Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway.

Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel-/- cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel-/- lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747. Further analysis demonstrated that this is a consequence of Eµ-Myc/cRel-/- lymphomas having lost expression of CHK1 protein itself, an effect that also results in resistance to CCT244747 treatment in vivo. Similar down-regulation of CHK1 protein levels was also seen in CHK1i resistant U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells. Further investigation revealed that the deubiquitinase USP1 regulates CHK1 proteolytic degradation and that its down-regulation in our model systems is responsible, at least in part, for these effects. We demonstrate that treating WT Eµ-Myc lymphoma cells with the USP1 inhibitor ML323 was highly effective at reducing tumour burden in vivo. Targeting USP1 activity may thus be an alternative therapeutic strategy in MYC-driven tumours.

Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Eµ-Myc lymphoma cells.

The development of resistance and the activation of bypass pathway signalling represents a major problem for the clinical application of protein kinase inhibitors. While investigating the effect of either a c-Rel deletion or RelAT505A phosphosite knockin on the Eµ-Myc mouse model of B-cell lymphoma, we discovered that both NF-κB subunit mutations resulted in CHK1 inhibitor resistance, arising from either loss or alteration of CHK1 activity, respectively. However, since Eµ-Myc lymphomas depend on CHK1 activity to cope with high levels of DNA replication stress and consequent genomic instability, it was not clear how these mutant NF-κB subunit lymphomas were able to survive. To understand these survival mechanisms and to identify potential compensatory bypass signalling pathways in these lymphomas, we applied a multi-omics strategy. With c-Rel-/- Eµ-Myc lymphomas we observed high levels of Phosphatidyl-inositol 3-kinase (PI3K) and AKT pathway activation. Moreover, treatment with the PI3K inhibitor Pictilisib (GDC-0941) selectively inhibited the growth of reimplanted c-Rel-/- and RelAT505A, but not wild type (WT) Eµ-Myc lymphomas. We also observed up-regulation of a RHO/RAC pathway gene expression signature in both Eµ-Myc NF-κB subunit mutation models. Further investigation demonstrated activation of the RHO/RAC effector p21-activated kinase (PAK) 2. Here, the PAK inhibitor, PF-3758309 successfully overcame resistance of RelAT505A but not WT lymphomas. These findings demonstrate that up-regulation of multiple bypass pathways occurs in CHK1 inhibitor resistant Eµ-Myc lymphomas. Consequently, drugs targeting these pathways could potentially be used as either second line or combinatorial therapies to aid the successful clinical application of CHK1 inhibitors.

Neuroticism mediates the relationship between industrial history and modern-day regional obesity levels.

OBJECTIVE: The historical factors and contemporary mechanisms underlying geographical inequalities in obesity levels remain uncertain. In this study, we examine whether modern regional variation in obesity is partly a result of the impact of large-scale industry on the personality traits of those living in regions once at the center of the Industrial Revolution. METHOD: Exposure to the effects of the Industrial Revolution was assessed using unique historical data from English/Welsh counties (N = 111). Specifically, we examined the relationship between the regional employment share in large-scale coal-based industries in 1813-1820 and contemporary regional obesity levels (2013-2015). The Big Five personality traits and regional unemployment levels were examined as potential mediators of this association. RESULTS: The historical regional employment share in large-scale industries positively predicted the modern-day regional prevalence of obesity. Mediation analysis showed that areas exposed to the decline of large-scale industries experienced elevated Neuroticism and unemployment levels that explained almost half of the association between the historical dominance of large-scale industry and modern-day obesity levels. CONCLUSIONS: Our results provide initial evidence that raised regional Neuroticism levels may play a key role in explaining why exposure to the rapid growth and subsequent decline of large-scale industries forecasts modern-day obesity levels.

Height and health in late eighteenth-century England.

Adult stature has become a widely used indicator of childhood nutritional status in historical populations and may provide insights into health inequalities that are not discernible in mortality rates. However, most pre-twentieth-century British data on heights suffer from selection biases. Here we present unique evidence on heights of adult males by occupation from an unbiased sample of adult males in Dorset in 1798-99. The mean height of fully grown (married) men was very similar to that of older military recruits, and our sample therefore confirms the taller stature of English males relative to males of other European countries in the same period. In contrast to previous evidence of negligible or U-shaped socio-economic gradients in mortality in this period, we found a fairly linear gradient in height by socio-economic status, that is similar in magnitude to class differences in adult height among English males born in the mid-twentieth century.Supplementary material for this article is available at: https://doi.org/10.1080/00324728.2020.1823011.

Choose who's in your circle: how women's relationship actions during and following residential treatment help create recovery-oriented networks.

Women in recovery from substance use disorders often have difficulty establishing recovery-supportive networks. This exploratory study uses qualitative thematic analysis to examine how 88 women in recovery describe the actions they take to manage their personal social networks 12 months after intake into residential substance use treatment. Participants describe disconnecting or limiting contact with recovery-endangering people and adding recovery-supportive people to their networks as primary relationship actions for maintaining recovery. Their actions to build recovery-supportive networks can provide a focus for clinical work to help them become integrated into their communities.

Cholera as a 'sanitary test' of British cities, 1831-1866.

The malign contribution of northern industrial cities to the stagnation of national life expectancy over the period 1820-1870 forms part of one of the most long-running debates in English economic history, regarding the impact of early industrialisation on living standards. The deteriorating quality of urban water supplies often features in these arguments as the key driver of worsening mortality in this period. Here we use mortality reported from cholera in the epidemic years 1831-1832 and 1848-1849 as an indicator of the extent of sewage contamination of water in English and Welsh towns in this period. Surprisingly, the geography of reported mortality did not indicate that northern manufacturing and industrial towns were especially deficient in this respect. However, logistic regression analyses identified a number of risk factors for high cholera mortality, including location on coal-bearing strata, which was a feature of many industrial towns. Notably, however, textile-manufacturing towns, although often located in coal-rich districts, were associated with low levels of cholera mortality, and high population growth rates did not influence the risk of cholera. Reductions in cholera mortality after 1849 raise the possibility of widespread improvements in water quality after mid-century, rather earlier than is often assumed. However, in contrast to cholera, infant and diarrhoeal mortality remained high especially in northern towns until at least 1900. Several lines of evidence suggest that infants were relatively protected from waterborne diseases such as cholera and typhoid, and therefore did not benefit greatly from improvements in water quality. We conclude (1) that any worsening of water quality in urban areas c.1800-1850 was not confined to new͛ or rapidly growing industrial or manufacturing towns; and (2) infants probably rarely drank untreated water, so high infant or diarrhoeal mortality rates should not be read as indicators of poor water quality, in the English context.

The Importance of a Recovery Friendly Environment Following Treatment for Substance Use Disorder: A Setup for Successful Reentry for Health Care Professionals.

Substance use disorder (SUD) continues to be a public health concern for state boards of nursing and returning to work after treatment can be a challenging experience. A Recovery Friendly Workplace (RFW) supports the workplace community by recognizing recovery from SUD as a strength and the willingness to work intentionally with people in recovery. RFW fosters an environment that encourages healthy and safety among employees to decrease barriers for those impacted by SUD. This article describes the risks of SUD in health care, barriers to returning to work during recovery, and the important aspects of an RFW in health care.

Pharmacist Assisted Medication Program Enhancing the Regulation of Diabetes (PAMPERED) study.

OBJECTIVES: To demonstrate that pharmacists working with physicians and other providers in an ambulatory care setting can improve glucose, blood pressure, and lipid control for patients with type 2 diabetes and to report patient adherence to screening and general preventive measures. DESIGN: Prospective, randomized, clinical practice study. SETTING: Burlington, MA, between January 2001 and August 2003. PATIENTS: 164 patients patients with type 2 diabetes older than 18 years with glycosylated hemoglobin (A1C) greater than 8%. INTERVENTION: Pharmacist-patient clinic visits included obtaining a comprehensive medication review; performing targeted physical assessment; ordering laboratory tests; reviewing, modifying, and monitoring patients' medication therapy and providing detailed counseling on all therapies; facilitating self-monitoring of blood glucose; and providing reinforcement of dietary guidelines and exercise. MAIN OUTCOME MEASURE: Effect of clinical pharmacists working with physicians in an ambulatory setting on health measures (e.g., A1C, blood pressure, cholesterol) of patients with diabetes. RESULTS: Baseline characteristics were similar between the two groups. After 1 year, significant improvements occurred for A1C and low-density lipoprotein (LDL) cholesterol in the intervention group compared with the control group (A1C, 7.7% vs. 8.4%; LDL, 93.7 vs. 105.1 mg/dL; P < 0.05). Systolic blood pressure improved for all study patients without a difference between the two groups. Diastolic blood pressure improved significantly in the intervention group compared with the control group (73.4 mm Hg vs. 77.6 mm Hg, P < 0.05). Significantly more intervention patients were screened for retinopathy, neuropathy, and microalbuminuria than control patients ( P < 0.05). CONCLUSION: For all indices measured, this study demonstrated that collaborative diabetes management with a clinical pharmacist can improve overall care.

Chorioamnionitis and Risk for Maternal and Neonatal Sepsis: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the risk of maternal and neonatal sepsis associated with chorioamnionitis. DATA SOURCES: PubMed, BIOSIS, and ClinicalTrials.gov databases were systematically searched for full-text articles in English from inception until May 11, 2020. METHODS OF STUDY SELECTION: We screened 1,251 studies. Randomized controlled trials, case-control, or cohort studies quantifying a relationship between chorioamnionitis and sepsis in mothers (postpartum) or neonates born at greater than 22 weeks of gestation were eligible. Studies were grouped for meta-analyses according to exposures of histologic or clinical chorioamnionitis and outcomes of maternal or neonatal sepsis. TABULATION, INTEGRATION, AND RESULTS: One hundred three studies were included, and 55 met criteria for meta-analysis (39 studies of preterm neonates, 10 studies of general populations of preterm and term neonates, and six studies of late preterm and term neonates). Study details and quantitative data were abstracted. Random-effects models were used to generate pooled odds ratios (ORs); most studies only reported unadjusted results. Histologic chorioamnionitis was associated with confirmed and any early-onset neonatal sepsis (unadjusted pooled ORs 4.42 [95% CI 2.68-7.29] and 5.88 [95% CI 3.68-9.41], respectively). Clinical chorioamnionitis was also associated with confirmed and any early-onset neonatal sepsis (unadjusted pooled ORs 6.82 [95% CI 4.93-9.45] and 3.90 [95% CI 2.74-5.55], respectively). Additionally, histologic and clinical chorioamnionitis were each associated with higher odds of late-onset sepsis in preterm neonates. Confirmed sepsis incidence was 7% (early-onset) and 22% (late-onset) for histologic and 6% (early-onset) and 26% (late-onset) for clinical chorioamnionitis-exposed neonates. Three studies evaluated chorioamnionitis and maternal sepsis and were inconclusive. CONCLUSION: Both histologic and clinical chorioamnionitis were associated with early- and late-onset sepsis in neonates. Overall, our findings support current guidelines for preventative neonatal care. There was insufficient evidence to determine the association between chorioamnionitis and maternal sepsis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42020156812.

Substance Abuse and Misuse Identification and Prevention: An Evidence-Based Protocol for CRNAs in the Workplace.

Healthcare providers are susceptible to substance abuse, and anesthesia personnel are some of the most vulnerable. Substance abuse is the principal cause of professional impairment for Certified Registered Nurse Anesthetists (CRNAs), with 1 of 10 experiencing addiction to drugs or alcohol. Despite this problem, there is no standardized screening protocol for the identification of substance abuse or misuse for CRNAs. The purpose of this evidence-based protocol is to provide a standardized approach for the prevention and early identification of substance abuse and misuse in the practicing nurse anesthetist. An evidence-based protocol was created for workplace prevention of substance abuse and misuse. This article addresses the need for a protocol by including occurrences of accidents and injuries, consequences to anesthesia practice and patient care, costs, and the culture in an anesthesia group or department. Components of the protocol are formation of a committee, risk assessment, clear workplace policy, annual continuing education, annual supervisor training, drug screening of anesthesia personnel, pharmacy accountability, and access to treatment. The article describes the protocol and provides supplemental information to aid in implementation at other anesthesia departments. Substance abuse among CRNAs is a complex issue. This protocol is only an attempt to abate this problem.

An introduction to the history of infectious diseases, epidemics and the early phases of the long-run decline in mortality.

This article, written during the COVID-19 epidemic, provides a general introduction to the long-term history of infectious diseases, epidemics and the early phases of the spectacular long-term improvements in life expectancy since 1750, primarily with reference to English history. The story is a fundamentally optimistic one. In 2019 global life expectancy was approaching 73 years. In 1800 it was probably about 30. To understand the origins of this transition, we have to look at the historical sequence by which so many causes of premature death have been vanquished over time. In England that story begins much earlier than often supposed, in the years around 1600. The first two 'victories' were over famine and plague. However, economic changes with negative influences on mortality meant that, despite this, life expectancies were either falling or stable between the late sixteenth and mid eighteenth centuries. The late eighteenth and early nineteenth century saw major declines in deaths from smallpox, malaria and typhus and the beginnings of the long-run increases in life expectancy. The period also saw urban areas become capable of demographic growth without a constant stream of migrants from the countryside: a necessary precondition for the global urbanization of the last two centuries and for modern economic growth. Since 1840 the highest national life expectancy globally has increased by three years in every decade.

Plasma volume variation across the menstrual cycle among healthy women of reproductive age: A prospective cohort study.

Increases in reproductive hormones like estrogen, play an important role in the remarkable increases in plasma volume observed in pregnancy. Accurate estimates of plasma volume expansion during pregnancy depend on correctly timing and measuring plasma volume in nonpregnant women. However, to date, there is no consensus on the pattern of plasma volume across the menstrual cycle. We prospectively measured plasma volume in 45 women across a single menstrual cycle. A urine-based fertility monitor was used to time three clinic visits to distinct points in the menstrual cycle: the early follicular phase (~day 2), periovulation (~day 12), and the mid-point of the luteal phase (~day 21)-based on a 28-day cycle length. Healthy women aged 18-41 years with regular menstrual cycles and a healthy body weight were enrolled in the study. At each visit, blood samples were collected before and after injection of 0.25 mg/kg body weight of indocyanine green dye (ICG). Pre- and post-ICG injection plasma samples were used to measure plasma volume. Preinjection samples were used to measure ovarian hormones and plasma osmolality. Mean plasma volume was highest during the early follicular phase (2,276 ± 478 ml); it declined to 2,232 ± 509 ml by the late follicular phase and to 2,228 ± 502 ml by the midluteal phase. This study found that overall variations in plasma volume are small across the menstrual cycle. Therefore, in clinical practice and research, the menstrual cycle phase may not be an important consideration when evaluating plasma volume among women of reproductive age.

Leisure participation and satisfaction in autistic adults and neurotypical adults.

Leisure participation is important for well-being and has been attributed to improved quality of life for autistic individuals. Rigorous studies exploring the leisure participation of autistic adults are sparse. This study aimed to compare the type of leisure activity and frequency of participation between autistic adults and neurotypical adults as well as compare and identify factors associated with their leisure satisfaction. Data for 145 autistic and 104 neurotypical adults were obtained from time point one of the Australian Longitudinal Study of Adults with Autism. The primary outcome measure used was the Leisure Satisfaction Scale. Autistic adults were less satisfied with their leisure overall (mean = 3.29, standard deviation = 0.75) compared with neurotypical adults (mean = 3.69, standard deviation = 0.55). Multiple linear regression revealed being younger and reporting less depressive symptoms were significantly associated with higher leisure satisfaction in autistic but not neurotypical adults. Engagement in solitary leisure activities was comparable across participants, but socialising in person was predominated by neurotypical adults. Leisure activity preferences of autistic adults' and the frequency of their leisure participation are important factors for clinicians to understand when working with this population and tailoring well-being interventions.

The geography of smallpox in England before vaccination: A conundrum resolved.

Smallpox is regarded as an ancient and lethal disease of humans, however very little is known about the prevalence and impact of smallpox before the advent of vaccination (c.1800). Here we use evidence from English burial records covering the period 1650-1799 to confirm a striking geography to smallpox patterns. Smallpox apparently circulated as a childhood disease in northern England and Sweden, even where population densities were low and settlement patterns dispersed. However, smallpox was a relatively rare epidemic disease in southern England outside the largest cities, despite its commercialised economy and the growing spatial interconnectedness of its settlements. We investigated a number of factors hypothesised to influence the regional circulation of smallpox, including exposure to naturally occurring orthopox viruses, settlement patterns, and deliberate preventative measures. We concluded that transmission was controlled in southern England by local practices of avoidance and mass inoculation that arose in the seventeenth and eighteenth centuries. Avoidance measures included isolation of victims in pest houses and private homes, as well as cancellation of markets and other public gatherings, and pre-dated the widespread use of inoculation. The historical pattern of smallpox in England supports phylogenetic evidence for a relatively recent origin of the variola strains that circulated in the twentieth century, and provides evidence for the efficacy of preventative strategies complementary to immunisation.

In the shadow of coal: How large-scale industries contributed to present-day regional differences in personality and well-being.

Recent research has identified regional variation of personality traits within countries but we know little about the underlying drivers of this variation. We propose that the Industrial Revolution, as a key era in the history of industrialized nations, has led to a persistent clustering of well-being outcomes and personality traits associated with psychological adversity via processes of selective migration and socialization. Analyzing data from England and Wales, we examine relationships between the historical employment share in large-scale coal-based industries (coal mining and steam-powered manufacturing industries that used this coal as fuel for their steam engines) and today's regional variation in personality and well-being. Even after controlling for possible historical confounds (historical energy supply, education, wealth, geology, climate, population density), we find that the historical local dominance of large-scale coal-based industries predicts today's markers of psychological adversity (lower Conscientiousness [and order facet scores], higher Neuroticism [and anxiety and depression facet scores], lower activity [an Extraversion facet], and lower life satisfaction and life expectancy). An instrumental variable analysis, using the historical location of coalfields, supports the causal assumption behind these effects (with the exception of life satisfaction). Further analyses focusing on mechanisms hint at the roles of selective migration and persisting economic hardship. Finally, a robustness check in the U.S. replicates the effect of the historical concentration of large-scale industries on today's levels of psychological adversity. Taken together, the results show how today's regional patterns of personality and well-being (which shape the future trajectories of these regions) may have their roots in major societal changes underway decades or centuries earlier. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Psychosis-proneness and the rubber hand illusion of body ownership.

Psychosis and psychosis-proneness are associated with abnormalities in subjective experience of the self, including distortions in bodily experience that are difficult to study experimentally due to lack of structured methods. In 55 healthy adults, we assessed the relationship between self-reported psychosis-like characteristics and susceptibility to the rubber hand illusion of body ownership. In this illusion, a participant sees a rubber hand being stroked by a brush at the same time that they feel a brush stroking their own hand. In some individuals, this creates the bodily sense that the rubber hand is their own hand. Individual differences in positive (but not negative) psychosis-like characteristics predicted differences in susceptibility to experiencing the rubber hand illusion. This relationship was specific to the subjective experience of rubber hand ownership, and not other unusual experiences or sensations, and absent when a small delay was introduced between seeing and feeling the brush stroke. This indicates that individual differences in susceptibility are related to visual-tactile integration and cannot be explained by differences in the tendency to endorse unusual experiences. Our findings suggest that susceptibility to body representation distortion by sensory information may be related or contribute to the development of psychosis and positive psychosis-like characteristics.

The rise of agrarian capitalism and the decline of family farming in England.

Historians have documented rising farm sizes throughout the period 1450­1850. Existing studies have revealed much about the mechanisms underlying the development of agrarian capitalism. However, we currently lack any consensus as to when the critical developments occurred. This is largely due to the absence of sufficiently large and geographically wide-ranging datasets but is also attributable to conceptual weaknesses in much of the literature. This article develops a new approach to the problem and argues that agrarian capitalism was dominant in southern and eastern England by 1700 but that in northern England the critical developments came later.