Lipid nanoparticle mRNA therapy improves survival and reduces serum branched-chain amino acids in mouse models of maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare, inherited, metabolic disorder characterized by dysfunction of the multi-subunit, mitochondrial enzyme complex branched-chain alpha-keto acid dehydrogenase (BCKDH). BCKDH catalyzes the oxidative decarboxylation of branched-chain amino acids (BCAAs). BCAAs and their neurotoxic alpha-keto intermediates can accumulate in the blood and tissues in the absence of functional BCKDH. We evaluated a lipid nanoparticle (LNP)-based treatment approach to address all possible genetic mutations that can cause MSUD (BCKDHA, BCKDHB, and DBT). In the intermediate MSUD mouse model, which harbors a mutation in the dihydrolipoamide branched-chain transacylase E2 (DBT) subunit of BCKDH, repeated administration of LNP-encapsulated mRNA therapy significantly extended survival and reduced serum leucine levels. We also evaluated our LNP approach in several models of classic MSUD, namely DBT knockout (KO) mice and the new BCKDHA KO and BCKDHB KO mice. The latter two were generated by CRISPR/Cas9 gene editing and contain the highly prevalent classic MSUD-causing mutations seen in the Mennonite and Costa Rican populations. Intravenous LNP-encapsulated mRNA administration extended survival and increased body weight in the DBT KO and BCKDHA KO models of classic MSUD but was not effective in BCKDHB KO mice. Our data provide a promising proof-of-concept that a universal, mutation-independent approach to treating MSUD is possible and viable.

A comparative analysis of ChatGPT, ChatGPT-4 and Google Bard performances at the Advanced Burn Life Support Exam.

Artificial intelligence and Large Language Models (LLM) have recently gained attention as promising tools in various healthcare domains, offering potential benefits in clinical decision-making, medical education and research. The Advanced Burn Life Support (ABLS) program is a didactic initiative endorsed by the American Burn Association, aiming to provide knowledge on the immediate care of the severely burn patient. The aim of the study was to compare the performance of three LLMs (ChatGPT-3.5, ChatGPT-4 and Google Bard) on the ABLS exam. The ABLS exam consists of 50 questions with 5 multiple choice answers. The passing threshold is 80% of correct answers. The three LLMs were queried with the 50 questions included in the latest version of the ABLS exam, on July 18th, 2023. ChatGPT-3.5 scored 86% (43 out of 50), ChatGPT-4 scored 90% (45 out of 50), and Bard scored 70% (35 out of 50). No difference was measured between ChatGPT-3.5 and ChatGPT-4 (p=0.538) and between ChatGPT-3.5 and Bard (p=0.054), despite the borderline p-value. ChatGPT-4 performed significantly better than Bard (p=0.012). Out of the 50 questions, 78% (n=39) were direct questions, while 12% (n=11) were presented as clinical scenarios. No difference in the rate of wrong answers was found based on the type of question for the three LLMs. ChatGPT-3.5 and ChatGPT-4 demonstrated high accuracy at the ABLS exam, and outperformed Google Bard. However, the potential multiple applications of LLMs in emergency burn and trauma care necessitate appropriate surveillance and most likely should represent a tool to complement human cognition.

Experiential Learning with Ketamine: A Mixed-Methods Exploratory Study on Prescription and Perception.

Background: Incorporating unfamiliar therapies into practice requires effective longitudinal learning and the optimal way to achieve this is debated. Though not a novel therapy, ketamine in critical care has a paucity of data and variable acceptance, with limited research describing intensivist perceptions and utilization. The Coronavirus-19 pandemic presented a particular crisis where providers rapidly adapted analgosedation strategies to achieve prolonged, deep sedation due to a surge of severe acute respiratory distress syndrome (ARDS). Question: How does clinical experience with ketamine impact the perception and attitude of clinicians toward this therapy? Methods: We conducted a mixed-methods study using quantitative ketamine prescription data and qualitative focus group data. We analyzed prescription patterns of ketamine in a tertiary academic ICU during two different time points: pre-COVID-19 (March 1-June 30, 2019) and during the COVID-19 surge (March 1-June 30, 2020). Two focus groups (FG) of critical care attendings were held, and data were analyzed using the Framework Method for content analysis. Results: Four-hundred forty-six medical ICU patients were mechanically ventilated (195 pre-COVID-19 and 251 during COVID-19). The COVID-19 population was more likely to receive ketamine (81[32.3%] vs 4 [2.1%], p < 0.001). Thirteen respondents participated across two FG sessions (Pre-COVID = 8, Post-COVID=5). The most prevalent attitude among our respondents was discomfort, with three key themes identified as follows: 1) lack of evidence regarding ketamine, 2) lack of personal experience, and 3) desire for more education and protocols. Conclusion: Despite a substantial increase in ketamine prescription during COVID-19, intensivists continued to feel discomfort with utilization. Factors contributing to this discomfort include a lack of evidence, a lack of experience, and a desire for more education and protocols. Increase in experience with ketamine alone was not sufficient to minimize provider discomfort. These findings should inform future curricula and call for process improvement to optimize continuing education.

Clinical phenotypes of adults with monogenic and syndromic genetic obesity.

OBJECTIVE: Considering limited evidence on diagnostics of genetic obesity in adults, we evaluated phenotypes of adults with genetic obesity. Additionally, we assessed the applicability of Endocrine Society (ES) recommendations for genetic testing in pediatric obesity. METHODS: We compared clinical features, including age of onset of obesity and appetite, between adults with non-syndromic monogenic obesity (MO), adults with syndromic obesity (SO), and adults with common obesity (CO) as control patients. RESULTS: A total of 79 adults with genetic obesity (32 with MO, 47 with SO) were compared with 186 control patients with CO. Median BMI was similar among the groups: 41.2, 39.5, and 38.7 kg/m2 for patients with MO, SO, and CO, respectively. Median age of onset of obesity was 3 (IQR: 1-6) years in patients with MO, 9 (IQR: 4-13) years in patients with SO, and 21 (IQR: 13-33) years in patients with CO (p < 0.001). Patients with genetic obesity more often reported increased appetite: 65.6%, 68.1%, and 33.9% in patients with MO, SO, and CO, respectively (p < 0.001). Intellectual deficit and autism spectrum disorder were more prevalent in patients with SO (53.2% and 21.3%) compared with those with MO (3.1% and 6.3%) and CO (both 0.0%). The ES recommendations were fulfilled in 56.3%, 29.8%, and 2.7% of patients with MO, SO, and CO, respectively (p < 0.001). CONCLUSIONS: We found distinct phenotypes in adult genetic obesity. Additionally, we demonstrated low sensitivity for detecting genetic obesity in adults using pediatric ES recommendations, necessitating specific genetic testing recommendations in adult obesity care.

The Role of Anti-Müllerian Hormone in Ovarian Function.

Anti-Müllerian hormone (AMH) is a member of the transforming growth factor ß (TGFß) superfamily, whose actions are restricted to the endocrine-reproductive system. Initially known for its role in male sex differentiation, AMH plays a role in the ovary, acting as a gatekeeper in folliculogenesis by regulating the rate of recruitment and growth of follicles. In the ovary, AMH is predominantly expressed by granulosa cells of preantral and antral follicles (i.e., post primordial follicle recruitment and prior to follicle-stimulating hormone (FSH) selection). AMH signals through a BMP-like signaling pathway in a manner distinct from other TGFß family members. In this review, the latest insights in AMH processing, signaling, its regulation of spatial and temporal expression pattern, and functioning in folliculogenesis are summarized. In addition, effects of AMH variants on ovarian function are reviewed.

Spatial Variation in Mercury Accumulation in Bottlenose Dolphins (Tursiops spp.) in Southeastern U.S.A.

Bottlenose dolphins (Tursiops spp.) inhabit bays, sounds, and estuaries (BSEs) throughout the southeast region of the U.S.A. and are sentinel species for human and ecosystem-level health. Dolphins are vulnerable to the bioaccumulation of contaminants through the coastal food chain because they are high-level predators. Currently, there is limited information on the spatial dynamics of mercury accumulation in these dolphins. Total mercury (THg) was measured in dolphin skin from multiple populations across the U.S. Southeast Atlantic and Gulf of Mexico coasts, and the influence of geographic origin, sex, and age class was investigated. Mercury varied significantly among sampling sites and was greatest in dolphins in St. Joseph Bay, Florida Everglades, and Choctawhatchee Bay (14,193 ng/g ± 2196 ng/g, 10,916 ng/g ± 1532 ng/g, and 7333 ng/g ± 1405 ng/g wet mass (wm), respectively) and lowest in dolphins in Charleston and Skidaway River Estuary (509 ng/g ± 32.1 ng/g and 530 ng/g ± 58.4 ng/g wm, respectively). Spatial mercury patterns were consistent regardless of sex or age class. Bottlenose dolphin mercury exposure can effectively represent regional trends and reflect large-scale atmospheric mercury input and local biogeochemical processes. As a sentinel species, the bottlenose dolphin data presented here can direct future studies to evaluate mercury exposure to human residents in St. Joseph Bay, Choctawhatchee Bay, and Florida Coastal Everglades, as well as additional sites with similar geographical, oceanographic, or anthropogenic parameters. These data may also inform state and federal authorities that establish fish consumption advisories to determine if residents in these locales are at heightened risk for mercury toxicity.

Clustering Identifies Subtypes With Different Phenotypic Characteristics in Women With Polycystic Ovary Syndrome.

CONTEXT: Hierarchical clustering (HC) identifies subtypes of polycystic ovary syndrome (PCOS). OBJECTIVE: This work aimed to identify clinically significant subtypes in a PCOS cohort diagnosed with the Rotterdam criteria and to further characterize the distinct subtypes. METHODS: Clustering was performed using the variables body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), testosterone, insulin, and glucose. Subtype characterization was performed by analyzing the variables estradiol, androstenedione, dehydroepiandrosterone, cortisol, anti-Müllerian hormone (AMH), total follicle count (TFC), lipid profile, and blood pressure. Study participants were girls and women who attended our university hospital for reproductive endocrinology screening between February 1993 and February 2021. In total, 2502 female participants of European ancestry, aged 13 to 45 years with PCOS (according to the Rotterdam criteria), were included. A subset of these (n = 1067) fulfilled the National Institutes of Health criteria (ovulatory dysfunction and hyperandrogenism). Main outcome measures included the identification of distinct PCOS subtypes using cluster analysis. Additional clinical variables associated with these subtypes were assessed. RESULTS: Metabolic, reproductive, and background PCOS subtypes were identified. In addition to high LH and SHBG levels, the reproductive subtype had the highest TFC and levels of AMH (all P < .001). In addition to high BMI and insulin levels, the metabolic subtype had higher low-density lipoprotein levels and higher systolic and diastolic blood pressure (all P < .001). The background subtype had lower androstenedione levels and features of the other 2 subtypes. CONCLUSION: Reproductive and metabolic traits not used for subtyping differed significantly in the subtypes. These findings suggest that the subtypes capture distinct PCOS causal pathways.

Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

GNB1 and obesity: Evidence for a correlation between haploinsufficiency and syndromic obesity.

Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication.

Changes in Dynamic Mean Ankle Moment Arm in Unimpaired Walking Across Speeds, Ramps, and Stairs.

Understanding the natural biomechanics of walking at different speeds and activities is crucial to develop effective assistive devices for persons with lower-limb impairments. While continuous measures such as joint angle and moment are well-suited for biomimetic control of robotic systems, whole-stride summary metrics are useful for describing changes across behaviors and for designing and controlling passive and semi-active devices. Dynamic mean ankle moment arm (DMAMA) is a whole-stride measure representing the moment arm of the ground reaction impulse about the ankle joint-effectively, how "forefoot-dominated" or "hindfoot-dominated" a movement is. DMAMA was developed as a target and performance metric for semi-active devices that adjust once per stride. However, for implementation in this application, DMAMA must be characterized across various activities in unimpaired individuals. In our study, unimpaired participants walked at "slow," "normal," and "fast" self-selected speeds on level ground and at a normal self-selected speed while ascending and descending stairs and a 5-degree incline ramp. DMAMA measured from these activities displayed a borderline-significant negative sensitivity to walking speed, a significant positive sensitivity to ground incline, and a significant decrease when ascending stairs compared to descending. The data suggested a nonlinear relationship between DMAMA and walking speed; half of the participants had the highest average DMAMA at their "normal" speed. Our findings suggest that DMAMA varies substantially across activities, and thus, matching DMAMA could be a valuable metric to consider when designing biomimetic assistive lower-limb devices.

MC4R variants modulate α-MSH and setmelanotide induced cellular signaling at multiple levels.

CONTEXT: Melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity. OBJECTIVE: We have identified 17 MC4R variants in adult and pediatric patients with obesity. Here, we aimed to functionally characterize these variants by analyzing four different aspects of MC4R signaling. In addition, we aimed to analyze the effect of setmelanotide, a potent MC4R agonist, on these MC4R variants. MATERIALS AND METHODS: Cell surface expression and α-MSH- or setmelanotide-induced cAMP response, ß-arrestin-2 recruitment, and ERK activation were measured in cells expressing either wild type (WT) or variant MC4R. RESULTS: We found a large heterogeneity in the function of these variants. We identified variants with a loss of response for all studied MC4R signaling, variants with no cAMP accumulation or ERK activation but normal ß-arrestin-2 recruitment, and variants with normal cAMP accumulation and ERK activation but decreased ß-arrestin-2 recruitment, indicating disrupted desensitization and signaling mechanisms. Setmelanotide displayed a greater potency and similar efficacy as α-MSH, and induced significantly increased maximal cAMP responses of several variants compared to α-MSH. Despite the heterogeneity in functional response, there was no apparent difference in the obesity phenotype in our patients. DISCUSSION: We show that these obesity-associated MC4R variants affect MC4R signaling differently, yet leading to a comparable clinical phenotype. Our results demonstrate the clinical importance of assessing the effect of MC4R variants on a range of molecular signaling mechanisms to determine their association with obesity, which may aid in improving personalized treatment.

Adeno-associated virus-mediated trastuzumab delivery to the central nervous system for human epidermal growth factor receptor 2+ brain metastasis.

Trastuzumab improves overall survival for HER2+ breast cancer, but its short half-life in the cerebrospinal fluid (~2-4 days) and delivery limitations restrict the ability to target HER2+ central nervous system (CNS) disease. We developed an adeno-associated virus (AAV) vector expressing a codon-optimized, ubiquitin C (UbC)-promoter-driven trastuzumab sequence (AAV9.UbC.trastuzumab) for intrathecal administration. Transgene expression was evaluated in adult Rag1 knockout mice and rhesus nonhuman primates (NHPs) after a single intracerebroventricular (ICV) or intra-cisterna magna (ICM) AAV9.UbC.trastuzumab injection, respectively, using real-time PCR, ELISA, Western blot, in situ hybridization, single-nucleus RNA sequencing, and liquid chromatography-mass spectrometry; antitumor efficacy was evaluated in brain xenografts using HER2+ breast cancer cell lines (BT-474, MDA-MB-453). Transgene expression was detected in brain homogenates of Rag1 knockout mice following a single ICV injection of AAV9.UbC.trastuzumab (1 × 1011 vector genome copies [GC]/mouse) and tumor progression was inhibited in xenograft models of breast-to-brain metastasis. In NHPs, ICM delivery of AAV9.UbC.trastuzumab (3 × 1013 GC/animal) was well tolerated (36-37 days in-life) and resulted in transgene expression in CNS tissues and cerebrospinal fluid at levels sufficient to induce complete tumor remission in MDA-MB-453 brain xenografts. With AAV9's proven clinical safety record, this gene therapy may represent a viable approach for targeting HER2 + CNS malignancies.

Long-term glucocorticoid exposure and incident cardiovascular diseases - the Lifelines cohort.

CONTEXT: Long-term glucocorticoid levels in scalp hair (HairGCs), including cortisol and the inactive form cortisone, represent the cumulative systemic exposure to glucocorticoids over months. HairGCs have repeatedly shown associations with cardiometabolic and immune parameters, but longitudinal data are lacking. DESIGN: We investigated 6341 hair samples of participants from the Lifelines cohort study for cortisol and cortisone levels, and associated these to incident cardiovascular diseases (CVD) during 5-7 years of follow-up. We computed the odds ratio (OR) of HairGC levels for incident CVD via logistic regression, adjusting for classical cardiovascular risk factors, and performed a sensitivity analysis in subcohorts of participants <60 years and >= 60 years. Also, we associated HairGC levels to immune parameters (total leukocytes and subtypes). RESULTS: Hair cortisone levels (available in n = 4701) were independently associated with incident CVD (p < 0.001), particularly in younger individuals (multivariate-adjusted OR 4.21, 95% confidence interval (CI) 1.91-9.07 per point increase in 10-log cortisone concentration (pg/mg), p < 0.001). All immune parameters except eosinophils were associated with hair cortisone (all multivariate-adjusted p < 0.05). CONCLUSIONS: In this large, prospective cohort study, we found that long-term cortisone levels, measured in scalp hair, represent a relevant and significant predictor for future cardiovascular diseases in younger individuals. These results highlight glucocorticoid action as possible treatment target for CVD prevention, where hair glucocorticoid measurements could help identify individuals that may benefit from such treatments.

Maternal death surveillance and response system reports from 32 low-middle income countries, 2011-2020: What can we learn from the reports?

Maternal Death Surveillance and Response (MDSR) systems generate information that may aid efforts to end preventable maternal deaths. Many countries report MDSR data, but comparability over time and across settings has not been studied. We reviewed MDSR reports from low-and-middle income countries (LMICs) to examine core content and identify how surveillance data and data dissemination could be improved to guide recommendations and actions. We conducted deductive content analysis of 56 MDSR reports from 32 LMICs. A codebook was developed assessing how reports captured: 1) MDSR system implementation, 2) monitoring of maternal death notifications and reviews, and 3) response formulation and implementation. Reports published before 2014 focused on maternal death reviews only. In September 2013, the World Health Organization and partners published the global MDSR guidance, which advised that country reports should also include identification, notification and response activities. Of the 56 reports, 33 (59%) described their data as incomplete, meaning that not all maternal deaths were captured. While 45 (80%) reports presented the total number of maternal deaths that had been notified (officially reported), only 16 (29%) calculated notification rates. Deaths were reported at both community and facility levels in 31 (55%) reports, but 25 (45%) reported facility deaths only. The number of maternal deaths reviewed was reported in 33 (59%) reports, and 17 (30%) calculated review completion rates. While 48 (86%) reports provided recommendations for improving MDSR, evidence of actions based on prior recommendations was absent from 40 (71%) of subsequent reports. MDSR reports currently vary in content and in how response efforts are documented. Comprehensive reports could improve accountability and effectiveness of the system by providing feedback to MDSR stakeholders and information for action. A standard reporting template may improve the quality and comparability of MDSR data and their use for preventing future maternal deaths.

Surgical Excision of Burn Wounds.

Burn injuries affect patients of all ages, and timely surgical debridement and excision commence to protect dermal vascularity and integrity, improve healing, and minimize scarring. Several tools may be used for burn wound excision, which is performed either tangentially or down to muscular fascia. Once wounds are optimized from a tissue viability and healing standpoint, coverage may be obtained through grafts or secondary intention healing for more superficial injuries. A collaborative team of plastic and general surgeons, anesthesiologists, nutritionists, and therapists can provide improved patient care throughout the perioperative period, leading to improvements in overall patient morbidity and mortality.

Prevention and Management of Wound Infections in Burn Patients.

The leading cause of morbidity in burn patients is infection with pneumonia, urinary tract infection, cellulitis, and wound infection being the most common cause. High mortality is due to the immunocompromised status of patients and abundance of multidrug-resistant organisms in burn units. Despite the criteria set forth by American Association of Burn, the diagnosis and treatment of burn infections are not always straightforward. Topical antimicrobials, isolation, hygiene, and personal protective equipment are common preventive measures. Additionally medical and nutritional optimization of the patients is crucial to reverse the immunocompromised status triggered by burn injury.

Challenges in the Management of Large Burns.

Large burns provoke profound pathophysiological changes. Survival rates of patients with large burns have improved significantly with the advancement of critical care and adaptation of early excision protocols. Nevertheless, care of large burn wounds remains challenging secondary to limited donor sites, prolonged time to wound closure, and immunosuppression. The development of skin substitutes and new grafting techniques decreased time to wound closure. Individually, these methods have limited success, but a combination of them may yield more successful outcomes. Early identification of patients with likely poor prognosis should prompt goals of care discussion and involvement of a palliative care team when possible.

First implantable cardiac defibrillator insertions in New South Wales, 2005-2020: an analysis of linked administrative data.

OBJECTIVES: To determine the annual numbers of first ICD insertions in New South Wales during 2005-2020; to examine health outcomes for people who first received ICDs during this period. STUDY DESIGN: Retrospective cohort study; analysis of linked administrative health data. SETTING, PARTICIPANTS: All first insertions of ICDs in NSW, 2005-2020. MAIN OUTCOME MEASURES: Annual numbers of first ICD insertions, and of emergency department presentations and hospital re-admissions 30 days, 90 days, 365 days after first ICD insertions; all-cause and disease-specific mortality (to ten years after ICD insertion). RESULTS: During 2005-2020, ICDs were first inserted into 16 867 people (18.5 per 100 000 population); their mean age was 65.7 years (standard deviation, 13.5 years; 7376 aged 70 years or older, 43.7%), 13 214 were men (78.3%). The annual number of insertions increased from 791 in 2005 to 1256 in 2016; the first ICD insertion rate increased from 15.5 in 2005 to 18.9 per 100 000 population in 2010, after which the rate was stable until 2019 (19.8 per 100 000 population). Of the 16 778 people discharged alive from hospital after first ICD insertions, 54.4% presented to emergency departments within twelve months, including 1236 with cardiac arrhythmias (7.4%) and 434 with device-related problems (2.6%); 56% were re-admitted to hospital, including 1944 with cardiac arrhythmias (11.5%) and 2045 with device-related problems (12.1%). A total of 5624 people who received first ICDs during 2005-2020 (33.3%) died during follow-up (6.7 deaths per 100 person-years); the survival rate was 94.4% at one year, 76.5% at five years, and 54.2% at ten years. CONCLUSIONS: The annual number of new ICDs inserted in NSW has increased since 2005. A substantial proportion of recipients experience device-related problems that require re-admission to hospital. The potential harms of ICD insertion should be considered when assessing the likelihood of preventing fatal ventricular arrhythmia.

High-dose systemic adeno-associated virus vector administration causes liver and sinusoidal endothelial cell injury.

We analyzed retrospective data from toxicology studies involving administration of high doses of adeno-associated virus expressing different therapeutic transgenes to 21 cynomolgus and 15 rhesus macaques. We also conducted prospective studies to investigate acute toxicity following high-dose systemic administration of enhanced green fluorescent protein-expressing adeno-associated virus to 10 rhesus macaques. Toxicity was characterized by transaminitis, thrombocytopenia, and alternative complement pathway activation that peaked on post-administration day 3. Although most animals recovered, some developed ascites, generalized edema, hyperbilirubinemia, and/or coagulopathy that prompted unscheduled euthanasia. Study endpoint livers from animals that recovered and from unscheduled necropsies of those that succumbed to toxicity were analyzed via hypothesis-driven histopathology and unbiased single-nucleus RNA sequencing. All liver cell types expressed high transgene transcript levels at early unscheduled timepoints that subsequently decreased. Thrombocytopenia coincided with sinusoidal platelet microthrombi and sinusoidal endothelial injury identified via immunohistology and single-nucleus RNA sequencing. Acute toxicity, sinusoidal injury, and liver platelet sequestration were similarly observed with therapeutic transgenes and enhanced green fluorescent protein at doses ≥1 × 1014 GC/kg, suggesting it was the consequence of high-dose systemic adeno-associated virus administration, not green fluorescent protein toxicity. These findings highlight a potential toxic effect of high-dose intravenous adeno-associated virus on nonhuman primate liver microvasculature.