Quantifying the Impact of Alternative Definitions of Sepsis-Associated Acute Kidney Injury on its Incidence and Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVES: To derive a pooled estimate of the incidence and outcomes of sepsis-associated acute kidney injury (SA-AKI) in ICU patients and to explore the impact of differing definitions of SA-AKI on these estimates. DATA SOURCES: Medline, Medline Epub, EMBASE, and Cochrane CENTRAL between 1990 and 2023. STUDY SELECTION: Randomized clinical trials and prospective cohort studies of adults admitted to the ICU with either sepsis and/or SA-AKI. DATA EXTRACTION: Data were extracted in duplicate. Risk of bias was assessed using adapted standard tools. Data were pooled using a random-effects model. Heterogeneity was assessed by using a single covariate logistic regression model. The primary outcome was the proportion of participants in ICU with sepsis who developed AKI. DATA SYNTHESIS: A total of 189 studies met inclusion criteria. One hundred fifty-four reported an incidence of SA-AKI, including 150,978 participants. The pooled proportion of patients who developed SA-AKI across all definitions was 0.40 (95% CI, 0.37-0.42) and 0.52 (95% CI, 0.48-0.56) when only the Risk Injury Failure Loss End-Stage, Acute Kidney Injury Network, and Improving Global Outcomes definitions were used to define SA-AKI. There was significant variation in the incidence of SA-AKI depending on the definition of AKI used and whether AKI defined by urine output criteria was included; the incidence was lowest when receipt of renal replacement therapy was used to define AKI (0.26; 95% CI, 0.24-0.28), and highest when the Acute Kidney Injury Network score was used (0.57; 95% CI, 0.45-0.69; p < 0.01). Sixty-seven studies including 29,455 participants reported at least one SA-AKI outcome. At final follow-up, the proportion of patients with SA-AKI who had died was 0.48 (95% CI, 0.43-0.53), and the proportion of surviving patients who remained on dialysis was 0.10 (95% CI, 0.04-0.17). CONCLUSIONS: SA-AKI is common in ICU patients with sepsis and carries a high risk of death and persisting kidney impairment. The incidence and outcomes of SA-AKI vary significantly depending on the definition of AKI used.

Burden and distribution of mortality due to sepsis and severe infection in children and adolescents in Aotearoa/New Zealand.

AIM: The aims of this research were to determine the mortality from sepsis and severe infection in the paediatric and adolescent populations of Aotearoa/New Zealand, and to determine the distribution of mortality by sub-populations. METHODS: We used three different methods to identify deaths from sepsis and severe infection and compared the groups: All deaths primarily coded with any ICD-10-AM code relating to sepsis; The presence of A40, A41 and P36 in any cause of death field; Deaths due to pneumonia and meningitis. Cases were selected from a national mortality database, with cause of death as ascribed in the national mortality collection for the years 2002-2020 inclusive. Overall sepsis and severe infection rates were calculated from the sum of unique cases from all three methods for determining sepsis and severe infection cases. RESULTS: Substantially different results were obtained depending on the method of identifying cases. In total, 577 deaths due to sepsis and severe infection were detected, with an overall rate of 1.99/100 000 age-specific population and statistically significant disparity by ethnic grouping. Rates were highest in post-neonatal infants at 22.7 per 100 000, regardless of the method of identification. CONCLUSIONS: There is a considerable opportunity to improve the mortality from sepsis and severe infection in children and young people. The ethnic disparities described in this paper show the need to ensure a high level of care for those most marginalised in society through the development and provision of systems and structures that meet, rather than fail to meet need.

Multisite sentinel surveillance of self-harm in New Zealand: protocol for an observational study.

INTRODUCTION: New Zealand (NZ) has a persistently high rate of suicide, particularly among young people. Hospital presentation for self-harm (SH) is one of the strongest predictors of death by suicide. Improving the monitoring of SH and suicide is a key recommendation for suicide prevention by WHO. This study will establish the first ever sentinel surveillance for SH at several large hospitals and a monthly survey of all practicing paediatricians in NZ. The study will provide robust information about the epidemiology of SH, factors associated with SH and the types of interventions required for those presenting to hospital with SH. METHOD AND ANALYSIS: This observational study will establish SH surveillance in the emergency departments of three public hospitals for the first time in NZ, where study population will include individuals of all ages who present with SH or suicidal ideation. The study methodology is in line with the WHO Best Practice guidelines and international collaborators in Australia and Europe. Electronic triage records will be reviewed manually by the research team to identify potential cases that meet inclusion criteria. For all eligible cases, variables of interest will be extracted from routine clinical records by the research team and recorded on a secure web-based survey application. Additionally, SH surveillance data for the national paediatric population (<15 years) will be obtained via the New Zealand Paediatric Surveillance Unit (NZPSU); paediatricians will report on included cases using the same variables using a secure survey application. A deidentified dataset will be produced for aggregated statistical analysis. ETHICS AND DISSEMINATION: The University of Otago Health Ethics Committee granted ethical approval for this study in addition to local ethics approval at participating hospital sites. The study findings will be disseminated to relevant stakeholders in NZ, in addition to international audiences through publications in peer-reviewed scientific journals and conference presentations.

Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia.

The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.

Infant Sleep Hazards and the Risk of Sudden Unexpected Death in Infancy.

OBJECTIVE: To examine the effects of infant sofa-sleeping, recent use by caregivers of alcohol, cannabis, and/or other drugs, and bed type and pillows, on the risk of sudden unexpected death in infancy (SUDI) in New Zealand. STUDY DESIGN: A nationwide prospective case-control study was implemented between March 2012 and February 2015. Data were collected during interviews with parents/caregivers. "Hazards" were defined as infant exposure to 1 or more of sofa-sleeping and recent use by caregivers of alcohol, cannabis, and other drugs. The interaction of hazards with tobacco smoking in pregnancy and bed sharing, including for very young infants, and the difference in risk for Maori and non-Maori infants, also were assessed. RESULTS: The study enrolled 132 cases and 258 controls. SUDI risk increased with infant sofa-sleeping (imputed aOR [IaOR] 24.22, 95% CI 1.65-356.40) and with hazards (IaOR 3.35, 95% CI 1.40-8.01). The SUDI risk from the combination of tobacco smoking in pregnancy and bed sharing (IaOR 29.0, 95% CI 10.10-83.33) increased with the addition of 1 or more hazards (IaOR 148.24, 95% CI 15.72-1398), and infants younger than 3 months appeared to be at greater risk (IaOR 450.61, 95% CI 26.84-7593.14). CONCLUSIONS: Tobacco smoking in pregnancy and bed sharing remain the greatest SUDI risks for infants and risk increases further in the presence of sofa-sleeping or recent caregiver use of alcohol and/or cannabis and other drugs. Continued implementation of effective, appropriate programs for smoking cessation, safe sleep, and supplying safe sleep beds is required to reduce New Zealand SUDI rates and SUDI disparity among Maori.

Suicide among Asian young people aged under 25 years in Aotearoa New Zealand: different methods warrant different preventive initiatives.

BACKGROUND: The Asian population is growing rapidly in New Zealand and is expected to overtake Maori and Pacific population groups by 2038. Although there has been research on suicide in elderly Asian people in New Zealand, there is relatively little knowledge regarding suicide within Asian young people. AIMS: To describe the characteristics and prevalence of suicide among Asian young people aged 10-24 years between 2002 and 2017. METHODS: A retrospective review of all child and adolescent suicide deaths in New Zealand was conducted using a national database. RESULTS: Results include a pattern of increasing deaths with increasing age, with 87.5% over the age of 16 years, and two-thirds of deaths occurring in the Auckland region. The majority of Asian young people who died by suicide were born outside of New Zealand (80.7%), consistent with the fact that the majority (77%) of the Asian population in New Zealand were born overseas. However, deaths tended to decrease with longer duration of residence in New Zealand. That certain methods of suicide were more prominent among Asian young people has important implications for suicide prevention. CONCLUSIONS: Overall, there has been no significant change in the rates of suicide between 2002 and 2017. Young Asian people who die by suicide come from heterogeneous cultural and linguistic traditions, so prevention strategies need to be culturally responsive and delivered across multiple settings, including education, primary care and mental health services. However, certain methods are more common in many Asian countries, such as jumping from a height. We found this method was more commonly used by Asian young people compared with NZ Europeans, which should be a consideration in town planning, particularly in areas where there is a significant Asian population as part of a multilevel approach to suicide prevention.

Shoulder dystocia, umbilical cord blood gases and neonatal encephalopathy.

The interpretation of umbilical cord gases may not be straightforward following shoulder dystocia. We reviewed Perinatal and Maternal Mortality Review Committee data from New Zealand infants with moderate and severe neonatal encephalopathy (NE) for 2010-2017 inclusive. If one or more of: pH of ≤7.1; base excess of ≤-12 mmol/L; or lactate of ≥6 mmol/L were present it was considered an abnormal result. One-third (12/36) of infants born following shoulder dystocia had documented umbilical cord gases within the normal range. It is important for clinicians to be aware of this possibility when assessing newborn infants with NE.

Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase.

Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.

A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition.

Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.

Accelerated Systemic Autoimmunity in the Absence of Somatic Hypermutation in 564Igi: A Mouse Model of Systemic Lupus with Knocked-In Heavy and Light Chain Genes.

564Igi mice have knocked-in immunoglobulin (Ig) heavy (H) and light (L) chain genes that encode an autoantibody recognizing RNA. Previously, we showed that these mice produce pathogenic IgG autoantibodies when activation-induced deaminase (AID) is expressed in pre-B and immature B cells but not when it is expressed only in mature B cells. AID has two functions; it is necessary for somatic hypermutation (SHM) and class switch recombination (CSR). To determine the role of each of these functions in the generation of pathogenic autoantibodies, we generated 564Igi mice that carry a mutant AID-encoding gene, Aicda (AicdaG23S), which is capable of promoting CSR but not SHM. We found that 564Igi AicdaG23S mice secreted class-switched antibodies (Abs) at levels approximately equal to 564Igi mice. However, compared to 564Igi mice, 564Igi Aicda G23S mice had increased pathogenic IgG Abs and severe systemic lupus erythematosus-like disease, including, glomerulonephritis, and early death. We suggest that in 564Igi mice SHM by AID changes Ig receptors away from self reactivity, thereby mitigating the production of autoantibody, providing a novel mechanism of tolerance.

The combination of bed sharing and maternal smoking leads to a greatly increased risk of sudden unexpected death in infancy: the New Zealand SUDI Nationwide Case Control Study.

BACKGROUND: Despite a major reduction in overall infant mortality, sudden unexpected death in infancy (SUDI) continues to be of concern in New Zealand, as the rate is high by international standards, and is even higher in indigenous Maori. AIM: To identify modifiable risk factors for SUDI. METHODS: A three-year (1 March 2012-28 February 2015) nationwide case-control study was conducted in New Zealand. RESULTS: There were 137 SUDI cases, giving a SUDI mortality rate of 0.76/1,000 live births. The rate for Maori was 1.41/1,000, Pacific 1.01/1,000 and non-Maori non-Pacific (predominantly European) 0.50/1,000. The parent(s) of 97% of the SUDI cases were interviewed. Six hundred and forty-nine controls were selected and 258 (40%) were interviewed. The two major risk factors for SUDI were: maternal smoking in pregnancy (adjusted OR=6.01, 95% CI=2.97, 12.15) and bed sharing (aOR=4.96, 95% CI=2.55, 9.64). There was a significant interaction (p=0.002) between bed sharing and antenatal maternal smoking. Infants exposed to both risk factors had a markedly increased risk of SUDI (aOR=32.8, 95% CI=11.2, 95.8) compared with infants not exposed to either risk factor. Infants not sharing the parental bedroom were also at increased risk of SUDI (aOR=2.77, 95% CI=1.45, 5.30). Just 21 cases over the three-year study were not exposed to smoking in pregnancy, bed sharing or front or side sleeping position. CONCLUSIONS: This study has shown that many of the risk factors that were identified in the original New Zealand Cot Death Study (1987-1989) are still relevant today. The combination of maternal smoking in pregnancy and bed sharing is extremely hazardous for infants. Furthermore, our findings indicate that the SUDI prevention messages are still applicable today and should be reinforced. SUDI mortality could be reduced to just seven p.a. in New Zealand (approximately one in 10,000 live births).

Coding paediatric outpatient data to provide health planners with information on children with chronic conditions and disabilities.

AIM: In New Zealand, there is a paucity of information on children with chronic conditions and disabilities (CCD). One reason is that many are managed in hospital outpatients where diagnostic coding of health-care events does not occur. This study explores the feasibility of coding paediatric outpatient data to provide health planners with information on children with CCD. METHODS: Thirty-seven clinicians from six District Health Boards (DHBs) trialled coding over 12 weeks. In five DHBs, the International Classification of Diseases and Related Health Problems, 10th Edition, Australian Modification (ICD-10-AM) and Systematised Nomenclature of Medicine Clinical Terms (SNOMED-CT) were trialled for 6 weeks each. In one DHB, ICD-10-AM was trialled for 12 weeks. A random sample (30%) of ICD-10-AM coded events were also coded by clinical coders. A mix of paper and electronic methods were used. RESULTS: In total 2,604 outpatient events were coded in ICD-10-AM and 693 in SNOMED-CT. Dual coding occurred for 770 (29.6%) ICD-10-AM events. Overall, 34% of ICD-10-AM and 40% of SNOMED-CT events were for developmental and behavioural disorders. Chronic medical conditions were also common. Clinicians were concerned about the workload impacts, particularly for paper-based methods. Coder's were concerned about clinician's adherence to coding guidelines and the poor quality of documentation in some notes. CONCLUSION: Coded outpatient data could provide planners with a rich source of information on children with CCD. However, coding is also resource intensive. Thus its costs need to be weighed against the costs of managing a much larger health budget using very limited information.

Female Bias in Systemic Lupus Erythematosus is Associated with the Differential Expression of X-Linked Toll-Like Receptor 8.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of anti-nuclear antibodies. SLE is one of many autoimmune disorders that have a strong gender bias, with 70-90% of SLE patients being female. Several explanations have been postulated to account for the severity of autoimmune diseases in females, including hormonal, microbiota, and gene dosage differences. X-linked toll-like receptors (TLRs) have recently been implicated in disease progression in females. Our previous studies using the 564Igi mouse model of SLE on a Tlr7 and Tlr9 double knockout background showed that the presence of Tlr8 on both X chromosomes was required for the production of IgG autoantibodies, Ifn-I expression and granulopoiesis in females. Here, we show the results of our investigation into the role of Tlr8 expression in SLE pathogenesis in 564Igi females. Female mice have an increase in serum pathogenic anti-RNA IgG2a and IgG2b autoantibodies. 564Igi mice have also been shown to have an increase in neutrophils in vivo, which are major contributors to Ifn-α expression. Here, we show that neutrophils from C57BL/6 mice express Ifn-α in response to 564 immune complexes and TLR8 activation. Bone marrow-derived macrophages from 564Igi females have a significant increase in Tlr8 expression compared to male-derived cells, and RNA fluorescence in situ hybridization data suggest that Tlr8 may escape X-inactivation in female-derived macrophages. These results propose a model by which females may be more susceptible to SLE pathogenesis due to inefficient inactivation of Tlr8.

Infant suffocation in place of sleep: New Zealand national data 2002-2009.

BACKGROUND: Accidental suffocation during sleep, leading to death, has been described as due to overlay or wedging of infants, particularly in a bed-sharing situation. Bed sharing is a risk factor for sudden infant death syndrome but the mechanism of death is not clearly defined. Accidental suffocation may be one such mechanism. OBJECTIVE: To describe accidental suffocation deaths during sleep in New Zealand between 2002 and 2009. DESIGN: The New Zealand mortality database, which holds data collected by the Child Youth Mortality Review Committee and the Perinatal and Maternal Mortality Review Committee, was searched for potential deaths by accidental suffocation in infants less than 1 year of age. Deaths underwent a detailed analysis by demographic data and qualitative report. RESULTS: There were 48 deaths due to accidental suffocation between 2002 and 2009 in New Zealand, equating to a rate of 0.10 deaths per 1000 live births. The most common age at death was 1 month or under (n=11, 23%). Deaths were due to overlay (n=30, 63%) or wedging (n=18, 37%) and two-thirds (n=34, 71%) were in a bed-sharing situation. A quarter of deaths (n=12, 25%) occurred in makeshift bedding arrangements, some of which were away from home. CONCLUSIONS: Accidental suffocation in bed was responsible for 48 preventable deaths. Prevention of these accidental deaths needs to focus on supporting changes in family behaviour with safety messages that are consistent, persistent and disseminated widely.

Production of IgG autoantibody requires expression of activation-induced deaminase in early-developing B cells in a mouse model of SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of pathogenic IgG antinuclear antibodies. Pathogenic IgG autoantibody production requires B-cell activation, leading to the production of activation-induced deaminase (AID) and class switching of IgM genes to IgG. To understand how and when B cells are activated to produce these IgG autoantibodies, we studied cells from 564Igi, a mouse model of SLE. 564Igi mice develop a disease profile closely resembling that found in human SLE patients, including the presence of IgG antinucleic acid Abs. We have generated 564Igi mice that conditionally express an activation-induced cytidine deaminase transgene (Aicda(tg) ), either in all B cells or only in mature B cells. Here, we show that class-switched pathogenic IgG autoantibodies were produced only in 564Igi mice in which AID was functional in early-developing B cells, resulting in loss of tolerance. Furthermore, we show that the absence of AID in early-developing B cells also results in increased production of self-reactive IgM, indicating that AID, through somatic hypermutation, contributes to tolerance. Our results suggest that the pathophysiology of clinical SLE might also be dependent on AID expression in early-developing B cells.

Validity of police-reported information on injury severity for those hospitalized from motor vehicle traffic crashes.

OBJECTIVE: The objective of this study was to assess the validity of police-reported information on the severity of injury for non-fatal motor vehicle traffic crashes (crashes) in New Zealand that resulted in hospitalization. METHODS: Details of crashes reported to the police resulting in non-fatal injury in New Zealand from January 2000 to December 2004 were obtained from Land Transport New Zealand Traffic crash reports (crash reports). Data about individuals' injuries were matched to New Zealand Health Information Service hospital discharge data. A severity score was assigned to the hospital International Classification of Diseases-10 (ICD-10) diagnosis codes, using a threat-to-life tool, the ICD-based Injury Severity Score (ICISS). RESULTS: Of the linked data, 49.3 percent of crash victims were recorded by police as having "serious" injuries on the crash report but given the police definition of serious injury, all 14,869 records should have been recorded as serious on the crash report. Of these, only 48 percent had an injury with a significant threat to life. Fifteen percent of those with a "minor" injury on the crash report had an injury with a significant threat to life. CONCLUSIONS: The subjective police assessment of severity of injury was discordant in many instances with an objective measure of severity. There was variation in the concordance by personal, vehicle, and crash variables. This has implications for interpreting New Zealand's road safety statistics, the assessment of road safety programs, and the allocation of funding to target specific road safety problems.