Localization of Intramuscular mRNA Delivery Using Deep Eutectic-Lipid Nanocomposites.

Messenger ribonucleic acid (mRNA) has long been touted as a next-generation therapeutic modality for infectious disease, cancer, and genetic disorders. Lipid nanoparticles (LNPs) provide an elegant delivery strategy for mRNA cargo to help realize this potential for vaccination. However, systemic exposure seen with traditional LNP formulations can have significant implications on efficacy and safety. Efforts to mitigate this have largely been focused on laborious lipid or LNP redesign. Here, the use of a deep eutectic-lipid nanocomposite delivery system for the tuning of mRNA expression for intramuscular injections in vivo is reported. One deep eutectic, cholinium malonate, allows for the linear control of percent expression at the muscular injection site based solely on its concentration in the formulation. The same deep eutectic solvent (DES) can increase local muscle expression by 68% and significantly decrease off-target liver expression by 72%. Physico-chemical studies suggest that the DES incorporates into or onto the pre-formed LNPs thus impacting endosomal escape and in situ interactions. These nanocomposites provide new possibilities for previously approved LNP formulations and without the need for lipid redesign to induce localized expression.

Polymer Backpack-Loaded Tissue Infiltrating Monocytes for Treating Cancer.

Adoptive cell therapies are dramatically altering the treatment landscape of cancer. However, treatment of solid tumors remains a major unmet need, in part due to limited adoptive cell infiltration into the tumor and in part due to the immunosuppressive tumor microenvironment. The heterogeneity of tumors and presence of nonresponders also call for development of antigen-independent therapeutic approaches. Myeloid cells offer such an opportunity, given their large presence in the immunosuppressive tumor microenvironment, such as in triple negative breast cancer. However, their therapeutic utility is hindered by their phenotypic plasticity. Here, the impressive trafficking ability of adoptively transferred monocytes is leveraged into the immunosuppressive 4T1 tumor to develop an antitumor therapy. To control monocyte differentiation in the tumor microenvironment, surface-adherent "backpacks" stably modified with interferon gamma (IFNγ) are developed to stimulate macrophage plasticity into a pro-inflammatory, antitumor phenotype, a strategy as referred to as Ornate Polymer backpacks on Tissue Infiltrating Monocytes (OPTIMs). Treatment with OPTIMs substantially reduces tumor burden in a mouse 4T1 model and significantly increases survival. Cytokine and immune cell profiling reveal that OPTIMs remodeled the tumor microenvironment into a pro-inflammatory state.

Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs.

The choroid plexus (ChP) of the brain plays a central role in orchestrating the recruitment of peripheral leukocytes into the central nervous system (CNS) through the blood-cerebrospinal fluid (BCSF) barrier in pathological conditions, thus offering a unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging of the ChP could be optimized for mild traumatic brain injury (mTBI). mTBI induces subtle, yet influential, changes in the brain and is currently severely underdiagnosed. We hypothesized that mTBI induces sufficient alterations in the ChP to cause infiltration of circulating leukocytes through the BCSF barrier and developed macrophage-adhering gadolinium [Gd(III)]-loaded anisotropic micropatches (GLAMs), specifically designed to image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles that adhere to macrophages without phagocytosis. We present a fabrication process to prepare GLAMs at scale and demonstrate their loading with Gd(III) at high relaxivities, a key indicator of their effectiveness in enhancing image contrast and clarity in medical imaging. In vitro experiments with primary murine and porcine macrophages demonstrated that GLAMs adhere to macrophages also under shear stress and did not affect macrophage viability or functions. Studies in a porcine mTBI model confirmed that intravenously administered macrophage-adhering GLAMs provide a differential signal in the ChP and lateral ventricles at Gd(III) doses 500- to 1000-fold lower than those used in the current clinical standard Gadavist. Under the same mTBI conditions, Gadavist did not offer a differential signal at clinically used doses. Our results suggest that macrophage-adhering GLAMs could facilitate mTBI diagnosis.

A novel method for the percutaneous induction of myocardial infarction by occlusion of small coronary arteries in the rabbit.

Arrhythmic sudden cardiac death (SCD) is an important cause of mortality following myocardial infarction (MI). The rabbit has similar cardiac electrophysiology to humans and is therefore an important small animal model to study post-MI arrhythmias. The established approach of surgical coronary ligation results in thoracic adhesions that impede epicardial electrophysiological studies. Adhesions are absent following a percutaneously induced MI, which is also associated with reduced surgical morbidity and so represents a clear refinement of the approach. Percutaneous procedures have previously been described in large rabbits (3.5-5.5 kg). Here, we describe a novel method of percutaneous MI induction in smaller rabbits (2.5-3.5 kg) that are readily available commercially. New Zealand White rabbits (n = 51 males, 3.1 ± 0.3 kg) were anesthetized using isoflurane (1.5-3%) and underwent either a percutaneous MI procedure involving microcatheter tip deployment (≤1.5 Fr, 5 mm), coronary ligation surgery, or a sham procedure. Electrocardiography (ECG) recordings were used to confirm ST-segment elevation indicating coronary occlusion. Blood samples (1 and 24 h) were taken for cardiac troponin I (cTnI) levels. Ejection fraction (EF) was measured at 6-8 wk. Rabbits were then euthanized (Euthatal) and hearts were processed for magnetic resonance imaging and histology. Mortality rates were similar in both groups. Scar volume, cTnI, and EF were similar between both MI groups and significantly different from their respective sham controls. Thus, percutaneous coronary occlusion by microcatheter tip deployment is feasible in rabbits (2.5-3.5 kg) and produces an MI with similar characteristics to surgical ligation with lower procedural trauma and without epicardial adhesions.NEW & NOTEWORTHY Surgical coronary ligation is the standard technique to induce myocardial infarction (MI) in rabbits but is associated with procedural trauma and the generation of thoracic adhesions. Percutaneous coronary occlusion avoids these shortcomings and is established in pigs but has only been applicable to large rabbits because of a mismatch between the equipment used and target vessel size. Here, we describe a new scalable approach to percutaneous MI induction that is safe and effective in 2.5-3.5-kg rabbits.

Backpack-mediated anti-inflammatory macrophage cell therapy for the treatment of traumatic brain injury.

Traumatic brain injury (TBI) is a debilitating disease with no current therapies outside of acute clinical management. While acute, controlled inflammation is important for debris clearance and regeneration after injury, chronic, rampant inflammation plays a significant adverse role in the pathophysiology of secondary brain injury. Immune cell therapies hold unique therapeutic potential for inflammation modulation, due to their active sensing and migration abilities. Macrophages are particularly suited for this task, given the role of macrophages and microglia in the dysregulated inflammatory response after TBI. However, maintaining adoptively transferred macrophages in an anti-inflammatory, wound-healing phenotype against the proinflammatory TBI milieu is essential. To achieve this, we developed discoidal microparticles, termed backpacks, encapsulating anti-inflammatory interleukin-4, and dexamethasone for ex vivo macrophage attachment. Backpacks durably adhered to the surface of macrophages without internalization and maintained an anti-inflammatory phenotype of the carrier macrophage through 7 days in vitro. Backpack-macrophage therapy was scaled up and safely infused into piglets in a cortical impact TBI model. Backpack-macrophages migrated to the brain lesion site and reduced proinflammatory activation of microglia in the lesion penumbra of the rostral gyrus of the cortex and decreased serum concentrations of proinflammatory biomarkers. These immunomodulatory effects elicited a 56% decrease in lesion volume. The results reported here demonstrate, to the best of our knowledge, a potential use of a cell therapy intervention for a large animal model of TBI and highlight the potential of macrophage-based therapy. Further investigation is required to elucidate the neuroprotection mechanisms associated with anti-inflammatory macrophage therapy.

Measuring Violence Against Children: A COSMIN Systematic Review of the Psychometric and Administrative Properties of Adult Retrospective Self-report Instruments on Child Abuse and Neglect.

Valid, meaningful, and reliable adult retrospective measures of violence against children (VAC) are essential for establishing the prevalence, risk factors, and long-term effects of VAC. We aim to summarize the available evidence on the psychometric properties of adult retrospective VAC measures and to provide evidence-based recommendations for appropriate measure selection. We searched six electronic databases and gray literature for studies that report on the development, content validity, or psychometric properties of adult retrospective child abuse and neglect measures for this review (PROSPERO: CRD4201706). We used the 2018 Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) criteria to evaluate each included study and measure. We assessed if measures included questions on frequency or severity, the perpetrator, or the location of the violence, and noted the administrative practicalities for each instrument such as length, readability, available translations, and cost to access. We identified 288 studies and 77 measures. The quality of evidence ranged from "low" to "high," depending on the measure and the psychometric properties assessed. The measures with the most robust evidence available across multiple contexts are the: ACE and ACE-IQ; FBQ and FBQ-U; CTQ and CTQ-SF; and ICAST-R. This review shows the strengths and weaknesses of retrospective VAC measures. The substantial evidence presented in this review can be used by researchers to make psychometrically sound decisions for measurement selection which should be supported by extensive piloting and adaptation to the respective local context.

Antithrombotic Prophylaxis with Rivaroxaban in Patients with Prehospital COVID-19: A Meta-analysis of Two Placebo-Controlled Trials.

BACKGROUND: We conducted a prespecified meta-analysis of two randomized, placebo-controlled trials of rivaroxaban 10 mg daily in prehospital patients with acute coronavirus disease 2019 (COVID-19). Individually, the trials had limited power to detect a treatment effect due to recruitment stopping ahead of plan. MATERIAL AND METHODS: The statistical analysis plan for the meta-analysis was finalized before unblinding of PREVENT-HD, the larger of the two trials. Pooled risk ratios and pooled risk differences along with the two-sided 95% confidence intervals were calculated using random-effect models. RESULTS: Rivaroxaban did not reduce the occurrence of either the primary prespecified endpoint, a composite of symptomatic arterial and venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, all-cause hospitalization, and all-cause mortality (risk difference: 0.0044; 95% confidence interval: -0.0263, 0.0175; p = 0.69 for pooled risk difference) or the secondary endpoint of all-cause hospitalization (p = 0.76). Although thrombotic events were infrequent, pooled analysis did reveal that rivaroxaban reduced arterial and venous thrombotic events (placebo 6 events, rivaroxaban 0 events; pooled risk difference: -0.0068; 95% confidence interval: -0.0132, -0.0006; p = 0.03). In the pooled studies, only one major bleeding event was observed in a rivaroxaban-allocated patient with no critical site or fatal bleeding events. CONCLUSION: Although this meta-analysis does not support antithrombotic prophylaxis with rivaroxaban in a broad prehospital population with acute COVID-19, the prevention of arterial and venous thrombotic events among rivaroxaban-allocated patients is consistent with the known thromboprophylactic effect of the drug in medically ill patients.

Data demonstrating the in vivo anti-tumor efficacy of thermosensitive liposome formulations of a drug combination in pre-clinical models of breast cancer.

Thermosensitive liposomes in combination with localized mild hyperthermia can improve the delivery of drug to solid tumor sites. For this reason, thermosensitive liposome formulations of a range of chemotherapy drugs have been designed. Our group previously developed and characterized a thermosensitive liposome formulation of the heat shock protein 90 inhibitor alvespimycin as a companion therapeutic to a thermosensitive liposome formulation equivalent in composition to ThermoDox (i.e., ThermoDXR), with the goal of increasing the therapeutic index of doxorubicin as the combination was revealed to be highly synergistic in a panel of human breast cancer cell lines including MDA-MB-231 (Dunne et al., 2019). The data presented here further describes the effect of the doxorubicin (DXR) and alvespimycin (ALV) combination in vitro and in vivo. Specifically, the combination effect in mouse breast cancer 4T1 cells and the in vivo efficacy of this heat-activated chemotherapy combination in both immunocompromised (MDA-MB-231 tumor bearing female SCID mice) and immunocompetent (4T1 tumor bearing female BALB/c mice) models of breast cancer.

Electrically stimulated in vitro heart cell mimic of acute exercise reveals novel immediate cellular responses to exercise: Reduced contractility and metabolism, but maintained calcium cycling and increased myofilament calcium sensitivity.

Cardiac cellular responses to acute exercise remain undescribed. We present a model for mimicking acute aerobic endurance exercise to freshly isolated cardiomyocytes by evoking exercise-like contractions over prolonged periods of time with trains of electrical twitch stimulations. We then investigated immediate contractile, Ca2+ , and metabolic responses to acute exercise in perfused freshly isolated left ventricular rat cardiomyocytes, after a matrix-design optimized protocol and induced a mimic for acute aerobic endurance exercise by trains of prolonged field twitch stimulations. Acute exercise decreased cardiomyocyte fractional shortening 50%-80% (p < .01). This was not explained by changes to intracellular Ca2+ handling (p > .05); rather, we observed a weak insignificant Ca2+ transient increase (p = .11), while myofilament Ca2+ sensitivity increased 20%-70% (p < .05). Acidic pH 6.8 decreased fractional shortening 20%-70% (p < .05) because of 20%-30% decreased Ca2+ transients (p < .05), but no difference occurred between control and acute exercise (p > .05). Addition of 1 or 10 mM La- increased fractional shortening in control (1 mM La- : no difference, p > .05; 10 mM La- : 20%-30%, p < .05) and acute exercise (1 mM La- : 40%-90%, p < .01; 10 mM La- : 50%-100%, p < .01) and rendered acute exercise indifferent from control (p > .05). Intrinsic autofluorescence showed a resting NADstate of 0.59 ± 0.04 and FADstate of 0.17 ± 0.03, while acute exercise decreased NADH/FAD ratio 8% (p < .01), indicating intracellular oxidation. In conclusion, we show a novel approach for studying immediate acute cardiomyocyte responses to aerobic endurance exercise. We find that acute exercise in cardiomyocytes decreases contraction, but Ca2+ handling and myofilament Ca2+ sensitivity compensate for this, while acidosis and reduced energy substrate and mitochondrial ATP generation explain this.

Why do consumers choose private over public health services? Reflective accounts of health providers in Vietnam.

BACKGROUND: In Vietnam and many developing countries, private healthcare is increasingly being leveraged by governments to complement public services and increase health service access and utilisation. Extensive understanding of patterns of utilisation of private over public health services, and the rationale for such consumer decisions, is important to ensure and promote safe, affordable and patient-centred care in the two sectors. Few studies within the Southeast Asian Region have explored how private and public providers interact (via social networks, marketing, and direct contact) with consumers to affect their service choices. This study investigates providers' views on social factors associated with the use of private over public health services in Vietnam. METHOD: A thematic analysis was undertaken of 30 semi-structured interviews with experienced health system stakeholders from the Vietnam national assembly, government ministries, private health associations, health economic association, as well as public and private hospitals and clinics. RESULTS: Multiple social factors were found to influence the choice of private over public services, including word-of-mouth, the patient-doctor relationship and relationships between healthcare providers, healthcare staff attitudes and behaviour, and marketing. While private providers maximise their use of these social factors, most public providers seem to ignore or show only limited interest in using marketing and other forms of social interaction to improve services to meet patients' needs, especially those needs beyond strictly medical intervention. However, private providers faced their own particular challenges related to over-advertisement, over-servicing, excessive focus on patients' demands rather than medical needs, as well as the significant technical requirements for quality and safety. CONCLUSIONS: This study has important implications for policy and practice in Vietnam. First, public providers must embrace social interaction with consumers as an effective strategy to improve their service quality. Second, appropriate regulations of private providers are required to protect patients from unnecessary treatments, costs and potential harm. Finally, the insights from this study have direct relevance to many developing countries facing a similar challenge of appropriately managing the growth of the private health sector.

Exploring the outcomes of a reflective teaching strategy with students: A feasibility study.

Purpose: Reflection can be a valuable learning strategy for connecting theory with practice and illuminating insights and understandings from complex or messy experiences. This learning is critical for educators and health professionals who work or teach students in complex contexts. In anticipation of their future needs, speech-language pathology students, like many health profession students in Australia, are expected to demonstrate the ability to reflect on their practice as part of their professional practice or clinical education. It is challenging to support educators to facilitate reflection and students to learn when, why, and how to reflect for personally and professionally meaningful outcomes given the diversity in understandings and capabilities present in the literature. The purpose of this study was to investigate the feasibility of an evidence-based reflection intervention to clarify and support student reflective practice.Method: A convergent mixed methods design captured quantitative and qualitative results from 16 participants for a better understanding of the feasibility of a reflection intervention.Result: The diversity in the reflection literature also appears to be present in students' reflection approaches. This diversity can encourage student engagement and ownership of reflecting when considered within a rich learning environment.Conclusion: Findings are discussed for timely, intellectually and emotionally safe reflection interventions that develop students' reflective inquiry in the real-world.

Contribution of private health services to universal health coverage in low and middle-income countries: Factors affecting the use of private over public health services in Vietnam.

The private sector's contribution to Universal health coverage (UHC) has been increasingly recognised by policymakers in low- and middle-income countries. This study aimed to identify service-provider and consumer-level factors affecting choice of private over public health services in Vietnam. A concurrent mixed-method design was adopted. A quantitative phase explored consumers' health service choice by analysing data from a random national sample of 10,354 individuals aged 16 and over. The qualitative phase investigated how private and public providers organise their services to influence consumer choices by conducting interviews with policymakers, hospital and clinic managers, and health practitioners. The combined results demonstrate that at the individual level, absence of any type of health insurance was the factor most closely associated with the use of private services. Private health services were more likely to be used by people from ethnic majority groups compared to ethnic minorities (odds ratio [OR]: 1.6, 95% CI: 1.4-2.0), and by people living in urban compared to rural areas (OR: 1.1, 95% CI: 1.0-1.3). The service providers suggested that consumers opted for private services that were perceived to have poorer quality in the public sector, such as counselling, physical therapy and rehabilitative care. Additional motivational factors include the private sector's more flexible working hours, shorter waiting times, flexible pricing of services, personalised care and better staff behaviour. The findings can inform national health system planning and coordination activities in Vietnam and other countries that aim to harness the attributes of both the public and private sectors to achieve UHC.

The association between child maltreatment and health risk behaviours and conditions throughout life in the Australian Child Maltreatment Study.

OBJECTIVE: To estimate associations between all five types of child maltreatment (emotional abuse, neglect, physical abuse, sexual abuse, and exposure to domestic violence) and health risk behaviours and conditions. DESIGN, SETTING, PARTICIPANTS: Nationally representative survey of Australian residents aged 16 years and older conducted by computer-assisted telephone interviewing. MAIN OUTCOME MEASURES: Associations between child maltreatment and the following health risk behaviours and conditions: current smoker, binge drinking (at least weekly in past 12 months), cannabis dependence (according to the Cannabis Severity of Dependence Scale), obesity (based on body mass index), self-harm in past 12 months, and suicide attempt in past 12 months. RESULTS: A total of 8503 participants completed the survey. All five types of child maltreatment were associated with increased rates of all of the health risk behaviours and conditions that we considered. The strongest associations were in the youngest age group (16-24-year-olds). Sexual abuse and emotional abuse were associated with the highest odds of health risk behaviours and conditions. Cannabis dependence, self-harm and suicide attempts were most strongly associated with child maltreatment. Experiencing more than one type of child maltreatment was associated with higher rates of health risk behaviours and conditions than experiencing one type of child maltreatment. CONCLUSIONS: Child maltreatment is associated with substantially increased rates of health risk behaviours and conditions. Prevention and intervention efforts should be informed by trauma histories, and holistic psychosocial care should be incorporated into programs focusing on behaviour change.

The Australian Child Maltreatment Study (ACMS), a national survey of the prevalence of child maltreatment and its correlates: methodology.

OBJECTIVES: To describe the aims, design, methodology, and respondent sample representativeness of the Australian Child Maltreatment Study (ACMS). DESIGN, SETTING: Cross-sectional, retrospective survey; computer-assisted mobile telephone interviewing using random digit dialling (computer-generated), Australia, 9 April - 11 October 2021. PARTICIPANTS: People aged 16 years or more. The target sample size was 8500 respondents: 3500 people aged 16-24 years and 1000 respondents each from five further age groups (25-34, 35-44, 45-54, 55-64, 65 years or more). MAIN OUTCOME MEASURES: Primary outcomes: Emotional abuse, neglect, physical abuse, sexual abuse, exposure to domestic violence during childhood, assessed with the Juvenile Victimization Questionnaire-R2 Adapted Version (Australian Child Maltreatment Study). SECONDARY OUTCOMES: selected mental disorder diagnoses (Mini International Neuropsychiatric Interview, MINI), selected physical health conditions, health risk behaviours, health service use. RESULTS: The demographic characteristics of the ACMS sample were similar to those of the Australian population in 2016 with respect to gender, Indigenous status, region and remoteness category of residence, and marital status, but larger proportions of participants were born in Australia, lived in areas of higher socio-economic status, had tertiary qualifications, and had income greater than $1250 per week. Population weights were derived to adjust for these differences. Associations between the number of calls required to recruit participants and maltreatment rates and health outcomes were not statistically significant. CONCLUSIONS: The ACMS provides the first reliable estimates of the prevalence of each type of child maltreatment in Australia. These estimates, and those of associated mental health and health risk behaviours reported in this supplement can inform policy and practice initiatives for reducing the prevalence of child maltreatment and its consequences. Our benchmark study also provides baseline data for repeated waves of the ACMS that will assess the effectiveness of these initiatives.

The prevalence of child maltreatment in Australia: findings from a national survey.

OBJECTIVES: To estimate the prevalence in Australia of each type of child maltreatment; to identify gender- and age group-related differences in prevalence. DESIGN, SETTING: Cross-sectional national survey; mobile telephone interviews using random digit dialling (computer-generated), Australia, 9 April - 11 October 2021. Retrospective self-report data using validated questionnaire (Juvenile Victimisation Questionnaire-R2 Adapted Version (Australian Child Maltreatment Study). PARTICIPANTS: People aged 16 years or more. The target sample size was 8500 respondents: 3500 people aged 16-24 years and 1000 respondents each from five further age groups (25-34, 35-44, 45-54, 55-64, 65 years or more). MAIN OUTCOME MEASURES: Proportions of respondents reporting physical abuse, sexual abuse, emotional abuse, neglect, and exposure to domestic violence to age 18 years, assessed with the Juvenile Victimization Questionnaire-R2 Adapted Version (Australian Child Maltreatment Study), overall and by gender and age group, and weighted to reflect characteristics of the Australian population aged 16 years or more in 2016. RESULTS: Complete survey data were available for 8503 eligible participants (14% response rate). Physical abuse was reported by 32.0% of respondents (95% confidence interval [CI], 30.7-33.3%), sexual abuse by 28.5% (95% CI, 27.3-29.8%), emotional abuse by 30.9% (95% CI, 29.7-32.2%), neglect by 8.9% (95% CI, 8.1-9.7%), and exposure to domestic violence by 39.6% (95% CI, 38.3-40.9%). The proportions of respondents who reported sexual abuse, emotional abuse, or neglect were each statistically significantly larger for women than men. The reported prevalence of physical abuse by respondents aged 16-24 years was lower than for those aged 25-34 years, and that of sexual abuse was lower than for those aged 35-44 years, suggesting recent declines in the prevalence of these maltreatment types. CONCLUSIONS: Child maltreatment is common in Australia, and larger proportions of women than men report having experienced sexual abuse, emotional abuse, and neglect during childhood. As physical and sexual abuse may have declined recently, public health policy and practice may have positive effects, justifying continued monitoring and prevention activities.

The prevalence and nature of multi-type child maltreatment in Australia.

OBJECTIVES: To determine the prevalence in Australia of multi-type child maltreatment, defined as two or more maltreatment types (physical abuse, sexual abuse, emotional abuse, neglect, or exposure to domestic violence) and to examine its nature, family risk factors, and gender and age cohort differences. DESIGN: Retrospective cross-sectional survey using a validated questionnaire. SETTING AND PARTICIPANTS: Mobile phone random digit-dial sample of the Australian population aged 16 years and older. MAIN OUTCOME MEASURES: National estimates of multi-type child maltreatment up to age 18 years using the Juvenile Victimisation Questionnaire-R2: Adapted Version (Australian Child Maltreatment Study). RESULTS: Of 8503 participants, 62.2% (95% CI, 60.9-63.6%) experienced one or more types of child maltreatment. Prevalence of single-type maltreatment was 22.8% (95% CI, 21.7-24.0%), whereas 39.4% (95% CI, 38.1-40.7%) of participants reported multi-type maltreatment and 3.5% (95% CI, 3.0-4.0%) reported all five types. Multi-type maltreatment was more common for gender diverse participants (66.1% [95% CI, 53.7-78.7%]) and women (43.2% [95% CI, 41.3-45.1%]) than for men (34.9% [95% CI, 33.0-36.7%]). Multi-type maltreatment prevalence was highest for those aged 25-44 years. Family-related adverse childhood experiences - especially mental illness and alcohol or substance misuse - increased risk. Exposure to domestic violence was the maltreatment type most often present in multi-type maltreatment patterns. CONCLUSIONS: Multi-type child maltreatment is prevalent in Australia and more common in women and gender diverse individuals. Child protection services, health practitioners, and prevention and intervention services must assess and manage multi-type maltreatment in children and address its health consequences across the lifespan. Public health policy should consider prevention services or strategies that target multi-type child maltreatment.

Child maltreatment and health service use: findings of the Australian Child Maltreatment Study.

OBJECTIVES: To examine associations between child maltreatment and health service use, both overall, by type and by the number of types of maltreatment reported. DESIGN, SETTING: Cross-sectional, retrospective survey using the Juvenile Victimization Questionnaire-R2: Adapted Version (Australian Child Maltreatment Study); computer-assisted mobile telephone interviews using random digit dialling, Australia, 9 April - 11 October 2021. PARTICIPANTS: Australians aged 16 years or more. The target sample size was 8500 respondents: 3500 people aged 16-24 years and 1000 respondents each from the five age groups (25-34, 35-44, 45-54, 55-64, 65 years or more). MAIN OUTCOME MEASURES: Self-reported health service use during the past twelve months: hospital admissions, length of stay, and reasons for admission; and numbers of consultations with health care professionals, overall and by type. Associations between maltreatment and health service use are reported as odds ratios adjusted for age group, gender, socio-economic status, financial hardship (childhood and current), and geographic remoteness. RESULTS: A total of 8503 participants completed the survey. Respondents who had experienced child maltreatment were significantly more likely than those who had not to report a hospital admission during the preceding twelve months (adjusted odds ratio [aOR], 1.39; 95% confidence interval [CI], 1.16-1.66), particularly admission with a mental disorder (aOR, 2.4; 95% CI, 1.03-5.6). The likelihood of six or more visits to general practitioners (aOR, 2.37; 95% CI, 1.87-3.02) or of a consultation with a mental health nurse (aOR, 2.67; 95% CI, 1.75-4.06), psychologist (aOR, 2.40; 95% CI, 2.00-2.88), or psychiatrist (aOR, 3.02; 95% CI, 2.25-4.04) were each higher for people who reported maltreatment during childhood. People who reported three or more maltreatment types were generally most likely to report greater health service use. CONCLUSIONS: Child maltreatment has a major impact on health service use. Early, targeted interventions are vital, not only for supporting children directly, but also for their longer term wellbeing and reducing their health system use throughout life.

The association between child maltreatment and mental disorders in the Australian Child Maltreatment Study.

OBJECTIVES: To examine the associations between experiences of child maltreatment and mental disorders in the Australian population. DESIGN: Population-representative survey conducted by computer-assisted telephone interviewing. SETTING, PARTICIPANTS: Australian residents aged 16 years and older. MAIN OUTCOME MEASURES: Mental disorder diagnoses of lifetime major depressive disorder, current alcohol use disorder (mild, moderate and severe), current generalised anxiety disorder and current post-traumatic stress disorder. RESULTS: More than one in three Australians (3606/8503 surveyed participants; 38.0%; 95% CI, 36.7-39.3%) met the diagnostic criteria for a mental disorder. The prevalence of mental disorders in non-maltreated participants was 21.6% (95% CI, 19.9-23.3%; n = 851). This increased to 36.2% (95% CI, 33.5-38.9%; n = 764) for those who experienced a single type of maltreatment and 54.8% (95% CI, 52.6-56.9%; n = 1991) for participants who experienced multi-type maltreatment. Compared with non-maltreated Australians, maltreated participants had about three times the odds of any mental disorder (odds ratio [OR], 2.82; 95% CI, 2.47-3.22), generalised anxiety disorder (OR, 3.14; 95% CI, 2.48-3.97), major depressive disorder (OR, 3.19; 95% CI, 2.68-3.80) and severe alcohol use disorder (OR, 2.62; 95% CI, 1.83-3.76), and almost five times the odds of post-traumatic stress disorder (OR, 4.60; 95% CI, 3.00-7.07). Associations between experiences of child maltreatment and mental disorders were strongest for sexual abuse, emotional abuse and multi-type maltreatment. The strength of the associations did not differ by gender. Adjustment for childhood and current financial hardship and for current socio-economic status did not significantly attenuate the associations. CONCLUSIONS: Mental disorders are significantly more likely to occur in individuals who experience child maltreatment, particularly multi-type maltreatment. Prevention of child maltreatment provides an opportunity to substantially reduce the prevalence of mental illness and improve the health of the Australian population.

A backpack-based myeloid cell therapy for multiple sclerosis.

Multiple sclerosis (MS) is an incurable autoimmune disease and is currently treated by systemic immunosuppressants with off-target side effects. Although aberrant myeloid function is often observed in MS plaques in the central nervous system (CNS), the role of myeloid cells in therapeutic intervention is currently overlooked. Here, we developed a myeloid cell-based strategy to reduce the disease burden in experimental autoimmune encephalomyelitis (EAE), a mouse model of progressive MS. We developed monocyte-adhered microparticles ("backpacks") for activating myeloid cell phenotype to an anti-inflammatory state through localized interleukin-4 and dexamethasone signals. We demonstrate that backpack-laden monocytes infiltrated into the inflamed CNS and modulated both the local and systemic immune responses. Within the CNS, backpack-carrying monocytes regulated both the infiltrating and tissue-resident myeloid cell compartments in the spinal cord for functions related to antigen presentation and reactive species production. Treatment with backpack-monocytes also decreased the level of systemic pro-inflammatory cytokines. Additionally, backpack-laden monocytes induced modulatory effects on TH1 and TH17 populations in the spinal cord and blood, demonstrating cross talk between the myeloid and lymphoid arms of disease. Backpack-carrying monocytes conferred therapeutic benefit in EAE mice, as quantified by improved motor function. The use of backpack-laden monocytes offers an antigen-free, biomaterial-based approach to precisely tune cell phenotype in vivo, demonstrating the utility of myeloid cells as a therapeutic modality and target.