ATM-Inhibitor AZD1390 Is a Radiosensitizer for Breast Cancer CNS Metastasis.

PURPOSE: Limited effective treatments are currently available for central nervous system (CNS) metastasis (CM). This is largely driven by the inability of current therapeutics to penetrate the blood brain barrier (BBB) and the lack of preclinical models for testing new therapies. Here we study the efficacy of AZD1390, a BBB penetrating ataxia-telangiectasia mutated inhibitor, as a radiosensitizer for breast cancer CM treatment. EXPERIMENTAL DESIGN: Three patient-derived xenograft (PDX) tumors including 2 HER2+ and 1 triple-negative breast cancer harboring DNA damage response (DDR) gene mutations, were implanted subcutaneously in the flank of mice to assess tumor growth inhibition by AZD1390 combined with radiation. Animal survival was further assessed by implanting the best responding PDX model orthotopically in the brain. RESULTS: Pretreatment with AZD1390 followed by radiation therapy inhibited growth of PDX tumors implanted in the flank, and improved survival in orthotopic models with average survival of 222 days compared with 123 days in controls. Administration of AZD1390 posttreatment for 21 days had no further benefits. While the combination therapy resulted in sustained tumor inhibition, sporadic regrowth was observed in some mice 50 to 100 days posttreatment in all models. Gene expression comparing these tumors with complete responders demonstrated changes in upregulation of oncogenic proteins, which are potential drivers of tumor growth after treatment. CONCLUSIONS: Our results demonstrate that AZD1390 effectively sensitizes breast cancer CM to radiation therapy in DDR mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CM.

Violent Victimization During Childhood in the United States: Associations With Revictimization and Health.

Childhood violence victimization is a serious adverse childhood experience with lasting health impacts. This study examined the prevalence and characteristics of five forms of childhood violence victimization and their association with revictimization and negative health conditions among adults. Data are from the 2010-2012 National Intimate Partner and Sexual Violence Survey. Age at first victimization and perpetrator sex were assessed; adjusted odds ratios assessed associations with revictimization and health. Ages 14-17 were the most common age at first victimization for most violence types; almost half of male (46.7%) and a quarter of female (27.0%) rape victims reported first victimization before age 10. Most victimization was associated with revictimization and negative health, controlling for adult victimization. Primary prevention of childhood violence may reduce later health risks.

Prevalence of Adverse Childhood Experiences Among U.S. Adults - Behavioral Risk Factor Surveillance System, 2011-2020.

Adverse childhood experiences (ACEs) are defined as preventable, potentially traumatic events that occur among persons aged <18 years and are associated with numerous negative outcomes; data from 25 states indicate that ACEs are common among U.S. adults (1). Disparities in ACEs are often attributable to social and economic environments in which some families live (2,3). Understanding the prevalence of ACEs, stratified by sociodemographic characteristics, is essential to addressing and preventing ACEs and eliminating disparities, but population-level ACEs data collection has been sporadic (1). Using 2011-2020 Behavioral Risk Factor Surveillance System (BRFSS) data, CDC provides estimates of ACEs prevalence among U.S. adults in all 50 states and the District of Columbia, and by key sociodemographic characteristics. Overall, 63.9% of U.S. adults reported at least one ACE; 17.3% reported four or more ACEs. Experiencing four or more ACEs was most common among females (19.2%), adults aged 25-34 years (25.2%), non-Hispanic American Indian or Alaska Native (AI/AN) adults (32.4%), non-Hispanic multiracial adults (31.5%), adults with less than a high school education (20.5%), and those who were unemployed (25.8%) or unable to work (28.8%). Prevalence of experiencing four or more ACEs varied substantially across jurisdictions, from 11.9% (New Jersey) to 22.7% (Oregon). Patterns in prevalence of individual and total number of ACEs varied by jurisdiction and sociodemographic characteristics, reinforcing the importance of jurisdiction and local collection of ACEs data to guide targeted prevention and decrease inequities. CDC has released prevention resources, including Preventing Adverse Childhood Experiences: Leveraging the Best Available Evidence, to help provide jurisdictions and communities with the best available strategies to prevent violence and other ACEs, including guidance on how to implement those strategies for maximum impact (4-6).

The cholinergic anti-inflammatory pathway inhibits inflammation without lymphocyte relay.

The magnitude of innate inflammatory immune responses is dependent on interactions between peripheral neural and immune cells. In particular, a cholinergic anti-inflammatory pathway (CAP) has been identified in the spleen whereby noradrenaline (NA) released by splenic nerves binds to ß2-adrenergic receptors (ß2-AR) on CD4+ T cells which, in turn, release acetylcholine (ACh). The binding of ACh to α7 acetylcholine receptors (α7-AChR) expressed by splenic macrophages inhibits the production of inflammatory cytokines, including tumor necrosis factor (TNF). However, the role of ACh-secreting CD4+ T-cells in the CAP is still controversial and largely based on the absence of this anti-inflammatory pathway in mice lacking T-cells (nude, FoxN1-/-). Using four conscious, non-lymphopenic transgenic mouse models, we found that, rather than acting on CD4+ T-cells, NA released by splenic nerve terminals acts directly onto ß2-AR on splenic myeloid cells to exert this anti-inflammatory effect. We also show that, while larger doses of LPS are needed to trigger CAP in nude mouse strain compared to other strains, TNF production can be inhibited in these animals lacking CD4+ T-cell by stimulating either the vagus or the splenic nerve. We demonstrate that CD4+ T-cells are dispensable for the CAP after antibody-mediated CD4+ T-cell depletion in wild type mice. Furthermore, we found that NA-mediated inhibition of in vitro LPS-induced TNF secretion by human or porcine splenocytes does not require α7-AChR signaling. Altogether our data demonstrate that activation of the CAP by stimulation of vagus or splenic nerves in mice is mainly mediated by direct binding of NA to ß2-AR on splenic macrophages, and suggest that the same mechanism is at play in larger species.

Emergency Department Visits for Firearm Injuries Before and During the COVID-19 Pandemic - United States, January 2019-December 2022.

During the COVID-19 pandemic, the U.S. firearm homicide rate increased by nearly 35%, and the firearm suicide rate remained high during 2019-2020 (1). Provisional mortality data from the National Vital Statistics System indicate that rates continued to increase in 2021: the rates of firearm homicide and firearm suicide in 2021 were the highest recorded since 1993 and 1990, respectively (2). Firearm injuries treated in emergency departments (EDs), the primary setting for the immediate medical treatment of such injuries, gradually increased during 2018-2019 (3); however, more recent patterns of ED visits for firearm injuries, particularly during the COVID-19 pandemic, are unknown. Using data from the National Syndromic Surveillance Program (NSSP),* CDC examined changes in ED visits for initial firearm injury encounters during January 2019-December 2022, by year, patient sex, and age group. Increases in the overall weekly number of firearm injury ED visits were detected at certain periods during the COVID-19 pandemic. One such period during which there was a gradual increase was March 2020, which coincided with both the declaration of COVID-19 as a national emergency† and a pronounced decrease in the total number of ED visits. Another increase in firearm injury ED visits occurred in late May 2020, concurrent with a period marked by public outcry related to social injustice and structural racism (4), changes in state-level COVID-19-specific prevention strategies,§ decreased engagement in COVID-19 mitigation behaviors (5), and reported increases in some types of crime (4). Compared with 2019, the average number of weekly ED visits for firearm injury was 37% higher in 2020, 36% higher in 2021, and 20% higher in 2022. A comprehensive approach is needed to prevent and respond to firearm injuries in communities, including strategies that engage community and street outreach programs, implement hospital-based violence prevention programs, improve community physical environments, enhance secure storage of firearms, and strengthen social and economic supports.

Environmental signals perceived by the brain abate pro-metastatic monocytes by dampening glucocorticoids receptor signaling.

While positive social-behavioral factors predict longer survival in cancer patients, the underlying mechanisms are unknown. Since tumor metastasis are the major cancer mortality factor, we investigated how an enriched environment (EE) conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in lungs following intravasation in the circulation. We find that mice housed in EE exhibited reduced number of lung metastatic foci compared to control mice housed in a standard environment (SE). Compared to SE mice, EE mice increased lung inflammation as early as 4 days after circulating tumor cells extravasation. The impact of environmental signals on lung metastasis is independent of adrenergic receptors signaling. By contrast, we find that serum corticosterone levels are lower in EE mice and that glucocorticoid receptor (GR) antagonist reduces the number of lung metastasis in SE mice. In addition, the difference of the number of lung metastasis between SE and EE mice is abolished when inflammatory monocytes are rendered deficient in GR signaling. This decreased GR signaling in inflammatory monocytes of SE mice results in an exacerbated inflammatory profile in the lung. Our study shows that not only EE reduces late stages of metastatic progression in lungs but disclose a novel anti-tumor mechanism whereby GR-dependent reprogramming of inflammatory monocytes can inhibit metastatic progression in lungs. Moreover, while inflammatory monocytes have been shown to promote cancer progression, they also have an anti-tumor effect, suggesting that their role is more complex than currently thought.

SARS-CoV-2 Vaccination-Induced Immunogenicity in Heart Transplant Recipients.

Among heart transplant (HT) recipients, a reduced immunological response to SARS-CoV-2 vaccination has been reported. We aimed to assess the humoral and T-cell response to SARS-CoV-2 vaccination in HT recipients to understand determinants of immunogenicity. HT recipients were prospectively enrolled from January 2021 until March 2022. Anti-SARS-CoV-2-Spike IgG levels were quantified after two and three doses of a SARS-CoV-2 vaccine (BNT162b2, mRNA1273, or AZD1222). Spike-specific T-cell responses were assessed using flow cytometry. Ninety-one patients were included in the study (69% male, median age 55 years, median time from HT to first vaccination 6.1 years). Seroconversion rates were 34% after two and 63% after three doses. Older patient age (p = 0.003) and shorter time since HT (p = 0.001) were associated with lower antibody concentrations after three vaccinations. There were no associations between vaccine types or immunosuppressive regimens and humoral response, except for prednisolone, which was predictive of a reduced response after two (p = 0.001), but not after three doses (p = 0.434). A T-cell response was observed in 50% after two and in 74% after three doses. Despite three vaccine doses, a large proportion of HT recipients exhibits a reduced immune response. Additional strategies are desirable to improve vaccine immunogenicity in this vulnerable group of patients.

[Update on fast-track concepts in operative medicine : Improved outcome and higher patient satisfaction through interdisciplinary multimodal treatment concepts]. / Update zu "Fast-track"-Konzepten in der operativen Medizin : Verbessertes Outcome und höhere Patientenzufriedenheit durch interdisziplinäre, multimodale Behandlungskonzepte.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been propagated in general surgery since the mid-1990s due to medical and health economic advantages for patients as well as hospitals. A comprehensive implementation in Germany is not yet established, although the demographic change requires more than ever concepts for the safe treatment of multimorbid frail patients. The aim of this review is to present modern ERAS concepts, to discuss an extension to prehabilitation measures for frail patients and to present aspects of structural feasibility. MATERIAL AND METHOD: A selective literature search in the PubMed database was performed and national as well as international guidelines up to the cut-off date of 1 July 2022 were considered. RESULTS: From an anesthesiological point of view, preoperative optimization, individual anesthesia management and postoperative analgesia are prioritized. The implementation of ERAS protocols requires a high degree of interdisciplinarity and needs in addition to medical know-how, appropriate information systems and structures. Modern ERAS concepts can reduce hospital costs and improve patient outcome. CONCLUSION: The implementation of ERAS protocols is beneficial for patients as well as economically and should be further promoted. In addition, the benefit of an extension of ERAS concepts, e.g. in older multimorbid patients, should be further scientifically analyzed.

A quantitative characterization of the spatial distribution of brain metastases from breast cancer and respective molecular subtypes.

PURPOSE: Brain metastases (BM) remain a significant cause of morbidity and mortality in breast cancer (BC) patients. Specific factors promoting the process of BM and predilection for selected neuro-anatomical regions remain unknown, yet may have major implications for prevention or treatment. Anatomical spatial distributions of BM from BC suggest a predominance of metastases in the hindbrain and cerebellum. Systematic approaches to quantifying BM location or location-based analyses based on molecular subtypes, however, remain largely unavailable. METHODS: We analyzed stereotactic Cartesian coordinates derived from 134 patients undergoing gamma- knife radiosurgery (GKRS) for treatment of 407 breast cancer BMs to quantitatively study BM spatial distribution along principal component axes and by intrinsic molecular subtype (ER, PR, Herceptin). We used kernel density estimators (KDE) to highlight clustering and distribution regions in the brain, and we used the metric of mutual information (MI) to tease out subtle differences in the BM distributions associated with different molecular subtypes of BC. BM location maps according to vascular and anatomical distributions using Cartesian coordinates to aid in systematic classification of tumor locations were additionally developed. RESULTS: We corroborated that BC BMs show a consistent propensity to arise posteriorly and caudally, and that Her2+ tumors are relatively more likely to arise medially rather than laterally. To compare the distributions among varying BC molecular subtypes, the mutual information metric reveal that the ER-PR-Her2+ and ER-PR-Her2- subtypes show the smallest amount of mutual information and are most molecularly distinct. The kernel density contour plots show a propensity for triple negative BC to arise in more superiorly or cranially situated BMs. CONCLUSIONS: We present a novel and shareable workflow for characterizing and comparing spatial distributions of BM which may aid in identifying therapeutic or diagnostic targets and interactions with the tumor microenvironment. Further characterization of these patterns with larger multi-institutional data-sets may have major impacts on treatment or management of cancer patients.

Hypoxia briefly increases diuresis but reduces plasma volume by fluid redistribution in women.

We have recently reported that hypobaric hypoxia (HH) reduces plasma volume (PV) in men by decreasing total circulating plasma protein (TCPP). Here, we investigated whether this applies to women and whether an inflammatory response and/or endothelial glycocalyx shedding could facilitate the TCCP reduction. We further investigated whether acute HH induces a short-lived diuretic response that was overlooked in our recent study, where only 24-h urine volumes were evaluated. In a strictly controlled crossover protocol, 12 women underwent two 4-day sojourns in a hypobaric chamber: one in normoxia (NX) and one in HH equivalent to 3,500-m altitude. PV, urine output, TCPP, and markers for inflammation and glycocalyx shedding were repeatedly measured. Total body water (TBW) was determined pre- and postsojourns by deuterium dilution. PV was reduced after 12 h of HH and thereafter remained 230-330 mL lower than in NX (P < 0.0001). Urine flow was 45% higher in HH than in NX throughout the first 6 h (P = 0.01) but lower during the second half of the first day (P < 0.001). Twenty-four-hour urine volumes (P ≥ 0.37) and TBW (P ≥ 0.14) were not different between the sojourns. TCPP was lower in HH than in NX at the same time points as PV (P < 0.001), but inflammatory or glycocalyx shedding markers were not consistently increased. As in men, and despite initially increased diuresis, HH-induced PV contraction in women is driven by a loss of TCPP and ensuing fluid redistribution, rather than by fluid loss. The mechanism underlying the TCPP reduction remains unclear but does not seem to involve inflammation or glycocalyx shedding.NEW & NOTEWORTHY This study is the first to investigate the mechanisms underlying plasma volume (PV) contraction in response to hypoxia in women while strictly controlling for confounders. PV contraction in women has a similar time course and magnitude as in men and is driven by the same mechanism, namely, oncotically driven redistribution rather than loss of fluid. We further report that hypoxia facilitates an increase in diuresis, that is, however, short-lived and of little relevance for PV regulation.

Suicide Among Males Across the Lifespan: An Analysis of Differences by Known Mental Health Status.

INTRODUCTION: Suicide among males is a major public health challenge. In 2019, males accounted for nearly 80% of the suicide deaths in the U.S., and suicide was the eighth leading cause of death for males aged ≥10 years. Males who die by suicide are less likely to have known mental health conditions than females; therefore, it is important to identify prevention points outside of mental health systems. The purpose of this analysis was to compare suicide characteristics among males with and without known mental health conditions by age group to inform prevention. METHODS: Suicides among 4 age groups of males were examined using the 3 most recent years of data at the time of the analysis (2016-2018) from the Centers for Disease Control and Prevention's National Violent Death Reporting System. Decedents with and without known mental health conditions were compared within age groups. The analysis was conducted in August 2021. RESULTS: Most male suicide decedents had no known mental health conditions. More frequently, those without known mental health conditions died by firearm, and many tested positive for alcohol. Adolescents, young adults, and middle-aged males without known mental health conditions more often had relationship problems, arguments, and/or a crisis as a precipitating circumstance than those with known mental health conditions. CONCLUSIONS: Acute stressors more often precipitated suicides of males without known mental health conditions, and they more often involved firearms. These findings underscore the importance of mitigating acute situational stressors that could contribute to emotionally reactive/impulsive suicides. Suicide prevention initiatives targeting males might focus on age-specific precipitating circumstances in addition to standard psychiatric markers.

Gun Carrying Among Youths, by Demographic Characteristics, Associated Violence Experiences, and Risk Behaviors - United States, 2017-2019.

Suicide and homicide are the second and third leading causes of death, respectively, among youths aged 14-17 years (1); nearly one half (46%) of youth suicides and most (93%) youth homicides result from firearm injuries (1). Understanding youth gun carrying and associated outcomes can guide prevention initiatives (2). This study used the updated measure of gun carrying in the 2017 and 2019 administrations of CDC's Youth Risk Behavior Survey* (YRBS) to describe the national prevalence of gun carrying for reasons other than hunting or sport among high school students aged <18 years and to examine the associations between gun carrying and experiencing violence, suicidal ideation or attempts, or substance use. Gun carrying during the previous 12 months was reported by one in 15 males and one in 50 females. Gun carrying was significantly more likely among youths with violence-related experiences (adjusted prevalence ratio [aPR] range = 1.5-10.1), suicidal ideation or attempts (aPR range = 1.8-3.5), or substance use (aPR range = 4.2-5.6). These results underscore the importance of comprehensive approaches to preventing youth violence and suicide, including strategies that focus on preventing youth substance use and gun carrying (3).

County-Level Social Vulnerability and Emergency Department Visits for Firearm Injuries - 10 U.S. Jurisdictions, January 1, 2018-December 31, 2021.

At least 100,000 persons in the United States experience a fatal or nonfatal firearm injury each year.* CDC examined rates of firearm injury emergency department (ED) visits by community social vulnerability using data from CDC's Firearm Injury Surveillance Through Emergency Rooms (FASTER) program.† ED visit data, shared with CDC's National Syndromic Surveillance Program (NSSP)§ during 2018-2021, were analyzed for 647 counties in 10 FASTER-funded jurisdictions.¶ County-level social vulnerability data were obtained from the 2018 Social Vulnerability Index (SVI).** Rates of ED visits for firearm injuries (number of firearm injury ED visits per 100,000 ED visits) were calculated across tertile levels of social vulnerability. Negative binomial regression models were used to estimate rate ratios (RRs) and associated 95% CIs comparing rates of ED visits across social vulnerability levels. During 2018-2021, compared with rates in counties with low overall social vulnerability, the firearm injury ED visit rate was 1.34 times as high in counties with medium social vulnerability and 1.80 times as high in counties with high social vulnerability. Similar patterns were observed for the SVI themes of socioeconomic status and housing type and transportation, but not for the themes of household composition and disability status or racial and ethnic minority status and language proficiency. More timely data†† on firearm injury ED visits by social vulnerability can help identify communities disproportionately experiencing elevated firearm injury rates. States and communities can use the best available evidence to implement comprehensive prevention strategies that address inequities in the social and structural conditions that contribute to risk for violence, including creating protective community environments, strengthening economic supports, and intervening to reduce harms and prevent future risk (e.g., with hospital-based violence intervention programs) (1,2).

State impulsivity amplifies urges without diminishing self-control.

A disproportionate amount of research on impulsivity has focused on trait-related aspects rather than state fluctuations. As a result, the relationship between state impulsivity and moment-to-moment behaviour is unclear. Impulsivity is assumed to negatively affect self-control, but an alternative explanation, yet to be tested, could be that changes in state impulsivity and its homeostatic drivers influence the intensity of urges. We tested whether state impulsivity and hunger affected behaviour through a dual-process model, affecting both the experience of various urges, and self-control, using a smartphone-based experience sampling approach. We found that state impulsivity is associated with stronger urges, but we found no evidence of an association with diminished self-control. Being hungry amplifies urges across different types of urges, and both hunger and late hours are negatively related to the likelihood of controlling urges. These findings imply that the influence of hunger is not limited to the food domain, and provide new insight into the role of state impulsivity in daily life.

Electrical stimulation of the splenic nerve bundle ameliorates dextran sulfate sodium-induced colitis in mice.

BACKGROUND: Vagus nerve stimulation has been suggested to affect immune responses, partly through a neuronal circuit requiring sympathetic innervation of the splenic nerve bundle and norepinephrine (NE) release. Molecular and cellular mechanisms of action remain elusive. Here, we investigated the therapeutic value of this neuromodulation in inflammatory bowel disease (IBD) by applying electrical splenic nerve bundle stimulation (SpNS) in mice with dextran sulfate sodium (DSS)-induced colitis. METHODS: Cuff electrodes were implanted around the splenic nerve bundle in mice, whereupon mice received SpNS or sham stimulation. Stimulation was applied 6 times daily for 12 days during DSS-induced colitis. Colonic and splenic tissues were collected for transcriptional analyses by qPCR and RNA-sequencing (RNA-seq). In addition, murine and human splenocytes were stimulated with lipopolysaccharide (LPS) in the absence or presence of NE. Single-cell RNA-seq data from publicly available data sets were analyzed for expression of ß-adrenergic receptors (ß-ARs). RESULTS: Colitic mice undergoing SpNS displayed reduced colon weight/length ratios and showed improved Disease Activity Index scores with reduced Tumor Necrosis Factor α mRNA expression in the colon compared with sham stimulated mice. Analyses of splenocytes from SpNS mice using RNA-seq demonstrated specific immune metabolism transcriptome profile changes in myeloid cells. Splenocytes showed expression of ß-ARs in myeloid and T cells. Cytokine production was reduced by NE in mouse and human LPS-stimulated splenocytes. CONCLUSIONS: Together, our results demonstrate that SpNS reduces clinical features of colonic inflammation in mice with DSS-induced colitis possibly by inhibiting splenic myeloid cell activation. Our data further support exploration of the clinical use of SpNS for patients with IBD.

Vital Signs: Changes in Firearm Homicide and Suicide Rates - United States, 2019-2020.

INTRODUCTION: The majority of homicides (79%) and suicides (53%) in the United States involved a firearm in 2020. High firearm homicide and suicide rates and corresponding inequities by race and ethnicity and poverty level represent important public health concerns. This study examined changes in firearm homicide and firearm suicide rates coinciding with the emergence of the COVID-19 pandemic in 2020. METHODS: National vital statistics and population data were integrated with urbanization and poverty measures at the county level. Population-based firearm homicide and suicide rates were examined by age, sex, race and ethnicity, geographic area, level of urbanization, and level of poverty. RESULTS: From 2019 to 2020, the overall firearm homicide rate increased 34.6%, from 4.6 to 6.1 per 100,000 persons. The largest increases occurred among non-Hispanic Black or African American males aged 10-44 years and non-Hispanic American Indian or Alaska Native (AI/AN) males aged 25-44 years. Rates of firearm homicide were lowest and increased least at the lowest poverty level and were higher and showed larger increases at higher poverty levels. The overall firearm suicide rate remained relatively unchanged from 2019 to 2020 (7.9 to 8.1); however, in some populations, including AI/AN males aged 10-44 years, rates did increase. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: During the COVID-19 pandemic, the firearm homicide rate in the United States reached its highest level since 1994, with substantial increases among several population subgroups. These increases have widened disparities in rates by race and ethnicity and poverty level. Several increases in firearm suicide rates were also observed. Implementation of comprehensive strategies employing proven approaches that address underlying economic, physical, and social conditions contributing to the risks for violence and suicide is urgently needed to reduce these rates and disparities.