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Systemic sclerosis is an autoimmune disorder which frequently affects the gastrointestinal tract. Anorectal dysfunction is common in systemic sclerosis and is manifested mainly by atrophy of internal anal sphincter. Faecal incontinence is the result of internal anal sphincter atrophy secondary to systemic sclerosis. In this study, we aimed to assess the internal anal sphincter in 17 patients with faecal incontinence and systemic sclerosis using anorectal manometry and endoanal ultrasound and compare them with an age and gender-matched control group without systemic sclerosis. Most patients have limited cutaneous systemic sclerosis. Majority of the patients with systemic sclerosis and faecal incontinence presented with symptoms of faecal leakage and urgency. Systemic sclerosis patients had low basal sphincter pressures. The mean thickness of internal anal sphincter in systemic sclerosis group was significantly lower than the control group (p < 0.001). Rectal sensation is preserved in systemic sclerosis. There was no difference in the mean thickness of the external anal sphincter between the two groups. To conclude internal anal sphincter is atrophic in systemic sclerosis resulting in decreased resting sphincter pressures and passive faecal leakage. Further investigations and studies are needed to determine the natural course of faecal incontinence in systemic sclerosis, associated risk factors and efficacy of therapeutic interventions., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

Background: For many patients with lung disease the only proven intervention to improve survival and quality of life is lung transplantation (LTx). Esophageal dysmotility and gastroesophageal reflux (GER) are common in patients with respiratory disease, and often associate with worse prognosis following LTx. Which, if any patients, should be excluded from LTx based on esophageal concerns remains unclear. Our aim was to understand the effect of LTx on esophageal motility diagnosis and examine how this and the other physiological and mechanical factors relate to GER and clearance of boluses swallowed., Methods: We prospectively recruited 62 patients with restrictive (RLD) and obstructive (OLD) lung disease (aged 33-75 years; 42 men) who underwent high resolution impedance manometry and 24-h pH-impedance before and after LTx., Key Results: RLD patients with normal motility were more likely to remain normal (p = 0.02), or if having abnormal motility to change to normal (p = 0.07) post-LTx than OLD patients. Esophageal length (EL) was greater in OLD than RLD patients' pre-LTx (p < 0.001), reducing only in OLD patients' post-LTx (p = 0.02). Reduced EL post-LTx associated with greater contractile reserve (r = 0.735; p = 0.01) and increased likelihood of motility normalization (p = 0.10). Clearance of reflux improved (p = 0.01) and associated with increased mean nocturnal baseline impedance (p < 0.001) in RLD but not OLD. Peristaltic breaks and thoraco-abdominal pressure gradient impact both esophageal clearance of reflux and boluses swallowed (p < 0.05)., Conclusions and Inferences: RLD patients are more likely to show improvement in esophageal motility than OLD patients post-LTx. However, the effect on GER is more difficult to predict and requires other GI, anatomical and pulmonary factors to be taken into consideration., (© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: Interest in using primary care data for research is growing with increasing recognition of its potential for improving healthcare. Many issues exist, some inherent in the data and others external., Objective: This paper explores the main issues associated with the use of primary care data for research and proposed solutions to address them., Discussion: Issues related to the use of primary care data for research are complex. Government reimbursement system administrative data have limitations as they lack clinical detail. General practice electronic medical record data are more suitable; however, challenges include variable data quality and interoperability. There are concerns from general practices and the public about data access and use. Strategies to address these issues include incorporating best-practice principles, implementing standards and data quality frameworks, creating partnerships between data custodians and ensuring robust governance systems exist. Leadership and the will of key stakeholders to reform, with governmental support in implementing required actions, must be prioritised.

Background: Pharmacists routinely interpret and optimize tobramycin dosing for people with cystic fibrosis (PwCF)., Objectives: To determine the impact of tobramycin therapeutic drug monitoring (TDM) education on pharmacist dose recommendations, and to explore nurses' and medical doctors' perceptions toward pharmacist-led TDM charting., Methods: This study involved 3 phases: a 12-month retrospective audit of PwCF prescribed tobramycin to identify the appropriateness of pharmacists' dose recommendations, a pharmacist tobramycin educational intervention utilizing a voiceover presentation with pre- and post-online tobramycin TDM assessment (involving multiple choice pharmacokinetics and case-based scenario questions), and a cross-sectional survey of respiratory nurses' and doctors' perceptions toward pharmacist-led TDM charting. The pharmacists' dose recommendations, in the audit and case-based questions, were considered appropriate if subsequent levels achieved the targeted area under the curve (AUC)., Results: Audit results revealed that 44.4% of the 277 pharmacist dose recommendations identified were appropriate. The pre- and post-interventional assessments were completed by 51 and 52 pharmacists, respectively. Post intervention, correct scores were significantly higher than pre-intervention, evident in both the pharmacokinetics (median score 75% vs 100%; P = 0.048) and case-based scenario (median score 60% vs 90%; P < 0.0001) questions. Of the 54 nurses and medical doctors surveyed, 92.6% supported the implementation of pharmacist-led tobramycin charting., Conclusion: The study demonstrated an increased accuracy and appropriateness of pharmacists' tobramycin pharmacokinetics knowledge and TDM dose recommendations post-educational intervention and highlighted nurses' and medical doctors' support of pharmacist-led tobramycin TDM charting.

Background: Fibrinogen is an abundant plasma protein with an essential role in blood coagulation and haemostasis thus receiving significant research interest. However, protein purification is time consuming and commercial preparations often have protein contaminants. The aim of this study was to develop a new method to purify high quality and functional fibrinogen., Methods: Fibrinogen-specific Affimer protein, isolated using phage display systems, was immobilised to SulfoLink resin column and employed for fibrinogen purification from plasma samples. Fibrinogen was eluted using a high pH solution. Commercial human fibrinogen was also further purified using the Affimer column. Fibrinogen purity was determined by SDS-PAGE and mass spectrometry, while functionality was assessed using turbidimetric analysis., Results: Affimer-purified fibrinogen from human plasma showed purity at least comparable to commercially available preparations and was able to form physiological fibrin networks. Further purification of commercially available fibrinogen using the Affimercolumn eliminated multiple contaminant proteins, a significant number of which are key elements of the coagulation cascade, including plasminogen and factor XIII., Conclusions: The Affimercolumn represents a proof of concept novel, rapid method for isolating functional fibrinogen from plasma and for further purification of commercially available fibrinogen preparations., General Significance: Our methodology provides an efficient way of purifying functional fibrinogen with superior purity without the need of expensive pieces of equipment or the use of harsh conditions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Objectives: Australia has relatively high rates of antibiotic prescribing in the community. The aim of this study was to identify clinical insights regarding antibiotic prescribing choices for the management of common upper respiratory tract infections through analysis of anonymised primary care electronic medical records (EMRs)., Method: EMR data relating to 1926 antimicrobial prescriptions for tonsillitis, pharyngitis and acute rhinosinusitis in adults and acute otitis media (AOM) in children were extracted from 11 general practices in Victoria and analysed for consistency with Australian Therapeutic Guidelines recommendations., Results: The analysis suggests that underdosing of amoxicillin for AOM in children, prescription of phenoxymethylpenicillin at doses not consistent with Therapeutic Guidelines recommendations for tonsillitis and pharyngitis in adults, and potential overprescription of antibiotics for patients with acute rhinosinusitis are not infrequent in general practice., Discussion: Anonymised EMR data provide an opportunity to analyse antibiotic prescribing practices at scale and provide insights relevant to clinical practice.

Background: Australian residential aged care facilities (RACFs) are encouraged to participate in an annual Aged Care National Antimicrobial Prescribing Survey. This data source was analysed to describe patterns of topical antimicrobial prescribing and thereby provide insight into antimicrobial stewardship (AMS) changes that might be required., Methods: 2018 and 2019 survey data was analysed., Results: The overall prevalence of the 52,431 audited residents (629 facilities) who were prescribed 1 or more topical antimicrobials was 2.9%. Of all prescribed antimicrobials (n=4899), 33.0% were for topical application. Most frequently prescribed topical antifungals were clotrimazole (85.3%) and miconazole (9.1%), and antibacterials chloramphenicol (64.1%) and mupirocin (21.8%). Tinea (38.3%) and conjunctivitis (23.8%) were the 2 most common indications. Topical antimicrobials were sometimes prescribed for pro re nata administration (38.8%) and greater than 6 months (11.3%). The review or stop date was not always documented (38.7%)., Conclusions: To reduce the possibility of adverse consequences associated with antimicrobial use, antimicrobial stewardship programs in Australian residential aged care facilities should at least ensure mupirocin is appropriately used, first line antimicrobial therapy is prescribed for tinea, chloramphenicol is prescribed for conjunctivitis only if necessary, pro re nata orders for prescriptions are discouraged and to avoid prolonged duration of prescriptions, review or stop dates are always documented., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Inappropriate antimicrobial prescribing contributes to increasing antimicrobial resistance. An antimicrobial stewardship (AMS) program in the form of quality improvement activities that included audit and feedback, clinical decision support and education was developed to help optimise prescribing in general practice. The aim of this study was to evaluate the implementation of this program (Guidance GP) in three general practices in Melbourne, Australia, between November 2019 and August 2020. Thirty-one general practitioners (GPs) participated in the program, with 11 GPs and three practice managers participating in follow-up focus groups and interviews to explore the acceptability and feasibility of the program. Our findings showed that the quality improvement activities were acceptable to GPs, if they accurately fit GPs' decision-making process and workflow. It was also important that they provided clinically meaningful information in the form of audit and feedback to GPs. The time needed to coordinate the program, and costs to implement the program were some of the potential barriers identified. Facilitators of success were a "whole of practice" approach with enthusiastic GPs and practice staff, and an identified practice champion. The findings of this research will inform implementation strategies for both the Guidance GP program and AMS programs more broadly in Australian general practice, which will be critical for general practice participation and engagement.

Introduction: Gastroesophageal reflux plays a significant role in idiopathic pulmonary fibrosis (IPF). Given the morbidity and mortality associated with IPF, understanding the mechanisms responsible for reflux is essential if patients are to receive optimal treatment and management, especially given the lack of clear benefit of antireflux therapies. Our aim was to understand the inter-relationships between esophageal motility, lung mechanics and reflux (particularly proximal reflux-a prerequisite of aspiration), and pulmonary function in patients with IPF., Methods: We prospectively recruited 35 patients with IPF (aged 53-75 years; 27 men) who underwent high-resolution impedance manometry and 24-hour pH-impedance, together with pulmonary function assessment., Results: Twenty-two patients (63%) exhibited dysmotility, 16 (73%) exhibited ineffective esophageal motility (IEM), and 6 (27%) exhibited esophagogastric junction outflow obstruction. Patients with IEM had more severe pulmonary disease (% forced vital capacity: P = 0.032) and more proximal reflux (P = 0.074) than patients with normal motility. In patients with IEM, intrathoracic pressure inversely correlated with the number of proximal events (r = -0.429; P = 0.098). Surprisingly, inspiratory lower esophageal sphincter pressure (LESP) positively correlated with the percentage of reflux events reaching the proximal esophagus (r = 0.583; P = 0.018), whereas in patients with normal motility, it inversely correlated with the bolus exposure time (r = -0.478; P = 0.098) and number of proximal events (r = -0.542; P = 0.056). % forced vital capacity in patients with IEM inversely correlated with the percentage of reflux events reaching the proximal esophagus (r = -0.520; P = 0.039) and inspiratory LESP (r = -0.477; P = 0.062) and positively correlated with intrathoracic pressure (r = 0.633; P = 0.008)., Discussion: We have shown that pulmonary function is worse in patients with IEM which is associated with more proximal reflux events, the latter correlating with lower intrathoracic pressures and higher LESPs., (Copyright © 2021 by The American College of Gastroenterology.)

The pharmacist's role in hospital antimicrobial stewardship (AMS) programs is known to improve patient safety and the quality of care. Despite this, many Australian hospitals struggle to provide adequate pharmacy AMS program resourcing and need to explore newer models of care. The Pharmacy Board of Australia's Guidelines for Dispensing Medicines permit suitably qualified, competent and experienced pharmacy technicians to assist pharmacists in 'tasks in a pharmacy department'. The pharmacy technician workforce is expanding, and there is growing interest in career advancement and expansion of the pharmacy technician role. We propose that the pharmacy technician, a well-integrated member of many Australian hospital pharmacy departments, can play an important role in hospital AMS programs. To bolster AMS initiatives in Australian hospitals, this paper explores the existing evidence for pharmacy technicians in AMS programs and describes how this role may be better supported in Australia.

Background: Though the management of malignancies has improved vastly in recent years, many treatment options lack the desired efficacy and fail to adequately augment patient morbidity and mortality. It is increasingly clear that patient response to therapy is unique to each individual, necessitating personalised, or 'precision' medical care. This demand extends to thyroid cancer; ~ 10% patients fail to respond to radioiodine treatment due to loss of phenotypic differentiation, exposing the patient to unnecessary ionising radiation, as well as delaying treatment with alternative therapies., Methods: Human thyroid tissue (n = 23, malignant and benign) was live-sliced (5 mm diameter × 350-500 μm thickness) then analysed or incorporated into a microfluidic culture device for 96 h (37 °C). Successful maintenance of tissue was verified by histological (H&E), flow cytometric propidium iodide or trypan blue uptake, immunohistochemical (Ki67 detection/ BrdU incorporation) and functional analysis (thyroxine [T4] output) in addition to analysis of culture effluent for the cell death markers lactate dehydrogenase (LDH) and dead-cell protease (DCP). Apoptosis was investigated by Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Differentiation was assessed by evaluation of thyroid transcription factor (TTF1) and sodium iodide symporter (NIS) expression (western blotting)., Results: Maintenance of gross tissue architecture was observed. Analysis of dissociated primary thyroid cells using flow cytometry both prior to and post culture demonstrated no significant change in the proportion of viable cells. LDH and DCP release from on-chip thyroid tissue indicated that after an initial raised level of release, signifying cellular damage, detectable levels dropped markedly. A significant increase in apoptosis (p < 0.01) was observed after tissue was perfused with etoposide and JNK inhibitor, but not in control tissue incubated for the same time period. No significant difference in Ki-67 positivity or TTF1/NIS expression was detected between fresh and post-culture thyroid tissue samples, moreover BrdU positive nuclei indicated on-chip cellular proliferation. Cultured thyroid explants were functionally viable as determined by production of T4 throughout the culture period., Conclusions: The described microfluidic platform can maintain the viability of thyroid tissue slices ex vivo for a minimum of four days, providing a platform for the assessment of thyroid tissue radioiodine sensitivity/adjuvant therapies in real time.

Bleeding complications secondary to surgery, trauma, or coagulation disorders are important causes of morbidity and mortality. Although fibrin sealants are considered to minimize blood loss, this is not widely adopted because of its high cost and/or risk for infection. We present a novel methodology employing nonantibody fibrinogen-binding proteins, termed Affimers, to stabilize fibrin networks with the potential to control excessive bleeding. Two fibrinogen-specific Affimer proteins, F5 and G2, were identified and characterized for their effects on clot structure/fibrinolysis, using turbidimetric and permeation analyses and confocal and electron microscopy. Binding studies and molecular modeling identified interaction sites, whereas plasmin generation assays determined effects on plasminogen activation. In human plasma, F5 and G2 prolonged clot lysis time from 9.8 ± 1.1 minutes in the absence of Affimers to 172.6 ± 7.4 and more than 180 minutes ( P < .0001), respectively, and from 7.6 ± 0.2 to 28.7 ± 5.8 ( P < .05) and 149.3 ± 9.7 ( P < .0001) minutes in clots made from purified fibrinogen. Prolongation in fibrinolysis was consistent across plasma samples from healthy control patients and individuals at high bleeding risk. F5 and G2 had a differential effect on clot structure and G2 profoundly altered fibrin fiber arrangement, whereas F5 maintained physiological clot structure. Affimer F5 reduced fibrin-dependent plasmin generation and was predicted to bind fibrinogen D fragment close to tissue plasminogen activator (tPA; residues γ312-324) and plasminogen (α148-160) binding sites, thus interfering with tPA-plasminogen interaction and representing 1 potential mechanism for modulation of fibrinolysis. Our Affimer proteins provide a novel methodology for stabilizing fibrin networks with potential future clinical implications to reduce bleeding risk., (© 2019 by The American Society of Hematology.)

Radiotherapy is the standard treatment for head and neck squamous cell carcinoma (HNSCC), however, radioresistance remains a major clinical problem despite significant improvements in treatment protocols. Therapeutic outcome could potentially be improved if a patient's tumour response to irradiation could be predicted ex vivo before clinical application. The present study employed a bespoke microfluidic device to maintain HNSCC tissue whilst subjecting it to external beam irradiation and measured the responses using a panel of cell death and proliferation markers. HNSCC biopsies from five newly-presenting patients [2 lymph node (LN); 3 primary tumour (PT)] were divided into parallel microfluidic devices and replicates of each tumour were subjected to single-dose irradiation (0, 5, 10, 15 and 20 Gy). Lactate dehydrogenase (LDH) release was measured and tissue sections were stained for cytokeratin (CK), cleaved-CK18 (cCK18), phosphorylated-H2AX (γH2AX) and Ki‑67 by immunohistochemistry. In addition, fragmented DNA was detected using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Compared with non‑irradiated controls, higher irradiation doses resulted in elevated CK18-labelling index in two lymph nodes [15 Gy; 34.8% on LN1 and 31.7% on LN2 (p=0.006)] and a single laryngeal primary tumour (20 Gy; 31.5%; p=0.014). Significantly higher levels of DNA fragmentation were also detected in both lymph node samples and one primary tumour but at varying doses of irradiation, i.e., LN1 (20 Gy; 27.6%; p=0.047), LN2 (15 Gy; 15.3%; p=0.038) and PT3 (10 Gy; 35.2%; p=0.01). The γH2AX expression was raised but not significantly in the majority of samples. The percentage of Ki‑67 positive nuclei reduced dose-dependently following irradiation. In contrast no significant difference in LDH release was observed between irradiated groups and controls. There is clear inter- and intra-patient variability in response to irradiation when measuring a variety of parameters, which offers the potential for the approach to provide clinically valuable information.