Safety and feasibility of hyperthermic intraperitoneal chemotherapy during interval cytoreductive surgery in patients with advanced high-grade serous ovarian, fallopian tube, peritoneal cancer in an Australian context.

AIMS: To assess the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreduction surgery (CRS) in advanced high-grade serous ovarian, fallopian tube and peritoneal cancer within an Australian context. METHODS: Data were collected from 25 consecutive patients undergoing CRS and HIPEC from December 2018 to July 2022 at the Peritoneal Malignancy Service at the Mater Hospital Brisbane, Australia. Data collected included demographics, clinical variables, surgical procedures and complications and intra-operative and post-operative indexes of morbidity. RESULTS: Twenty-five women who underwent CRS and HIPEC from December 2018 to July 2022 were included in analysis. Findings indicate that CRS with HIPEC is associated with low morbidity. CONCLUSION: While judicious patient selection is imperative, HIPEC during CRS was well tolerated by all patients and morbidity was comparable to results from the previously reported OVHIPEC-1 trial. HIPEC appears to be a safe and feasible addition to CRS for the treatment of advanced ovarian cancer in Australian practice.

Triple Threat: Three Primary Malignancies Simultaneously Involving Three Genitourinary Organs.

Statistically, the chance of having concurrent renal cell carcinoma (RCC), urothelial carcinoma of the bladder (UC), and a neuroendocrine tumor (NET) of the renal parenchyma is less than one in a trillion. Herein, we describe an unusual case of a 67-year-old female who presented with bilateral flank pain and severe gross hematuria. Cross-sectional imaging revealed two large heterogeneous, endophytic renal masses with a single enlarged paracaval lymph node. Diagnostic cystoscopy was performed for completion of gross hematuria evaluation and revealed a concurrent papillary bladder tumor. Percutaneous biopsies of bilateral renal masses revealed clear cell RCC involving the left kidney and well-differentiated NET involving the right kidney, and transurethral resection of the bladder tumor revealed high-grade nonmuscle invasive urothelial carcinoma. The patient elected to undergo bilateral nephroureterectomy, radical cystectomy, and retroperitoneal and pelvic lymphadenectomy. Final pathology confirmed the presence of three different malignancies: noninvasive high-grade papillary UC of the bladder (pTaN0), left renal clear cell RCC (pT2bN0), right renal well-differentiated NET, and a single paracaval lymph nodes positive for metastatic NET (pT2aN1).

A single-centre retrospective case series of Anakinra for incident calcium pyrophosphate deposition disease.

In this 2-year retrospective case series, we characterise the calcium pyrophosphate deposition disease (CPPD) inpatient cohort at a single centre and assess the efficacy and safety of anakinra in its treatment. Adult inpatients with CPPD between 1st September 2020 and 30th September 2022 were identified by ICD-10 codes and confirmed based on clinical diagnosis and either CPP crystals on aspirate or chondrocalcinosis on imaging. Charts were reviewed for demographic, clinical, biochemical data, treatment choice, and response. Response to treatment was determined from chart documentation and calculated from time of first CPPD treatment. Daily responses to anakinra were recorded if anakinra was used. Seventy patients accounting for 79 cases of CPPD were identified. Twelve cases received anakinra, whilst 67 cases received conventional therapy only. Patient receiving anakinra were predominantly male, had multiple comorbidities, and had higher CRPs and serum creatinine when compared to the non-anakinra group. Anakinra was rapidly effective with the mean time to substantial and complete response being 1.7 and 3.6 days respectively. Anakinra was well tolerated. This study adds to the small amount of retrospective data present about the use of anakinra in CPPD. We observed a rapid response to anakinra in our cohort with minimal adverse drug reactions. Key Points • Treatment of CPPD with anakinra appears to be rapidly efficacious without safety concerns.

Representation Rate and Management of Gout for Patients Discharged From Emergency Departments in Illawarra Shoalhaven Local Health District.

Introduction: The estimated prevalence of gout in Western societies is 2.7% to 6.7%. In Australia, there have been increasing rates of hospitalisations for gout flares. Urate-lowering therapy (ULT) is effective in reducing urate burden, which can prevent gout flares and destructive arthropathy. This study assessed the representation rate of patients presenting to the Emergency Department (ED) with crystal arthropathy and the utilisation of ULT in the community for patients with a pre-existing history of gout. Methods: A retrospective review of electronic records of patients presenting to the ED from the Illawarra Shoalhaven Local Health District was performed. Patients included were coded as per the 10th revision of the International Classification of Diseases coding for crystal arthropathy. Results: In all, 18.8% of all crystal arthropathy encounters to the ED were repeat presentations. Of the 70% of patients with a history of gout, only 30.8% were on ULT. Discussion: Despite evidence-based recommendations for a 'treat-to-target' approach, most patients with a previous history of gout were not on ULT. One in five encounters were re-presentations for crystal arthropathy. Effective adherence to treatment guidelines may reduce the number of repeat encounters for gout flare in the ED.

Incidence of urinary ketosis and the effect of carbohydrate drink supplementation during fasting for elective caesarean section: Audit.

Elective lower segment caesarean section patients are routinely instructed to fast from food for 6h before surgery, with clear fluids up until 2h before surgery. We conducted an audit examining the true fasting times of mothers undergoing an elective caesarean section and the incidence of urinary ketones before and after introducing a preop carbohydrate drink (Nutricia preOp 400ml) to be administered to all patients at 6am on the day of surgery. We audited 50 patients prior to introducing the preop carbohydrate drink and 54 patients after the introduction of a carbohydrate drink. We found the mean fasting time from last caloric intake was reduced from 13h 35min to 5h 5min after the introduction of a preoperative carbohydrate drink. We found that the incidence of urinary ketones was 40.4% prior to the introduction of a preoperative carbohydrate drink and 38.3% after the introduction of a preop drink (p = 1). If fasting times were limited to under 4h, the incidence of urinary ketones is 10%. Our audit demonstrates that reducing preoperative fasting times is possible and preventing metabolic derangements may be possible, requiring an approach targeted at keeping fasting times to a minimum.

Development and Validation of a Visual Symptom-Specific Patient-Reported Outcomes Instrument for Adults With Cataract Intraocular Lens Implants.

PURPOSE: To develop a patient-reported outcome measure for capturing visual and ocular symptoms before and after implantation of intraocular lenses (IOLs) for treatment of cataracts. DESIGN: Questionnaire development and validation study. METHODS: The Questionnaire for Visual Disturbances (QUVID) was developed based on a literature and instrument review; 13 clinician interviews among ophthalmologists in the United States and Europe; and 67 hybrid qualitative patient interviews among adult patients in the United States and Australia before and/or after monofocal, traditional multifocal, or trifocal IOL implantation. Assessment of the QUVID's psychometric properties was conducted via a noninterventional cross-sectional study of previously treated cataract patients in the United States, Canada, and Australia (n = 150), and assessment of ability to detect meaningful change via 2 pivotal US clinical trials among patients with trifocal or extended vision IOL compared with monofocal IOL controls (n = 457). RESULTS: The QUVID includes subitems about the bothersomeness of 7 visual symptoms: starburst, halo, glare, hazy vision, blurred vision, double vision, and dark areas. The postoperative version contains 1 item asking the respondents whether their symptoms bothered them enough to want another surgery, if the IOL was the cause. CONCLUSIONS: The QUVID was reviewed by the US Food and Drug Administration and found appropriate as a fit-for-purpose measure, demonstrating requisite evidence for content validity, construct validity, reliability, and ability to detect change.

Giant Cell Arteritis Presenting as Cholestatic Hepatitis.

BACKGROUND: Severely deranged liver function tests (LFTs) are an atypical presentation of giant cell arteritis (GCA). Atypical presentations of GCA may result in missed or delayed diagnosis. This increases the risk of visual loss, the most feared outcome of GCA. Our patient presented with significant cholestatic derangement of his LFTs with a peak alkaline phosphatase level (ALP) of 3091 IU/L, which is the highest published level for patients with GCA. Case Presentation. Our patient was investigated for abnormal LFTs associated with sinus pain, fevers, and a dry cough. Bilateral temporal artery biopsies confirmed GCA. His symptoms and LFTs improved with corticosteroids. CONCLUSION: This is an unusual presentation of GCA and highlights the need to consider GCA in patients with unexplained cholestatic LFT abnormalities.

Fabrication and characterization of mechanically competent 3D printed polycaprolactone-reduced graphene oxide scaffolds.

The ability to produce constructs with a high control over the bulk geometry and internal architecture has situated 3D printing as an attractive fabrication technique for scaffolds. Various designs and inks are actively investigated to prepare scaffolds for different tissues. In this work, we prepared 3D printed composite scaffolds comprising polycaprolactone (PCL) and various amounts of reduced graphene oxide (rGO) at 0.5, 1, and 3 wt.%. We employed a two-step fabrication process to ensure an even mixture and distribution of the rGO sheets within the PCL matrix. The inks were prepared by creating composite PCL-rGO films through solvent evaporation casting that were subsequently fed into the 3D printer for extrusion. The resultant scaffolds were seamlessly integrated, and 3D printed with high fidelity and consistency across all groups. This, together with the homogeneous dispersion of the rGO sheets within the polymer matrix, significantly improved the compressive strength and stiffness by 185% and 150%, respectively, at 0.5 wt.% rGO inclusion. The in vitro response of the scaffolds was assessed using human adipose-derived stem cells. All scaffolds were cytocompatible and supported cell growth and viability. These mechanically reinforced and biologically compatible 3D printed PCL-rGO scaffolds are a promising platform for regenerative engineering applications.

Domain-interface dynamics of CFTR revealed by stabilizing nanobodies.

The leading cause of cystic fibrosis (CF) is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation affects the thermodynamic stability of the domain and the integrity of the interface between NBD1 and the transmembrane domain leading to its clearance by the quality control system. Here, we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein. Crystal structures of NBD1-nanobody complexes provide an atomic description of the epitopes and reveal the molecular basis for stabilization. Furthermore, our data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures. This unexpected interface rearrangement is likely to have major relevance for CF pathogenesis but also for the normal function of CFTR and other ABC proteins.

Licking microstructure and hedonic changes after flavour preference learning in rats.

Pairing a neutral flavour conditioned stimulus (CS) with a nutrient reward will create a learned preference for that CS. Prior studies suggest that this is accompanied by an increase in the hedonic value of the CS, although the reliability of this effect is yet to be fully established. Here, flavour CS+s were mixed with either 16% sucrose or maltodextrin (with control CS-s mixed with 2% solutions of the same carbohydrate). While a reliable preference for the CS+ was seen in every case, and there was a learned increase in lick cluster size when all conditions were considered together, this difference was significant in only one experimental condition considered alone. A meta-analysis of these results and similar published licking microstructure analysis studies found that the Cohen's dav effect size for changes in licking microstructure after flavour preference learning was 0.16. This is far smaller than the effect sizes reported when assessing learned hedonic changes in flavour preference based on other test or training methods. Although this confirms that flavour preference learning produces hedonic changes in the cue flavours, the analysis of licking microstructure with training based on voluntary consumption of CS and unconditioned stimulus (US) compounds may be an insensitive means of assessing such effects.

Does a Provider in Triage and Rapid Medical Evaluation Help With Left Without Being Seen Rates and ED Crowding?

INTRODUCTION: Attempting to reduce ED crowding, the ED team at a rural academic medical center and specialty hospital implemented rapid medical evaluation (RME) with and without a provider in triage (PIT). The purpose of this performance improvement project was to explore how these interventions affected crowding metrics of door-to-disposition time, ED length of stay (LOS), and left without being seen (LWBS) rates for all patients. METHODS: Using a prospective 2-group design, the pre-RME population served as the historical control group, and postintervention groups included both RME with and without PIT. Group comparisons of crowding metrics included pre- and post-RME with and without PIT. RESULTS: There were no statistically significant differences in any of the crowding metrics for the emergency severity index (ESI) 3 groups pre- or post-RME. However, mean door-to-disposition times for the post-RME ESI 5 population were shorter compared with the pre-RME ESI 5 patients (2:59:23 vs. 2:00: 42; P = 0.037). Analysis of the post-RME population with and without PIT did not demonstrate significant differences across ESI 3 or 5 groups. Comparisons of post-RME data revealed a significant increase in ED LOS for all admitted patients regardless of their ESI (P = 0.023) and also door-to-disposition times for ESI level-4 patient groups, both with and without PIT (P = 0.022). IMPLICATIONS FOR PRACTICE: The findings support other studies demonstrating that RME can have positive impact on ED crowding metrics for some patients. Although PIT took longer for some patients, anecdotal findings revealed benefits related to direct discharges and admission occurring during the RME process.

Cryo-EM Visualization of an Active High Open Probability CFTR Anion Channel.

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, crucial to epithelial salt and water homeostasis, and defective due to mutations in its gene in patients with cystic fibrosis, is a unique member of the large family of ATP-binding cassette transport proteins. Regulation of CFTR channel activity is stringently controlled by phosphorylation and nucleotide binding. Structural changes that underlie transitions between active and inactive functional states are not yet fully understood. Indeed the first 3D structures of dephosphorylated, ATP-free, and phosphorylated ATP-bound states were only recently reported. Here we have determined the structure of inactive and active states of a thermally stabilized CFTR, the latter with a very high channel open probability, confirmed after reconstitution into proteoliposomes. These structures, obtained at nominal resolution of 4.3 and 6.6 Å, reveal a unique repositioning of the transmembrane helices and regulatory domain density that provide insights into the structural transition between active and inactive functional states of CFTR. Moreover, we observe an extracellular vestibule that may provide anion access to the pore due to the conformation of transmembrane helices 7 and 8 that differs from the previous orthologue CFTR structures. In conclusion, our work contributes detailed structural information on an active, open state of the CFTR anion channel.

A Practical Approach to the Use of Conventional Synthetic, Biologic and Targeted Synthetic Disease Modifying Anti-Rheumatic Drugs for the Treatment of Inflammatory Arthritis in Patients with a History of Malignancy.

PURPOSE OF REVIEW: Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) have been used in the treatment of inflammatory arthritis (IA) for many years. More recently, biologic (bDMARDs) and targeted synthetic (tsDMARDs) DMARDs have further improved treatment. Due to increased patient longevity and effective oncology treatment, rheumatologists often encounter patients with IA and previous malignancy. The immunosuppressive effect of DMARDs causes concern regarding impaired tumour surveillance with a potential increased risk of malignancy. We reviewed the literature regarding the risk of malignancy in patients on cs-/b-/tsDMARDS and sought to provide practical advice regarding use of these drugs in patients with previous malignancy. RECENT FINDINGS: Data from randomised controlled trials is limited as patients with pre-existing malignancy are often excluded. Reassuringly, an increasing range of "real world" data from various national b/tsDMARD registries has not provided a convincing signal that these drugs increase tumour recurrence. Nevertheless, awareness of, and adherence to, national screening guidelines for malignancy is important. Given the improvement in quality of life achieved with these novel and well-tolerated therapeutic agents, the benefit/risk profile remains overwhelmingly favourable in most patients.

R-Domain Phosphorylation by Protein Kinase A Stimulates Dissociation of Unhydrolyzed ATP from the First Nucleotide-Binding Site of the Cystic Fibrosis Transmembrane Conductance Regulator.

The cystic fibrosis transmembrane conductance regulator (CFTR) is an asymmetric ATP-binding cassette transporter in which ATP hydrolysis occurs only at the second of the two composite nucleotide-binding sites whereas there are noncanonical substitutions of key catalytic residues in the first site. Therefore, in widely accepted models of CFTR function, ATP is depicted as remaining bound at the first site while it is hydrolyzed at the second site. However, the long lifetime of ATP at nucleotide-binding domain 1 (NBD1) had been measured under conditions where the channel had not been activated by phosphorylation. Here we show that phosphorylation by protein kinase A (PKA), obligatory for channel activation, strongly accelerates dissociation of the unhydrolyzed ATP from NBD1 of both full-length and NBD2-deleted CFTR. This stimulation of nucleotide release results from phosphorylation of the CFTR regulatory domain (residues 634-835) (R-domain). Mimicking phosphorylation by mutating the eight phosphorylation sites in the R-domain (8SE) has the same robust effect on accelerating the dissociation of ATP from NBD1. These findings provide new insight into relationships between R-domain phosphorylation and ATP binding and hydrolysis, the two main CFTR regulatory pathways.

Ligand binding to a remote site thermodynamically corrects the F508del mutation in the human cystic fibrosis transmembrane conductance regulator.

Many disease-causing mutations impair protein stability. Here, we explore a thermodynamic strategy to correct the disease-causing F508del mutation in the human cystic fibrosis transmembrane conductance regulator (hCFTR). F508del destabilizes nucleotide-binding domain 1 (hNBD1) in hCFTR relative to an aggregation-prone intermediate. We developed a fluorescence self-quenching assay for compounds that prevent aggregation of hNBD1 by stabilizing its native conformation. Unexpectedly, we found that dTTP and nucleotide analogs with exocyclic methyl groups bind to hNBD1 more strongly than ATP and preserve electrophysiological function of full-length F508del-hCFTR channels at temperatures up to 37 °C. Furthermore, nucleotides that increase open-channel probability, which reflects stabilization of an interdomain interface to hNBD1, thermally protect full-length F508del-hCFTR even when they do not stabilize isolated hNBD1. Therefore, stabilization of hNBD1 itself or of one of its interdomain interfaces by a small molecule indirectly offsets the destabilizing effect of the F508del mutation on full-length hCFTR. These results indicate that high-affinity binding of a small molecule to a remote site can correct a disease-causing mutation. We propose that the strategies described here should be applicable to identifying small molecules to help manage other human diseases caused by mutations that destabilize native protein conformation.

Opioid Prescribing: Where Should Academic Emergency Departments Focus Their Efforts?

BACKGROUND: Opioid prescriptions from the emergency department (ED) are being heavily scrutinized. This has resulted in prescribing guidelines and laws. OBJECTIVE: We analyzed the "current state" of opioid prescribing practices by emergency medicine (EM) trainees to gain understanding where operational, educational, or supervisory efforts should be directed to comply with current guidelines and future legislation. METHODS: Our retrospective, observational, study was performed at an academic ED with an annual census of 61,289 visits. We extracted all 6962 opioid prescriptions attributed to the ED during calendar year 2015 from the electronic health record. Error prescriptions were excluded from the analysis. Overall prescribing by opioid class was performed. Prescriptions written by EM trainees were categorized by postgraduate year and compared with other prescribers. Prescribing patterns for recurrent visits were also analyzed. RESULTS: Of the 6962 opioid discharge prescriptions, 5515 were written by EM providers. No refills were provided. A mean of 15.4 pills (95% confidence interval 13.9-16.9) were prescribed. Analysis of variance did not detect a significant difference between mean numbers of pills prescribed by EM providers. However, there was a significant difference between EM and non-EM prescribers. Less-experienced EM providers exhibited greater variability with regard to class and preparation. There were 389 prescriptions written for patients who received at least one other opioid prescription in the preceding 30 days. The number of pills dispensed decreased with increasing prior visits. CONCLUSION: EM providers prescribe short courses of opiates regardless of postgraduate year. Patients returning to the ED received fewer pills on subsequent visits. Non-EM providers prescribe larger numbers of pills per prescription. This information will help focus future operational efforts and educational efforts to comply with guidelines and laws.

Structural stability of purified human CFTR is systematically improved by mutations in nucleotide binding domain 1.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is an ABC transporter containing two transmembrane domains forming a chloride ion channel, and two nucleotide binding domains (NBD1 and NBD2). CFTR has presented a formidable challenge to obtain monodisperse, biophysically stable protein. Here we report a comprehensive study comparing effects of single and multiple NBD1 mutations on stability of both the NBD1 domain alone and on purified full length human CFTR. Single mutations S492P, A534P, I539T acted additively, and when combined with M470V, S495P, and R555K cumulatively yielded an NBD1 with highly improved structural stability. Strategic combinations of these mutations strongly stabilized the domain to attain a calorimetric Tm > 70 °C. Replica exchange molecular dynamics simulations on the most stable 6SS-NBD1 variant implicated fluctuations, electrostatic interactions and side chain packing as potential contributors to improved stability. Progressive stabilization of NBD1 directly correlated with enhanced structural stability of full-length CFTR protein. Thermal unfolding of the stabilized CFTR mutants, monitored by changes in intrinsic fluorescence, demonstrated that Tm could be shifted as high as 67.4 °C in 6SS-CFTR, more than 20 °C higher than wild-type. H1402S, an NBD2 mutation, conferred CFTR with additional thermal stability, possibly by stabilizing an NBD-dimerized conformation. CFTR variants with NBD1-stabilizing mutations were expressed at the cell surface in mammalian cells, exhibited ATPase and channel activity, and retained these functions to higher temperatures. The capability to produce enzymatically active CFTR with improved structural stability amenable to biophysical and structural studies will advance mechanistic investigations and future cystic fibrosis drug development.

A survey on the beliefs and knowledge of gout management in new medical graduates - New South Wales, Australia.

AIM: To assess the beliefs and knowledge of gout management in new medical graduates. METHOD: A survey on gout management was sent to new medical graduates during their orientation week, New South Wales, Australia. RESULTS: Of 15 hospital networks, 11 agreed to participate. From these, 168 graduates responded (23.7% response rate). Most (81.1%) felt that gout was a serious disease, 51.2% answered that they had been taught adequately to manage acute gout, only 37.2% for chronic gout. In an acute gout flare, 63.4% answered they would continue urate lowering therapy and 67.2% were aware of first-line pharmacological management options; 28% answered the correct dosing regimen for colchicine. Chronic management was answered poorly. Only 42.0% stated they would titrate allopurinol dosing to a target urate level; 23.5% would check the urate level monthly. More than half, 56.8%, were aware that medical prophylaxis is indicated when initiating urate lowering therapy. Of this subgroup, 46.7% (25.9% overall) knew that non-steroidal anti-inflammatory drugs and colchicine were recommended and 28.4% (15.4% overall) answered the correct timeframe of use. Close to one-third (35.0%), were aware of febuxostat, probenecid and benzbromarone as second-line urate lowering therapy. CONCLUSION: The findings of this study suggest that new graduates' knowledge of gout management, especially chronic management, is suboptimal. Many felt their teaching on gout management inadequate; this is a potential target for intervention. Up to date university education which covers chronic management may lead to better clinical outcomes for this burdensome disease.