Forensic intelligence in Australia and New Zealand: Status and future directions.

Forensic science is underutilised. Operating models restricted to the support of court outcomes do not address core requirements of contemporary policing and public security, which are to disrupt criminal activity and prevent crime. Forensic intelligence (FORINT) is a principal means of enhancing the role of forensic science, emphasising proactivity and cross-case, cross-crime domain insights. To catalyse implementation, a FORINT Specialist Advisory Group (SAG) has been established under the Australia & New Zealand Policing Advisory Agency (ANZPAA) National Institute of Forensic Science (NIFS). The SAG has established a concept of operations with four lines of effort - namely, to (i) promote awareness and consistency, (ii) shape the workforce, (iii) develop information management frameworks and (iv) guide operational implementation. This aims to shift Australia & New Zealand from its present state (of substantial interagency variability) to a state of widespread, consistent and effective FORINT delivery in terms of: (a) culture, (b) information management, (c) education & training, and (d) organisation & operating environment. There are risks to implementing FORINT, in terms of privacy/confidentiality, bias/misinterpretation, and resource impost. However, these are not necessarily FORINT-specific, and solutions or mitigations exist. Moreover, these issues are outweighed by the risks of not implementing FORINT - such as a failure to reveal threats, missed opportunities, and poor resource efficiency. This paper is a call to arms. For policing and laboratories - now is the time to implement and entrench FORINT. For academia - now is the time to build foundations for this future. For supporting industries - now is the time to develop partnerships and facilitate delivery.

Glycemic Control in Diabetic Patients Improved Overall Lung Cancer Survival across Diverse Populations.

BACKGROUND: The consequence of diabetes on lung cancer overall survival (OS) is debated. This retrospective study used two large lung cancer databases to assess comprehensively diabetes effects on lung cancer OS in diverse demographic populations, including health disparity. METHODS: The University of Texas MD Anderson Cancer Center database (32,643 lung cancer cases with 11,973 diabetics) was extracted from electronic health records (EHRs) using natural language processing (NLP). Associations were between diabetes and lung cancer prognostic features [age, sex, race, body mass index (BMI), insurance status, smoking, stage, and histopathology]. Hemoglobin A1C (HgbA1c) and glucose levels assessed glycemic control. Validation was with a Louisiana cohort (17,768 lung cancer cases with 4,746 diabetics) enriched for health disparity cases. Kaplan-Meier analysis, log-rank test, multivariable Cox proportional hazard models, and survival tree analyses were employed. RESULTS: Lung cancer patients with diabetes exhibited marginally elevated OS or no statistically-significant difference versus non-diabetic patients. When examining OS for two glycemic levels (HgbA1c > 7.0 or glucose > 154 mg/dL versus HgbA1c > 9.0 or glucose > 215 mg/dL), a statistically significant improvement in OS occurred in lung cancers with controlled versus uncontrolled glycemia (P < 0.0001). This improvement spanned gender, age, smoking status, insurance status, stage, race, BMI, histopathology and therapy. Survival tree analysis revealed that obese and morbidly obese patients with controlled glycemia or no known diabetes had higher lung cancer OS than comparison groups. CONCLUSION: These findings indicate a need for optimal glycemic control to improve lung cancer OS in diverse populations with diabetes.

Perpendicular crossing chains enable high mobility in a noncrystalline conjugated polymer.

The nature of interchain π-system contacts, and their relationship to hole transport, are elucidated for the high-mobility, noncrystalline conjugated polymer C16-IDTBT by the application of scanning tunneling microscopy, molecular dynamics, and quantum chemical calculations. The microstructure is shown to favor an unusual packing motif in which paired chains cross-over one another at near-perpendicular angles. By linking to mesoscale microstructural features, revealed by coarse-grained molecular dynamics and previous studies, and performing simulations of charge transport, it is demonstrated that the high mobility of C16-IDTBT can be explained by the promotion of a highly interconnected transport network, stemming from the adoption of perpendicular contacts at the nanoscale, in combination with fast intrachain transport.

A phase 2 feasibility study of nab-paclitaxel and carboplatin in epithelial carcinoma of the uterus.

BACKGROUND: We evaluated the feasibility of completing 6 cycles of nab-paclitaxel (nab-P) and carboplatin (C) in a single arm prospective clinical trial for advanced/recurrent EC and safety and efficacy of day (D) 1, 8 nab-P in combination with D1 C q3weeks. METHODS: Patients with early-stage, high-risk, advanced primary/recurrent EC without prior platinum/taxane exposure were enrolled in an open-label, single-institution trial (NCT02744898). Patients received 6 cycles of D1 nab-P 100 mg/m2 IV with C AUC 6 IV and D8 nab-P 100 mg/m2 IV q21D. The trial tested the null hypothesis that subjects completing 6 cycles was ≤0.50 versus the alternative that the proportion is ≥0.75 in a single stage design with alpha = 0.05 and power = 80% with 23 subjects. Patients who completed 6 cycles (primary outcome), objective response rate (ORR) and clinical benefit rate (CBR) were estimated with exact 95% Clopper-Pearson confidence intervals. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. RESULTS: From 08/2016-03/2018, 23 patients were enrolled. Nineteen patients (82.6%, 95% CI: 61.2%, 95.0%) completed 6 cycles, thus we could reject our null. Twelve patients (52.2%) experienced ≥1 grade 3/4 treatment-related adverse events including: anemia, 6 (26.1%); neutropenia, 5 (21.7%); diarrhea, 3 (13.0%). Fourteen patients (60.1%) reported grade 1 neuropathy. Of 9 patients with measurable target lesions, the ORR was 33.3% (95% CI: 7.5%, 70.1%) and CBR was 55.6% (95% CI: 21.2%, 86.3%). Median PFS in the advanced/recurrent patients was 23.2 (95% CI: 12.1, NR) months. CONCLUSIONS: The nab-P/C D1, 8 regimen met pre-specified feasibility criteria with acceptable toxicity and efficacy. Use of nab-P decreases need for steroid pre-medications, and this carboplatin doublet may prove advantageous for trials assessing combinations with immune checkpoint inhibitors in advanced EC.

The Effect of Resisted Sprint Training on Acceleration: A Systematic Review and Meta-Analysis.

Resisted sprint (RS) training, such as sled or parachute towing, is commonly used for sprint training among field sport athletes. While RS training is frequently employed by athletes and coaches, there is little research on its benefits, especially compared to unresisted running (UR) training programs with similar training volumes. This systematic review and meta-analysis compared the effectiveness of RS training on acceleration compared to UR training. Potential sources were limited to peer-reviewed articles published in English prior to June 12, 2022, and gathered from the EBSCOhost, PubMed, and Web of Science online databases identified using combinations of the following terms: towing, sled, "resisted sprint," "sprint acceleration," "sprint performance," and "sprint speed." The search returned 1,159 sources, from which 15 were eligible for inclusion. Fifty effects were used to estimate the impact of RS training on initial sprint speed. Based on the cumulative results from these studies, RS training yielded a small improvement in acceleration but was not different from same volume of UR training (Hedges' d Effect Size=0.11, 95% CI: -0.01 to 0.23; p=0.08). These results do not support the use of RS training over UR training for improving initial sprint speed; however, further research should be conducted.

Preventing recurrence of endometriosis-related pain by means of long-acting progestogen therapy: the PRE-EMPT RCT.

Background: Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. Objectives: To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. Design: A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women's lived experience of endometriosis and a pretrial economic model. Setting: Thirty-four United Kingdom hospitals. Participants: Women of reproductive age undergoing conservative surgery for endometriosis. Interventions: Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). Main outcome measures: The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Results: Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: -0.8, 95% confidence interval -5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval -0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. Limitations: Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. Conclusions: At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. Future work: Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Trial registration: This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word 'woman' is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary.

Endometriosis is a condition where cells similar to ones that line the womb are found elsewhere in the body. Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Unfortunately, symptoms often return and some women will need repeat operations. Hormonal contraceptives can prevent the return of endometriosis-related pain: either long-acting reversible contraceptives (injections or a coil, fitted inside the womb) or the combined oral contraceptive pill (often called 'the pill'). We do not know which is the best option. The aim of this trial was to find out which of these two hormone treatments was more effective in terms of symptom relief, avoidance of further surgery and costs. Four hundred and five women with endometriosis, who were not intending to get pregnant, participated in a clinical trial. Half of the participants took long-acting reversible contraceptives, and the other half took the pill for 3 years following endometriosis surgery. The choice of treatment was made at random by a computer to ensure a fair comparison, although those allocated to the long-acting contraceptive could choose between injections or the coil. Participants completed questionnaires about their symptoms and life quality at intervals up to 3 years. Both treatments were equally good at reducing pain but more women using the pill had repeat operations. The pill was a little more costly overall but associated with a slightly higher quality of life. Both treatments are equally effective in reducing pain up to 3 years after surgery for endometriosis. The differences in costs are small and the choice of treatment should be based on personal preference.

Long genetic and social isolation in Neanderthals before their extinction.

Neanderthal genomes have been recovered from sites across Eurasia, painting an increasingly complex picture of their populations' structure that mostly indicates that late European Neanderthals belonged to a single metapopulation with no significant evidence of population structure. Here, we report the discovery of a late Neanderthal individual, nicknamed "Thorin," from Grotte Mandrin in Mediterranean France, and his genome. These dentognathic fossils, including a rare example of distomolars, are associated with a rich archeological record of Neanderthal final technological traditions in this region ∼50-42 thousand years ago. Thorin's genome reveals a relatively early divergence of ∼105 ka with other late Neanderthals. Thorin belonged to a population with a small group size that showed no genetic introgression with other known late European Neanderthals, revealing some 50 ka of genetic isolation of his lineage despite them living in neighboring regions. These results have important implications for resolving competing hypotheses about causes of the disappearance of the Neanderthals.

Electron cyclotron emission calibration with Thomson scattering using a wide scan of toroidal magnetic field of KSTAR.

The Korea Superconducting Tokamak Advanced Research (KSTAR) tokamak is capable of operating at a wide range of toroidal magnetic fields up to 3.5 T at the major radius. The electron cyclotron emission (ECE) diagnostic on KSTAR is required to cover a broad frequency range for electron temperature profile measurements in both the low and high field sides. To meet these broadband requirements, the ECE system consists of W-band (78-110 GHz) and D-band (110-162 GHz) heterodyne radiometers. The two radiometers are connected to 28 and 48 detection channels, respectively. However, since the absolute ECE calibration based on the hot-cold calibration has been very challenging, an alternative method of calibration was performed using Thomson scattering measurements and varying toroidal magnetic fields. As the toroidal magnetic field is scanned from 1.6 to 3.2 T in steps of 0.2 T, most of the 76 ECE channels are calibrated relatively by the electron temperature values of Thomson scattering in a narrow region (0.2 < r/a <0.6). In this article, the methodological details of the ECE calibration are described. In addition, to demonstrate the robustness of the ECE calibration factors, the calibrated electron temperature profiles from ECE measurements are compared with the ion temperature profiles in terms of the plasma position as the plasma positon shifts outward.

Deep learning reconstruction for zero echo time lung magnetic resonance imaging: impact on image quality and lesion detection.

AIMS: This study aimed to examine the impact of deep-learning reconstruction (DLR) on zero echo time (ZTE) lung MRI. MATERIALS AND METHODS: Fifty-nine patients who underwent both chest CT and ZTE lung magnetic resonance imaging (MRI) were enrolled. Noise reduction in ZTE lung MRI was compared using various DLR intensities (DLR-M, DLR-H) and conventional image filtering techniques (NF1 âˆ¼ NF4). The normalized noise power spectrum (NPS) was analysed through phantom experiments. Image sharpness was evaluated using a blur metric. We compared subjective image quality and the detection of sub-centimetre nodules and emphysema between the original and noise-reduced images. Statistical analyses included the Wilcoxon signed-rank and McNemar's tests, with inter-reader agreement assessed via Kappa coefficients. RESULTS: NPS peaks were lower in NF1 through NF4, DLR-M, and DLR-H compared to the original images. While the average spatial frequency of the NPS shifted towards lower frequencies with increasing NF levels, it remained unchanged with DLR. Blur metric values of NF1∼NF4 were significantly higher than those of the original images (p<0.008). However, there were no significant differences in blur metric values between DLR-M, DLR-H, and the original images. Image quality was rated highest for DLR-H, with a statistically significant improvement over the original (p<0.05). DLR-H showed higher diagnostic confidence for detecting sub-centimetre nodules than the original images. DLR-H showed higher diagnostic performance than the original for detecting emphysema. CONCLUSIONS: DLR can improve ZTE lung MRI quality while preserving image texture and sharpness, thereby enhancing the potential of ZTE for evaluating pulmonary parenchymal disease.

Telehealth Mindfulness-Based Interventions for Chronic Pain: The LAMP Randomized Clinical Trial.

Importance: Although mindfulness-based interventions (MBIs) are evidence-based treatments for chronic pain and comorbid conditions, implementing them at scale poses many challenges, such as the need for dedicated space and trained instructors. Objective: To examine group and self-paced, scalable, telehealth MBIs, for veterans with chronic pain, compared to usual care. Design, Setting, and Participants: This was a randomized clinical trial of veterans with moderate to severe chronic pain, recruited from 3 Veterans Affairs facilities from November 2020 to May 2022. Follow-up was completed in August 2023. Interventions: Two 8-week telehealth MBIs (group and self-paced) were compared to usual care (control). The group MBI was done via videoconference with prerecorded mindfulness education and skill training videos by an experienced instructor, accompanied by facilitated discussions. The self-paced MBI was similar but completed asynchronously and supplemented by 3 individual facilitator calls. Main Outcomes and Measures: The primary outcome was pain-related function using the Brief Pain Inventory interference scale at 3 time points: 10 weeks, 6 months, and 1 year. Secondary outcomes included biopsychosocial outcomes: pain intensity, physical function, anxiety, fatigue, sleep disturbance, participation in social roles and activities, depression, patient ratings of improvement of pain, and posttraumatic stress disorder. Results: Among 811 veterans randomized (mean [SD] age, 54.6 [12.9] years; 387 [47.7%] women), 694 participants (85.6%) completed the trial. Averaged across all 3 time points, pain interference scores were significantly lower for both MBIs compared to usual care (group MBI vs control difference: -0.4 [95% CI, -0.7 to -0.2]; self-paced vs control difference: -0.7 [95% CI, -1.0 to -0.4]). Additionally, both MBI arms had significantly better scores on the following secondary outcomes: pain intensity, patient global impression of change, physical function, fatigue, sleep disturbance, social roles and activities, depression, and posttraumatic stress disorder. Both group and self-paced MBIs did not significantly differ from one another. The probability of 30% improvement from baseline compared to control was greater for group MBI at 10 weeks and 6 months, and for self-paced MBI, at all 3 time points. Conclusions and Relevance: In this randomized clinical trial, scalable telehealth MBIs improved pain-related function and biopsychosocial outcomes compared to usual care among veterans with chronic pain. Relatively low-resource telehealth-based MBIs could help accelerate and improve the implementation of nonpharmacological pain treatment in health care systems. Trial Registration: ClinicalTrials.gov Identifier: NCT04526158.

Proportional Hazards Violations in Phase 3 Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.

BACKGROUND: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHVs) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase 3 oncology trials and assess the utility of restricted mean survival time (RMST) and MaxCombo as additional analyses. METHODS: Clinicaltrials.gov and PubMed were searched to identify 2-arm, randomized, phase 3 superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. RESULTS: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 (23.8%; 95%CI 19.7%, 28.5%) comparisons. In multivariable analysis, non-OS endpoints (odds ratio [OR] 2.16 [95%CI 1.21, 3.87]; P=.009) were associated with higher odds of PHVs, and immunotherapy comparisons (OR 1.94 [95%CI 0.98, 3.86]; P=.058) were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) pre-specified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with RMST or MaxCombo, of which ten (71%) reported negative results. CONCLUSION: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting non-proportional hazards to be misinterpreted.

Relationships Between Applied Mindfulness Practice, Chronic Pain, and Pain-Related Functioning in Veterans.

Mindfulness-based interventions (MBIs) have been shown to improve chronic pain and associated conditions like depression, anxiety, and sleep disorders. However, there is limited research on how veterans with chronic pain apply mindfulness skills to manage pain in daily life. This cross-sectional study examined the association between applied mindfulness practice, pain, and several pain-related conditions among 1,737 veterans with chronic pain prior to enrollment in a trial of 2 MBIs. Applied mindfulness practice was assessed using the Applied Mindfulness Process Scale (AMPS). The outcomes included pain interference, pain intensity, pain catastrophizing, fatigue, sleep disturbance, anxiety, depression, post-traumatic stress disorder, physical function, and social participation. Higher overall AMPS scores, as well as the positive and negative emotional regulation subscales of the AMPS, were associated with less pain interference and catastrophizing, as well as better outcomes for all pain-related conditions. The positive emotional regulation subscale had the strongest associations with outcomes. There was no significant association between the AMPS and pain intensity. The results suggest applied mindfulness practice, especially positive emotional regulation, may improve pain and functioning. In addition, the AMPS shows promise as a process measure of mindfulness skills applied in daily life. Additional research is needed to examine different aspects of mindfulness in the context of MBIs. PERSPECTIVE: This article describes the relationship between applied mindfulness practice and pain-related outcomes, prior to a MBI, using a novel measure of mindfulness practice. These findings underscore the importance of measuring applied mindfulness practice prior to and during clinical interventions to treat chronic pain.

Persistence of advanced systemic pharmacological treatment of moderate-to-severe psoriasis among bio-naïve patients-A retrospective register-based cohort study in Finland and Sweden.

BACKGROUND: Plaque psoriasis (PsO) requires long-term treatment for symptom control and remission; thus, a long-term pharmacological intervention is necessary. Treatment persistence reflects long-term therapeutic effectiveness and tolerance. OBJECTIVES: This study investigates drug persistence and compares treatment discontinuation rates across biologic agents and apremilast used by PsO patients in Finland and Sweden. METHODS: This retrospective register-based cohort study included bio-naïve patients (≥18 years) with moderate-to-severe PsO, who initiated treatment with abatacept, adalimumab, brodalumab, certolizumab pegol, etanercept, golimumab, guselkumab, ixekizumab, risankizumab, secukinumab, tildrakizumab, ustekinumab or apremilast during 2008-2020 in Finland or Sweden. The main analysis evaluated persistence (based on duration of continuous treatment) and compared rates of treatment discontinuation using guselkumab as reference drug, during 2018-2020 in Finland. Treatment discontinuation was assessed by survival analysis of the time to first drug discontinuation, including switching to other study drugs. Due to limited sample size (n < 20), certain biologics (abatacept, brodalumab, certolizumab pegol, etanercept, golimumab, risankizumab and tildrakizumab) were excluded from the persistence analysis. RESULTS: In Finland, 709 patients fulfilled the inclusion criteria during 2018-2020 for the main analysis. The highest persistence was observed for guselkumab and ustekinumab with 90 and 85% of treated patients, respectively, continuing treatment for ≥1 year. Comparable results were observed in the expanded cohort analysis (index starting in 2008; 2745 bio-naïve patients in Finland and 10,970 in Sweden). Furthermore, patients treated with guselkumab in Finland showed lower treatment discontinuation rates compared to other study drugs. CONCLUSION: Guselkumab and ustekinumab demonstrated high persistence as measured by continued treatment for at least 1 year. Furthermore, these treatments demonstrated lower rates of discontinuation compared to other study drugs included in the analysis. Understanding the balance between efficacy and feasibility in treatment decisions is crucial, as feasibility may impact persistency outcomes and potentially increase persistency rates.

Obtaining assent for research involving children in Malaysia: a position statement from the Academy of Medicine of Malaysia College of Paediatrics.

The Academy of Medicine of Malaysia College of Paediatrics acknowledges the role of children in research and this position statement explores the ethical considerations in obtaining assent from minors in the Malaysian context. It highlights the importance in respecting children's agency and navigating cultural complexities. The College proposes flexibility in the minimum age for assent of at least nine years old, while emphasising the need for a tailored assent procedure. Addressing language and cultural diversities and expanding local empirical research on a formal assent process are some building blocks in developing a standardised nationwide process in obtaining assent from children.

Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage.

Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1's nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6-14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology.

The use of sedimentary metals to assess anthropogenic change, ecological risk, model past and future impacts and identify contaminant sources in the eleven estuaries of Greater Sydney (Australia): A review and critical assessment.

The Greater Sydney (Australia) region is dissected by eleven major estuaries comprising a wide range of sizes, sediment and contaminant types, while the catchments also vary in size, land use type, populations size and geology/soils. The magnitude and breadth of the current study are rare and offered an unusual opportunity to provide new information on interactions between source, fate and effect relationships of a highly diverse estuarine-catchment environment using sedimentary metals (Co, Cr, Cu, Ni, Pb and Zn). Advanced methodologies used in this study revealed that although metal concentrations were generally high, ecological risk was surprisingly reduced due to the presence of metal-poor coarse sediment. Stormwater was identified as the dominant source of metals to estuaries of Greater Sydney and relates to development of high-density road networks. Industrial sources, frequently identified as a major contributor to estuarine contamination, was significantly reduced due to the decline of industry through decentralisation and gentrification and because waste is discharged to the sewer system, which is released offshore, or tertiary-treated to the Hawkesbury. Groundwater leachate associated with shoreline reclamation and wetland infilling and metals related to boating activities were important sources of metals impacting local bays and coastal lagoons. Temporal monitoring and unique modelling approaches indicated that the concentration of sedimentary metals is generally declining in these estuaries, (especially for Pb), except for areas with rapidly increasing urban populations. Multivariate statistical modelling was able to differentiate the 11 estuaries on a chemical basis by aligning Cu, Pb, Zn vectors with metal-rich estuaries and also identified catchment attributes (percent area, total yield, anthropogenic yield and population density) normalised to catchment areas as having a major influence on estuarine condition. The new knowledge derived from this study should be used to assess the environmental status of estuaries and to prioritise management actions in future investigations.

Development and Validation of Electronic Health Record Measures of Safety Planning Practices as Part of Zero Suicide Implementation.

OBJECTIVE: Safety planning for suicide prevention is an important quality metric for Zero Suicide implementation. We describe the development, validation, and application of electronic health record (EHR) programs to measure uptake of safety planning practices across six integrated healthcare systems as part of a Zero Suicide evaluation study. METHODS: Safety planning was documented in narrative notes and structured EHR templates using the Stanley Brown Safety Planning Intervention (SBSPI) in response to a high-risk cutoff score on the Columbia Suicide Severity Rating Scale (CSSRS). Natural Language Processing (NLP) metrics were developed and validated using chart review to characterize practices documented in narrative notes. We applied NLP to measure frequency of documentation in the narrative text and standard programming methods to examine structured SBSPI templates from 2010-2022. RESULTS: Chart reviews found three safety planning practices documented in narrative notes that were delivered to at least half of patients at risk: professional contacts, lethal means counseling for firearms, and lethal means counseling for medication access/storage. NLP methods were developed to identify these practices in clinical text with high levels of accuracy (Sensitivity, Specificity, & PPV ≥ 82%). Among visits with a high-risk CSSRS, 40% (Range 2-73% by health system) had an SBSPI template within 1 year of implementation. CONCLUSIONS: This is one of the first reports describing development of measures that leverage electronic health records to track use of suicide prevention safety plans. There are opportunities to use the methods developed here in future evaluations of safety planning.

Measuring safety planning delivery in real-world systems to understand quality of suicide prevention care is challenging.Natural Language Processing (NLP) methods effectively identified some safety planning practices in electronic health records (EHR) from all notes ensuring a comprehensive measurement, but NLP will require updates/testing for local documentation practices.Structured safety planning templates in the EHR using the Stanley Brown Safety Planning Intervention improve ease and accuracy of measurement but may be less comprehensive than NLP for capturing all instances of safety planning documentation.