Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth.

Ras is mutated in up to 30% of cancers, including 90% of pancreatic ductal adenocarcinomas, causing it to be constitutively GTP-bound, and leading to activation of downstream effectors that promote a tumorigenic phenotype. As targeting Ras directly is difficult, there is a significant effort to understand the downstream biological processes that underlie its protumorigenic activity. Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer. Finally, this phosphorylation is required for Ras-associated mitochondrial fission, and its inhibition is sufficient to block xenograft growth. Collectively, these data suggest mitochondrial fission may be a target for treating MAPK-driven malignancies.

Population-Level Study on Fetal Deaths and Preterm Births during SARS-CoV-2 Pandemic in the State of Michigan.

OBJECTIVE: The aim of the study is to explore the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on preterm birth at different gestational ages and fetal death in the state of Michigan. STUDY DESIGN: Data on live births and fetal deaths in the state of Michigan from March to November in the years 2017 through 2020 were obtained from Michigan Department of Health and Human Services (MDHHS). Preterm birth rate, fetal death rate (per 1,000 live births) overall and stratified by race and maternal comorbidities during the period of pandemic (March-November 2020) were compared with the same period (March-November) in the prepandemic years (2017-2019). RESULTS: Of 328,879 live births and 1,470 fetal deaths during the study period, 77,983 live births and 242 fetal deaths were reported in 2020. Compared with prepandemic years, fetal death rate per 1,000 live births was significantly lower in 2020 (3.1 vs. 4.7 [2017], 5.2 [2018], 4.4 [2019], p-value <0.001). The adjusted risk for fetal death in 2020 was decreased (odds ratio [OR] = 0.64 [95% confidence interval (CI): 0.56-0.74], p <0.0001), compared with prepandemic years. Fetal death was significantly associated with African-American race, pregnancy hypertension and prepregnancy diabetes. No significant difference in the proportion of preterm births (<37 weeks' gestation) was noted between pandemic and prepandemic years (9.9 vs. 10.0%, p = 0.50). There was no significant difference in the risk of preterm birth across gestational age strata (<28, 28-316/7, 32-366/7, 37-416/7, and >42 weeks) between pandemic and prepandemic years on multinomial analysis. Significant associations with preterm birth across all years included African American race, lower level of maternal education, pregnancy-induced hypertension, chronic hypertension, prepregnancy diabetes, congenital anomalies, previous preterm birth, and prolonged rupture of membranes >12 hours. CONCLUSION: Fetal death rate was significantly lower whereas preterm births remained unchanged during pandemic in comparison with prepandemic years in the state of Michigan. KEY POINTS: · A decrease in fetal death rate was noted during SARS CoV-2 pandemic in the State of Michigan.. · Overall state-wide rates of preterm birth did not change in 2020, compared to previous years.. · Significant risk factors associated with preterm birth and fetal deaths did not differ between prepandemic and pandemic years..

Epidemiologic assessment of benzodiazepine exposure among suicide deaths in Colorado, 2015-2017.

BACKGROUND: Suicide rates have been climbing in the U.S., particularly in Rocky Mountain states such as Colorado. Benzodiazepines have been linked with suicidal ideation, but there have been few population level assessments of this link. We conducted a public health assessment to determine the epidemiology and prevalence of recent benzodiazepine exposure, among suicide deaths in Colorado from 2015 to 17. METHODS: This epidemiologic assessment linked Colorado's Prescription Drug Monitoring Program, death certificate data, and Violent Death Reporting System to determine patterns of benzodiazepine exposure among suicide deaths in Colorado between 2015 and 2017. Recent benzodiazepine exposure was defined as receiving a prescription within 30 days of death or having a positive toxicology screen post-mortem. RESULTS: Among the 3465 suicide deaths in Colorado between 2015 and 2017, 20% had recent benzodiazepine exposure, and nearly 50% of those also had recent opioid exposure. Recent benzodiazepine exposure was more common among females than males (34% versus 16%). Among suicide deaths, those who died via drug overdose were more likely to have had recent benzodiazepine exposure (48%), compared to suicides by firearm (17%), hanging/asphyxiation (13%) and all other methods (approximately 20%). CONCLUSIONS: Benzodiazepines have been linked to suicidal ideation, but population level assessments of benzodiazepine exposure among suicide deaths are rare. Our epidemiologic assessment indicates a relatively high prevalence of recent benzodiazepine exposure that warrants further investigation from both clinical and public health perspectives.

Connecting the Dots: State Health Department Approaches to Addressing Shared Risk and Protective Factors Across Multiple Forms of Violence.

Violence takes many forms, including intimate partner violence, sexual violence, child abuse and neglect, bullying, suicidal behavior, and elder abuse and neglect. These forms of violence are interconnected and often share the same root causes. They can also co-occur together in families and communities and can happen at the same time or at different stages of life. Often, due to a variety of factors, separate, "siloed" approaches are used to address each form of violence. However, understanding and implementing approaches that prevent and address the overlapping root causes of violence (risk factors) and promote factors that increase the resilience of people and communities (protective factors) can help practitioners more effectively and efficiently use limited resources to prevent multiple forms of violence and save lives. This article presents approaches used by 2 state health departments, the Maryland Department of Health and Mental Hygiene and the Colorado Department of Public Health and Environment, to integrate a shared risk and protective factor approach into their violence prevention work and identifies key lessons learned that may serve to inform crosscutting violence prevention efforts in other states.

State Injury Programs' Response to the Opioid Epidemic: The Role of CDC's Core Violence and Injury Prevention Program.

The Centers for Disease Control and Prevention's (CDC's) Core Violence and Injury Prevention Program (Core) supports capacity of state violence and injury prevention programs to implement evidence-based interventions. Several Core-funded states prioritized prescription drug overdose (PDO) and leveraged their systems to identify and respond to the epidemic before specific PDO prevention funding was available through CDC. This article describes activities employed by Core-funded states early in the epidemic. Four case examples illustrate states' approaches within the context of their systems and partners. While Core funding is not sufficient to support a comprehensive PDO prevention program, having Core in place at the beginning of the emerging epidemic had critical implications for identifying the problem and developing systems that were later expanded as additional resources became available. Important components included staffing support to bolster programmatic and epidemiological capacity; diverse and collaborative partnerships; and use of surveillance and evidence-informed best practices to prioritize decision-making.

A psychological predictor of elders' driving performance: social-comparisons on the road.

Older individuals often believe they can drive better than their contemporaries. This belief is an example of downward social-comparisons; they can be self-enhancing tools that lead to beneficial outcomes. As predicted, we found that drivers who engaged in downward social-comparisons were significantly less likely to have adverse driving events over time, after controlling for relevant factors (p = .02). This effect was particularly strong among women, who tend to experience more negative driving stereotypes (p = .01). The study was based on 897 interviews of 117 elder drivers, aged 70-89 years, over 2 years. Our findings suggest that interventions to reduce adverse driving events among elders could benefit from including a psychological component.

Exploring maternal reflective functioning as a predictor of mother-child dyadic behaviour over time in a clinical context.

The current study examined 20 participants from group attachment based intervention (GABI), who completed the adult attachment interviews (AAI; George, et al., 1985) as part of a RCT to test the efficacy of GABI compared with treatment as usual, in order to explore the possible benefits higher RF for treatment outcome in terms of interactive mother and child behaviour. Mothers' AAIs were analyzed using the reflective functioning (RF) rating scale (Fonagy, et al., 1998), yielding overall RF scores, prompted/demand RF scores, and spontaneous RF scores, and parent-child dyadic interactive behaviour was coded utilizing the coding interactive behaviour (CIB: Feldman, 1998) manual. Children's age ranged from 2-25 months, mean=14 months. 86.7% of the sample identified English as their primary language, with 13.3% identified speaking both Spanish and English. RF in AAIs obtained at intake from some GABI mothers was expected to be linked to the quality of the parent-child interaction (observed with the CIB), at intake (T1), at end-of treatment T2), and at sixmonth follow-up (T3). Results confirmed this impression insofar as lower overall RF was linked to T1 levels of higher intrusiveness from mothers. At end of treatment (T2), mothers' higher spontaneous RF scores were significantly linked to maternal praising (of the child), child positive affect, child alertness. At 6-month follow up (T3), mother's spontaneous RF scores correlated significantly and positively with maternal elaborating with child positive affect. Discussion focuses on the importance of assessing RF in parents entering therapy with their children as it may provide insight into what parent or child behaviours may be targeted. And the RF scores will highlight which mothers need special attention to stimulate their interest and attention to attachment-related processes in themselves, and in their children.

Navigating uncharted waters? How international experience can inform the funding of mental health care in England.

BACKGROUND: Activity-based funding mechanisms are widely used in acute care. In England, payment by results is being extended to mental health care, but its financial viability is unclear. AIMS: To identify international examples of activity-based funding systems for mental health care and to inform the development of a national tariff in England. METHOD: The international literature on payment systems for mental healthcare services was reviewed. Payment systems were appraised from an economic perspective. Variations in cost between English mental healthcare providers were explored using routine inpatient data on length of stay in 2007/8. RESULTS: The review identified activity-based mental healthcare payment systems in five countries. International experience highlights the need for gradual and stepwise implementation; the use of budget neutrality adjustments; top-slicing of budgets to stabilise provider income; and use of the classification system to drive improvements in quality and cost-effectiveness. All systems adjusted for length of stay, but methods varied. Comparing English mental healthcare providers, median length of stay ranged from 2 to 42 days for emergency admissions and from 0 to 56 days for elective admissions. CONCLUSIONS: New payment systems must account for the economic incentives they embody, and appropriate adjustments for variations in length of stay are essential.

Racial disparities in COVID-19 mortality across Michigan, United States.

BACKGROUND: Black populations in the United States are being disproportionately affected by the COVID-19 pandemic, but the increased mortality burden after accounting for health and other demographic characteristics is not well understood. We examined characteristics of individuals who died from COVID-19 in Michigan by race stratified by their age, sex and comorbidity prevalence to illustrate and understand this disparity in mortality risk. METHODS: We evaluate COVID-19 mortality in Michigan by demographic and health characteristics, using individual-level linked death certificate and surveillance data collected by the Michigan Department of Health and Human Services from March 16 to October 26, 2020. We identified differences in demographics and comorbidity prevalence across race among individuals who died from COVID-19 and calculated mortality rates by age, sex, race, and number of comorbidities. FINDINGS: Among the 6,065 COVID-19 related deaths in Michigan, Black individuals are experiencing 3·6 times the mortality rate of White individuals (p<0.001), with a mortality rate for Black individuals under 65 years without comorbidities that is 12·6 times that of their White counterparts (p<0.001). After accounting for age, race, sex, and number of comorbidities, we find that Black individuals in all strata are at higher risk of COVID-19 mortality than their White counterparts. INTERPRETATION: Our findings demonstrate that Black populations are disproportionately burdened by COVID-19 mortality, even after accounting for demographic and underlying health characteristics. We highlight how disparities across race, which result from systemic racism, are compounded in crises. FUNDING: ASP, AP and APG were funded by NSF Expeditions grant 1918784, NIH grant 1R01AI151176-01, NSF Rapid Response Research for COVID-19 grant RAPID-2027755, and the Notsew Orm Sands Foundation. MCF was supported by NIH grant K01AI141576.

Glycopeptide vs. non-glycopeptide antibiotics for prophylaxis of surgical site infections: a systematic review.

BACKGROUND: Patients receive prophylactic antibiotics against surgical site infections (SSIs) before or during many procedures. Glycopeptide antibiotics are effective against most strains of methicillin-resistant Staphylococcus aureus (MRSA), but their wider use risks increasing resistance. Our objective was to review the evidence for clinical effectiveness that might help to determine whether there is a threshold of MRSA prevalence at which switching from non-glycopeptide to glycopeptide antibiotic prophylaxis might be justified. METHODS: We performed a systematic review of randomized trials comparing a glycopeptide with an alternative antibiotic regimen for SSI prophylaxis in adults undergoing clean or clean-contaminated surgical procedures. The evidence was used to inform development of a decision-analytic model. We subsequently updated the review to May 2008. RESULTS: Fourteen studies were identified that provided evidence concerning clinical effectiveness. The studies were too heterogeneous clinically for meta-analysis. Only one of 12 trials found that glycopeptides reduced SSIs significantly at 30 days compared with non-glycopeptide antibiotics. Of the two trials that reported on MRSA infection, neither found a significant difference between glycopeptide and comparator drugs. CONCLUSIONS: This systematic review did not find any evidence to support the use of glycopeptides in preference to other antibiotics for the prevention of MRSA infections and SSIs. The limitations of the evidence make it difficult to identify a threshold at which a switch from non-glycopeptide to glycopeptide prophylaxis should be recommended. Given the difficulties of addressing this issue through randomized trials, further research should focus on hospital infection control policies, MRSA screening, and the isolation and treatment of anyone infected with MRSA prior to surgery.

An economic model for the prevention of MRSA infections after surgery: non-glycopeptide or glycopeptide antibiotic prophylaxis?

AIM: Surgical site infection is commonly caused by Staphylococcus aureus. The multiresistant strains (MRSA) are resistant to most antibiotic prophylaxis regimens. Our aim was to explore whether there is a threshold of MRSA prevalence at which switching to routine glycopeptide-based antibiotic prophylaxis becomes cost-effective. METHODS: An indicative model was designed to explore the cost-effectiveness of vancomycin, cephalosporin or a combination, in patients undergoing primary hip arthroplasty. RESULTS: If the MRSA infection rate is equal to or above 0.25% and the rate of other infections with cephalosporin prophylaxis is equal to or above 0.2%, use of the combination antibiotic prophylaxis is optimal. DISCUSSION: Modelling the cost-effectiveness of interventions for MRSA prevention is complex due to uncertainty around resistance and effectiveness of glycopeptides. CONCLUSIONS: The indicative model provides a framework for evaluation. More work is needed to understand the impact of antibiotic resistance over time in these currently effective antibiotics.

Effects of a booster seat education and distribution program in child care centers on child restraint use among children aged 4 to 8 years.

OBJECTIVE: To compare child care center-based booster seat education and distribution with no intervention when implemented immediately after booster seat legislation. DESIGN: Cluster randomized controlled trial. SETTING: Thirty-nine urban child care centers. PARTICIPANTS: Eight hundred fifty-four parents and 1010 children aged 4 to 8 years in vehicles leaving centers. Intervention We trained 168 staff members at 20 centers to give parents and children messages promoting booster seats and supplied lesson plans, children's activities, and free booster seats. MAIN OUTCOME MEASURES: Observed booster seat use, "good practice" restraint use, and legal restraint use. RESULTS: Parents at intervention centers were more likely to report receiving restraint information from the center (adjusted odds ratio [AOR], 4.06; 95% confidence interval [CI], 2.48-6.67), speaking with staff about booster seats (AOR, 3.95; 95% CI, 2.26-6.88), and using fit to decide when to move children into seat belts (AOR, 3.39; 95% CI, 1.91-5.99). Groups did not differ in proportions using booster seats (44% vs 43%; AOR, 1.03; 95% CI, 0.62-1.73), good practice (42% vs 41%; AOR, 1.11; 95% CI, 0.70-1.74), or legal restraints (65% vs 65%; AOR, 0.79; 95% CI, 0.48-1.31). Results were similar for children aged 4 to 5 and 6 to 8 years. All outcomes were significantly less likely among children riding in pickup trucks or with Hispanic or black drivers. CONCLUSIONS: The intervention increased parents' receipt of information from center staff and knowledge about booster seats but not booster seat use. Research is needed to identify methods and messages that will empower center providers to promote booster seats effectively and reach high-risk populations.

Impact of presumed consent for organ donation on donation rates: a systematic review.

OBJECTIVES: To examine the impact of a system of presumed consent for organ donation on donation rates and to review data on attitudes towards presumed consent. DESIGN: Systematic review. DATA SOURCES: Studies retrieved by online searches to January 2008 of Medline, Medline In-Process, Embase, CINAHL, PsycINFO, HMIC, PAIS International, and OpenSIGLE. Studies reviewed Five studies comparing donation rates before and after the introduction of legislation for presumed consent (before and after studies); eight studies comparing donation rates in countries with and without presumed consent systems (between country comparisons); 13 surveys of public and professional attitudes to presumed consent. RESULTS: The five before and after studies represented three countries: all reported an increase in donation rates after the introduction of presumed consent, but there was little investigation of any other changes taking place concurrently with the change in legislation. In the four best quality between country comparisons, presumed consent law or practice was associated with increased organ donation-increases of 25-30%, 21-26%, 2.7 more donors per million population, and 6.14 more donors per million population in the four studies. Other factors found to be important in at least one study were mortality from road traffic accidents and cerebrovascular causes, transplant capacity, gross domestic product per capita, health expenditure per capita, religion (Catholicism), education, public access to information, and a common law legal system. Eight surveys of attitudes to presumed consent were of the UK public. These surveys varied in the level of support for presumed consent, with surveys conducted before 2000 reporting the lowest levels of support (28-57%). The most recent survey, in 2007, reported that 64% of respondents supported a change to presumed consent. CONCLUSION: Presumed consent alone is unlikely to explain the variation in organ donation rates between countries. Legislation, availability of donors, organisation and infrastructure of the transplantation service, wealth and investment in health care, and public attitudes to and awareness of organ donation may all play a part, but their relative importance is unclear. Recent UK surveys show support for presumed consent, though with variation in results that may reflect differences in survey methods.

Exclusion of elderly persons from health-risk behavior clinical trials.

BACKGROUND: It has been found that the elderly population is underrepresented in clinical trials aimed at disease treatment. It is unknown to what extent this group is also excluded from clinical trials aimed at reducing health-risk behaviors. METHOD: We systematically reviewed clinical trials targeting the leading health-risk behaviors, as identified by Healthy People 2010: tobacco use, overweight/obesity, physical inactivity, substance abuse, and irresponsible sexual behavior. Using MEDLINE, we identified clinical trials published in the five most cited medical journals between January 1990 and May 2004. RESULTS: The majority (53%) of the 198 health-risk behavior clinical trials excluded persons over the age of 65; the exclusion percentage increased to 72% for those over the age of 75. The exclusion of elderly persons in these five medical journals did not decline over the 14 years studied. This age exclusion pattern was not explained by the intervention's intrusiveness or whether illness was an exclusion criterion. The trials that included those over the age of 65 were more likely to report a significant finding in the predicted direction. CONCLUSIONS: Although elderly persons are most at risk for diseases linked to lifestyle behavior, such as heart disease, they were excluded from the majority of health-risk behavior clinical trials in five major medical journals.

Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review.

PURPOSE: Several new extended prostate biopsy schemes (greater than 6 cores) have been proposed. We compared the cancer detection rates and complications of different extended prostate biopsy schemes for diagnostic evaluation in men scheduled for biopsy to identify the optimal scheme. MATERIALS AND METHODS: In a systematic review we searched 13 electronic databases, screened relevant urological journals and the reference lists of included studies, and contacted experts. We included studies that compared different systematic prostate biopsy methods using sequential sampling or a randomized design in men scheduled for biopsy due to suspected prostate cancer. We pooled data using a random effects model when appropriate. RESULTS: We analyzed 87 studies with a total of 20,698 patients. We pooled data from 68 studies comparing a total of 94 extended schemes with the standard sextant scheme. An increasing number of cores were significantly associated with the cancer yield. Laterally directed cores increased the yield significantly (p = 0.003), whereas centrally directed cores did not. Schemes with 12 cores that took additional laterally directed cores detected 31% more cancers (95% CI 25 to 37) than the sextant scheme. Schemes with 18 to 24 cores did not detect significantly more cancers. Adverse events for schemes up to 12 cores were similar to those for the sextant pattern. Adverse event reporting was poor for schemes with 18 to 24 cores. CONCLUSIONS: Prostate biopsy schemes consisting of 12 cores that add laterally directed cores to the standard sextant scheme strike the balance between the cancer detection rate and adverse events. Taking more than 12 cores added no significant benefit.

Preventive health behaviors influenced by self-perceptions of aging.

BACKGROUND: Research has found that the elderly are the age group that is the least likely to engage in preventive health behaviors, even though these behaviors continue to benefit individuals throughout the life span. We investigated for the first time whether an age-specific factor, older individuals' beliefs about their own aging, predicts their likelihood of engaging in preventive health behaviors over time. METHODS: We conducted multivariate linear regression to test the predictive value of aging self-perceptions on the preventive health behaviors of 241 individuals, who participated in the Ohio Longitudinal Study of Aging and Retirement (OLSAR) aged 50-80 years old. The preventive health behaviors included eating a balanced diet, exercising, and following directions for taking prescribed medications. RESULTS: Individuals with more positive self-perceptions of aging tended to practice more preventive health behaviors over the next two decades after controlling for age, education, functional health, gender, self-rated health, and race (P = 0.032). CONCLUSIONS: Our findings suggest that addressing views about aging could help improve efforts to increase preventive health behaviors in the older population.