpha phosphatase GADD34. A genetic screen of 3000 transposon insertions identified grapes, the gene that encodes the Drosophila orthologue of checkpoint kinase 1 (CHK1). Knockdown of grapes by RNAi rescued eye development despite ongoing PERK activation. In mammalian cells, CHK1 was activated by agents that induce ER stress, which resulted in a G2 cell cycle delay. PERK was both necessary and sufficient for CHK1 activation. These findings indicate that non-genotoxic misfolded protein stress accesses DNA-damage-induced cell cycle checkpoints to couple the ISR to cell cycle arrest.

Need and evolution of need for device therapy in a community heart failure population.

BACKGROUND: New guidelines for implantable cardiac defibrillators (ICD) and cardiac resynchronisation therapy (CRT) have expanded the potential use for device therapy. The implications of this on a community heart failure (HF) population are unknown. AIM: To assess the need for device therapy and the change in need over time. METHODS: We reviewed device need in a community HF population using ESC guidelines. Change in need was assessed by comparing data between an annual visit called TP2 and an earlier visit called TP1. Patients' need and change in need between TP1 and TP2 was determined. RESULTS: 210 patients were included; mean age 70+/-12 years, 67% male and 54% ischaemic. At TP1, 34% of patients were suitable for ICD and 3% for CRT. At TP2, 22% and 1% were suitable respectively. Of those suitable for ICD at TP1, 19% lost the need at TP2; in addition 9% of patients unsuitable for ICD at TP1 had acquired the need by TP2. Fifty five percent of patients were unsuitable for ICD at either time point, and 16% were suitable at both time points. CRT need was negligible but also noted to change. CONCLUSION: ICD need is substantial in a community HF population, but CRT need is limited. ICD need changes significantly. Identifying those likely to change their need may optimise ICD use.

Daptomycin.

There has been a steady rise in the prevalence of resistant Gram-positive pathogens and concerns about the clinical effectiveness of glycopeptides in treating infections due to Staphylococcus aureus. Daptomycin is a novel lipopeptide antimicrobial agent with activity against Gram-positive organisms, including multi-resistant strains. It is licensed in the USA and Europe for the treatment of complicated skin and soft tissue infections caused by Gram-positive organisms at a dose of 4mg/kg once daily. It has also been licensed in the USA for the treatment of S. aureus bacteraemia and right-sided endocarditis at 6mg/kg once daily. It is a safe and well-tolerated antibiotic, particularly at the current dosing regimen. Antimicrobial resistance, whilst being increasingly reported, still remains relatively rare. Further studies are required to determine the role of daptomycin for the treatment of osteomyelitis and septic arthritis, as well as its use in combination therapy.