Trends in utilization and clinical outcomes with and without the use of distal filter wire embolic protection devices.

BACKGROUND: Embolic protection devices were developed to reduce the risk of common complications encountered during percutaneous coronary intervention (PCI) of saphenous vein grafts, however, in the setting of contemporary multi-modality medical management, their overall efficacy has been called into question. This study aimed to assess the evolving utilization and clinical outcomes associated with distal filter wire embolic protection devices in saphenous vein PCI. METHODS: Consecutive patients undergoing PCI to a saphenous vein graft in a registry were included. Peri-procedural and long-term outcomes including 12-month mortality and 30-day MACCE rates were compared between PCI using a distal filter wire embolic protection device and unprotected PCI. RESULTS: From 2005 to 2020, a total of 753 patients underwent PCI to a saphenous vein graft with 256 using a distal filter wire embolic protection device. At one year, the use of a distal filter wire embolic protection devices was not associated with a decrease in mortality (4.7 % vs 5.4 %, p = 0.19) and there was no difference in 30-day MACCE rates between protected and unprotected saphenous vein PCI (3.1 % vs 5.8 %, p = 0.10). CONCLUSION: In this 12-month analysis of saphenous vein graft PCI, there was no evidence that distal filter wire embolic protection devices improved short term post procedural or long-term mortality outcomes.

Can clinical guidelines reduce variation in transfusion practice? A pre-post study of blood transfusions during cardiac surgery.

BACKGROUND AND OBJECTIVES: Previously published studies have consistently identified significant variation in red blood cell (RBC) transfusions during cardiac surgery. Clinical guidelines can be effective at improving the average quality of care; however, their impact on variation in practice is rarely studied. Herein, we estimated how variation in RBC use across cardiac surgeons changed after the publication of national patient blood management guidelines. MATERIALS AND METHODS: We performed a pre-post study estimating change in variation in RBC transfusions across 80 cardiac surgeons in 29 hospitals using a national cardiac surgery registry. Variation across surgeons was estimated using fixed-effects regressions controlling for surgery and patient characteristics and an empirical Bayes shrinkage to adjust for sampling error. RBC use was measured by three metrics-the total number of units transfused, the proportion of patients transfused and the number of units transfused, conditional on receiving RBC. RESULTS: The primary analysis utilized 35,761 elective cardiac surgeries performed between March 2009 and February 2015 and identified a 24.5% reduction (p < 0.0001) in mean total units transfused accompanied by a 37.2% reduction (p = 0.040) in the variation across surgeons. The reduction in mean total units was driven by both the proportion of patients transfused and the number of units transfused, conditional on receiving RBC, while the reduction in variation was only driven by the latter. CONCLUSION: In our study of RBC transfusions across cardiac surgeons, the surgeons who used more RBC in the pre-guideline period experienced larger reductions in RBC use after the guidelines were published.

National outcomes of cardiac surgery in patients receiving kidney replacement therapy.

BACKGROUND: Studies estimating risks following cardiac surgery for patients receiving kidney replacement therapy have been limited by the size and generalizability of those cohorts. This study used data linked between registries to estimate short-term postoperative outcomes for large patient cohorts receiving kidney replacement therapy at the time of surgery. METHODS: This population-based observational cohort study included adult patients who had undergone cardiac surgery in Australia between 2010 and 2019. Patient data were linked with a kidney replacement therapy registry to accurately identify cohorts and extract relevant data. Multivariable logistic regression estimated risk of operative (30-day) mortality and other postoperative outcomes for long-term dialysis and functioning kidney transplant cohorts compared with each other and the general cardiac surgical population. RESULTS: Of 114,496 surgeries, 1,241 were for patients receiving long-term dialysis and 298 for those with a kidney transplant. The mortality rate was highest for valve-with-coronary artery bypass grafting for dialysis (18.78 per 100 surgeries (95% CI 13.37,25.25) and transplant patients (14.00 [5.82,26.74]). Dialysis patients had higher adjusted odds of mortality (odds ratio [OR] 4.17 [95% CI 3.31,5.25]) and all other measured outcomes than the general population. Kidney transplant recipients had similarly elevated odds of mortality (OR 3.52 [95% CI 2.16,5.72]). CONCLUSIONS: Despite the younger age of dialysis and transplant cohorts at surgery, operative mortality rates were higher, and for valve-with-coronary artery bypass grafting were 3.7- to 5-fold those of the general population. Dialysis patients were a high risk for cardiac surgery, and the prognosis for kidney transplant recipients was similarly poor.

Polygenic risk, aspirin and primary prevention of coronary artery disease.

AIMS: Recent aspirin primary prevention trials failed to identify a net benefit of aspirin for preventing cardiovascular disease versus the harms of bleeding. This study aimed to investigate whether a high-risk subgroup, individuals with elevated genetic predisposition to coronary artery disease (CAD), might derive more benefit than harm with aspirin, compared to those with lower genetic risk. METHODS AND RESULTS: We performed genetic risk stratification of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial using a CAD polygenic risk score (GPSMult). For 12,031 genotyped participants (5,974 aspirin, 6,057 placebo) overall, we stratified them by GPSMult quintiles (q1-5), then examined risk of CAD (composite of myocardial infarction and coronary heart disease death) and bleeding events using Cox models. During a median 4.6 years of follow-up with randomization to 100 mg/day aspirin versus placebo, 234 (1.9%) participants had CAD and 373 (3.1%) had bleeding events. In the overall cohort, aspirin resulted in higher bleeding risk (adjusted Hazard Ratio [aHR]=1.30 [1.06-1.61], P=0.01) but no significant CAD reduction (aHR=0.84 [0.64-1.09], P=0.19). However, among the highest quintile of polygenic risk (q5, top 20% of the GPSMult distribution), there was a 47% reduction in risk of CAD events with aspirin (aHR=0.53 [0.31-0.90], P=0.02) without increased bleeding risk (aHR=1.05 [0.60-1.82], P=0.88). Interaction between the GPSMult and aspirin was significant for CAD (q5 versus q1, P=0.02) but not bleeding (P=0.80). CONCLUSION: The balance between net benefit and harm on aspirin in the primary prevention setting shifts favourably in individuals with an elevated genetic predisposition.

Coronary artery bypass grafting vs. percutaneous coronary intervention in severe ischaemic cardiomyopathy: long-term survival.

BACKGROUND AND AIMS: The optimal revascularization strategy in patients with ischaemic cardiomyopathy remains unclear with no contemporary randomized trial data to guide clinical practice. This study aims to assess long-term survival in patients with severe ischaemic cardiomyopathy revascularized by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). METHODS: Using the Australian and New Zealand Society of Cardiac and Thoracic Surgeons and Melbourne Interventional Group registries (from January 2005 to 2018), patients with severe ischaemic cardiomyopathy [left ventricular ejection fraction (LVEF) <35%] undergoing PCI or isolated CABG were included in the analysis. Those with ST-elevation myocardial infarction and cardiogenic shock were excluded. The primary outcome was long-term National Death Index-linked mortality up to 10 years following revascularization. Risk adjustment was performed to estimate the average treatment effect using propensity score analysis with inverse probability of treatment weighting (IPTW). RESULTS: A total of 2042 patients were included, of whom 1451 patients were treated by CABG and 591 by PCI. Inverse probability of treatment weighting-adjusted demographics, procedural indication, coronary artery disease extent, and LVEF were well balanced between the two patient groups. After risk adjustment, patients treated by CABG compared with those treated by PCI experienced reduced long-term mortality [adjusted hazard ratio 0.59, 95% confidence interval (CI) 0.45-0.79, P = .001] over a median follow-up period of 4.0 (inter-quartile range 2.2-6.8) years. There was no difference between the groups in terms of in-hospital mortality [adjusted odds ratio (aOR) 1.42, 95% CI 0.41-4.96, P = .58], but there was an increased risk of peri-procedural stroke (aOR 19.6, 95% CI 4.21-91.6, P < .001) and increased length of hospital stay (exponentiated coefficient 3.58, 95% CI 3.00-4.28, P < .001) in patients treated with CABG. CONCLUSIONS: In this multi-centre IPTW analysis, patients with severe ischaemic cardiomyopathy undergoing revascularization by CABG rather than PCI showed improved long-term survival. However, future randomized controlled trials are needed to confirm the effect of any such benefits.

Outcomes After Percutaneous Coronary Intervention in Patients with Prior Coronary Artery Bypass Grafting.

In patients with prior CABG requiring subsequent PCI there is uncertainty whether bypass grafts or native coronary arteries should be targeted. We analysed data from 2,764 patients with prior CABG in the Melbourne Interventional Group registry (2005-2018), divided into two groups: those undergoing PCI to a native vessel (n=1,928) and those with PCI to a graft vessel (n=836).Patients with a graft vessel PCI were older, had more high-risk clinical characteristics (prior MI, heart failure, ejection fraction <50%, renal impairment, peripheral and cerebrovascular disease), and high-risk procedural features (ACC/AHA types B2/C lesions). However, patients in the native vessel group were more likely to have PCI to chronic total occlusions. The majority of graft PCI were to saphenous vein grafts (84%), with 10% to radial and 6% to LIMA/RIMA grafts. Distal embolic protection devices were used in 30% of graft PCI. Patients with graft PCI had higher rates of no reflow (6.3 vs. 1.5%; p<0.001), coronary perforation (p=0.02), and inpatient stent thrombosis (p=0.03). However, 30-day mortality and major adverse cardiovascular and cerebrovascular events (MACCE) were similar. Unadjusted long-term mortality (median follow up 4.8 years) was higher in patients who had undergone a graft PCI (44 vs. 32%, p<0.001), but following Cox proportional hazards modelling, PCI vessel type was not a predictor of long-term mortality (HR 1.13; 95% CI 0.96-1.33, p=0.14). In conclusion, early clinical outcomes and risk-adjusted long-term mortality are similar for patients with prior CABG undergoing PCI to a native vessel or a bypass graft.

Slc35a2 mosaic knockout impacts cortical development, dendritic arborisation, and neuronal firing.

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an important cause of drug-resistant epilepsy. A significant subset of individuals diagnosed with MOGHE display somatic mosaicism for loss-of-function variants in SLC35A2, which encodes the UDP-galactose transporter. We developed a mouse model to investigate how disruption of this transporter leads to a malformation of cortical development. We used in utero electroporation and CRISPR/Cas9 to knockout Slc35a2 in a subset of layer 2/3 cortical neuronal progenitors in the developing brains of male and female fetal mice to model mosaic expression. Mosaic Slc35a2 knockout was verified through next-generation sequencing and immunohistochemistry of GFP-labelled transfected cells. Histology of brain tissue in mosaic Slc35a2 knockout mice revealed the presence of upper layer-derived cortical neurons in the white matter. Reconstruction of single filled neurons identified altered dendritic arborisation with Slc35a2 knockout neurons having increased complexity. Whole-cell electrophysiological recordings revealed that Slc35a2 knockout neurons display reduced action potential firing, increased afterhyperpolarisation duration and reduced burst-firing when compared with control neurons. Mosaic Slc35a2 knockout mice also exhibited significantly increased epileptiform spiking and increased locomotor activity. We successfully generated a mouse model of mosaic Slc35a2 deficiency, which recapitulates features of the human phenotype, including impaired neuronal migration. We show that knockout in layer 2/3 cortical neuron progenitors is sufficient to disrupt neuronal excitability, increase epileptiform activity and cause hyperactivity in mosaic mice. Our mouse model provides an opportunity to further investigate the disease mechanisms that contribute to MOGHE and facilitate the development of precision therapies.

Clinical outcomes and coronary artery lesion characteristics of young patients with ST elevation myocardial infarction and no standard modifiable risk factors.

BACKGROUND: Among ST-elevation myocardial infarction (STEMI) patients, those with no standard modifiable risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia, and smoking) have higher 30-day mortality than those with SMuRFs. Differences in coronary lesion characteristics remain unclear. METHODS: Data from STEMI patients aged ≤60 years from the Asia Pacific Evaluation of Cardiovascular Therapies Network (Australia, Hong Kong, Malaysia, Singapore, and Vietnam) was retrospectively analysed. Exclusion criteria included incomplete SMuRF data, prior myocardial infarction, or prior coronary revascularisation. Lesion type was defined using the American College of Cardiology criteria. Major adverse cardiovascular events (MACE) were defined as peri-procedural myocardial infarction, emergency coronary artery bypass surgery, cerebrovascular event, or mortality. Multiple logistic regressions were used. RESULTS: Of 4404 patients, 767 (17.4%) were SMuRFless. SMuRFless patients were more frequently younger (median age 51 vs. 53 years; p < 0.001), female (22.6% vs. 15.5%; p < 0.001), thrombolysed (20.1% vs. 12.5%; p < 0.001), and in cardiogenic shock (11.2% vs. 8.6%; p = 0.020). SMuRFless patients had significantly higher in-hospital MACE (7.2% vs. 4.3%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 1.24-4.08; p = 0.008) but 1-year mortality was not significantly different (3.6% vs. 5.7%, aOR 0.58; 95% CI 0.06-6.12; p = 0.549). Compared with patients with SMuRFs (4918 lesions), the SMuRFless (940 lesions) had fewer type B2/C lesions (60.8% vs. 65.6%; p = 0.020) and fewer lesions ≥20 mm (51.1% vs. 57.1%; p = 0.002) but more procedural complications (5.1% vs. 2.7%; p < 0.001). CONCLUSIONS: Among young STEMI patients, the SMuRFless have shorter and less complex lesions, but worse procedural and short-term MACE outcomes.

Antihypertensive medications and dementia in older adults with hypertension.

Background: Studies on middle-aged or individuals with cognitive or cardiovascular impairments, have established that intensive blood pressure (BP) control reduces cognitive decline risk. However, uncertainty exists on differential effects between antihypertensive medications (AHM) classes on this risk, independent of BP-lowering efficacy, particularly in community-dwelling hypertensive older adults. Methods: A post-hoc analysis of the ASPREE study, a randomized trial of low-dose aspirin in adults aged 70+ years (65+ if US minorities) without baseline dementia, and followed for two years post-trial. Cox proportional-hazards regression models were used to estimate associations between baseline and time-varying AHM exposure and incident dementia (an adjudicated primary trial endpoint), in participants with baseline hypertension. Subgroup analyses included prespecified factors, APO ε4 carrier status and monotherapy AHM use. Results: Most hypertensive participants (9,843/13,916; 70.7%) used AHMs. Overall, 'any' AHM use was not associated with lower incident dementia risk, compared with untreated participants (HR 0.84, 95%CI 0.70-1.02, p=0.08), but risk was decreased when angiotensin receptor blockers (ARBs) were included (HR 0.73, 95%CI 0.59-0.92, p=0.007). ARBs and ß-blockers decreased dementia risk, whereas angiotensin-converting enzyme inhibitors (ACEIs) and diuretics increased risk. There was no association with RAS modulating or blood-brain-barrier crossing AHMs on dementia risk. Conclusions: Overall, AHM exposure in hypertensive older adults was not associated with decreased dementia risk, however, specific AHM classes were with risk direction determined by class; ARBs and ß-blockers were superior to ACEIs and other classes in decreasing risk. Our findings emphasize the importance of considering effects beyond BP-lowering efficacy when choosing AHM in older adults.

Obstructive Sleep Apnea and Cerebral Small Vessel disease in Community-based Older People: An ASPREE Imaging Substudy.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) may increase risk of dementia. A potential pathway for this risk is through cerebral small vessel disease (CSVD). In the context of an existing randomized trial of aspirin for primary prevention, we aimed to investigate OSA's impact on CSVD imaging measures and explore whether aspirin effects these measures over 3 years that differ in the presence or absence of OSA. METHODS: A sub-study of the ASPirin in Reducing Events in the Elderly randomized placebo-controlled trial of low-dose aspirin. Community-dwelling participants aged 70 years and above, without cognitive impairment, cardiovascular disease or known OSA completed an unattended limited-channel sleep study that calculated the oxygen desaturation index and apnea-hypopnea index. At baseline and 3 years later, volumes of white matter hyperintensities (WMH) and silent brain infarctions (SBI) were measured on 1.5 Tesla brain magnetic resonance imaging, and retinal vessel calibers were calculated from retinal vascular imaging. RESULTS: Mild and moderate/severe OSA was detected in 48.9% and 29.9%, respectively, of the 311 participants, who had a mean age of 73.7 years (SD 3.4 years), 38.6% female. OSA of any severity did not associate with WMH volumes, SBI, nor with retinal vessel calibers at baseline, nor with change in these measures in the 277 participants with repeated measures acquired after 3 years. OSA of any severity did not interact with aspirin on change in these measures over 3 years. CONCLUSION: In healthy older adults undiagnosed OSA was not associated with retinal vascular calibers and neuroimaging measures of CSVD.

Daily low-dose aspirin and blood pressure in community-dwelling older adults.

High-quality randomized trial evidence is lacking on whether low-dose aspirin exerts significant effects on blood pressure (BP) in older adults. The authors assessed longitudinal BP changes in participants enrolled in ASPirin in Reducing Events in the Elderly (ASPREE), a randomized, placebo-controlled trial of 100 mg daily aspirin in 19 114 community-dwelling Australian and U.S. adults without cardiovascular disease (CVD), dementia, or independence-limiting physical disability. Participants' BP was recorded at baseline and annual study visits, and managed by their usual care provider. BP trajectories for aspirin versus placebo during 4.7 years of follow-up were examined for systolic and diastolic BP separately, using linear mixed models to account for between and within-individual variability in BP. Analyses by subgroups were also explored with inclusion of interaction terms in the models. The difference in mean change in systolic BP between aspirin and placebo during study follow-up was -0.03 mm Hg (95% confidence interval [CI]: -0.13, 0.07; p = .541) (aspirin minus placebo), while the mean difference for change in diastolic BP was -0.05 mm Hg (95% CI: -0.11, 0.01; p = .094). These small, non-significant differences in BP change between the aspirin and placebo groups were consistent across baseline levels of BP and antihypertensive treatment status (treated/untreated). Likewise, subgroups of age, sex, chronic kidney disease, diabetes, and frailty revealed no interaction effect between the subgroup, aspirin treatment, and time. Interval-censored Cox proportional hazards regression showed no difference in rates of incident treated hypertension between aspirin and placebo-treated participants. The authors conclude that daily low-dose aspirin does not significantly affect BP in older adults when managed by usual care.

Immediate and delayed flap reconstruction have equivalent outcomes and associated costs following soft tissue sarcoma surgery.

BACKGROUND AND OBJECTIVES: Surgical treatment of soft tissue sarcoma (STS) involves wide resection of the tumor, which can necessitate soft tissue reconstruction with local or free tissue flaps. This retrospective study compares cost, surgical and oncologic outcomes between patients undergoing reconstruction with immediate versus delayed flap coverage following STS resection. METHODS: Thirty-four patients who underwent planned flap reconstruction following resection of primary STS were identified retrospectively. Twenty-four (71%) received immediate reconstruction during the index surgery and 10 (29%) underwent planned delayed reconstruction. Preoperative patient-specific metrics, tumor characteristics, and surgical and patient outcomes were collected. Total hospital charges associated with every encounter during the perioperative period were obtained. RESULTS: Patient demographics, comorbidities, tumor metrics, and surgical characteristics were equivalent between groups. Postoperative wound complications, reoperations, readmissions, and disease-specific survival did not differ between cohorts. Costs associated with each reconstruction strategy were equivalent on bivariate and multivariate testing, when accounting for operating room time, hospital length of stay, and reoperation rate. CONCLUSIONS: Our study identifies no significant difference in patient outcome measures or cost between planned immediate and delayed flap reconstruction following STS resection. These results support the implementation of either treatment strategy in keeping with patient-centered, multidisciplinary care principles.

The impact of stress testing to guide PCI in patients with chronic coronary disease.

BACKGROUND: Guidelines and international appropriate use criteria increasingly endorse non-invasive stress testing to evaluate patients with suspected chronic coronary disease (CCD). We sought to review the real-world utilisation of non-invasive stress testing and investigate whether their use prior to PCI associates with outcomes in patients with CCD. METHODS: Consecutive patients from a multicentre registry who underwent PCI for CCD between 2006 and 2018 were included. Clinical characteristics and outcomes were stratified according to whether stress testing was performed prior to PCI (stress vs no-stress groups). The primary outcome was 3-year all-cause mortality. RESULTS: Among the 8251 patients included, 4970 (60.2 %) underwent pre-PCI stress testing and this proportion increased over time (p-for-trend<0.001). The stress group had a lower prevalence of prior revascularization, myocardial infarction, or heart failure, and a lower incidence of triple vessel disease, in stent re-stenosis, and ACC/AHA class B2/C lesions (all p < 0.001). When comparing post-procedural outcomes, the stress group had lower rates of arrhythmia (1.5 % vs 2.6 %, p = 0.001), new heart failure (0.2 % vs 0.8 %, p = 0.001), renal impairment, and a shorter length of stay (1.6 vs 2.1 days, p < 0.001). Mortality at 3-years was lower in those undergoing PCI following stress testing (5.8 % vs 8.8 %, p < 0.001). After adjusting for key clinical variables, stress guided revascularization was associated with a significantly lower risk of 3-year mortality (adjusted Hazard Ratio 0.77, 95 % CI 0.64-0.92). CONCLUSIONS: In patients with CCD, PCI guided by non-invasive stress testing is increasingly utilized and associated with improved survival. Further studies are necessary to investigate whether this results from differences in patient characteristics, optimized patient selection, or refined choice of target vessel.

Counseling Intervention and Cardiovascular Events in People With Peripheral Artery Disease: A Post Hoc Analysis of the BIP Randomized Clinical Trial.

Importance: It is unclear whether counseling to promote walking reduces the risk of major adverse cardiovascular events (MACE) in people with peripheral artery disease (PAD). Objective: To test whether a counseling intervention designed to increase walking reduced the risk of MACE in patients with PAD. Design, Setting, and Participants: The BIP trial was a randomized clinical trial, with recruitment performed between January 2015 and July 2018 and follow-up concluded in August 2023. Participants with walking impairment due to PAD from vascular departments in the Australian cities of Brisbane, Sydney, and Townsville were randomly allocated 1:1 to the intervention or control group. Data were originally analyzed in March 2024. Intervention: Four brief counseling sessions aimed to help patients with the challenges of increasing physical activity. Main Outcomes and Measures: The primary outcome was the between-group difference in risk of MACE, which included myocardial infarction (MI), stroke, and cardiovascular death. The relationship between Intermittent Claudication Questionnaire (ICQ) scores, PAD Quality of Life (PADQOL) scores, and MACE was examined with Cox proportional hazard regression analyses. Results: A total of 200 participants were included, with 102 allocated to the counseling intervention (51.0%) and 98 to the control group (49.0%).Participants were followed up for a mean (SD) duration of 3.5 (2.6) years. Median (IQR) participant age was 70 (63-76) years, and 56 of 200 participants (28.0%) were female. A total of 31 individuals had a MACE (composed of 19 MIs, 4 strokes, and 8 cardiovascular deaths). Participants allocated to the intervention were significantly less likely to have a MACE than participants in the control group (10 of 102 participants [9.8%] vs 21 of 98 [21.4%]; hazard ratio [HR], 0.43; 95% CI, 0.20-0.91; P = .03). Greater disease-specific quality of life (QOL) scores at 4 months (ICQ: HR per 1-percentage point increase, 0.97; 95% CI, 0.95-0.99; P < .001; PADQOL factor 3 [symptoms and limitations in physical functioning]: HR per 1-unit increase, 0.91; 95% CI, 0.84-0.98; P = .01) and at 12 months (ICQ: HR per 1-percentage point increase, 0.97; 95% CI, 0.95-0.99; P = .003; PADQOL factor 3: HR per 1-unit increase, 0.91; 95% CI, 0.84-0.98; P = .02) were associated with a lower risk of MACE. In analyses adjusted for ICQ or PADQOL factor 3 scores at either 4 or 12 months, allocation to the counseling intervention was no longer significantly associated with a lower risk of MACE. Conclusions and Relevance: This post hoc exploratory analysis of the BIP randomized clinical trial suggested that the brief counseling intervention designed to increase walking may reduce the risk of MACE, possibly due to improvement in QOL. Trial Registration: anzctr.org.au Identifier: ACTRN12614000592640.

Innervated breast reconstruction: a narrative review of neurotization techniques and outcomes.

Background and Objective: While significant sensation recovery improvements in neurotized breasts following reconstruction have been reported, sensation testing methods and surgical techniques have been widely variable. This narrative review aims to summarize available literature on current neurotization practices and sensory recovery outcomes in patients undergoing innervated breast reconstruction. Methods: A comprehensive literature search of PubMed Medline, Web of Science, and Embase was conducted to identify all studies reporting outcomes of neurotization in breast reconstruction surgeries. Data analyzed included operative times, neurotization techniques, sensory outcomes, and methods as well as patient reported outcomes. Key Content and Findings: Despite the heterogeneity of various studies reviewed, all forms of neurotization achieved earlier and superior sensory recovery throughout the reconstructed breast skin compared to non-innervated breasts. In absence of randomized controlled trials or high-quality comparative studies, further evidence is required to objectively confirm this technique offers better sensory recovery. Conclusions: Neurotization at the time of breast reconstruction may lead to improved sensation and patient reported outcomes delineating improved quality of life compared to non-innervated breasts. Future studies need to standardize the way that breast sensation is measured and determine pre-operative variables leading to expected changes in final sensation recovery to help manage surgical outcome expectations of both the surgeon and the patient.

Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Bi-National Outcomes of Redo Surgical Aortic Valve Replacement in the Era of Valve-in-Valve Transcatheter Aortic Valve.

BACKGROUND: Implantation of bioprosthetic valves is more common as the population ages and there is a shift towards implanting bioprosthetic aortic valves in an increasingly younger surgical population. Bioprosthetic heart valve insertion, however, carries the long-term risk of valve failure through structural valve degeneration. Re-operative surgical aortic valve replacement has historically been the only definitive management option for patients with prosthetic valve dysfunction, however, data on the short- and long-term outcomes following re-operative surgery in Australia and New Zealand is limited. METHOD: Data on all patients who underwent redo aortic valve surgery, over a 20-year period (up to 2021) was obtained from the Australian and New Zealand Society of Cardiothoracic Surgery Registry. RESULTS: A total of 1,199 patients (770 males; 64.2% and 429 females; 35.8%) were included in the overall analysis. The 30-day mortality was 6.4% with operative urgency status the most important risk factor for peri-operative mortality. The long-term survival rate of 1,145 patients was 90.5% (95% confidence interval [CI] 88.8%-92.3%), 77% (95% CI 73.9%-80.2%) and 57.2% (95% CI 55.2%-62.8%) at 1-, 5- and 10-years post-procedure, respectively, with a median survival of 12.7 years. Pre-existing chronic kidney disease was strongly associated with poorer long-term survival. For patients under 70 years of age the 1-, 5- and 10-year survival rates were 92.9% (95% CI 90.9%-95.1%), 83.6% (95% CI 80.1%-87.3%) and 73.1% (95% CI 67.4%-79.3%), respectively. CONCLUSIONS: The results from this registry study indicate that in Australia and New Zealand, a repeat surgical aortic valve replacement can result in a relatively low mortality rate, serving as a reference point for medical procedures in these regions.

Impact of elevated fine particulate matter (PM 2.5 ) during landscape fire events on cardiorespiratory hospital admissions in Perth, Western Australia.

BACKGROUND: Australia has experienced extreme fire weather in recent years. Information on the impact of fine particulate matter (PM 2.5 ) from landscape fires (LFs) on cardiorespiratory hospital admissions is limited. METHODS: We conducted a population-based time series study to assess associations between modelled daily elevated PM 2.5 at a 1.5×1.5 km resolution using a modified empirical PM 2.5 exposure model during LFs and hospital admissions for all-cause and cause-specific respiratory and cardiovascular diseases for the study period (2015-2017) in Perth, Western Australia. Multivariate Poisson regressions were used to estimate cumulative risk ratios (RR) with lag effects of 0-3 days, adjusted for sociodemographic factors, weather and time. RESULTS: All-cause hospital admissions and overall cardiovascular admissions increased significantly across each elevated PM 2.5 concentration on most lag days, with the strongest associations of 3% and 7%, respectively, at the high level of ≥12.60 µg/m3 on lag 1 day. For asthma hospitalisation, there was an excess relative risk of up to 16% (RR 1.16, 95% CI 1.00 to 1.35) with same-day exposure for all people, up to 93% on a lag of 1 day in children and up to 52% on a lag of 3 days in low sociodemographic groups. We also observed an increase of up to 12% (RR 1.12, 95% CI 1.02 to 1.24) for arrhythmias on the same exposure day and with over 154% extra risks for angina and 12% for heart failure in disadvantaged groups. CONCLUSIONS: Exposure to elevated PM 2.5 concentrations during LFs was associated with increased risks of all-cause hospital admissions, total cardiovascular conditions, asthma and arrhythmias.

WONOEP appraisal: Modeling early onset epilepsies.

Epilepsy has a peak incidence during the neonatal to early childhood period. These early onset epilepsies may be severe conditions frequently associated with comorbidities such as developmental deficits and intellectual disability and, in a significant percentage of patients, may be medication-resistant. The use of adult rodent models in the exploration of mechanisms and treatments for early life epilepsies is challenging, as it ignores significant age-specific developmental differences. More recently, models developed in immature animals, such as rodent pups, or in three-dimensional organoids may more closely model aspects of the immature brain and could result in more translatable findings. Although models are not perfect, they may offer a more controlled screening platform in studies of mechanisms and treatments, which cannot be done in pediatric patient cohorts. On the other hand, more simplified models with higher throughput capacities are required to deal with the large number of epilepsy candidate genes and the need for new treatment options. Therefore, a combination of different modeling approaches will be beneficial in addressing the unmet needs of pediatric epilepsy patients. In this review, we summarize the discussions on this topic that occurred during the XVI Workshop on Neurobiology of Epilepsy, organized in 2022 by the Neurobiology Commission of the International League Against Epilepsy. We provide an overview of selected models of early onset epilepsies, discussing their advantages and disadvantages. Heterologous expression models provide initial functional insights, and zebrafish, rodent models, and brain organoids present increasingly complex platforms for modeling and validating epilepsy-related phenomena. Together, these models offer valuable insights into early onset epilepsies and accelerate hypothesis generation and therapy discovery.

Different fluorescent labels report distinct components of spHCN channel voltage sensor movement.

We used voltage clamp fluorometry to probe the movement of the S4 helix in the voltage-sensing domain of the sea urchin HCN channel (spHCN) expressed in Xenopus oocytes. We obtained markedly different fluorescence responses with either ALEXA-488 or MTS-TAMRA covalently linked to N-terminal Cys332 of the S4 helix. With hyperpolarizing steps, ALEXA-488 fluorescence increased rapidly, consistent with it reporting the initial inward movement of S4, as previously described. In contrast, MTS-TAMRA fluorescence increased more slowly and its early phase correlated with that of channel opening. Additionally, a slow fluorescence component that tracked the development of the mode shift, or channel hysteresis, could be resolved with both labels. We quantitated this component as an increased deactivation tail current delay with concomitantly longer activation periods and found it to depend strongly on the presence of K+ ions in the pore. Using collisional quenching experiments and structural predictions, we established that ALEXA-488 was more exposed to solvent than MTS-TAMRA. We propose that components of S4 movement during channel activation can be kinetically resolved using different fluorescent probes to reveal distinct biophysical properties. Our findings underscore the need to apply caution when interpreting voltage clamp fluorometry data and demonstrate the potential utility of different labels to interrogate distinct biophysical properties of voltage-gated membrane proteins.