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.

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.

Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial.

BACKGROUND: Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. METHODS: Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). RESULTS: Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum ß-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. CONCLUSIONS: Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. CLINICAL TRIAL REGISTRATION: NCT03357614.

Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial.

BACKGROUND: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. METHODS: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. RESULTS: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). CONCLUSIONS: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. CLINICAL TRIAL REGISTRATION: NCT03354598.

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.

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.

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.

Randomized Study of Rivaroxaban vs Placebo on Disease Progression and Symptoms Resolution in High-Risk Adults With Mild Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection may be associated with a prothrombotic state, predisposing patients for a progressive disease course. We investigated whether rivaroxaban, a direct oral anticoagulant factor Xa inhibitor, would reduce coronavirus disease 2019 (COVID-19) progression. METHODS: Adults (N = 497) with mild COVID-19 symptoms and at high risk for COVID-19 progression based on age, body mass index, or comorbidity were randomized 1:1 to either daily oral rivaroxaban 10 mg (N = 246) or placebo equivalent (N = 251) for 21 days and followed to day 35. Primary end points were safety and progression. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method. RESULTS: The study was terminated after 497 of the target 600 participants were enrolled due to a prespecified interim analysis of the first 200 participants that crossed the futility boundary for the primary efficacy end point in the intent-to-treat population. Enrollees were 85% aged <65 years; 60% female; 27% Hispanic, Black, or other minorities; and 69% with ≥2 comorbidities. Rivaroxaban was well tolerated. Disease progression rates were 46 of 222 (20.7%) in rivaroxaban vs 44 of 222 (19.8%) in placebo groups, with a risk difference of -1.0 (95% confidence interval, -6.4 to 8.4; P = .78). CONCLUSIONS: We did not demonstrate an impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19. There remains a critical public health gap in identifying scalable effective therapies for high-risk people in the outpatient setting to prevent COVID-19 progression.

A multicenter analysis of trends in resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 2011-2020.

BACKGROUND: Urinary tract infections (UTIs), which are usually caused by bacteria in the Enterobacterales family, are a common reason for outpatient visits. Appropriate empiric therapy for UTIs requires an understanding of antibiotic resistance in the community. In this nationwide study, we examined trends in antibiotic resistance in urinary Enterobacterales isolates from ambulatory patients in the United States (US). METHODS: We analyzed the antimicrobial susceptibility profiles (extended-spectrum beta-lactamase [ESBL]-producing phenotype and not susceptible [NS] to beta-lactams, trimethoprim/sulfamethoxazole [TMP/SMX], fluoroquinolones [FQ], or nitrofurantoin [NFT]) of 30-day non-duplicate Enterobacterales isolates from urine cultures tested at ambulatory centers in the BD Insights Research Database (2011-2020). The outcome of interest was the percentage of resistant isolates by pathogen and year. Multi-variable generalized estimating equation models were used to assess trends in resistance over time and by additional covariates. RESULTS: A total of 338 US facilities provided data for > 2.2 million urinary Enterobacterales isolates during the 10-year study. Almost three-quarters (72.8%) of Enterobacterales isolates were Escherichia coli. Overall unadjusted resistance rates in Enterobacterales isolates were 57.5%, 23.1%, 20.6%, and 20.2% for beta-lactams, TMP/SMX, FQ, and NFT, respectively, and 6.9% had an ESBL-producing phenotype. Resistance to two or more antibiotic classes occurred in 16.4% of isolates and 5.5% were resistant to three or more classes. Among isolates with an ESBL-producing phenotype, 70.1%, 59.9%, and 33.5% were NS to FQ, TMP/SMX, and NFT, respectively. In multivariable models, ESBL-producing and NFT NS Enterobacterales isolates increased significantly (both P < 0.001), while other categories of resistance decreased. High rates (≥ 50%) of beta-lactam and NFT resistance were observed in Klebsiella isolates and in non-E. coli, non-Klebsiella Enterobacterales isolates. CONCLUSIONS: Antimicrobial resistance was common in urinary Enterobacterales isolates. Isolates with an ESBL-producing phenotype increased by about 30% between 2011 and 2020, and significant increases were also observed in NFT NS Enterobacterales isolates. Resistance rates for all four antibiotic classes were higher than thresholds recommended for use as empiric therapy. Non-E. coli Enterobacterales isolates showed high levels of resistance to commonly used empiric antibiotics, including NFT. These data may help inform empiric therapy choices for outpatients with UTIs.

Patterns of adverse childhood experiences and associations with prenatal substance use and poor infant outcomes in a multi-country cohort of mothers: a latent class analysis.

BACKGROUND: This paper enumerates and characterizes latent classes of adverse childhood experiences and investigates how they relate to prenatal substance use (i.e., smoking, alcohol, and other drugs) and poor infant outcomes (i.e., infant prematurity and low birthweight) across eight low- and middle-income countries (LMICs). METHODS: A total of 1189 mother-infant dyads from the Evidence for Better Lives Study cohort were recruited. Latent class analysis using the Bolck, Croon, and Hagenaars (BCH) 3-step method with auxiliary multilevel logistic regressions was performed. RESULTS: Three high-risk classes and one low-risk class emerged: (1) highly maltreated (7%, n = 89), (2) emotionally and physically abused with intra-familial violence exposure (13%, n = 152), (3), emotionally abused (40%, n = 474), and (4) low household dysfunction and abuse (40%, n = 474). Pairwise comparisons between classes indicate higher probabilities of prenatal drug use in the highly maltreated and emotionally abused classes compared with the low household dysfunction and abuse class. Additionally, the emotionally and physically abused with intra-familial violence exposure class had higher probability of low birthweight than the three remaining classes. CONCLUSION: Our results highlight the multifaceted nature of ACEs and underline the potential importance of exposure to childhood adversities on behaviors and outcomes in the perinatal period. This can inform the design of antenatal support to better address these challenges.

Understanding Vietnam's drug policy for amphetamine-type stimulants misuse.

INTRODUCTION: The emergence of widespread amphetamine-type stimulants (ATSs) usage has created significant challenges for drug control and treatment policies in Southeast Asian countries. This study analyses the development of drug policies and examines current treatment program constraints in Vietnam to deal with ATS misuse. The aim was to gain insights that may be useful for national and international drug-related policy development and revision. METHODS: A desk review of national policy documents and 22 in-depth key informant interviews were conducted from 2019 to 2021. Thematic content analysis was employed to identify key themes and their connections. RESULTS: Analysis identified Vietnam's 30-year history of developing policies and formulating strategies to reduce supply, demand, and harm from illicit drugs. With the increasing number of people who use ATS (PWUA), Vietnam has recently promoted harsh policy and law enforcement to deter drug use and supply. This policy trend prevails in many Asian countries. The three main constraints in dealing with ATS misuse emerged from punitive and restrictive drug policies. First, the general public believed that Centre-based compulsory treatment (CCT) is the only appropriate treatment for all types of illicit drug addiction despite its low-quality service provision. The rigid drug policy has led to social persuasion with impractical expectations for CCT effectiveness. Second, the emphasis on punishment and detention has hampered new drug treatment service development in Vietnam. CCT has become monopolistic in the context of impoverished services. Third, people who use drugs tend to hide their needs and avoid formal treatment and support services, resulting in declined social coherence. CONCLUSION: While new drugs are constantly evolving, the current law enforcement approach potentially constrains expertise to adopt effective treatment services. This study suggests that the top-down policing mechanism presently hinders the development of an appropriate intervention strategy for ATS misuse and diminishes social support to service providers.

Effect of intimate partner violence during pregnancy on maternal mental health: a cohort study in central Vietnam.

This study aims to explore the effects of intimate partner violence during pregnancy (p-IPV) on postpartum depression among women in central Vietnam. p-IPV was defined among 150 women aged 18 years and older in the third trimester of their pregnancy. Baseline data was collected between February and May 2019, and then those women were followed up to 3-5 months after childbirth to assess depression using the Patient Health Questionnaire-9 (PHQ-9). Data collection was completed in September 2019. Relative risk was estimated to identify the effect of p-IPV on maternal postpartum depression. Twenty-one women reported IPV during pregnancy. In the follow-up assessment, 8 of 21 mothers exposed to p-IPV and 23 of 127 mothers not exposed to p-IPV developed postpartum depression. p-IPV including emotional and physical violence were increased the risk of postpartum depression. The findings support evidence that p-IPV increases the risk of postpartum depression among women in central Vietnam.

A novel surgical model for the preclinical assessment of the osseointegration of dental implants: a surgical protocol and pilot study results.

BACKGROUND: Dental implants are considered the gold standard replacement for missing natural teeth. The successful clinical performance of dental implants is due to their ability to osseointegrate with the surrounding bone. Most dental implants are manufactured from Titanium and it alloys. Titanium does however have some shortcomings so alternative materials are frequently being investigated. Effective preclinical studies are essential to transfer the innovations from the benchtop to the patients. Many preclinical studies are carried out in the extra-oral bones of small animal models to assess the osseointegration of the newly developed materials. This does not simulate the oral environment where the dental implants are subjected to several factors that influence osseointegration; therefore, they can have limited clinical value. AIM: This study aimed to develop an appropriate in-vivo model for dental implant research that mimic the clinical setting. The study evaluated the applicability of the new model and investigated the impact of the surgical procedure on animal welfare. MATERIALS AND METHODS: The model was developed in male New Zealand white rabbits. The implants were inserted in the extraction sockets of the secondary incisors in the maxilla. The model allows a split-mouth comparative analysis. The implants' osseointegration was assessed clinically, radiographically using micro-computed tomography (µ-CT), and histologically. A randomised, controlled split-mouth design was conducted in 6 rabbits. A total of twelve implants were inserted. In each rabbit, two implants; one experimental implant on one side, and one control implant on the other side were applied. Screw-shaped implants were used with a length of 8 mm and a diameter of 2 mm. RESULTS: All the rabbits tolerated the surgical procedure well. The osseointegration was confirmed clinically, histologically and radiographically. Quantitative assessment of bone volume and mineral density was measured in the peri-implant bone tissues. The findings suggest that the new preclinical model is excellent, facilitating a comprehensive evaluation of osseointegration of dental implants in translational research pertaining to the human application. CONCLUSION: The presented model proved to be safe, reproducible and required basic surgical skills to perform.

Intergenerational effects of violence on women's perinatal wellbeing and infant health outcomes: evidence from a birth cohort study in Central Vietnam.

BACKGROUND: Girls exposed to violence have a high risk of being victimized as adults and are more likely than non-abused women to have children who are treated violently. This intergenerational transmission may be especially serious when women suffer violence during pregnancy and early motherhood, as it impairs maternal wellbeing and infant health and development. This study examined the intergenerational effects of being exposed to childhood maltreatment (CM) and prenatal intimate partner violence (p-IPV) on perinatal mental distress and birth outcomes in central Vietnam. METHODS: A birth cohort study in Hue City, Vietnam was conducted with 150 women in the third trimester of pregnancy (Wave 1) and 3 months after childbirth (Wave 2). Using multivariable logistic regression models, augmented inverse-probability-weighted estimators and structural equation modelling (SEM), we analyzed a theoretical model by evaluating adjusted risk differences and pathways between CM, p-IPV and subsequent perinatal adversity and indicators of infant health problems. RESULTS: One in two pregnant women experienced at least one form of CM (55.03%) and one in ten pregnant women experienced both CM and p-IPV (10.67%). Mothers who experienced p-IPV or witnessed IPV as a child were approximately twice as likely to experience poor mental health during pregnancy [ARR 1.94, 95% CI (1.20-3.15)]. Infants had a two-fold higher risk of adverse birth outcomes (low birth weight, preterm birth, admission to neonatal intensive care) [ARR 2.45 95% CI (1.42, 4.25)] if their mothers experienced any form of p-IPV, with greater risk if their mothers were exposed to both CM and p-IPV [ARR 3.45 95% CI (1.40, 8.53)]. Notably, significant pathways to p-IPV were found via adverse childhood experience (ACE) events (ß = 0.13), neighborhood disorder (ß = 0.14) and partner support (ß = - 1.3). CONCLUSION: These results emphasize the detrimental and prolonged nature of the effect of violence during childhood and pregnancy. Exposure to childhood maltreatment and violence during pregnancy increases the risk of maternal mental health difficulties and adverse birth outcomes. Antenatal care systems need to be responsive to women's previous experiences of violence and maternal mental health. The significant protective role of partner support and social support should also be considered when designing tailored interventions to address violence during pregnancy.