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Thora Y Chai,1– 3 Karen Byth,2,4 Jacob George,2,5,6 Dharmintra Pasupathy,3 N Wah Cheung1– 3 1Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, Australia; 2Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; 3Reproduction and Perinatal Centre, The University of Sydney, Sydney, NSW, Australia; 4Western Sydney Local Health District Research Education Network, Westmead, NSW, Australia; 5Storr Liver Centre, Westmead Millennium Institute for Medical Research, Westmead, NSW, Australia; 6Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW, AustraliaCorrespondence: Thora Y Chai, Email thora.chai@sydney.edu.auObjective: To determine whether an elevated hepatic steatosis index (HSI), a non-invasive test for possible metabolic dysfunction-associated fatty liver disease (MAFLD), is associated with the development of adverse pregnancy outcomes.Material and Methods: A retrospective cohort study was conducted on adult women with singleton pregnancies who delivered at two tertiary hospitals from August 2014 to December 2017. Aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) levels obtained 12 months pre-gravid, or during pregnancy but prior to screening for gestational diabetes mellitus (GDM), were extracted and linked with oral glucose tolerance test results. The HSI was calculated using the following equation: 8 × (ALT/AST ratio) + BMI (+2 if female; +2 if diabetes mellitus present) and considered elevated if > 36. Multiple logistic regression analysis was used to quantify the association between elevated HSI and each composite adverse pregnancy outcome after adjusting for independent maternal risk factors.Results: Over 40-months, 11929 women were eligible and of these, 1885 had liver enzymes collected. Women with an elevated HSI (> 36) were more likely multiparous and overweight/obese compared to those women with a non–elevated HSI (≤ 36). Elevated HSI was significantly associated with a composite of adverse maternal outcomes (adjusted odds ratio (aOR) 1.55 95% CI 1.11– 2.17, p=0.01), although a non-significant increased risk of a composite of adverse neonatal outcomes occurred after multivariable adjustment (aOR 1.17, 95% CI 0.94– 1.45, p=0.17).Conclusion: Over and above known maternal risk factors, women with elevated HSI were more likely to develop adverse maternal, but not adverse neonatal outcomes.Keywords: liver steatosis, pregnancy outcomes, liver function tests, maternal health, neonatal health

Rate of disease progression (ΔFS), measured as change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and body mass index (BMI), are predictors of survival in amyotrophic lateral sclerosis (ALS). Our aim in this study was to assess the utility of these clinical biomarkers along with neurophysiological measures, such as the split hand index (SI), in monitoring disease progression.Clinical trial data were collected from 107 patients recruited into the Tecfidera in ALS trial. The prognostic utility of clinical and neurophysiological measures, including ΔFS, BMI, SI, and neurophysiological index (NPI), were assessed cross-sectionally and longitudinally (40 weeks). The outcome measures of disease severity and progression included: (i) ALSFRS-R score; (ii) Medical Research Council (MRC) score; and (iii) forced vital capacity and sniff nasal inspiratory pressure.Fast-progressor ALS patients (ΔFS ≥1.1) exhibited significantly lower ALSFRS-R and total MRC scores at baseline. A baseline ΔFS score ≥1.1 was associated with a greater reduction in ALSFRS-R (P = .002) and MRC (P = .002) scores over 40 weeks. Baseline BMI25 was also associated with faster reduction of ALSFRS-R and MRC scores. SI and NPI were associated with disease severity at baseline, but not with subsequent rate of disease progression.Implementation of the assessed clinical and neurophysiological biomarkers may assist in patient management and stratification into clinical trials.

Endoscopic mucosal resection (EMR) is a cornerstone in the management of large (≥20 mm) non-pedunculated colorectal polyps. Clinically significant post-EMR bleeding occurs in 7% of cases and is most frequently encountered in the right colon. We aimed to assess the use of prophylactic clip closure in preventing clinically significant post-EMR bleeding within the right colon.We conducted a randomised controlled trial at a tertiary centre in Australia. Patients referred for the EMR of large non-pedunculated colorectal polyps in the right colon were eligible. Patients were randomly assigned (1:1) into the clip or control (no clip) group, using a computerised random-number generator. The primary endpoint was clinically significant post-EMR bleeding, defined as haematochezia necessitating emergency department presentation, hospitalisation, or re-intervention within 14 days post-EMR, which was analysed on the basis of intention-to-treat principles. The trial is registered with ClinicalTrials.gov, NCT02196649, and has been completed.Between Feb 4, 2016, and Dec 15, 2020, 231 patients were randomly assigned: 118 to the clip group and 113 to the control group. In the intention-to-treat analysis, clinically significant post-EMR bleeding was less frequent in the clip group than in the control group (four [3·4%] of 118 patients vs 12 [10·6%] of 113; p=0·031; absolute risk reduction 7·2% [95% CI 0·7-13·8]; number needed to treat 13·9). There were no differences between groups in adverse events, including delayed perforation (one [1%] in the clip group vs one [1%] in the control group) and post-EMR pain (four [3%] vs six [5%]). No deaths were reported.Prophylactic clip closure can be performed following the EMR of large non-pedunculated colorectal polyps of 20 mm or larger in the right colon to reduce the risk of clinically significant post-EMR bleeding.None.

BackgroundLocal anesthetic wound infusion catheters are increasingly used postmidline laparotomy to reduce pain and opioid use, however there is little evidence to support any particular infusion regime.MethodsA retrospective cohort study was undertaken of patients after midline laparotomy who had bilateral local anesthetic wound infusion catheters surgically placed. Patients were recruited into 3 cohorts: ropivacaine 0.2% 5–8 mL/hour continuous wound infusion, 10 mL programmed intermittent bolus 2 hourly, 20 mL programmed intermittent bolus 4 hourly. The primary outcome was the maximum daily Numerical Rating Pain Score with movement (dynamic pain score) recorded during first 96 hours postprocedure. Secondary outcomes included the maximum daily resting pain score and opioid utilization.ResultsIn three cohorts of 70 patients (n=210), the maximum daily dynamic pain score in the intermittent bolus 2-hourly and 4-hourly cohorts was lower when compared with the continuous infusion group over the first 4 postoperative days. The mean difference in maximum daily pain score with respect to the continuous infusion regime was 0.8 (95% CI 0.2 to 1.4) for the intermittent bolus 2-hourly group and 0.6 (95% CI 0.0 to 1.2) for the 4-hourly group. Generalized estimating equation modeling indicates the reduction in dynamic pain score is greatest with the intermittent bolus 2-hourly regime over the first 72 hours postprocedure. The 2-hourly intermittent bolus regime was also associated with lower opioid utilization and local anesthetic exposure.ConclusionsIntermittent wound infusion catheter infusion regimes were associated with lower maximum daily dynamic pain scores, although the magnitude of this change may be of limited clinical significance.

Supplementary Figure S1 from Poor-Prognosis Estrogen Receptor–Positive Breast Cancer Identified by Histopathologic Subclassification

Supplementary Data from Molecular Grading of Ductal Carcinoma In situ of the Breast

Purpose: Increased incidence of ductal carcinoma in situ (DCIS) associated with mammographic screening for breast cancer has emphasized the challenges of managing this condition. The aim of this study was to identify informative clinical indicators of DCIS biology by molecular profiling.Experimental Design: Areas of in situ carcinoma, atypical ductal hyperplasia, and benign epithelium were microdissected from 46 invasive breast cancers. Oligonucleotide probes showing differential expression between DCIS associated with grade 1 and 3 invasive cancer were identified by microarray-based gene expression profiling. Expression at these probes was used to define a “molecular grade” subcategorization of all samples. The genomic basis of molecular grade was examined by array-based comparative genomic hybridization. Clinical course was examined in a cohort of 134 patients with DCIS treated by surgery alone.Results: DCIS samples were designated as low or high molecular grade based on expression at 173 probes. The low molecular grade subgroup included low (n = 10) and intermediate (n = 11) nuclear grade DCIS as well as all samples of atypical ductal hyperplasia (n = 4) and benign epithelium (n = 7). The high molecular grade subgroup included DCIS of intermediate (n = 7) and high (n = 19) nuclear grade. The character and degree of genomic aberration were distinct between molecular grade subgroups. A classification tree model including nuclear grade and Ki67 score accurately predicted molecular grade for 95.7% of samples. In an independent cohort, this showed a pattern of rapid disease recurrence for high molecular grade DCIS.Conclusions: Molecular profiling indicates a binary grading scheme for DCIS. This practical approach has potential to improve clinical evaluation of DCIS.

Purpose: Identification of biologically and clinically distinct breast cancer subtypes could improve prognostic assessment of primary tumors. The characteristics of “molecular” breast cancer subtypes suggest that routinely assessed histopathologic features in combination with limited biomarkers may provide an informative classification for routine use.Experimental Design: Hierarchical cluster analysis based on components of histopathologic grade (tubule formation, nuclear pleomorphism, and mitotic score), expression of ER, cytokeratin 5/6, and HER2 amplification identified four breast cancer subgroups in a cohort of 270 cases. Cluster subgroup membership was compared with observed and Adjuvant! Online predicted 10-year survival. Survival characteristics were confirmed in an independent cohort of 300 cases assigned to cluster subgroups using a decision tree model.Results: Four distinct breast cancer cluster subgroups (A-D) were identified that were analogous to molecular tumor types and showed a significant association with survival in both the original and validation cohorts (P < 0.001). There was a striking difference between survival for patients in cluster subgroups A and B with ER+ breast cancer (P < 0.001). Outcome for all tumor types was well estimated by Adjuvant! Online, with the exception of cluster B ER+ cancers where Adjuvant! Online was too optimistic.Conclusions: Breast cancer subclassification based on readily accessible pathologic features could improve prognostic assessment of ER+ breast cancer.

Purpose: Compare differences in serum and follicular fluid thyroid hormone levels in euthyroid versus levothyroxine-replaced women undergoing controlled ovarian hyperstimulation. Methods: Prospective cohort study involving 46 euthyroid (anti-TPO antibody negative) and 16 levothyroxine-replaced women with baseline TSH < 2.5 mIU/L attending a university-based reproductive medical centre. TSH, free T3 and T4 measurements (serum and follicular fluid) were measured at various time points across controlled ovarian stimulation and numbers of mature oocytes retrieved, fertilisation and pregnancy rates were compared between groups. Results: Median TSH levels were similar at baseline, 1.76 vs 1.24 mIU/L (p=0.053), but free T3 levels were lower (4.5 vs 4.8 pmol/L, p=0.029) in levothyroxine-replaced compared with euthyroid (anti-TPO antibody) women. Serum TSH levels in levothyroxine-replaced women increased across controlled ovarian hyperstimulation (p=0.006) and remained significantly higher than baseline (p=0.030) at pregnancy testing. Follicular fluid free T3 levels were lower in levothyroxine-replaced (median 4.3 vs 4.6 pmol/L, p=0.032) and fertilisation rates fewer (52% vs 71%, p=0.043). Numbers of mature oocytes retrieved, early pregnancy loss and live birth rates did not differ. Conclusion: Levothyroxine women, with baseline TSH levels < 2.5 mIU/L, have lower serum and follicular fluid free T3 levels and poorer fertilisation rates than euthyroid women undergoing a cycle of controlled ovarian stimulation.

Background Cardiac rehabilitation (CR) programs reduce the risk of further cardiac events and improve the ability of people living with cardiovascular disease to manage their symptoms. However, many people who experience a cardiac event do not attend or fail to complete their CR program. Little is known about the characteristics of people who drop out compared to those who complete CR. Aims To identify subgroups of patients attending a cardiac rehabilitation program who are more likely to dropout prior to final assessment by (1) calculating the dropout rate from the program, (2) quantifying the association between dropout and socio-demographic, lifestyle, and cardiovascular risk factors, and (3) identifying independent predictors of dropout. Methods The study population is from a large metropolitan teaching hospital in Sydney, Australia, and consists of all participants consecutively enrolled in an outpatient CR program between 2006 and 2017. Items assessed included diagnoses and co-morbidities, quality of life (SF-36), psychological health (DASS-21), lifestyle factors and physical assessment. Dropout was defined as failure to complete the outpatient CR program and post CR assessment. Results Of the 3,350 patients enrolled in the CR program, 784 (23.4%; 95%CI: 22.0–24.9%) dropped out prior to completion. The independent predictors of dropout were smoking (OR 2.4; 95%CI: 1.9–3.0), being separated or divorced (OR 2.0; 95%CI: 1.5–2.6), younger age (

Objectives This study hypothesized that catheter ablation in healthy ovine ventricular myocardium using low ionic 0.45% saline (half-normal saline [HNS]) and nonionic 5% dextrose in water (D5W) would result in larger lesions compared with use of 0.9% saline (normal saline [NS]). Background Limited data exist regarding the safety and efficacy of catheter ablation using low and nonionic irrigants. Methods Open irrigated ablation was performed on 14 beating ovine hearts (NS, n = 5; HNS, n = 4; D5W, n = 5). Ablation was delivered by using identical parameters (ie, 30 W in power control mode, 60-second duration, contact force of 10-20 g in the endocardial ventricles and 5-10 g in the epicardium). Catheter orientation and tissue contact were optimized by using intracardiac echocardiography. Lesion width, depth, and volume and number of steam pops were compared. Results Overall, 196 lesions were analyzed (mean duration: 56.7 ± 8.3 seconds; mean contact force: 15.3 ± 6.1 g; and mean impedance drop: 31 ± 19.1 Ω). Compared with NS, HNS and D5W resulted in larger lesion volumes (NS 349.2 ± 245.1 mm3 vs HNS 645.7 ± 386.4 mm3 vs D5W 633.2 ± 387.1 mm3; HNS vs NS; P Conclusions Catheter ablation with HNS and D5W resulted in larger ablation lesions compared with NS but similar lesion dimensions between HNS and D5W. The increase in lesion size with HNS and D5W was associated with a higher incidence of steam pops, especially with D5W, compared with NS.

ObjectiveEndoscopic mucosal resection (EMR) in the colon has been widely adopted, but there is limited data on the histopathological effects of the differing electrosurgical currents (ESCs) used. We used an in vivo porcine model to compare the tissue effects of ESCs for snare resection and adjuvant margin ablation techniques.DesignStandardised EMR was performed by a single endoscopist in 12 pigs. Two intersecting 15 mm snare resections were performed. Resections were randomised 1:1 using either a microprocessor-controlled current (MCC) or low-power coagulating current (LPCC). The lateral margins of each defect were treated with either argon plasma coagulation (APC) or snare tip soft coagulation (STSC). Colons were surgically removed at 72 hours. Two specialist pathologists blinded to the intervention assessed the specimens.Results88 defects were analysed (median 7 per pig, median defect size 29×17 mm). For snare ESC effects, 156 tissue sections were assessed. LPCC was comparable to MCC for deep involvement of the colon wall. For margin ablation, 172 tissue sections were assessed. APC was comparable to STSC for deep involvement of the colon wall. Islands of preserved mucosa at the coagulated margin were more likely with APC compared with STSC (16% vs 5%, p=0.010).ConclusionFor snare resection, MCC and LPCC did not produce significantly different tissue effects. The submucosal injectate may protect the underlying tissue, and technique may more strongly dictate the depth and extent of final injury. For margin ablation, APC was less uniform and complete compared with STSC.

BackgroundABG samples are often obtained in trauma patients to assess shock severity. Venous blood gas (VBG) sampling, which is less invasive, has been widely used to assess other forms of shock. The study aim was to determine the agreement between VBG and ABG measurements in trauma.MethodsPatients were enrolled at an Australian trauma centre between October 2016 and October 2018. Bland-Altman limits of agreement (LOA) between paired blood gas samples taken ResultsDuring the study period 176 major trauma patients had valid paired blood gas samples available for analysis. The median time difference between paired measurements was 11 min (IQR 6–17). There was a predominance of men (81.8%) and blunt trauma (92.0%). Median Injury Severity Score was 13 (range 1–75) and inpatient mortality was 6.3%. Mean difference (ABG−VBG) and LOA between paired arterial and venous measurements were 0.036 (LOA −0.048 to 0.120) for pH, −1.27 mmol/L (LOA −4.35 to 1.81) for BD, −0.64 mmol/L (LOA −1.86 to 0.57) for lactate and −1.97 mmol/L (LOA −5.49 to 1.55) for bicarbonate. Independent assessment of the VBG ‘false negative’ cases (n=20) suggested an ABG would change circulatory management in two cases.ConclusionsIn trauma patients VBG and ABG parameters displayed suboptimal agreement. However, in cases flagged as VBG ‘false negative’ independent review indicated that the availability of an ABG was unlikely to change management.

Patients with chronic kidney disease (CKD) are at increased risk of adverse cardiovascular events, which is underestimated by traditional risk stratification algorithms. We sought to determine clinical and echocardiographic predictors of adverse outcomes in CKD patients.Two hundred forty-three prospectively recruited stage 3/4 CKD patients (male, 63%; mean age, 59.2 ± 14.4 years) without previous cardiac disease made up the study cohort. All participants underwent a transthoracic echocardiogram, with left ventricular (LV) and left atrial (LA) strain analysis. Participants were followed for 3.9 ± 2.7 years for the primary end point of cardiovascular death and major adverse cardiovascular event (MACE). The secondary end point was the composite of all-cause death and MACE.Fifty-four patients met the primary end point, and 65 the secondary end point. On log-rank tests, older age, diabetes mellitus, anemia, greater LV mass, reduced LV global longitudinal strain, larger indexed LA volume, higher E/e' ratio, and reduced LA reservoir strain (LASr; P .01 for all) were independent predictors of cardiovascular death and MACE. On multivariable regression analysis of univariate predictors, LASr (P .01) was the only independent predictor for the primary end point as well as for the secondary end point. Receiver operating characteristic curve analysis showed LASr was a stronger predictor of adverse events (area under the curve [AUC] = 0.84) compared to the Framingham (AUC = 0.58) and Atherosclerotic Cardiovascular Disease (AUC = 0.59) risk scores.LASr is an independent predictor of cardiovascular death and MACE in CKD patients, superior to clinical risk scores, LV parameters, and LA volume.

Left atrial strain (LAS) on transthoracic echocardiogram (TTE) is increasingly recognised to have clinical utility in cardiovascular disease. Differences in LAS measurements between vendors remains a barrier for clinical use. We sought to compare LAS between two commonly used software platforms; the layer-specific endocardial and mid-myocardial measurements of LAS on General Electric (GE) Echopac were compared to TomTec strain. LAS was measured in 88 individuals with no previous cardiac history and 40 paroxysmal AF (PAF) patients, in sinus rhythm at TTE. Conventionally, LAS measured using GE Echopac is mid-myocardial strain (GE-mid); additionally, endocardial (GE-endo) LAS was evaluated. Both LAS measurements by GE were compared to TomTec-Arena (v2.30.02) measurements. Reservoir (ƐR), contractile (ƐCT) and conduit (ƐCD) phasic strain were evaluated. Both GE-mid and GE-endo LAS correlated well with TomTec LAS. On Bland–Altman analysis, GE-mid LAS measurements were systematically lower than TomTec LAS (ƐR: mean difference (MD) − 6.08%, limits of agreement (LOA) − 12%, 0%, ƐCT: MD − 0.8%, LOA − 7%, 5%, ƐCD: MD − 5.2% LOA − 12%, 1%). GE-endo LAS demonstrated no systematic difference from TomTec LAS, but had wider limits of agreement (ƐR: MD 0.41%, LOA − 7%, 8%, ƐCT: MD 0.50%, LOA − 6%, 7%, ƐCD: MD − 0.08%, LOA − 7%, 7%). ƐR had the best reproducibility. Mid-myocardial LAS, routinely evaluated by GE Echopac software, systematically underestimates LAS compared to TomTec. Using GE endocardial LAS eliminated this bias, but introduced greater variation between measurements. Serial measurements of LAS should therefore be performed on the same vendor system.

To determine the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its association on adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM).380 women with GDM had a FibroScan® performed between 24 and 32 weeks. A Controlled Attenuation Parameter (CAP) ≥ 233.5 dB/m signified MAFLD. Gestational hypertension, pre-eclampsia and eclampsia contributed to a composite of adverse maternal outcomes. A composite of adverse neonatal outcomes included pre-term birth, hypoglycaemia, small/large-for-gestational age and admission to neonatal high dependency. Multiple logistic regression was used to determine independent associations with MAFLD.147 (38.7 %) women had MAFLD. Higher pre-pregnancy BMI (median 28.4, IQR 24.7-33.0 kg/mWithin this GDM cohort, almost 40% had FibroScan®-detected MAFLD in mid-to-late gestation. MAFLD was not associated with worse pregnancy outcomes.

BACKGROUND Left atrial (LA) deformation during the reservoir phase (LASr) has demonstrated strong prognostic value in different clinical settings. Although determinants of left atrial reservoir strain including left atrial relaxation, left atrial compliance, and left ventricular longitudinal systolic function are fairly well defined, there is incomplete information regarding the effect of left atrial volume on this relationship which is the focus of our study. METHOD Consecutive patients without prior cardiac disease referred for transthoracic echocardiography were prospectively recruited. All participants underwent clinical assessment, transthoracic echocardiography (TTE), and screening exercise stress test. Only patients with normal left ventricular ejection fraction (LVEF) without left ventricular hypertrophy (LVH) or myocardial ischemia on stress testing were included. RESULTS A total of 260 patients (57% male, mean age 59 ± 14 years) were included. 70% had hypertension, 33% had diabetes mellitus, and 31% had both HTN and DM. On multivariate analysis, age, e', LAVI, and LV GLS (P

ObjectiveLarge (≥20 mm) sessile serrated lesions (L-SSL) are premalignant lesions that require endoscopic removal. Endoscopic mucosal resection (EMR) is the existing standard of care but carries some risk of adverse events including clinically significant post-EMR bleeding and deep mural injury (DMI). The respective risk-effectiveness ratio of piecemeal cold snare polypectomy (p-CSP) in L-SSL management is not fully known.DesignConsecutive patients referred for L-SSL management were treated by p-CSP from April 2016 to January 2020 or by conventional EMR in the preceding period between July 2008 and March 2016 at four Australian tertiary centres. Surveillance colonoscopies were conducted at 6 months (SC1) and 18 months (SC2). Outcomes on technical success, adverse events and recurrence were documented prospectively and then compared retrospectively between the subsequent time periods.ResultsA total of 562 L-SSL in 474 patients were evaluated of which 156 L-SSL in 121 patients were treated by p-CSP and 406 L-SSL in 353 patients by EMR. Technical success was equal in both periods (100.0% (n=156) vs 99.0% (n=402)). No adverse events occurred in p-CSP, whereas delayed bleeding and DMI were encountered in 5.1% (n=18) and 3.4% (n=12) of L-SSL treated by EMR, respectively. Recurrence rates following p-CSP were similar to EMR at 4.3% (n=4) versus 4.6% (n=14) and 2.0% (n=1) versus 1.2% (n=3) for surveillance colonoscopy (SC)1 and SC2, respectively.ConclusionsIn a historical comparison on the endoscopic management of L-SSL, p-CSP is technically equally efficacious to EMR but virtually eliminates the risk of delayed bleeding and perforation. p-CSP should therefore be considered as the new standard of care for L-SSL treatment.

Grindr is a geolocation smartphone application popular among men who have sex with men (MSM) to find sexual partners. We conducted a study to assess if attendance and HIV testing amongst MSM increased due to advertisements on Grindr that promoted our service. We measured clinic website hits by users clicking through from Grindr; we counted self-reported registrations that nominated referral from Grindr; and we compared new patient attendances and HIV tests in MSM with heterosexual men, for the 18 months preceding the intervention and the 18 months of the intervention. During the intervention the clinic’s website received 11,799 unique hits from Grindr users. The average monthly rate of attendances by new MSM increased 70.3% from 19.0 to 32.3, compared with a 5.5% increase among new heterosexual men from 45.6 to 48.1. The average monthly rate of HIV tests among MSM increased 43.6% from 47.0 to 67.6, compared with a 3.9% increase amongst heterosexual men from 40.0 to 41.6. The MSM:heterosexual men rate ratio for new patient attendances changed from 0.42 to 0.67 ( p

Distinguishing between primary and secondary subtypes of membranous glomerulonephritis (MGN) is critical for its clinical management. We prospectively compared direct immunofluorescence (DIF) staining for phospholipase A2 receptor (PLA2R) on frozen renal biopsy with the presence of detectable serum PLA2R antibody assessed by enzyme linked immunosorbent assay (ELISA) in the diagnosis of primary MGN. Forty-six patients with biopsy-proven MGN were enrolled from April 2017 to June 2019 with 31/46 (67.4%) being primary and 15/46 (32.6%) being secondary as determined by comprehensive clinical assessment. This is currently deemed to be the gold standard for distinguishing primary from secondary MGN. Amongst the 31 primary MGN patients, 24/31 were positive on PLA2R DIF staining compared to 18/31 being positive on the PLA2R ELISA (p=0.03). Amongst the 15 secondary MGN patients, 1/15 was positive on PLA2R DIF compared to 0/15 on PLA2R ELISA (p=1.0). In conclusion, the presence of PLA2R staining on DIF demonstrated superior sensitivity and similar specificity compared to the detection of circulating PLA2R antibodies by ELISA in the diagnosis of primary MGN in a cohort of 46 patients with biopsy-proven MGN. We suggest that DIF should be considered as part of routine work-up in all newly diagnosed cases of MGN.

BACKGROUND As the availability of Mohs micrographic surgery (MMS) continues to expand in Australia and incidence of keratinocyte cancer increases in adolescents and young adults, there has been rising interest in the use of MMS in this population. OBJECTIVE This study aimed to evaluate the characteristics of MMS cases in patients younger than 40 years. METHODS A review was performed of all MMS cases in patients younger than 40 years at the time of their surgery from 2012 to 2017 at the Skin and Cancer Foundation Australia, with comparison to a control group, aged older than 40 years. Patient, tumor and management characteristics were analyzed. RESULTS Four hundred ninety-three cases were eligible. Study and control groups differed significantly regarding gender (p < .001), tumor pathology (p < .001), anatomic site of tumor (p < .001), Mohs surgery stages (p = .039), defect size (p < .001), and repair method (p < .001). LIMITATIONS Retrospective study at a single institution. CONCLUSION Mohs micrographic surgery cases in patients younger than 40 years exhibit unique patient and tumor characteristics influencing choice of repair method.

Background Research should inform clinical decision-making and evidence-based practice for all health professionals. To build research capacity among all health professionals, there is a need to measure the levels of research capacity and identify the gaps and needs of health-care professionals. The aim of the study was to better understand the research culture and capacity of health professionals (medical, nursing and allied health) in Western Sydney Local Health District, Sydney, Australia. Methods A research capacity and culture tool (RCCT) survey was electronically distributed to all health staff in WSLHD. Data were collected between November 2016 and January 2017. Participants were surveyed through a 10-point Likert scale that measured research capacity at the individual, team and organisational levels. Results A total of 393 health staff responded to the study: allied health practitioners (46.3%), nursing staff (35.4%) and medical practitioners (18.3%). Females made 76% of the sample, and 54% were aged between 35 and 54 years. Individual responses were different across professions, with an average median score for medical 6.3 (95% CI 5.8-6.9), allied health 5.3 (95% CI 4.9-5.7) and nursing 4.5 (95% CI 4.1-5.0) after adjustment for age and gender. Team responses for medical staff (average median score 5.9 95% CI 5.3-6.4) were higher than allied health (4.1 95% CI 3.7-4.6) and nursing (4.3 95% CI 3.8-4.8), after adjusting for age and gender. However, there were no differences between the three professions for the organisational responses. Allied health and nursing staff were less confident in obtaining research funding, submitting ethics applications, writing for publication and mentoring colleagues about research. Conclusion This study demonstrates the individual research capacity for medical, allied health and nursing professionals are different. Research capacity building needs to be individually tailored to the specific needs of each profession. This research will inform future capacity building activities and training for health professionals in a large public health organisation of Sydney, Australia.

Metabolic dysfunction-associated fatty liver disease (MAFLD) can develop in any patient, including those with chronic hepatitis C (CHC). The recently proposed diagnostic criteria for MAFLD provide a unique opportunity to investigate the impact of concomitant fatty liver in patients with another established cause for their liver disease. The objective of our study was to assess the characteristics and outcomes of patients with a dual etiology liver disease.We evaluated 1181 patients including 744 with CHC and 437 with MAFLD. All patients in both cohorts underwent liver biopsy indicating disease activity and fibrosis stage.Nearly half (43.1%) the patients with CHC had concomitant MAFLD. Comparing patients with CHC alone with those with a dual etiology disease, we found that the latter had more severe liver injury, hepatic inflammation and fibrosis (all P 0.001). Interestingly, lean or normal-weight patients with CHC and MAFLD had a similar fibrosis stage compared to the two other subgroups of MAFLD (obesity and/or diabetes mellitus). There was no statistical significance in hepatic steatosis and fibrosis between genotype 3 CHC and MAFLD group compared to other genotypes.Patients with CHC and concomitant MAFLD had more severe liver disease than those with viral hepatitis alone. Recognizing coexisting MAFLD in patients with CHC is important for the delivery of holistic care.

The risk of cancer in large nonpedunculated colorectal polyps ≥20 mm (LNPCPs) in the rectum relative to the remainder of the colon is unknown. We aimed to describe differences between rectal and colonic LNPCPs to better inform treatment decisions.Patients with LNPCPs referred to tertiary centers for endoscopic resection within a prospective, multicenter, observational cohort were evaluated. Data recorded were participant demographics, LNPCP location, morphology, resection modality, and histopathologic data. Multiple logistic regression analysis was used to identify those variables independently associated with rectal versus nonrectal location in the colon.Patients with LNPCPs referred for endoscopic resection between July 2008 and July 2021 were included. Rectal LNPCPs (n = 618) were larger (median size, 40 mm vs 30 mm; P .001) and more likely to be granular (79% vs 50%, P .001) with a nodular component (53% vs 17%, P .001) compared with nonrectal LNPCPs (n = 2787). Rectal LNPCPs were more likely to have tubulovillous histopathology (72% vs 47%, P .001) and contain cancer (15% vs 6%, P .001). After adjusting for the other features independently associated with location, cancer was more common in the rectum compared with the colon (odds ratio, 1.77; 95% confidence interval, 1.25-2.53).This study suggests that compared with LNPCPs in the rest of the colon, rectal LNPCPs are more likely to be larger and contain more advanced pathology. These findings have implications for curative endoscopic resection techniques particularly where early cancer is present. (Clinical trial registration numbers: NCT01368289 and NCT02000141.).

Objective: To determine the impact of a peer-led, school-based programme (Students As LifeStyle Activists; SALSA) on energy balance–related behaviours (EBRBs) in Grade 8 students, and the cost of implementing the programme. Design: Pre–post test Setting: High schools in New South Wales, Australia. Methods: Grade 10 students (15- to 16-year-olds) were trained by university students to deliver four lessons on healthy eating and physical activity to Grade 8 students (13- to 14-year-olds). Students completed an online questionnaire pre–post lessons on EBRBs and intentions to change EBRBs over the next month. Items included fruit, vegetable and sugar-sweetened beverage (SSB) intake, frequency of eating breakfast, participation in moderate-to-vigorous physical activity (MVPA) and school-day recreational screen-time. Pre–post changes were analysed using generalised estimating equations, adjusted for clustering. Standard methods were used to estimate implementation costs. Results: In total, 2,056 Grade 8 students from 23 high schools participated. Significant changes included 5.2% increase in eating >2 fruit serves/day ( p 4 vegetable serves/day ( p Conclusion: The SALSA peer education programme had a positive impact on most of the dietary EBRBs examined. The cost evaluation showed that it is a relatively low-cost programme to implement.

IntroductionMechanical cardiopulmonary resuscitation (M-CPR) is increasingly used in the management of cardiac arrest. There are no previously reported randomised studies investigating M-CPR training. This study of newly trained M-CPR providers hypothesised that a brief simulation-based intervention after 4 months would improve M-CPR performance at 6 months.MethodsThis study used a simulated ‘in situ’ cardiac arrest model. The M-CPR device used was a proprietary Lund University Cardiac Assist System 3 machine (Physio Control, Redmond, Washington, USA). Standardised baseline training was provided to all participants. Following training, baseline performance was assessed. The primary outcome measure was the time taken to initiate M-CPR and the secondary outcome was performance against a checklist of errors. Participants were then randomised to intervention group (simulation training) or control group (routine clinical use of M-CPR). After 6 months the outcome measures were reassessed. Comparative statistical tests used an intention-to-treat analysis.Results112 participants were enrolled. The intervention group (n=60) and control group (n=52) had similar demographic characteristics. At the 6-month assessment, median time to M-CPR initiation was 27.0 s (IQR 22.0–31.0) in the intervention group and 31.0 s (IQR 25.6–46.0) in the control group (p=0.003). The intervention group demonstrated fewer errors compared with controls at 6 months (pConclusionIn this randomised study of approaches to M-CPR training, providers receiving additional simulation-based training had higher retention levels of M-CPR skills. Therefore, when resuscitation skills are newly learnt, provision follow-up training should be an important consideration.

Background and Aims Clinically significant post-EMR bleeding (CSPEB) is the most-frequent serious adverse event after EMR of large laterally spreading colonic lesions (LSLs). There is no proven prophylactic therapy, and it remains a significant drawback of EMR. We aimed to systematically describe and evaluate the features of the post-EMR mucosal defect (PED) and their relationship to CSPEB. Methods A prospective study of LSLs referred for EMR at a tertiary center was performed. PEDs without visible features were recorded as bland blue. Nonbland blue (NBB) PED features included size, number, and herniation of submucosal vessels and presence of submucosal hemorrhage, fibrosis, fat, and exposed muscle. NBB PEDs were analyzed for association with CSPEB, defined as bleeding occurring after completion of the procedure necessitating readmission or reintervention. Results From April 2012 to May 2017, 501 lesions in 501 patients were eligible for analysis. The frequency of CSPEB was 30 of 501 (6.0%). More than or equal to 3 visible vessels was a significant predictor of CSPEB (P = .016). None of the following showed a significant correlation with CSPEB: presence of visible vessels, their diameter, herniation, or other nonvascular PED features. Submucosal vessels were more common in the left-sided colon segment (88.6% vs 78.3%, P = .004) and were significantly larger (20.8% vs 12.1% ≥1 mm, P = .037), more numerous (median 4 vessels [interquartile range, 2-7] vs 2 vessels [interquartile range, 1-4], P Conclusions More than or equal to 3 visible vessels within the PED may be predictive for CSPEB and may define a target group for real-time prophylactic intervention. No other endoscopically visible features of the PEDs were predictive of CSPEB. (Clinical trial registration number: NCT03117400 .)

ObjectiveThe aim of the study was to assess the utility of a novel amyotrophic lateral sclerosis (ALS) diagnostic index (ALSDI).MethodsA prospective multicenter study was undertaken on patients presenting with suspected ALS. The reference standard (Awaji criteria) was applied to all patients at recruitment. Patients were randomly assigned to a training (75%) and a test (25%) cohort. The ALSDI was developed in the training cohort and its diagnostic utility was subsequently assessed in the test cohort.ResultsA total of 407 patients were recruited, with 305 patients subsequently diagnosed with ALS and 102 with a non-ALS mimicking disorder. The ALSDI reliably differentiated ALS from neuromuscular disorders in the training cohort (area under the curve 0.92, 95% confidence interval 0.89–0.95), with ALSDI ≥4 exhibiting 81.6% sensitivity, 89.6% specificity, and 83.5% diagnostic accuracy. The ALSDI diagnostic utility was confirmed in the test cohort (area under the curve 0.90, 95% confidence interval 0.84–0.97), with ALSDI ≥4 exhibiting 83.3% sensitivity, 84% specificity, and 83.5% diagnostic accuracy. In addition, the diagnostic utility of the ALSDI was confirmed in patients who were Awaji negative at recruitment and in those exhibiting a predominantly lower motor neuron phenotype.ConclusionThe ALSDI reliably differentiates ALS from mimicking disorders at an early stage in the disease process.Classification of evidenceThis study provides Class I evidence that for patients with suspected ALS, the ALSDI distinguished ALS from neuromuscular mimicking disorders.

Iodine supplements are recommended for women planning pregnancy, but their impact on thyroid function during controlled ovarian hyperstimulation (COH) and into pregnancy is unknown. The aim of this study was to assess the impact of iodine supplementation on thyroid function during COH.One-hundred and six euthyroid women (thyroid stimulating hormone (TSH) 0.4-2.5 mIU/L) planning their first COH cycle were subdivided according to iodine supplementation (nil,6 months, ≥6 months) and compared to levothyroxine (LT4)-treated controls. Serial TSH, free thyroxine, free triiodothyronine and thyroglobulin (Tg) levels were recorded at four time points: (i) baseline, (ii) day 7 ovarian stimulation, (iii) ovulation trigger and (iv) two weeks post oocyte retrieval. Oocyte numbers, fertilisation rates and pregnancy outcome were recorded.TSH increased during COH for those women taking iodine supplements for ≥6 months (P = 0.025). One quarter recorded a TSH level2.5 mIU/L before embryo transfer. A similar increase in TSH was demonstrated by LT4-dependent controls (P = 0.024) but not the remaining subgroups. Tg levels did not change during COH in any group but decreased significantly post oocyte retrieval if nil iodine (P 0.0001) or supplemented for ≥6 months (P 0.005). Iodine supplementation did not influence oocyte count, fertilisation or implantation rates. Women taking iodine for6 months were four times more likely to achieve a live birth than women taking iodine for longer.Women taking iodine supplements for ≥6 months are less able to adapt to the thyroidal demands of COH, with responses comparable to LT4-dependent patients.

Background Subclinical left ventricular dysfunction detected by 2‐dimensional global longitudinal strain post breast radiotherapy has been described in patients with breast cancer. We hypothesized that left ventricular dysfunction postradiotherapy may be site specific, based on differential segmental radiotherapy dose received. Methods and Results Transthoracic echocardiograms were performed at baseline, 6 weeks, and 12 months postradiotherapy on 61 chemotherapy‐naïve women with left‐sided breast cancer undergoing tangential breast radiotherapy. Radiation received within basal, mid, and apical regions for the 6 left ventricular walls was quantified from the radiotherapy treatment planning system. Anterior, anteroseptal, and anterolateral walls received the highest radiation doses, while inferolateral and inferior walls received the lowest. There was a progressive increase in the radiation dose received from basal to apical regions. At 6 weeks, the most significant percentage deterioration in strain was seen in the apical region, with greatest reductions in the anterior wall followed by the anteroseptal and anterolateral walls, with a similar pattern persisting at 12 months. There was a within‐patient dose–response association between the segment‐specific percentage deterioration in strain at 6 weeks and 12 months and the radiation dose received. Conclusions Radiotherapy for left‐sided breast cancer causes differential segmental dysfunction, with myocardial segments that receive the highest radiation dose demonstrating greatest strain impairment. Percentage deterioration in strain observed 6 weeks postradiotherapy persisted at 12 months and demonstrated a dose–response relationship with radiotherapy dose received. Radiotherapy‐induced subclinical cardiac dysfunction is of importance because it could be additive to chemotherapy‐related cardiotoxicity in patients with breast cancer. Long‐term outcomes in patients with asymptomatic strain reduction require further investigation.

Objective To investigate the pattern of change in muscle overactivity during repetitive grasp/release using dynamic computerized dynamometry (DCD; objective 1) and the effect of botulinum toxin A (BTX-A; objective 2). Design Secondary analysis of an observational cohort study. Setting Hospital outpatient spasticity management service. Participants A convenience sample (N=65), comprising adults with upper motor neuron syndrome affecting the arm after acquired brain injury (ABI; n=38) and participants without ABI (n=27). Interventions After clinical assessment, a subgroup of participants with ABI (n=28) underwent BTX-A injections as part of their spasticity management. Main Outcome Measures Post hoc DCD data processing extracted the values of minimum force generation between 10 sequential contractions. The pattern of change was analyzed. Results The ABI injected group exerted greater force at baseline than both other groups (ABI injected=1.04 kg, ABI noninjected=0.74 kg, participants without ABI=0.53 kg; P=.011). After the first contraction, minimum force values increased for all groups and were greatest in the ABI injected group. With subsequent cycles, the group without ABI showed a linear pattern of decreasing force generation, whereas both ABI groups showed a quadratic increasing pattern, which was of greater magnitude in the ABI injected group. After injection, values for the ABI injected group showed a 51% reduction in inducible muscle overactivity (P=.003) to magnitudes similar to those of the ABI noninjected group. Conclusions This study showed that hand relaxation deteriorated during repetitive movements in people with spasticity, a feature hypothesized to adversely influence everyday hand function. After BTX-A injection, the magnitude but not the pattern of this inducible muscle overactivity improved.

Background While multidisciplinary teams (MDTs) are now considered an essential part of cancer care decision-making, how they perform varies widely. The authors hypothesised that a comprehensive, multipronged improvement program, and associated annual member survey, could strengthen MDT performance across a whole cancer service. Methods The study comprised the introduction of a structured program, the Tumour Program Strengthening Initiative (TPSI) linked with an annual survey of member’s perceptions of their performance. Three iterations of the survey have been completed (2017, 2018 and 2019). Generalised estimating equations (GEEs) were used to test for a difference in the proportion of positive survey responses between 2017 and 2019 adjusted for team clustering. Results Twelve teams participated in TPSI. One hundred twenty-nine, 118 and 146 members completed the survey in 2017, 2018 and 2019, respectively. Of the 17 questions that were asked in all three years, nine showed significant improvement and, of these, five were highly significant. Documenting consensus, developing Terms of Reference (TORs), establishing referral criteria and referring to clinical practice guidelines showed most improvement. Questions related to patient considerations, professional development and quality improvement (QI) activities showed no significant change. Conclusions TPSI resulted in sustained and significant improvement. The MDT survey not only allowed MDT members to identify their strengths and weaknesses but also provided insights for management to flag priority areas for further support. Overall program improvement reflected the strengthening of the weakest teams as well as further improvement in highly performing MDTs. Importantly, the initiative has the potential to achieve behaviour change amongst clinicians.

Most clinical studies, which investigate the impact of therapy simultaneously, record the frequency of adverse events in order to monitor safety of the intervention. Study reports typically summarise adverse event data by tabulating the frequencies of the worst grade experienced but provide no details of the temporal profiles of specific types of adverse events. Such 'toxicity profiles' are potentially important tools in disease management and in the assessment of newer therapies including targeted treatments and immunotherapy where different types of toxicity may be more common at various times during long-term drug exposure. Toxicity profiles of commonly experienced adverse events occurring due to exposure to long-term treatment could assist in evaluating the costs of the health care benefits of therapy. We show how to generate toxicity profiles using an adaptation of the ordinal time-to-event model comprising of a two-step process, involving estimation of the multinomial response probabilities using multinomial logistic regression and combining these with recurrent time to event hazard estimates to produce cumulative event probabilities for each of the multinomial adverse event response categories. Such a model permits the simultaneous assessment of the risk of events over time and provides cumulative risk probabilities for each type of adverse event response. The method can be applied more generally by using different models to estimate outcome/response probabilities. The method is illustrated by developing toxicity profiles for three distinct types of adverse events associated with two treatment regimens for patients with advanced breast cancer.

Background Left atrial (LA) function plays a pivotal role in modulating left ventricular performance. The aim of our study was to evaluate the relationship between resting LA function by strain analysis and exercise capacity in patients with chronic kidney disease (CKD) and evaluate its utility compared with exercise E/e'. Methods and Results Consecutive patients with stage 3 and 4 CKD without prior cardiac history were prospectively recruited from outpatient nephrology clinics and underwent clinical evaluation and resting and exercise stress echocardiography. Resting echocardiographic parameters including E/e' and phasic LA strain (LA reservoir [LASr], conduit, and contractile strain) were measured and compared with exercise E/e'. A total of 218 (63.9±11.7 years, 64% men) patients with CKD were recruited. Independent clinical parameters associated with exercise capacity were age, estimated glomerular filtration rate, body mass index, and sex ( P P P P =0.20 on DeLong test). A model combining LASr and clinical metrics showed robust association with metabolic equivalents achieved in patients with CKD. Conclusions LASr, a marker of decreased LA compliance is an independent correlate of exercise capacity in patients with stage 3 and 4 CKD, with similar diagnostic value to exercise E/e'. Thus, LASr may serve as a resting biomarker of functional capacity in this population.