BACKGROUND:The necessity of performing a sentinel lymph node biopsy in patients with clinically and radiologically node-negative breast cancer after neoadjuvant chemotherapy has been questioned. The aim of this study was to determine the rate of nodal positivity in these patients and to identify clinicopathological features associated with lymph node metastasis after neoadjuvant chemotherapy (ypN+). METHODS:A retrospective multicentre study was performed. Patients with cT1-3 cN0 breast cancer who underwent sentinel lymph node biopsy after neoadjuvant chemotherapy between 2016 and 2021 were included. Negative nodal status was defined as the absence of palpable lymph nodes, and the absence of suspicious nodes on axillary ultrasonography, or the absence of tumour cells on axillary nodal fine needle aspiration or core biopsy. RESULTS:A total of 371 patients were analysed. Overall, 47 patients (12.7%) had a positive sentinel lymph node biopsy. Nodal positivity was identified in 22 patients (29.0%) with hormone receptor+/human epidermal growth factor receptor 2- tumours, 12 patients (13.8%) with hormone receptor+/human epidermal growth factor receptor 2+ tumours, 3 patients (5.6%) with hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 10 patients (6.5%) with triple-negative breast cancer. Multivariable logistic regression analysis showed that multicentric disease was associated with a higher likelihood of ypN+ (OR 2.66, 95% c.i. 1.18 to 6.01; P = 0.018), whilst a radiological complete response in the breast was associated with a reduced likelihood of ypN+ (OR 0.10, 95% c.i. 0.02 to 0.42; P = 0.002), regardless of molecular subtype. Only 3% of patients who had a radiological complete response in the breast were ypN+. The majority of patients (85%) with a positive sentinel node proceeded to axillary lymph node dissection and 93% had N1 disease. CONCLUSION:The rate of sentinel lymph node positivity in patients who achieve a radiological complete response in the breast is exceptionally low for all molecular subtypes.

Background:Antifungal stewardship (AFS) is the judicious use of today's antifungal agents with the aim of improving patient outcomes and preserving their future effectiveness. Antifungal resistance (AFR) is increasing globally, with more patients at risk of Invasive Fungal Disease (IFD), highlighting the urgent need to standardize AFS practices in the UK. The aim of this position paper is to understand the current AFS landscape in the UK. Methods:A virtual panel discussion was held from September to October 2023 on an online platform followed by a virtual meeting with nine healthcare professionals from across the UK selected for their expertise on IFD management and AFS. The discussion was structured across four topics: current AFS landscape, key elements of an AFS programme, diagnostics and diagnostic stewardship, and unmet needs in education and training. A thematic analysis was carried out. The results represent the collated and summarized views from these activities. Results and discussion:Participants reported barriers to implementing AFS and its integration within antimicrobial stewardship (AMS) programmes in the UK. The primary challenge identified was a lack of resources, including funding and staff time. Sub-optimal fungal diagnostics and limited mycology expertise was reported as a barrier to AFS, clinical IFD and AFR surveillance. Approaches to combatting these challenges may include investing in formal mycology networks to serve as centres of clinical expertise and diagnostic hubs. Conclusion:National standards for AFS services and associated outcome metrics need to be established to set a benchmark for centres to improve AFS.

Thyroid hormones play an important role in many metabolic processes in the human body. However, these processes can often be disrupted by an over or underactivity of the thyroid gland which, if undiagnosed or untreated, can result in serious illness. Currently, therapeutic management of an underactive thyroid gland (hypothyroidism) is typically achieved via replacement therapy with levothyroxine (LEVO), a synthetic form of thyroxine. Conversely, anti-thyroid drugs (ATDs), radioactive iodine or thyroidectomy are established approaches in treating hyperthyroidism. With respect to the route of the administration, drugs to treat hypo and hyperthyroidism can typically be administered through oral (PO), intravenous (IV), and rectal (PR) routes. Despite the fact that thyroid disorders have been successfully treated for many years, several problems still exist in the conventional treatment approach. Due to issues such as poor patient compliance and concordance, poor gastrointestinal (GI) absorption when taken incorrectly, and interactions with food and other medications, the administration of these drugs often results in sub-optimal dosing with accompanying serious illness if not corrected. Other forms of drug delivery are currently being studied to overcome the dosing complications that frequently occur with LEVO and ATDs with a view to increasing both patient compliance and bioavailability of the drugs in question. This review will examine why there remains a need for novel approaches and discuss studies that have been carried out with regards to this.

Abstract Background Improving antibiotic stewardship whilst simultaneously optimizing patient safety is a perpetually vexing clinical conundrum, which has been compounded by the current COVID-19 pandemic. Procalcitonin (PCT) measurement has previously demonstrated utility in this regard, when combined with routine clinical investigation, in certain patient populations. Objectives To assess whether the inclusion of PCT measurement as part of routine clinical care, instituted during a quality improvement project (QIP), increases the appropriateness of antibiotic administration. Methods A retrospective analysis was performed on 6 month interim data obtained from May to October 2021 during a QIP, which assessed the effect of PCT measurement on antimicrobial stewardship. All patients included had a primary diagnosis of respiratory illness and were analysed both together and as COVID-19 and non-COVID-19 subgroups to assess how often antibiotics were commenced on admission, duration of treatment and appropriateness of use. Finally, as sending microbiological samples made up part of the protocol, sample sending frequency was also studied. Results Thirty patients were included in both the COVID-19 and non-COVID-19 baseline subgroups who did not have PCT testing performed. Fifty-two patients were included in the PCT subgroup (27 COVID-19 positive and 25 COVID-19 negative). Following introduction of PCT testing, commencement of antibiotics on admission was reduced overall and in the COVID-19 positive subgroup (P = 0.0426 and P = 0.0446, respectively) with a significant decrease in inappropriate antibiotic prescribing in these two groups (P = 0.011 and P = 0.0157, respectively) and a trend towards reduced prescribing of AWaRe watch group antibiotics such as ceftriaxone. However, once prescribed, there was no difference in duration of antibiotic treatment or the frequency of microbiological sampling. Conclusions The data from this interim data analysis demonstrate that PCT measurement, when combined with routine clinical investigations in the acute respiratory setting, can be used to reduce inappropriate antibiotic prescribing. This was significantly reduced overall and in the COVID-19 positive subgroup but lost statistical significance in the COVID-19 negative subgroup, where it could be hypothesized that heterogeneity and inclusion of respiratory diseases where PCT has previously encountered difficulty in determining the presence of acute bacterial infection may be the cause. The significant effect demonstrated in the COVID-19 positive subgroup suggests particular utility in this patient population.

Since first identified in late 2019, the acute respiratory syndrome coronavirus (SARS-CoV2) and the resulting coronavirus disease (COVID-19) pandemic has overwhelmed healthcare systems worldwide, often diverting key resources in a bid to meet unprecedented challenges. To measure its impact on national antimicrobial stewardship (AMS) activities, a questionnaire was designed and disseminated to antimicrobialstewardship leads in the United Kingdom (UK). Most respondents reported a reduction in AMS activity with 64% (61/95) reporting that COVID-19 had a negative impact on routine AMS activities. Activities reported to have been negatively affected by the pandemic include audit, quality improvement initiatives, education, AMS meetings, and multidisciplinary working including ward rounds. However, positive outcomes were also identified, with technology being increasingly used as a tool to facilitate stewardship, e.g., virtual meetings and ward rounds and increased the acceptance of using procalcitonin tests to distinguish between viral and bacterial infections. The COVID-19 pandemic has had a significant impact on the AMS activities undertaken across the UK. The long-term impact of the reduced AMS activities on incidence of AMR are not yet known. The legacy of innovation, use of technology, and increased collaboration from the pandemic could strengthen AMS in the post-pandemic era and presents opportunities for further development of AMS.

Hydrogel-forming microneedle array patches (MAPs) have been proposed as viable clinical tools for patient monitoring purposes, providing an alternative to traditional methods of sample acquisition, such as venepuncture and intradermal sampling. They are also undergoing investigation in the management of non-melanoma skin cancers. In contrast to drug or vaccine delivery, when only a small number of MAP applications would be required, hydrogel MAPs utilised for sampling purposes or for tumour eradication would necessitate regular, repeat applications. Therefore, the current study was designed to address one of the key translational aspects of MAP development, namely patient safety. We demonstrate, for the first time in human volunteers, that repeat MAP application and wear does not lead to prolonged skin reactions or prolonged disruption of skin barrier function. Importantly, concentrations of specific systemic biomarkers of inflammation (C-reactive protein (CRP); tumour necrosis factor-α (TNF-α)); infection (interleukin-1β (IL-1β); allergy (immunoglobulin E (IgE)) and immunity (immunoglobulin G (IgG)) were all recorded over the course of this fixed study period. No biomarker concentrations above the normal, documented adult ranges were recorded over the course of the study, indicating that no systemic reactions had been initiated in volunteers. Building upon the results of this study, which serve to highlight the safety of our hydrogel MAP, we are actively working towards CE marking of our MAP technology as a medical device.

Nanoparticles (NPs) have undergone extensive investigation as drug delivery and targeting vehicles. NP delivery is often via the parenteral route, reliant on administration using hypodermic needles, which can be associated with patient compliance issues and safety concerns. In the recent past, the intradermal delivery of NPs, via novel dissolving microneedle (MN) arrays has garnered interest in the pharmaceutical community. However, published studies using this combinatorial approach have been limited, in that they have focussed on the use of in vitro and ex vivo models only. The current study was designed to answer the fundamental question of how such NPs are distributed in an in vivo murine model, following MN-mediated delivery. Rhodamine B (RhB) was employed as a model tracer dye to facilitate study of biodistribution. Following MN application, RhB was detected in the livers, kidneys, spleens and superficial parotid lymph nodes of the mice. Uptake into the lymphatics was of particular note, as it points towards the potential for utilisation of a minimally-invasive MN delivery strategy in controlled targeting of active drug substances and vaccines to the lymphatics. The use of such a delivery system could, following further development, have far-reaching benefits in enhancement of immunomodulatory and anti-cancer therapies. As a consequence, further investigation of MN/NP combinatorial delivery strategies is warranted.

Northern Ireland (NI) has been in a post-conflict state for over twenty years. However, injuries sustained during paramilitary Punishment Attacks (PA) remain a common hospital presentation. The aim of this study was to compare the current province-wide frequency and cost with data collected from the same unit in 1994, the end of the so called, "Troubles". A ten month retrospective emergency chart analysis from all assault and gunshot wound (GSW) attendances to the Emergency Department, Royal Victoria Hospital Belfast (RVH) in 2012 was carried out. Age, sex, injury type, treatment outcome and associated cost of PA was documented. During the study period we recorded a total of thirty two PAs. Twenty seven were the result of gunshot wounds (GSWs), while five were assaults (punishment beatings). Seventeen required admission for definitive management. Nine cases required orthopaedic intervention, two required plastic surgery, two required maxillofacial input and one case required vascular surgery. All but two of those involved were male. Mean age of individuals admitted was 27.47. Total cost of patients both admitted and managed in the Emergency Department (ED) amounted to £91,362. On comparison with 1994, there are more PA presentations. Due to changing wound characteristics and evolving management overall cost is however less.

Caffeine is the mood-altering drug that is most widely consumed in the world. It is present in many common foods, beverages and medicines. Its daily intake in moderate doses does not have adverse effects; however, daily consumption of high doses (>400 mg) can lead to dependence, the development of tolerance and, most importantly, toxic effects, representing a significant health risk. In premature neonates, caffeine is used for the treatment of apnoea and its monitoring is especially indicated if there is a suspected lack of clinical response or toxicity. Blood sampling is the current method used for caffeine monitoring, which is invasive and associated with a number of undesirable effects, such as pain, bruising, fear or risk of infection. The use of microneedles (MNs) is a minimally invasive method that has been widely exploited for drug delivery and is now gaining importance in the drug monitoring field for its capacity to sample and monitor drugs and biomarkers from the interstitial fluid without causing any bleeding or stimulating dermal nerves. MNs would benefit a large proportion of other patient cohorts but, in particular, neonates.

Purpose. The purpose of this study was to develop an alternative, more clinically relevant approach to susceptibility reporting for implant-associated infections. Using 20 staphylococcal isolates, isolated from clinical implant infections, the majority (85 %) demonstrated biofilm-forming capabilities. A significantly increased minimum biofilm eradication concentration (MBEC) compared to minimum inhibitory concentration (MIC) breakpoint was obtained, with MBEC values greater than 256 mu g ml(-1) for the majority of bacteria. Such a vast increase was also demonstrated for isolates defined as negligible biofilm formers via crystal violet staining, likely due to the high protein content of biofilms, as confirmed by proteinase-K treatment.Methodology. This study employed a variety of techniques to assess MIC and MBEC of the isolates tested. In addition, the nature of bacterial biofilm across a range of clinical isolates was investigated using crystal violet staining, sodium metaperiodate and proteinase-K treatment, and PCR analysis.Results/Key findings. Infection of medical implants is associated with increased rates of infection and increased bacterial tolerance to antibiotic strategies. Clinical significance is due to the presence of pathogens attached to biomaterial surfaces enclosed in an extracellular polymeric matrix termed the biofilm. This article highlights the importance of defining the clinical susceptibility of implant-associated infections in vitro using methods that are relevant to the biofilm phenotype in vivo, and highlights how current planktonic-based antimicrobial susceptibility tests are often misleading.Conclusion. The use of biofilm-relevant susceptibility tests would improve patient outcomes by enabling correct antimicrobial regimens to be rapidly identified, reducing treatment failure and halting the spread of antimicrobial-resistant strains.

We describe, for the first time, hydrogel-forming microneedle (s) (MN) arrays for minimally-invasive extraction and quantification of lithium in vitro and in vivo. MN arrays, prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) and crosslinked by poly(ethyleneglycol), imbibed interstitial fluid (ISF) upon skin insertion. Such MN were always removed intact. In vitro, mean detected lithium concentrations showed no significant difference following 30min MN application to excised neonatal porcine skin for lithium citrate concentrations of 0.9 and 2mmol/l. However, after 1h application, the mean lithium concentrations extracted were significantly different, being appropriately concentration-dependent. In vivo, rats were orally dosed with lithium citrate equivalent to 15mg/kg and 30mg/kg lithium carbonate, respectively. MN arrays were applied 1h after dosing and removed 1h later. The two groups, having received different doses, showed no significant difference between lithium concentrations in serum or MN. However, the higher dosed rats demonstrated a lithium concentration extracted from MN arrays equivalent to a mean increase of 22.5% compared to rats which received the lower dose. Hydrogel-forming MN clearly have potential as a minimally-invasive tool for lithium monitoring in outpatient settings. We will now focus on correlation between serum and MN lithium concentrations.

Photodynamic therapy involves delivery of a photosensitising drug that is activated by light of a specific wavelength, resulting in generation of highly reactive radicals. This activated species can cause destruction of targeted cells. Application of this process for treatment of microbial infections has been termed “photodynamic antimicrobial chemotherapy” (PACT). In the treatment of chronic wounds, the delivery of photosensitising agents is often impeded by the presence of a thick hyperkeratotic/necrotic tissue layer, reducing their therapeutic efficacy. Microneedles (MNs) are an emerging drug delivery technology that have been demonstrated to successfully penetrate the outer layers of the skin, whilst minimising damage to skin barrier function. Delivering photosensitising drugs using this platform has been demonstrated to have several advantages over conventional photodynamic therapy, such as, painless application, reduced erythema, enhanced cosmetic results and improved intradermal delivery. The aim of this study was to physically characterise dissolving MNs loaded with the photosensitising agent, methylene blue and assess their photodynamic antimicrobial activity. Dissolving MNs were fabricated from aqueous blends of Gantrez® AN-139 co-polymer containing varying loadings of methylene blue. A height reduction of 29.8% was observed for MNs prepared from blends containing 0.5% w/w methylene blue following application of a total force of 70.56 N/array. A previously validated insertion test was used to assess the effect of drug loading on MN insertion into a wound model. Staphylococcus aureus, Escherichia coli and Candida albicans biofilms were incubated with various methylene blue concentrations within the range delivered by MNs in vitro (0.1–2.5 mg/mL) and either irradiated at 635 nm using a Paterson Lamp or subjected to a dark period. Microbial susceptibility to PACT was determined by assessing the total viable count. Kill rates of >96%, were achieved for S. aureus and >99% for E. coli and C. albicans with the combination of PACT and methylene blue concentrations between 0.1 and 2.5 mg/mL. A reduction in the colony count was also observed when incorporating the photosensitiser without irradiation, this reduction was more notable in S. aureus and E. coli strains than in C. albicans.

We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) (11.1% w/w) and poly(ethyleneglycol) 10,000 daltons (5.6% w/w) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min) analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration extracted from MN was 4.29 nmol/L, detected after 3 hours skin insertion in human volunteers. Whilst not directly correlated, concentrations extracted from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clinical insertion times and develop mathematical algorithms enabling determination of blood levels directly from MN measurements.

1A microwave (MW)-assisted crosslinking process to prepare hydrogel-forming microneedle (MN) arrays was evaluated. Conventionally, such MN arrays are prepared using processes that includes a thermal crosslinking step. Polymeric MN arrays were prepared using poly(methyl vinyl ether-alt-maleic acid) crosslinked by reaction with poly(ethylene glycol) over 24 h at 80 °C. Polymeric MN arrays were prepared to compare conventional process with the novel MW-assisted crosslinking method. Infrared spectroscopy was used to evaluate the crosslinking degree, evaluating the area of the carbonyl peaks (2000-1500 cm-1). It was shown that, by using the MW-assisted process, MN with a similar crosslinking degree to those prepared conventionally can be obtained in only 45 min. The effects of the crosslinking process on the properties of these materials were also evaluated. For this purpose swelling kinetics, mechanical characterisation, and insertion studies were performed. The results suggest that MN arrays prepared using the MW assisted process had equivalent properties to those prepared conventionally but can be produced 30 times faster. Finally, an in vitro caffeine permeation across excised porcine skin was performed using conventional and MW-prepared MN arrays. The release profiles obtained can be considered equivalent, delivering in both cases 3000-3500 μg of caffeine after 24 h.

Front Cover: Microwave radiation is used to crosslink poly(methyl vinyl ether-alt-maleic acid) and poly(ethylene glycol) mixtures yielding hydrogels. The crosslinking process is implemented in the production of hydrogel-forming microneedle arrays for transdermal drug delivery. The cover shows the crosslinking reaction between the two polymers and the transdermal permeation mechanism of the resulting hydrogel-forming microneedle arrays after skin insertion. Further details can be found in the article by E. Larrañeta, R. E. M. Lutton, A. J. Brady, E. M. Vicente-Pérez, A. D. Woolfson, R. R. S. Thakur, and R. F. Donnelly* on page 586.

Photodynamic therapy can be used in the treatment of pre-malignant and malignant diseases. It offers advantages over other therapies currently used in the treatment of skin lesions including avoidance of damage to surrounding tissue and minimal or no scarring. Unfortunately, systemic delivery of photosensitising agents can result in adverse effects, such as prolonged cutaneous photosensitivity; while topical administration lacks efficacy in the clearance of deeper skin lesions and those with a thick overlying keratotic layer. Therefore, enhancement of conventional photosensitiser delivery is desired. However, the physicochemical properties of photosensitising agents, such as extreme hydrophilicity or lipophilicity and large molecular weights make this challenging. This paper reviews the potential of microneedles as a viable method to overcome these delivery-limiting physicochemical characteristics and discusses the current benefits and limitations of solid, dissolving and hydrogel-forming microneedles. Clinical studies in which microneedles have successfully improved photodynamic therapy are also discussed, along with benefits which microneedles offer, such as precise photosensitiser localisation, painless application and reduction in waiting times between photosensitiser administration and irradiation highlighted.

OBJECTIVE:This study aimed to investigate antimicrobial treatment of an infected cochlear implant, undertaken in an attempt to salvage the infected device.METHODS:We used the broth microdilution method to assess the susceptibility of meticillin-sensitive Staphylococcus aureus isolate, cultured from an infected cochlear implant, to common antimicrobial agents as well as to novel agents such as tea tree oil. To better simulate in vivo conditions, where bacteria grow as microcolonies encased in glycocalyx, the bactericidal activity of selected antimicrobial agents against the isolate growing in biofilm were also compared.RESULTS:When grown planktonically, the S aureus isolate was susceptible to 17 of the 18 antimicrobials tested. However, when grown in biofilm, it was resistant to all conventional antimicrobials. In contrast, 5 per cent tea tree oil completely eradicated the biofilm following exposure for 1 hour.CONCLUSION:Treatment of infected cochlear implants with novel agents such as tea tree oil could significantly improve salvage outcome.