On the Feasibility of Rugose Lipid Microparticles in Pressurized Metered Dose Inhalers with Established and New Propellants.

Pressurized metered dose inhalers (pMDIs) require optimized formulations to provide stable, consistent lung delivery. This study investigates the feasibility of novel rugose lipid particles (RLPs) as potential drug carriers in pMDI formulations. The physical stability of RLPs was assessed in three different propellants: the established HFA-134a and HFA-227ea and the new low global-warming-potential (GWP) propellant HFO-1234ze. A feedstock containing DSPC and calcium chloride was prepared without pore forming agent to spray dry two RLP batches at inlet temperatures of 55 °C (RLP55) and 75 °C (RLP75). RLPs performance in pMDI formulations was compared to two reference samples that exhibit significantly different performance when suspended in propellants: well-established engineered porous particles and particles containing 80% trehalose and 20% leucine (80T20L). An accelerated stability study at 40 °C and relative humidity of 7% ± 5% was conducted over 3 months. At different time points, a shadowgraphic imaging technique was used to evaluate the colloidal stability of particles in pMDIs. Field emission electron microscopy with energy dispersive X-ray spectroscopy was used to evaluate the morphology and elemental composition of particles extracted from the pMDIs. After 2 weeks, all 80T20L formulations rapidly aggregated upon agitation and exhibited significantly inferior colloidal stability compared to the other samples. In comparison, both the RLP55 and RLP75 formulations, regardless of the propellant used, retained their rugose structure and demonstrated excellent suspension stability comparable with the engineered porous particles. The studied RLPs demonstrate great potential for use in pMDI formulations with HFA propellants and the next-generation low-GWP propellant HFO-1234ze.

Electrode positioning errors reduce current dose for focal tDCS set-ups: Evidence from individualized electric field mapping.

OBJECTIVE: Electrode positioning errors contribute to variability of transcranial direct current stimulation (tDCS) effects. We investigated the impact of electrode positioning errors on current flow for tDCS set-ups with different focality. METHODS: Deviations from planned electrode positions were determined using data acquired in an experimental study (N = 240 datasets) that administered conventional and focal tDCS during magnetic resonance imaging (MRI). Comparison of individualized electric field modeling for planned and empirically derived "actual" electrode positions was conducted to quantify the impact of positioning errors on the electric field dose in target regions for tDCS. RESULTS: Planned electrode positions resulted in higher current dose in the target regions for focal compared to conventional montages (7-12%). Deviations from planned positions significantly reduced current flow in the target regions, selectively for focal set-ups (26-30%). Dose reductions were significantly larger for focal compared to conventional set-ups (29-43%). CONCLUSIONS: Precise positioning is crucial when using focal tDCS set-ups to avoid significant reductions of current dose in the intended target regions. SIGNIFICANCE: Our results highlight the urgent need to routinely implement methods for improving electrode positioning, minimization of electrode drift, verification of electrode positions before and/or after tDCS and also to consider positioning errors when investigating dose-response relationships, especially for focal set-ups.

Characterizing regional drug delivery within the nasal airways.

INTRODUCTION: The nose has been receiving increased attention as a route for drug delivery. As the site of deposition constitutes the first point of contact of the body with the drug, characterization of the regional deposition of intranasally delivered droplets or particles is paramount to formulation and device design of new products. AREAS COVERED: This review article summarizes the recent literature on intranasal regional drug deposition evaluated in vivo, in vitro and in silico, with the aim of correlating parameters measured in vitro with formulation and device performance. We also highlight the relevance of regional deposition to two emerging applications: nose-to-brain drug delivery and intranasal vaccines. EXPERT OPINION: As in vivo studies of deposition can be costly and time-consuming, researchers have often turned to predictive in vitro and in silico models. Variability in deposition is high due in part to individual differences in nasal geometry, and a complete predictive model of deposition based on spray characteristics remains elusive. Carefully selected or idealized geometries capturing population average deposition can be useful surrogates to in vivo measurements. Continued development of in vitro and in silico models may pave the way for development of less variable and more effective intranasal drug products.

Outcomes of percutaneous vertebroplasty in multiple myeloma: a tertiary neurosciences experience with long-term follow-up.

Background: Multiple myeloma is diagnosed in 5,800 people in the United Kingdom (UK) each year with up to 64% having vertebral compression fractures at the time of diagnosis. Painful vertebral compression fractures can be of significant detriment to patients' quality of life. Percutaneous vertebroplasty aims to provide long-term pain relief and stabilize fractured vertebrae. Methods and materials: Data was collected from all cases of percutaneous vertebroplasty performed on patients with multiple myeloma from November 2017 to January 2019. Pain scores were measured using the Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) pre-procedure, 2 months post procedure and 4 years post-procedure. Procedure related complications and analgesia use were also documented. Results: 22 patients were included with a total of 119 vertebrae treated. Patients reported a significant improvement in overall pain score with a median pre-procedure VAS of 8 and a median post-procedure VAS of 3.5 (p<0.0001). There was a median pre-procedure ODI score of 60% and a median post-procedure ODI score of 36% (p<0000.1). There was improvement across all ODI domains and a 77% reduction in analgesic requirement. There were small cement leaks into paravertebral veins or endplates at 15 levels (12%) which were asymptomatic. There were 8 responders to the long-term follow-up questionnaire at 4 years. This demonstrated an overall stable degree of pain relief in responders with a median VAS of 3.5 and median ODI of 30%. Conclusion: At this center, vertebroplasty has been shown to reduce both VAS and ODI pain scores and reduce analgesia requirements in patients with VCFs secondary to multiple myeloma with long lasting relief at 4 years post-procedure.

Validation of Prognostic and Predictive Models for Therapeutic Response in Patients Treated with [177Lu]Lu-PSMA-617 Versus Cabazitaxel for Metastatic Castration-resistant Prostate Cancer (TheraP): A Post Hoc Analysis from a Randomised, Open-label, Phase 2 Trial.

BACKGROUND: Prognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [177Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [177Lu]Lu-PSMA compared with standard chemotherapy has not been established. OBJECTIVE: To determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective). DESIGN, SETTING, AND PARTICIPANTS: All 200 patients were randomised in the TheraP trial to receive [177Lu]Lu-PSMA-617 (n = 99) or cabazitaxel (n = 101) between February 2018 and September 2019. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [177Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis. RESULTS AND LIMITATIONS: The probability of PSA50 in patients classified as having a favourable outcome was greater in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69-30.80] vs 0.96 [95% CI 0.32-3.05]; p = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [177Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: p = 0.36 and p = 0.41, respectively). CONCLUSIONS: A previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [177Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [177Lu]Lu-PSMA-617 and cabazitaxel. PATIENT SUMMARY: In this report, we validated previously developed statistical models that can predict a response to Lu-PSMA radioligand therapy in patients with advanced prostate cancer. We found that the statistical models can predict patient survival, and aid in determining whether Lu-PSMA therapy or cabazitaxel yields a higher probability to achieve a serum prostate-specific antigen response.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Thermal Stability of Protic Ionic Liquids.

While protic ionic liquids (ILs) have found great success as solvents for a broad range of applications, little is known about their degradation when exposed to temperatures above ambient for extended periods of time. Here, we report the thermal stability of six protic ILs, namely, ethylammonium nitrate, ethylammonium formate, ethylammonium acetate, ethanolammonium nitrate, ethanolammonium formate, and ethanolammonium acetate. The effect of heating each ionic liquid to 60 °C for 1 h or 1 week (sealed or open to the atmosphere) was evaluated by considering the changes to water content, pH, mass, thermal phase transitions, and molecular structure after each treatment. Heating each of the six ILs when sealed led to measurable shifts in their water content and 10 wt % pH, but there was no significant change in their mass, thermal phase transitions according to differential scanning calorimetry (DSC), or molecular structure using proton nuclear magnetic resonance (1H NMR) spectra, indicating that the samples were largely unchanged. The samples that were heated open to the atmosphere also displayed no significant changes after 1 h but displayed significant changes after 1 week.

Enhancing missense variant pathogenicity prediction with protein language models using VariPred.

Computational approaches for predicting the pathogenicity of genetic variants have advanced in recent years. These methods enable researchers to determine the possible clinical impact of rare and novel variants. Historically these prediction methods used hand-crafted features based on structural, evolutionary, or physiochemical properties of the variant. In this study we propose a novel framework that leverages the power of pre-trained protein language models to predict variant pathogenicity. We show that our approach VariPred (Variant impact Predictor) outperforms current state-of-the-art methods by using an end-to-end model that only requires the protein sequence as input. Using one of the best-performing protein language models (ESM-1b), we establish a robust classifier that requires no calculation of structural features or multiple sequence alignments. We compare the performance of VariPred with other representative models including 3Cnet, Polyphen-2, REVEL, MetaLR, FATHMM and ESM variant. VariPred performs as well as, or in most cases better than these other predictors using six variant impact prediction benchmarks despite requiring only sequence data and no pre-processing of the data.

High-Flow and Low-Flow Oxygen Delivery by Nasal Cannula Evaluated in Infant and Adult Airway Replicas.

BACKGROUND: The nasal cannula is widely regarded as a safe and effective means of administering low- and high-flow oxygen to patients irrespective of their age. However, variability in delivered oxygen concentration (FDO2 FDO2 ) via nasal cannula has the potential to pose health risks. The present study aimed to evaluate predictive equations for FDO2 over a large parameter space, including variation in breathing, oxygen flow, and upper-airway geometry representative of both young children and adults. METHODS: Realistic nasal airway geometries were previously collected from medical scans of adults, infants, and neonates. Nasal airway replicas based on these geometries were used to measure the FDO2 for low-flow oxygen delivery during simulated spontaneous breathing. The present study extends previously published data sets to include higher oxygen flows. The extended data sets included nasal cannula oxygen flows that ranged from 6 to 65 L/min for the adult replicas, and from 0.5 to 6 L/min for the infant replicas. For both age groups, FDO2 was measured over a range of breathing frequencies, inspiratory to expiratory time ratios, and tidal volumes. Measured FDO2 values were compared with values predicted by using a previously derived flow-weighted equation. RESULTS: For both age groups, FDO2 was observed to increase nonlinearly with the ratio between oxygen flow supplied to the nasal cannula and the average inhalation flow. The previously derived flow-weighted equation over-predicted FDO2 at higher oxygen flows. A new empirical equation, therefore, was proposed to predict FDO2 for either age group as a function of nasal cannula flow, tidal volume, and inspiratory time. Predicted FDO2 values matched measured values, with average relative errors of 2.4% for infants and 4.3% for adults. CONCLUSIONS: A new predictive equation for FDO2 was obtained that accurately matched measured data in both adult and infant airway replicas for low- and high-flow regimens.

Real world performance of the 21st Century Cures Act population-level application programming interface.

OBJECTIVE: To evaluate the real-world performance of the SMART/HL7 Bulk Fast Health Interoperability Resources (FHIR) Access Application Programming Interface (API), developed to enable push button access to electronic health record data on large populations, and required under the 21st Century Cures Act Rule. MATERIALS AND METHODS: We used an open-source Bulk FHIR Testing Suite at 5 healthcare sites from April to September 2023, including 4 hospitals using electronic health records (EHRs) certified for interoperability, and 1 Health Information Exchange (HIE) using a custom, standards-compliant API build. We measured export speeds, data sizes, and completeness across 6 types of FHIR. RESULTS: Among the certified platforms, Oracle Cerner led in speed, managing 5-16 million resources at over 8000 resources/min. Three Epic sites exported a FHIR data subset, achieving 1-12 million resources at 1555-2500 resources/min. Notably, the HIE's custom API outperformed, generating over 141 million resources at 12 000 resources/min. DISCUSSION: The HIE's custom API showcased superior performance, endorsing the effectiveness of SMART/HL7 Bulk FHIR in enabling large-scale data exchange while underlining the need for optimization in existing EHR platforms. Agility and scalability are essential for diverse health, research, and public health use cases. CONCLUSION: To fully realize the interoperability goals of the 21st Century Cures Act, addressing the performance limitations of Bulk FHIR API is critical. It would be beneficial to include performance metrics in both certification and reporting processes.

Improving Breath Detection From Pulsed-Flow Oxygen Sources Using a New Nasal Interface.

BACKGROUND: Patients with COPD and other lung diseases are treated with long-term oxygen therapy (LTOT). Portable oxygen sources are required to administer LTOT while maintaining patient autonomy. Existing portable oxygen equipment has limitations that can hinder patient mobility. A novel nasal interface is presented in this study, aiming to enhance breath detection and triggering efficiency of portable pulsed-flow oxygen devices, thereby improving patient mobility and independence. METHOD: To examine the effectiveness of the new interface, 8 respiratory therapists participated in trials using different oxygen sources (tank with oxygen-conserving device, SimplyGo Mini portable oxygen concentrator [POC], and OxyGo NEXT POC) and breathing types (nasal and oral) while using either the new nasal interface or a standard cannula. Each trial was video recorded so participant breaths could be retroactively matched with a pulse/no-pulse response, and triggering success rates were calculated by dividing the number of oxygen pulses by the number of breaths in each trial. After each trial, volunteers were asked to rate their perceived breathing resistance. RESULTS: Nasal breathing consistently resulted in higher triggering success rates compared to oral breathing for pulsed-flow oxygen devices. POCs exhibited higher triggering success rates than did the oxygen tanks with conserving device. However, there were no significant differences in triggering success rates between the two POC models. The new nasal interface demonstrated improved triggering success rates compared to the standard cannula. Whereas the new nasal interface was associated with a slight increase in perceived breathing resistance during nasal breathing trials, participants reported manageable resistance levels when using the interface. CONCLUSIONS: This study demonstrates that the new nasal interface can improve triggering success rates of pulsed-flow oxygen devices during both nasal and oral breathing scenarios. Further research involving patient trials is recommended to understand the clinical implications of improved pulse triggering.

Do antibody CDR loops change conformation upon binding?

Antibodies have increasingly been developed as drugs with over 100 now licensed in the US or EU. During development, it is often necessary to increase or reduce the affinity of an antibody and rational attempts to do so rely on having a structure of the antibody-antigen complex often obtained by modeling. The antigen-binding site consists primarily of six loops known as complementarity-determining regions (CDRs), and an open question has been whether these loops change their conformation when they bind to an antigen. Existing surveys of antibody-antigen complex structures have only examined CDR conformational change in case studies or small-scale surveys. With an increasing number of antibodies where both free and complexed structures have been deposited in the Protein Data Bank, a large-scale survey of CDR conformational change during binding is now possible. To this end, we built a dataset, AbAgDb, that currently includes 177 antibodies with high-quality CDRs, each of which has at least one bound and one unbound structure. We analyzed the conformational change of the Cα backbone of each CDR upon binding and found that, in most cases, the CDRs (other than CDR-H3) show minimal movement, while 70.6% and 87% of CDR-H3s showed global Cα RMSD ≤ 1.0Å and ≤ 2.0Å, respectively. We also compared bound CDR conformations with the conformational space of unbound CDRs and found most of the bound conformations are included in the unbound conformational space. In future, our results will contribute to developing insights into antibodies and new methods for modeling and docking.

Genetic Testing Yield and Clinical Characteristics of Hypertrophic Cardiomyopathy in Understudied Ethnic Groups: Insights From a New Zealand National Registry.

BACKGROUND: Aotearoa/New Zealand has a multiethnic population. Patients with hypertrophic cardiomyopathy (HCM) are enrolled in the national Cardiac Inherited Diseases Registry New Zealand. Here, we report the characteristics of Cardiac Inherited Diseases Registry New Zealand HCM probands with and without pathogenic or likely pathogenic (P/LP) genetic variants for HCM, and assess genetic testing yield and variant spectrum by self-identified ethnicity. METHODS: Probands with HCM and enrolled in Cardiac Inherited Diseases Registry New Zealand who have undergone clinical genetic testing over a 17-year period were included. Clinical data, family history, and genetic test results were analyzed. RESULTS: Of 336 probands, 121 (36%) were women, 220 (66%) were European ethnicity, 41 (12%) were Maori, 26 (8%) were Pacific people, and 49 (15%) were other ethnicities. Thirteen probands (4%) presented with sudden death and 19 (6%) with cardiac arrest. A total of 134 (40%) had a P/LP variant identified; most commonly in the MYBPC3 gene (60%) followed by the MYH7 gene (24%). A P/LP variant was identified in 27% of Maori or Pacific probands versus 43% European or other ethnicity probands (P=0.022); 16% of Maori or Pacific probands had a variant of uncertain significance identified, compared with 9% of European or other ethnicity probands (P=0.092). Women more often had a P/LP variant identified than men (48% versus 35%; P=0.032), and variant-positive probands were younger at clinical diagnosis than variant of uncertain significance/variant-negative probands (39±17 versus 50±17 years; P<0.001) and more likely to have experienced cardiac arrest or sudden death events over their lifetime (P=0.002). CONCLUSIONS: Carriage of a P/LP variant in HCM probands is associated with presentation at younger age, and cardiac arrest or sudden death events. Maori or Pacific probands were less likely to have a P/LP variant identified than European or other ethnicity probands.

Predicting Emergence of Nanoscale Order in Surface Oxides through Preferential Interactivity Parameter.

Diffusion and surface oxidation are critical processes in metal alloy designs and use. Surface oxides provide opportunities to improve material properties or performance beyond bulk alterations. Surface oxidation is, however, often oversimplified into a classical diffusion process. Passivating oxide surfaces are also thought to be lacking in complexity or critical information. A closer look, however, shows inherent complexity with kinetics-driven competition between the elements in the process leading to redox-speciation across a very small (nm) thickness. Questions that remain to be answered for a comprehensive understanding of surface oxides are diverse and call for interdisciplinary approaches. By using the thermodynamics-based Preferential Interactivity Parameter (PIP) alongside kinetic consideration, we show how complexity in these oxides can be predicted allowing us to tailor these thin films. We use our work, and that of others, to illustrate predictability while also highlighting that there is still much more to be done.

Parasite-induced IFN-γ regulates host defense via CD115 and mTOR-dependent mechanism of tissue-resident macrophage death.

Host resistance to a common protozoan parasite Toxoplasma gondii relies on a coordinated immune response involving multiple cell types, including macrophages. Embryonically seeded tissue-resident macrophages (TRMs) play a critical role in maintaining tissue homeostasis, but their role in parasite clearance is poorly understood. In this study, we uncovered a crucial aspect of host defense against T. gondii mediated by TRMs. Through the use of neutralizing antibodies and conditional IFN-γ receptor-deficient mice, we demonstrated that IFN-γ directly mediated the elimination of TRMs. Mechanistically, IFN-γ stimulation in vivo rendered macrophages unresponsive to macrophage colony-stimulating factor (M-CSF) and inactivated mTOR signaling by causing the shedding of CD115 (CSFR1), the receptor for M-CSF. Further experiments revealed the essential role of macrophage IFN-γ responsiveness in host resistance to T. gondii. The elimination of peritoneal TRMs emerged as an additional host defense mechanism aimed at limiting the parasite's reservoir. The identified mechanism, involving IFN-γ-induced suppression of CD115-dependent mTOR signaling in macrophages, provides insights into the adaptation of macrophage subsets during infection and highlights a crucial aspect of host defense against intracellular pathogens.

Heart Rhythm New Zealand consensus statement on the practical management of cardiac implanted electronic devices in the peri-operative environment.

Electrosurgery is commonly used during a range of operations in order to maintain effective haemostasis. This can cause electromagnetic interference (EMI) with cardiac implanted electronic devices (CIEDs), which prevents normal device function. CIEDs include pacemakers (PPM), implantable cardiac defibrillators (ICD), cardiac resynchronisation therapy devices-both pacemakers and defibrillators (CRT-P/CRT-D)-and implantable loop recorders (ILRs). Damage to the generator, inhibition of pacing, activation of asynchronous pacing and ventricular fibrillation can all be induced by electrocautery. An active management plan for CIEDs during electrosurgery is critical to minimise these adverse effects of EMI. Purpose: To facilitate the safe and effective peri-operative management of CIED patients during electrosurgery.

Closing the gap: improving the percentage of Annual Wellness Visits among Medicare patients.

BACKGROUND: The Medicare Annual Wellness Visit (AWV) allows providers to acquire critical information about patients' health through a review of vitals, environmental risks, and medical and family history. These visits are free to those enrolled in Medicare and prioritize patient-provider relationship building and preventative care. Despite this, AWV completion rates are suboptimal. METHODS: A quality improvement project was aimed to increase the percentage of AWVs among Medicare patients in a primary care internal medicine practice from a baseline of 1.7% completion to 2.7% in 3 months from January to April 2023. INTERVENTION: With eligible patients identified, a standardized approach was created where an AWV appointment was ordered, and a patient message explaining the benefit of the appointment was sent by the patient portal. RESULTS: Our AWV intervention resulted in 72 patients being seen for an AWV, which increased the percentage of completed AWVs in the division by 2.1% from 1.7% to 3.8% in 3 months. CONCLUSION: This intervention will continue to improve AWV rates and improve patient care for Medicare patients in internal medicine. It could be applied to other areas of primary care and within other health systems.

Atomic Reconstruction of Au Thin Films through Interfacial Strains.

Interfaces play a critical thermodynamic role in the existence of multilayer systems. Due to their utility in bridging energetic and compositional differences between distinct species, the formation of interfaces inherently creates internal strain in the bulk due to the reorganization needed to accommodate such a change. We report the effect of scaling interfacial stress by deposition of different adlayers on a host thin metal film. Intrinsic property differences between host and deposited metal atoms result in varying degree of composition and energy gradient within the interface. Interfacial stress can increase defects in the host leading to (i) energy dissipation and reorganization to minimize surface energy, and (ii) increased material strength. We infer that dissipation of interfacial stress induces defect migration, hence bulk and surface atomic reconstruction as captured by the surface roughness and grain size reduction coupled with a concomitant increase in material strength.

Pragmatic Adaptive Trial for Respiratory Infection in Children (PATRIC) Clinical Registry protocol.

INTRODUCTION: Acute respiratory infections (ARI) are the most common cause of paediatric hospitalisation. There is an urgent need to address ongoing critical knowledge gaps in ARI management. The Pragmatic Adaptive Trial for Respiratory Infections in Children (PATRIC) Clinical Registry will evaluate current treatments and outcomes for ARI in a variety of paediatric patient groups. The registry will provide a platform and data to inform a number of PATRIC clinical trials, testing various interventions in ARI treatment and management to optimise paediatric ARI care. METHODS AND ANALYSIS: The PATRIC Clinical Registry is a single-centre, prospective observational registry recruiting from a tertiary paediatric Emergency Department in Western Australia. Through characterising demographic, clinical, treatment and outcome data, the PATRIC Clinical Registry will improve our understanding of antibiotic utilisation and ARI outcomes in children. ETHICS AND DISSEMINATION: The PATRIC Clinical Registry is conducted in accordance with the Declaration of Helsinki, and the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice (CPMP/ICH/13595) July 1996. Approval is provided by the Child and Adolescent Health Service Human Research Ethics Committee (HREC). Study results will be communicated by presentation and publication (HREC: RGS0000003078.) TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000903189. UTN: U1111-1231-3365.