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Osteosarcopenic individuals have poor muscle function and increased bone fragility, which results in a severe detriment to health outcomes. Hence, there is a necessity to discover easily accessible factors associated with osteosarcopenia to develop timely interventions. This study aimed to determine new sensitive balance and/or gait variables that are associated with osteosarcopenia in a population of older people with a history of falls and/or fractures. In a cross-sectional cohort study, 306 men and women aged ≥65 years completed a series of questionnaires, clinical assessments and muscle strength and function tests. Subsequently, participants were separated into osteopenia, osteoporosis and osteosarcopenia, groups for comparison and further analysis. Osteosarcopenia performed worse than osteopenia and osteoporosis in grip strength, gait speed, physical function scores and in multiple gait and balance indices (p<0.001). During posturography testing, there were larger elliptical areas with eyes open (p = 0.003), and eyes closed (p = 0.043) and increased sway velocity on a firm platform (p = 0.007) in the osteosarcopenia group, compared to osteoporosis. Limits of stability and eyes open ellipse area significantly contributed to the multivariable model (p = 0.029 and p = 0.038, respectively), suggesting that these balance parameters, along with grip strength, may be useful in identifying older adults with osteosarcopenia from those with only osteopenia/osteoporosis. Older adults with osteosarcopenia and a history of falls and/or fractures demonstrated inferior strength, function, and gait characteristics. This study identified indices of balance that were sensitive discriminators for osteosarcopenia and could be easily implemented into routine assessment.

Background: Opioid switching is common, however, conversion tables have limitations. Guidelines suggest postswitch dose reduction, yet, observations show opioid doses may increase postswitch. Objectives: To document the opioid conversion factor postswitch in cancer, and whether pain and adverse effect outcomes differ between switched opioid groups. Design/Setting: This multicenter prospective longitudinal study included people with advanced cancer in Australia. Clinical data (demographics, opioids) and validated instruments (pain, adverse effects) were collected twice, seven days apart. Results: Opioid switch resulted in dose increase (median oral morphine equivalent daily dose 90 mg [interquartile range {IQR} 45-184] to 150 mg [IQR 79-270]), reduced average pain (5.1 [standard deviation {SD} 1.7] to 3.8 [SD 1.6]), and reduced adverse effects. Hydromorphone dose increased 2.5 times (IQR 1.0-3.6) above the original conversion factor used. Conclusions: Opioid switching resulted in overall dose increase, particularly when switching to hydromorphone. Higher preswitch dosing may require higher dose conversion ratios. Dose reduction postswitch risks undertreatment and may not be always appropriate.

Background: Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR. Methods: Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites. Results: we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%). Conclusion: In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro/in vivo diagnostic strategies to ascertain drug causality. Trial registration: ANZCTR ACTRN1261900024113

BACKGROUND AND AIMS: Accurate biomarkers to predict outcomes following discontinuation of nucleos(t)ide analogue (NA) therapy are needed. We evaluated serum hepatitis B core-related antigen (HBcrAg) level as a biomarker for predicting outcomes after NA discontinuation. METHODS: Patients with HBeAg-negative chronic hepatitis B (CHB) without cirrhosis were enrolled in a prospective trial evaluating clinical outcomes until 96 weeks after NA discontinuation. End of treatment (EOT) and off-treatment levels of serum HBcrAg, HBsAg, HBV RNA and HBV DNA were used to predict key clinical outcomes including hepatitis flare (ALT ≥5 × ULN and HBV DNA > 2000 IU/mL). The SCALE-B score was calculated for the purposes of model validation. RESULTS: HBcrAg was tested amongst 65 participants. The median age was 54 years, 54% were male and 83% were Asian. HBcrAg was detectable in 86% patients. HBcrAg level ≥4 log U/mL at EOT was predictive of hepatitis flare [8/10 (80%) vs. 17/55 (31%), p = .001]. The presence of either HBcrAg ≥4 log U/mL or detectable HBV RNA at EOT predicted for both biochemical relapse and hepatitis flare. The SCALE-B model at EOT predicted for virological relapse, biochemical relapse, hepatitis flare and HBsAg loss in this cohort. An increase in the serum HBcrAg level off-treatment was also associated with hepatitis flare. No participant with EOT HBcrAg level ≥4 log U/mL achieved HBsAg loss. CONCLUSIONS: High levels of serum HBcrAg predict for hepatitis flare after stopping NA therapy and low likelihood of HBsAg loss at week 96. People with high levels of serum HBcrAg are not suitable candidates for NA discontinuation.

BACKGROUND: In 2014, infliximab (IFX) was listed on the Australian Pharmaceutical Benefits Scheme for acute severe ulcerative colitis (ASUC) and is now the preferred option for medical salvage, superseding cyclosporin A (CsA). Optimal dosing schedules for IFX remain unknown. AIM: The authors aim to evaluate the effect of changing from predominantly CsA to almost exclusively IFX for the treatment of steroid-refractory ASUC on colectomy rates. METHODS: A retrospective review was performed of patients admitted with ASUC between 2012 and 2020. Patients were categorised into two groups according to year of presentation - either 'historical treatment' cohort (2012-2014), when CsA was primarily used, or 'contemporary treatment' cohort (2014-2020), when IFX was mostly prescribed, in either standard or intensive doses. RESULTS: One hundred thirty-nine patients were included; 37 in the historical treatment cohort and 102 in the contemporary treatment cohort. In the historical treatment cohort, 12 of 37 received salvage therapy and eight (67%) received CsA. In the contemporary treatment cohort, 49 of 102 patients received salvage therapy, 40 (82%) with IFX, of whom 22 (53%) received intensified doses. Colectomy rates were similar at 30 days, 6 months and 12 months between historical and contemporary treatment cohorts (14% vs 12% [P = 0.77], 19% vs 18% [P > 0.99],and 22% vs 18% [P = 0.63], respectively). Difference in 12-month colectomy rates between standard versus intensive IFX did not meet statistical significance (three of 21 [14%] vs nine of 22 [41%]. respectively; P = 0.09). CONCLUSION: There was no difference in 30-day, 6-month or 12-month colectomy rates between the historical treatment and contemporary treatment cohorts. The use of IFX, rather than CsA, even at intensified dosing, does not appear to reduce the colectomy rate observed in our patients.

Aim: Associations between gene variants and opioid net effect are unclear. We conducted an exploratory pharmacogenetic analysis of 35 gene variants and opioid response in advanced cancer. Patients & methods: This multi-center prospective cohort study included clinical data, questionnaires (pain and adverse effects) and DNA (blood). Negative binomial regression and logistic regression were used. Results: Within 54 participants, eight statistically significant associations (p = 0.002-0.038) were observed between gene variants and opioid dose, pain scores or adverse effects, the majority being within the neuroimmune TLR4 pathway (IL1B [rs1143634], IL2 [rs2069762], IL6 [rs1800795], BDNF [rs6265]) and ARRB2 pathway (ARRB2 [rs3786047], DRD2 [rs6275]). Conclusion: Neuroimmune pathway genes may contribute to differences in opioid response in cancer and may be included in future similar studies.

BACKGROUND: Internationally, clinical and economic advantages of low-risk penicillin delabelling have been explored, supporting changes to healthcare delivery systems where penicillin delabelling is embedded into inpatient usual care. AIMS: To determine if economic advantages of low-risk inpatient penicillin delabelling, described in the international literature, are realised in the Australian context. METHODS: This explorative economic evaluation had prospective patient data collection between January and August 2019, across two Australian health services. Part 1: determine the cost per effectively delabelled patient for Penicillin Allergy Delabeling Program inpatients (PADP cohort) compared with Outpatient Antibiotic Allergy Testing Service outpatients (OAATS cohort). Part 2: a cost analysis to compare hospital costs for inpatients with low-risk penicillin allergy who did (PADP cohort) and did not (usual care cohort) undergo PADP delabelling. RESULTS: Part 1: the PADP (n = 350) and OAATS (n = 27 patients, n = 36 individual visits) cohorts were comparable. In PADP, costs/proportion delabelled was $20.10/0.98, equating to $20.51 per effectively delabelled patient; in OAATS, it was $181.24/0.50, equating to $362. Compared with OAATS, PADP was associated with savings of $341.97 per effectively delabelled patient, indicating the outpatient testing was the dominated strategy, being more costly and less effective. Part 2: the PADP (n = 218) and usual care (n = 32) cohorts were comparable. Significantly favouring the delabelled PADP cohort, the mean difference per patient was -4.41 days (95% confidence interval: -7.64, -1.18) and -$9467.72 (95% confidence interval: -$15 419.98, -$3515.46). CONCLUSIONS: Consistent with international literature, delabelling low-risk penicillin allergies in the inpatient setting had economic advantages in the Australian context. Fully powered economic evaluations are urgently required to consolidate these findings.

Inpatient direct oral challenge programs are increasingly deployed as part of antimicrobial stewardship initiatives to reduce the burden and impacts of penicillin allergy labels on antibiotic prescribing. Using data from a prospective, multicenter cohort inpatient penicillin allergy program, we identify the key targets for delabeling to aid health service implementation.

BACKGROUND: Different measures of muscle strength, physical performance and body size/composition are used in various sarcopenia definitions. This study investigated which baseline measures best predict incident mortality and falls, and prevalent slow walking speed in older women and men. MATERIALS AND METHODS: Data for 899 women (mean age±standard deviation, 68.7 ± 4.3 years) and 497 men (69.4 ± 3.9 years) from the Dubbo Osteoporosis Epidemiology Study 2, comprising sixty variables for muscle strength (quadriceps strength), physical performance (walking speed, timed up and go (TUG) test, sit to stand (STS) test), body size (weight, height, body mass index) and body composition (lean mass, body fat) were included. Sex-stratified Classification and Regression Tree (CART) analyses calculated baseline variable accuracy for predicting incident mortality and falls, and prevalent slow walking speed (<0.8 m/s). RESULTS: Over 14.5 years, 103/899 (11.5%) women and 96/497 (19.3%) men died, 345/899 (38.4%) women and 172/497 (34.6%) men had ≥1 fall, and 304/860 (35.3%) women and 172/461 (31.7%) had baseline slow walking speed (<0.8 m/s). CART models identified age and walking speed adjusted for height as the most important predictors for mortality in women, and quadriceps strength (with adjustments) as the most important predictor for mortality in men. In both sexes, STS (with adjustments) was the most important predictor for incident falls, and TUG test was the most important predictor for prevalent slow walking speed. Body composition measures were not important predictors for any outcome. CONCLUSIONS: Muscle strength and physical performance variables and cut points predict falls and mortality differently in women and men, suggesting targeted sex-specific application of selected measures may improve outcome prediction in older adults.

Background: This exploratory observational case–control study investigated the rate of referral to cardiac rehabilitation (CR) among patients hospitalised with heart failure (HF) and identified factors associated with referral. Methods: Patients hospitalised with HF as identified by the Victorian Cardiac Outcomes Registry HF study were included. Factors found to be univariately associated with referral were selected for multivariate logistic regression. Results: Among 1281 patients (mean age: 76.9 years; 32.8% HFrEF and 33.9% HfpEF), 125 (9.8%) were referred to CR. Patients referred were younger (73.6 (2.7, 81.5) vs. 80.2 (71.1, 86.5) p < 0.001) and were more likely to be men (72%, p < 0.001). Factors associated with referral included inpatient percutaneous coronary intervention (OR, 3.31; 95% CI, 1.04–10.48; p = 0.04), an aetiology of ischaemic or rhythm-related cardiomyopathy, and anticoagulants prescribed on discharge. Factors that lowered the likelihood of referral included older age, female, receiving inpatient oxygen therapy, and the presence of chronic obstructive pulmonary disease (COPD) or anaemia. Conclusions: The rate of referral to CR following hospitalisation with HF is low. Shortfalls are particularly evident among females, older patients, and in those with COPD or anaemia. Future studies should focus on improving referral processes and translating proven strategies that increase referrals to CR into practice.

INTRODUCTION: Immunosenescence leads to increased morbidity and mortality associated with viral infections and weaker vaccine responses. This has been well documented for seasonal influenza and the current pandemic with SARS-CoV-2 (COVID-19), which disproportionately impact older adults, particularly those in residential aged care facilities. Inadequate nutrient intakes associated with impaired immunity, respiratory and muscle function are likely to augment the effects of immunosenescence. In this study, we test whether the impact of inadequate nutrition can be reversed using multi-nutrient supplementation, consequently enhancing vaccine responses, reducing the risk of viral infections and improving respiratory and muscle function. METHODS AND ANALYSIS: The Pomerium Study is a 3-month, single-blind, randomised, controlled trial testing the effects of two daily servings of an oral multi-nutrient supplement (330 kcal, 20 g protein, 1.5 g calcium 3-hydroxy-3-methylbutyrate monohydrate (CaHMB), 449 mg calcium, 500 IU vitamin D3 and 25 vitamins and minerals) on the immune system and muscle and respiratory function of older adults in aged care in Melbourne, Australia. 160 older adults (≥75 years old) will be recruited from aged care facilities and randomised to treatment (multi-nutrient supplement) or control (usual care). The primary outcome is a change in T-cell subsets CD8 + and CD28null counts at months 1 and 3. Secondary outcomes measured at baseline and month 3 are multiple markers of immunosenescence (also at 1 month), body composition (bioimpedance), handgrip strength (dynamometer), physical function (short physical performance battery), respiratory function (spirometry) and quality of life (EQ-5D-5L). Incidence and complications of COVID-19 and/or viral infections (ie, hospitalisation, complications or death) will be recorded throughout the trial, including 3 months after supplementation is ceased. ETHICS AND DISSEMINATION: This study was approved by Melbourne He

Background Atmospheric changes in pollen concentration may affect human health by triggering various allergic processes. We sought to assess if changes in pollen concentrations were associated with different acute coronary syndrome (ACS) subtype presentations and short-term clinical outcomes. Methods and Results We analyzed data in consecutive patients presenting with ACS (unstable angina, non-ST-segment-elevation myocardial infarction, and ST-segment-elevation myocardial infarction) treated with percutaneous coronary intervention between January 2014 and December 2017 and enrolled in the VCOR (Victorian Cardiac Outcomes Registry). Baseline characteristics were compared among patients exposed to different grass and total pollen concentrations. The primary outcome was occurrence of ACS subtypes and 30-day major adverse cardiac and cerebrovascular events (composite of mortality, myocardial infarction, stent thrombosis, target vessel revascularization, or stroke). Of 15 379 patients, 7122 (46.3%) presented with ST-segment-elevation myocardial infarction, 6781 (44.1%) with non-ST-segment-elevation myocardial infarction, and 1476 (9.6%) with unstable angina. The mean age was 62.5 years, with men comprising 76% of patients. No association was observed between daily or seasonal grass and total pollen concentrations with the frequency of ACS subtype presentation. However, grass and total pollen concentrations in the preceding days (2-day average for grass pollen and 7-day average for total pollen) correlated with in-hospital mortality (odds ratio [OR], 2.17 [95% CI, 1.12-4.21]; P=0.021 and OR, 2.78 [95% CI, 1.00-7.74]; P=0.05), respectively, with a trend of 2-day grass pollen for 30-day major adverse cardiac and cerebrovascular events (OR, 1.50 [95% CI, 0.97-2.32]; P=0.066). Conclusions Increased pollen concentrations were not associated with differential ACS subtype presentation but were significantly related to in-hospital mortality following percutaneous coronary interve

Accurate quantification of bone, muscle, and their components is still an unmet need in the musculoskeletal field. Current methods to quantify tissue volumes in 3D images are expensive, labor-intensive, and time-consuming; thus, a reliable, valid, and quick application is highly needed. Tissue Compass is a standalone software for semiautomatic segmentation and automatic quantification of musculoskeletal organs. To validate the software, cross-sectional micro-CT scans images of rat femur (n = 19), and CT images of hip and abdomen (n = 100) from the Osteoporotic Fractures in Men (MrOS) Study were used to quantify bone, hematopoietic marrow (HBM), and marrow adipose tissue (MAT) using commercial manual software as a comparator. Also, abdominal CT scans (n = 100) were used to quantify psoas muscle volumes and intermuscular adipose tissue (IMAT) using the same software. We calculated Pearson's correlation coefficients, individual intra-class correlation coefficients (ICC), and Bland-Altman limits of agreement together with Bland-Altman plots to show the inter- and intra-observer agreement between Tissue Compass and commercially available software. In the animal study, the agreement between Tissue Compass and commercial software was r > 0.93 and ICC > 0.93 for rat femur measurements. Bland-Altman limits of agreement was - 720.89 (- 1.5e+04, 13,074.00) for MAT, 4421.11 (- 1.8e+04, 27,149.73) for HBM and - 6073.32 (- 2.9e+04, 16,388.37) for bone. The inter-observer agreement for QCT human study between two observers was r > 0.99 and ICC > 0.99. Bland-Altman limits of agreement was 0.01 (- 0.07, 0.10) for MAT in hip, 0.02 (- 0.08, 0.12) for HBM in hip, 0.05 (- 0.15, 0.25) for bone in hip, 0.02 (- 0.18, 0.22) for MAT in L1, 0.00 (- 0.16, 0.16) for HBM in L1, and 0.02 (- 0.23, 0.27) for bone in L1. The intra-observer agreement for QCT human study between the two applications was r > 0.997 and ICC > 0.99. Bland-Altman limits of agreement was 0.03 (- 0.13, 0.20) for MAT in hip

BACKGROUND: Older adults experience considerable muscle and bone loss that are closely interconnected. The efficacy of progressive resistance training programs to concurrently reverse/slow the age-related decline in muscle strength and bone mineral density (BMD) in older adults remains unclear. OBJECTIVES: We aimed to quantify concomitant changes in lower-body muscle strength and BMD in older adults following a progressive resistance training program and to determine how these changes are influenced by mode (resistance only vs. combined resistance and weight-bearing exercises), frequency, volume, load, and program length. METHODS: MEDLINE/PubMed and Embase databases were searched for articles published in English before 1 June, 2021. Randomized controlled trials reporting changes in leg press or knee extension one repetition maximum and femur/hip or lumbar spine BMD following progressive resistance training in men and/or women ≥ 65 years of age were included. A random-effects meta-analysis and meta-regression determined the effects of resistance training and the individual training characteristics on the percent change (∆%) in muscle strength (standardized mean difference) and BMD (mean difference). The quality of the evidence was assessed using the Cochrane risk-of-bias tool (version 2.0) and Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria. RESULTS: Seven hundred and eighty studies were identified and 14 were included. Progressive resistance training increased muscle strength (∆ standardized mean difference = 1.1%; 95% confidence interval 0.73, 1.47; p ≤ 0.001) and femur/hip BMD (∆ mean difference = 2.77%; 95% confidence interval 0.44, 5.10; p = 0.02), but not BMD of the lumbar spine (∆ mean difference = 1.60%; 95% confidence interval - 1.44, 4.63; p = 0.30). The certainty for improvement was greater for muscle strength compared with BMD, evidenced by less heterogeneity (I2 = 78.1% vs 98.6%) and a higher overall quality of eviden

Frailty is defined as a syndrome of physiological decline in late life, characterized by marked vulnerability to adverse health outcomes. A robust biomarker for frailty is still lacking. Tryptophan (TRP) metabolism through the kynurenine pathway (KP) plays essential roles in aging, the musculoskeletal system, and physical performance. In this study, we quantified 7 KP metabolites, including kynurenine (KYN), kynurenine acid (KYNA), quinolinic acid (QUIN), picolinic acid (PIC), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), and anthranilic acid (AA) using ultra-high-performance liquid chromatography and gas chromatography-mass spectrometry in the serum of 85 participants (median age 75; 65% female; 28 non-frail, 29 pre-frail, and 28 frail) at the Nepean Osteoporosis and Frailty (NOF) Study. We looked at the association between TRP metabolites and physical performance, sarcopenia, and frailty. After adjusting for age and sex, our results showed that KYN and KYN/TRP were associated with higher interleukin (IL)-6 levels (r = .324 and r = .390, respectively). KYNA and its ratios to other products (mainly KYNA/KYN, KYNA/QUIN, and KYNA/PIC) were associated with a lower likelihood of frailty by Fried's criteria (OR 0.93 [0.88, 0.98], P = .009) and Rockwood index (r = -.241, P = .028) as well as a lower likelihood of sarcopenia (OR 0.88 [0.78, 1.00], P = .049). QUIN and QUIN/KYN showed an association with increased IL-6 (r = .293 and .204 respectively), higher likelihood of frailty (OR 1.02 [1.00, 1.04], P = .029 and OR 6.43 [2.23, 18.51], P = .001 respectively) and lower physical function (r = -.205 and r = -.292). In conclusion, different TRP metabolites have various associations with physical performance, frailty, and sarcopenia. Defining the underlying mechanisms may permit the development and validation of new biomarkers and therapeutics for frailty and musculoskeletal conditions targeting specific metabolites of the TRP catabolic pathway.

BACKGROUND: Recurrent diabetic ketoacidosis (DKA) has been linked to mental health disorders, but less is known about single DKA episodes. Most studies are retrospective, lacking control groups. AIMS: To prospectively examine psychosocial factors in patients presenting with recurrent or single episode DKA and compare with people who have not had DKA. METHODS: Case-controlled study (consecutive adult DKA admissions April 2015 to December 2016) at Western Health, Melbourne. Data were prospectively collected regarding diagnosed mental health disorders, likely depression (Patient Health Questionnaire (PHQ-9)), diabetes distress (Problem Areas in Diabetes (PAID) questionnaire) and presence of adverse social factors. A control group without a history of DKA was also recruited. RESULTS: Of 123 patients admitted with DKA (164 consecutive episodes), 70 consented to participate and 73 age-matched Type 1 diabetes controls were recruited. Eleven (61%) of 18 with recurrent DKA had a diagnosed mental health disorder versus 8 (19%) of 42 in the single episode group (P = 0.016). The prevalence of likely depression using PHQ-9 was: recurrent 50%; single 40%; and controls 22% (recurrent vs controls, P = 0.036; single vs controls, P = 0.053). Severe diabetes distress (PAID) was present in 47% of recurrent and 34% of single episode DKA (P = 0.387). As a group, DKA patients had significantly more unemployment, illicit drug use and tobacco smoking, a lower level of formal education and less regular medical contact compared with controls. CONCLUSIONS: Mental health disorders and adverse socioeconomic factors appear to be common in patients with DKA. The diagnosis of DKA presents an excellent opportunity to screen for depression and offer appropriate intervention.

Modelling the interactions that arise from neural dynamics in seizure genesis is challenging but important in the effort to improve the success of epilepsy surgery. Dynamical network models developed from physiological evidence offer insights into rapidly evolving brain networks in the epileptic seizure. A limitation of previous studies in this field is the dependence on invasive cortical recordings with constrained spatial sampling of brain regions that might be involved in seizure dynamics. Here, we propose virtual intracranial electroencephalography (ViEEG), which combines non-invasive ictal magnetoencephalographic imaging (MEG), dynamical network models and a virtual resection technique. In this proof-of-concept study, we show that ViEEG signals reconstructed from MEG alone preserve critical temporospatial characteristics for dynamical approaches to identify brain areas involved in seizure generation. We show the non-invasive ViEEG approach may have some advantage over intracranial electroencephalography (iEEG). Future work may be designed to test the potential of the virtual iEEG approach for use in surgical management of epilepsy.

Introduction Penicillin allergies are highly prevalent in the healthcare setting and associated with the prescription of second-line inferior antibiotics. More than 85% of all penicillin allergy labels can be removed by skin testing and 96%–99% of low-risk penicillin allergy labels can be removed by direct oral challenge. An internally and externally validated clinical assessment tool for penicillin allergy, PEN-FAST, can identify a low-risk penicillin allergy without the need for skin testing; a score of less than 3 has a negative predictive value of 96.3% (95% CI, 94.1 to 97.8) for the presence of a penicillin allergy. It is hypothesised that PEN-FAST is a safe and effective tool for assessing penicillin allergy in an outpatient clinic setting. Methods and analysis This is an international, multicentre randomised control trial using the PEN-FAST tool to risk-stratify penicillin allergy labels in adult outpatients. The study’s primary objective is to evaluate the non-inferiority of using PEN-FAST score-guided management with direct oral challenge compared with standard care (defined as prick and intradermal skin testing followed by oral penicillin challenge). Participants will be randomised 1:1 to the intervention arm (direct oral penicillin challenge) or standard of care arm (skin testing followed by oral penicillin challenge, if skin testing is negative). The sample size of 380 randomised patients (190 per treatment arm) is required to demonstrate non-inferiority. Ethics and dissemination The study will be performed according to the guidelines of the Helsinki Declaration and is approved by the Austin Health Human Research Ethics Committee (HREC/62425/Austin-2020) in Melbourne Australia, Vanderbilt University Institutional Review Board (IRB #202174) in Tennessee, USA, Duke University Institutional Review Board (IRB #Pro00108461) in North Carolina, USA and McGill University Health Centre Research Ethics Board in Canada (PALACE/2022-7605). The results of this study

OBJECTIVES: This study sought to assess the association between cardiac surgery availability and percutaneous coronary intervention (PCI) volume with clinical outcomes of cardiogenic shock (CS) complicating acute coronary syndrome (ACS). BACKGROUND: CS remains a grave complication of ACS with high mortality rates despite timely reperfusion and improved heart failure therapies. METHODS: The study analyzed data from consecutive patients with CS complicating ACS who underwent PCI and were prospectively enrolled in the VCOR (Victorian Cardiac Outcomes Registry) from 26 hospitals in Victoria. We compared patients treated at cardiac surgical centers (CSCs) versus non-CSCs as well as the annual CS PCI volume (stratified into tiers of <10, 10-25, and >25 cases) for in-hospital major adverse cardiac and cerebrovascular events (MACCE) and long-term mortality. RESULTS: Of 1,179 patients with CS, the mean age of patients was 65 years; males comprised 74%, and 22% had diabetes mellitus. Cardiac arrest occurred in 38% of patients, while 90% presented with ST-segment elevation myocardial infarction and 26% received intra-aortic balloon pump support. Overall, in-hospital and long-term mortality were 42% and 51%, respectively. There was no difference among patients treated non-CSCs compared with a CSCs for in-hospital MACCE and mortality (both P > 0.05). Similarly, there was no association between tiers of annual CS PCI volume with in-hospital MACCE and mortality (both P > 0.05). CONCLUSIONS: Comparable short- and long-term mortality rates among patients with ACS complicated by CS treated by PCI irrespective of cardiac surgery availability and CS PCI volume support the emergent treatment of these gravely ill patients at their presenting PCI-capable hospital.

BACKGROUND: Preclinical studies have shown a therapeutic role of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin and its analogues (rapalogues) on several age-related musculoskeletal disorders (MSKD). However, the applicability to humans of these findings is unknown. OBJECTIVE: To assess the efficacy of rapalogues on age-related MSKD in humans. METHODS: We conducted a systematic review according to the PRISMA guidelines. MEDLINE, EMBase, EMCare, and Cochrane Central Registry of Controlled Trials were searched for original studies examining the effects of rapalogues on outcomes linked to the age-related MSKD in humans. This review is registered in the PROSPERO database (University of New York; registration number CRD42020208167). RESULTS: Fourteen studies met the inclusion criteria and were analyzed. The effect of rapamycin and other rapalogues, including everolimus and temsirolimus, on bone, muscle and joints have been evaluated in humans; however, considerable variability concerning the subjects' age, inclusion criteria, and drug administration protocols was identified. In bone, the use of rapamycin is associated with a decrease in bone resorption markers dependent on osteoclastic activity. In muscle, rapamycin and rapalogues are associated with a reduction in muscle protein synthesis in response to exercise. In the context of rheumatoid arthritis, rapamycin and rapalogues have been associated with clinical improvement and a decrease in inflammatory activity. CONCLUSION: Although there are studies that have evaluated the effect of rapamycin and rapalogues on MSKD in humans, the evidence supporting its use is still incipient, and the clinical implication of these results on the development of osteoporosis, sarcopenia, or osteosarcopenia has not been studied, opening an interesting field for future research.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and interstital lung disease (ILD) are incurable conditions characterised by airflow limitation, persisting respiratory symptoms, and progressive respiratory failure. People living with COPD or ILD often suffer from chronic and severe breathlessness, with limited treatment options and low engagement rates with current therapies. Group singing represents a potential community-based therapy to improve quality of life for patients with COPD or ILD and breathlessness. METHODS: This protocol papers describes SINFONIA, a parallel, double-arm, randomised, blinded-analysis, mixed-methods phase II/III trial of guided, online group singing that will be conducted over 24 months. Adults with confirmed COPD or ILD, on stable treatment for at least four weeks at time of recruitment, with a modified Medical Research Council (mMRC) dyspnoea score of two or greater, who are capable and willing to give consent, and not currently participating in pulmonary rehabilitation will be eligible to participate. Carers may optionally enrol in the trial. Data will be collected on quality of life, anxiety and depression, breathlessness, mastery of breathing, exercise tolerance, loneliness, healthcare utilisation, and carer quality of life (optional). Participants will be randomised 1:1 to intervention or control arms with intervention arm attending one 90 min, guided, online, group singing session per week for 12 weeks and control arm continuing routine care. Phase II of the trial aims to determine the feasibility and acceptability of guided, online group singing and will collect preliminary data on effectiveness. Phase III aims to determine whether guided, online group singing has an effect on quality of life with the primary outcome being a between arm difference in quality of life (36-item Short Form Survey) measured at 12 weeks. DISCUSSION: SINFONIA is the first study is the first of its kind in Australia and to our knowledge, the firs

BACKGROUND: Solid organ transplant recipients (SOTR) are at high risk of keratinocyte carcinoma (KC). Long-term evidence for acitretin as chemoprophylaxis in this population is lacking. OBJECTIVE: To determine the benefit of long-term acitretin for KC chemoprevention in SOTR. METHODS: A retrospective cohort study of SOTR treated with acitretin at an Australian transplant dermatology clinic was performed. General estimating equations were used to evaluate change in rates of histologically confirmed KC in the 6-12 months prior to acitretin and following a minimum 6 months of treatment. A control group of patients within the same service was included, comprising SOTR who were not treated with acitretin. RESULTS: Twenty-two patients received acitretin treatment for at least 6 months, eighteen for at least 5 years and four for at least 9 years. The median KC rate pretreatment was 3.31 per year (IQR 1.93, 5.40). There was a significant reduction in the rate of KC in the first year of acitretin treatment (IRR 0.41, 95% CI 0.22, 0.76, P = 0.005), and this effect was observed for 5 years (IRR at 5 years 0.34, 95% CI 0.17, 0.67, P = 0.002). The control group had no statistically significant change in KC rate over time in the study. CONCLUSIONS: Acitretin appears to be well-tolerated and effective in reducing KC in SOTR for at least 5 years. Study limitations include its retrospective nature, small sample size and lack of blinding.

This cohort study examines a clinical decision model for penicillin allergies among pediatric patients; the model considers when reactions occurred; whether patients experienced angioedema, anaphylaxis, or a severe cutaneous adverse reaction; and whether treatment was required.

BACKGROUND: Patient factors, such as sex and body mass index (BMI), are known to influence patient radiation exposure. Body surface area (BSA) and its association with patient radiation exposure has not been well studied. METHODS AND RESULTS: We analysed height, weight, BMI and BSA in consecutive patients undergoing cardiac catheterisation and percutaneous coronary intervention (PCI) at a high-volume Australian centre between September 2016 and April 2020 to assess their association with dose-area product (DAP, Gycm2). The mean age of the cohort was 64.5 ± 12.3 years with males comprising 68.8% (n = 8100, 5124 diagnostic cardiac catheterisation cases and 2976 PCI cases). Median male BMI was 28.4 kg/m2 [IQR 25.2-32.1] versus 28.8 kg/m2 [24.7-33.7] for females, p = 0.01. Males had higher BSA (2.0 ± 0.2 m2) than females (1.78 ± 0.2 m2), p = 0.001. Each 0.4 m2 increase in BSA conferred a 1.32x fold change in DAP (95% CI 1.29-1.36, p ≤ 0.001). Each 5 kg/m2 increase in BMI was linked to a 1.13x DAP fold change (1.12-1.14, p ≤ 0.001). Male sex conferred a 1.23x DAP fold change (1.20-1.26, p ≤ 0.001). Multivariable modelling with BMI or BSA explained 14% of DAP variance (R2 0.67 vs. 0.53 for both, p ≤ 0.001). CONCLUSIONS: BSA is an important anthropometric measure between the sexes and a key predictor of radiation dose and radiation exposure beyond sex, BMI, and weight.

BACKGROUND: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.

BACKGROUND AND AIMS: Sustained virological suppression and hepatitis B surface antigen (HBsAg) loss have been described after nucleot(s)ide analogue (NA) discontinuation for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We performed a meta-analysis of the clinical outcomes after NA discontinuation for HBeAg-negative CHB. METHODS: Studies involving NA cessation in HBeAg-negative CHB individuals with a median follow-up of ≥12 months were included. Participants were HBeAg-negative at the time of NA initiation. Random effects meta-analyses were performed for the following clinical outcomes: (1) virological relapse (VR) at 6 and 12 months; (2) clinical relapse (CR) at 6 and 12 months and (3) HBsAg loss. Effect of other variables was estimated using subgroup analysis and meta-regression. Studies including patients stopping entecavir (ETV) and/or tenofovir disoproxil fumarate (TDF) were considered separately to studies including patients stopping older generation NA. RESULTS: N=37 studies met inclusion criteria. Cumulative incidence of VR and CR after stopping ETV/TDF was 44% and 17% at 6 months and 63% and 35% at 12 months. Similar relapse rates were observed after stopping older NAs. Among patients stopping ETV/TDF, TDF cessation was associated with increased CR rates at 6 months versus ETV. There was an association between follow-up ≥4 years and HBsAg loss rates when stopping older NAs. Hepatic decompensation and hepatocellular carcinoma were rare but occurred more frequently in studies including cirrhotic individuals. CONCLUSION: VR is common after NA discontinuation, however, CR was only seen in one-third of patients at 12 months. Stopping NA therapy can be followed by HBsAg clearance, and rates are higher with longer follow-up.