Fear, "Discomfort," Anger, and Shame in the Night-Time Economy: Women's Responses to Unwanted Sexual Intrusions.

Despite a surge of attention to gender-based violence (GBV), research about the night-time economy (NTE) as a site of gendered violence is limited. Even less research examines women's emotional responses to "unwanted sexual intrusions" (USI) in the NTE. Analyzing women's emotional responses can generate deeper understanding of social phenomena, power and its operation, and is in keeping with feminist theorizing that uses a victim-survivor-centered approach. Analysis of qualitative data, from a survey we conducted in the United Kingdom, reveals women experience USI in the NTE as a frightening, shameful injustice. The article discusses these emotions in light of the changing "emotional climate" about GBV.

Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma.

Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation. Mitochondrial electron transport chain complex I inhibition induced venetoclax-resistant, but not venetoclax-sensitive, DLBCL cell death. Inhibition of IDH2 (mitochondrial redox regulator) synergistically overcame venetoclax resistance. Additionally, both acquired and intrinsic venetoclax-resistant DLBCL cells were similarly sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases. These approaches were also effective in DLBCL, follicular, and marginal zone lymphoma patient samples. Our results reveal there are multiple ways to circumvent or overcome the diverse venetoclax resistance mechanisms in DLBCL and other B-cell lymphomas and identify critical targetable pathways for future clinical investigations.

Plasticity of colonic enteric nervous system following spinal cord injury in male and female rats.

BACKGROUND: Neurogenic bowel is a dysmotility disorder following spinal cord injury (SCI) that negatively impacts quality of life, social integration, and physical health. Colonic transit is directly modulated by the enteric nervous system. Interstitial Cells of Cajal (ICC) distributed throughout the small intestine and colon serve as specialized pacemaker cells, generating rhythmic electrical slow waves within intestinal smooth muscle, or serve as an interface between smooth muscle cells and enteric motor neurons of the myenteric plexus. Interstitial Cells of Cajal loss has been reported for other preclinical models of dysmotility, and our previous experimental SCI study provided evidence of reduced excitatory and inhibitory enteric neuronal count and smooth muscle neural control. METHODS: Immunohistochemistry for the ICC-specific marker c-Kit was utilized to examine neuromuscular remodeling of the distal colon in male and female rats with experimental SCI. KEY RESULTS: Myenteric plexus ICC (ICC-MP) exhibited increased cell counts 3 days following SCI in male rats, but did not significantly increase in females until 3 weeks after SCI. On average, ICC-MP total primary arborization length increased significantly in male rats at 3-day, 3-week, and 6-week time points, whereas in females, this increase occurred most frequently at 6 weeks post-SCI. Conversely, circular muscle ICC (ICC-CM) did not demonstrate post-SCI changes. CONCLUSIONS AND INFERENCES: These data demonstrate resiliency of the ICC-MP in neurogenic bowel following SCI, unlike seen in other related disease states. This plasticity underscores the need to further understand neuromuscular changes driving colonic dysmotility after SCI in order to advance therapeutic targets for neurogenic bowel treatment.

Suicide attempts during adolescence: Testing the system dynamics of the interpersonal theory of suicide.

INTRODUCTION: Despite increased efforts to prevent suicide, attempts to die by suicide are rising amongst youth in the United States. Testing causal theories that depict suicide attempts from an adolescent development perspective could bolster prevention and intervention efforts. This study using system dynamics modeling to appraise whether a prevalent theory of suicide, the Interpersonal Theory of Suicide, predicts suicide attempts across adolescence. METHODS: A system dynamics computational simulation model was conceptualized based on the Interpersonal Theory of Suicide, as described by Joiner and Van Orden et al. This model was parameterized with representative longitudinal data on adolescents in the United States who attempted suicide across four waves from the National Longitudinal Survey of Adolescent and Adult Health. RESULTS: Though able to predict exponential growth in suicide attempts for early adolescents, the Interpersonal Theory of Suicide, when specified as a dynamic theory, did not adequately predict the nonlinear changes in suicide attempts from adolescence into adulthood. The theory was amended with potential feedback loops from literature and tested for fit. CONCLUSIONS: The study builds on a field of emerging views that suicide dynamics should be tested to account for nonlinear feedback effects. Results suggest that the Interpersonal Theory of Suicide should be amended to include the effect of interventions after an attempt and the dynamic developmental processes during adolescence that affect suicide behaviors over time.

The Role of Inhibition of Apoptosis in Acute Leukemias and Myelodysplastic Syndrome.

Avoidance of apoptosis is a key mechanism that malignancies, including acute leukemias and MDS, utilize in order to proliferate and resist chemotherapy. Recently, venetoclax, an inhibitor of the anti-apoptotic protein BCL-2, has been approved for the treatment of upfront AML in an unfit, elderly population. This paper reviews the pre-clinical and clinical data for apoptosis inhibitors currently in development for the treatment of AML, ALL, and MDS.

Mechanical Behavior of Stainless Steel Fiber-Reinforced Composites Exposed to Accelerated Corrosion.

Recent advancements in metal fibers have introduced a promising new type of stainless steel fiber with high stiffness, high failure strain, and a thickness < 100 µm (<0.00394 in.) that can be utilized in a steel fiber-reinforced polymer. However, stainless steel is known to be susceptible to pitting corrosion. The main goal of this study is to compare the impact of corrosion on the mechanical properties of steel fiber-reinforced composites with those of conventional types of stainless steel. By providing experimental evidences, this study may promote the application of steel fiber-reinforced composite as a viable alternative to conventional metals. Samples of steel fiber-reinforced polymer and four different types of stainless steel were subjected to 144 and 288 h of corrosion in ferric chloride solution to simulate accelerated corrosion conditions. The weight losses due to corrosion were recorded. The corroded and control samples were tested under monotonic tensile loading to measure the ultimate stresses and strains. The effect of corrosion on the mechanical properties of the different materials was evaluated. The digital image correlation (DIC) technique was used to investigate the failure mechanism of the corrosion-damaged specimens. Overall, steel fiber-reinforced composites had the greatest corrosion resistance.

Mechanical Behavior of Hybrid Glass/Steel Fiber Reinforced Epoxy Composites.

While conventional fiber-reinforced polymer composites offer high strength and stiffness, they lack ductility and the ability to absorb energy before failure. This work investigates hybrid fiber composites for structural applications comprised of polymer, steel fiber, and glass fibers to address this shortcoming. Varying volume fractions of thin, ductile steel fibers were introduced into glass fiber reinforced epoxy composites. Non-hybrid and hybrid composite specimens were prepared and subjected to monolithic and half-cyclic tensile testing to obtain stress-strain relationships, hysteresis behavior, and insight into failure mechanisms. Open-hole testing was used to assess the vulnerability of the composites to stress concentration. Incorporating steel fibers into glass/epoxy composites offered a significant improvement in energy absorption prior to failure and material re-centering capabilities. It was found that a lower percentage of steel fibers (8.2%) in the hybrid composite outperformed those with higher percentages (15.7% and 22.8%) in terms of energy absorption and re-centering, as the glass reinforcement distributed the plasticity over a larger area. A bilinear hysteresis model was developed to predict cyclic behavior of the hybrid composite.

Rehabilitation Therapy in Peripheral Arterial Disease.

Peripheral arterial disease (PAD) is the result of atherosclerosis in the lower limb arteries, which can give rise to intermittent claudication (IC), limb ulceration, infections, and, in some circumstances, amputation. As a result of PAD, patients are frequently limited in both walking duration and speed. These ambulatory deficits impact both functional capacity and quality of life. The prevalence of PAD is increasing, and patients with this diagnosis have high cardiovascular morbidity and mortality. A comprehensive approach is required to improve outcomes in patients with PAD and include tobacco cessation, pharmacologic management of metabolic fitness, risk-factor modification, and exercise training. Supervised exercise programs significantly improve functional capacity and quality of life in addition to reducing IC. These programs reduce morbidity and mortality and are cost-effective; yet they are uncommonly prescribed. Supervised exercise training is an accepted intervention in the PAD population and has been included in both Canadian and American guidelines for PAD management. This review describes (1) key background information related to PAD, (2) the initial approach to PAD diagnosis, (3) pharmacologic management options, (4) risk-factor modification, and (5) the currently accepted approach to exercise training. Key recommendations for enhancing PAD care in a Canadian context are also discussed.

Volunteering as a pathway to productive and social engagement among older adults.

INTRODUCTION: Research on outcomes of volunteering in later life largely focuses on the health of volunteers. This is in contrast to studies of youth, where attention is directed toward the effects of volunteering on subsequent productive and citizen behaviors. In this study, we examined the effects of volunteering on subsequent social and civic activity of older adults. METHOD: This study was conducted with volunteers from Experience Corps® (EC), a national program that brings older adults into schools to work with students. Data were derived from a baseline survey of older adults who were new EC volunteers in fall of 2006 and 2007. Follow-up interviews were conducted with 338 volunteers in fall 2010 to capture work, education, and community activities undertaken subsequent to joining EC. RESULTS: Subsequent to joining EC, 16% of volunteers reported that they started a new job, 53% started another volunteer position, 40% started a community activity, and 39% took a class/started educational program. When asked if and how EC participation played a role in their new involvements, 71% said it increased confidence, 76% said it increased realization of the importance of organized activities/daily structure, and more than 40% said they made social connections that led to new involvements. Most reported they were more likely to be involved in advocacy efforts for public education. DISCUSSION: Volunteering among older adults is a means as well as an end--just as it is for young people. Programs can do more to attract and serve older adults by promoting volunteering as a pathway to other engagements, including work, social, and civic activities.

The impact of international service on the development of volunteers' intercultural relations.

Approximately one million people from the United States perform international volunteer service each year, representing a significant flow of ideas, people, resources, and aid across international borders. This quasi-experimental study assesses the longitudinal impact of international volunteer service on volunteers' intercultural relations, international social capital, and concern about international affairs. Using linear mixed regression models that control for a counterfactual comparison group of individuals that did not travel abroad, international volunteers are more likely to report significant increases in international social capital and international concern two to three years after returning from service. Results indicate that intercultural relations may also continue to increase years after returning from service. International service may be a useful approach to helping people gain skills and networks that are needed in an increasingly global society.

Host defense and recruitment of Foxp3⁺ T regulatory cells to the lungs in chronic Mycobacterium tuberculosis infection requires toll-like receptor 2.

Acute resistance to low dose M. tuberculosis (Mtb) infection is not dependent on Toll-like receptor (TLR) 2. However, whether TLR2 contributes to resistance in chronic Mtb infection has remained uncertain. Here we report that, following low dose aerosol infection with Mtb, mice lacking TLR2 (TLR2KO), in comparison with wild type (WT) mice, exhibit enhanced cellular infiltration and inflammation in the lungs, and fail to stably control bacterial burden during chronic infection. IFNγ and IL-17 was expressed at equivalent levels in the two groups; however, the characteristic accumulation of Foxp3⁺ T regulatory cells (Tregs) in pulmonary granulomas was significantly reduced in TLR2KO mice. Nonetheless, this reduction in Tregs was independent of whether Tregs expressed TLR2 or not. To directly link the reduced number of Tregs to the increased inflammation present in the TLR2KO mice, we used a macrophage adoptive transfer model. At seven weeks post-Mtb infection, TLR2KO mice, which were adoptively transferred with WT macrophages, displayed enhanced accumulation of Tregs in the lungs and a concomitant reduction in inflammation in contrast with control mice that received TLR2KO macrophages. However, the pulmonary bacterial burden between the two groups remained similar indicating that TLR2's role in modulating immunopathology is functionally distinct from its role in restricting Mtb growth in chronic infection. Together, these findings unequivocally demonstrate that TLR2 contributes to host resistance against chronic Mtb infection and reveal a novel role for TLR2 in mediating the recruitment of Foxp3⁺ Tregs to the lungs to control inflammation.

Medication to prevent breast cancer--too much to swallow?

Selective oestrogen receptor modulators effectively reduce breast cancer in women at moderate to high risk, so why aren't they being discussed routinely?

Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway.

Tuberculosis and helminthic infections coexist in many parts of the world, yet the impact of helminth-elicited Th2 responses on the ability of the host to control Mycobacterium tuberculosis (Mtb) infection has not been fully explored. We show that mice infected with the intestinal helminth Nippostrongylus brasiliensis (Nb) exhibit a transitory impairment of resistance to airborne Mtb infection. Furthermore, a second dose of Nb infection substantially increases the bacterial burden in the lungs of co-infected mice. Interestingly, the Th2 response in the co-infected animals did not impair the onset and development of the protective Mtb-specific Th1 cellular immune responses. However, the helminth-induced Th2 environment resulted in the accumulation of alternatively activated macrophages (AAMs) in the lung. Co-infected mice lacking interleukin (IL) 4Rα exhibited improved ability to control Mtb infection, which was accompanied by significantly reduced accumulation of AAMs. Moreover, IL-4Rα(-/-) mice adoptively transferred with wild-type macrophages had a significantly higher Mtb load in their lungs compared with those that received IL-4Rα(-/-) macrophages, suggesting a direct contribution for the IL-4R pathway to the heightened susceptibility of co-infected animals. The Th2 response can thus enhance the intracellular persistence of Mtb, in part by mediating the alternative activation of macrophages via the IL-4Rα signaling pathway.

Development of a secondary immune response to Mycobacterium tuberculosis is independent of Toll-like receptor 2.

Published work indicates that the contribution of Toll-like receptor 2 (TLR2) to host resistance during acute Mycobacterium tuberculosis infection is marginal. However, in these studies, TLR2 participation in the memory immune response to M. tuberculosis was not determined. The substantial in vitro evidence that M. tuberculosis strongly triggers TLR2 on dendritic cells and macrophages to bring about either activation or inhibition of antigen-presenting cell (APC) functions, along with accumulating evidence that memory T cell development can be calibrated by TLR signals, led us to question the role of TLR2 in host resistance to secondary challenge with M. tuberculosis. To address this question, a memory immunity model was employed, and the response of TLR2-deficient (TLR2 knockout [TLR2KO]) mice following a secondary exposure to M. tuberculosis was compared to that of wild-type (WT) mice based on assessment of the bacterial burden, recall response, phenotype of recruited T cells, and granulomatous response. We found that upon rechallenge with M. tuberculosis, both WT and TLR2KO immune mice displayed similarly enhanced resistance to infection in comparison to their naïve counterparts. The frequencies of M. tuberculosis-specific gamma interferon (IFN-γ)-producing T cells, the phenotypes of recruited T cells, and the granulomatous responses were also similar between WT and TLR2KO immune mice. Together, the findings from this study indicate that TLR2 signaling does not influence memory immunity to M. tuberculosis.

Reliability, minimal detectable change, and normative values for tests of upper extremity function and power.

The purpose of this study was to examine the test-retest reliability, minimal detectable change (MDC), and determine normative values of 3 upper extremity (UE) tests of function and power. One hundred eighty participants, men (n = 69) and women (n = 111), were tested on 3 UE strength and power maneuvers in a multicenter study to determine baseline normative values. Forty-six subjects returned for a second day of testing within 5 days of the initial assessment for the reliability component of the investigation. Explosive power was assessed via a seated shot-put test for the dominant and nondominant arms. Relationships between the dominant and nondominant arms were also analyzed. A push-up and modified pull-up were performed to measure the amount of work performed in short (15-second) bursts of activity. The relationship between the push-up and modified pull-up was also determined. Analysis showed test-retest reliability for the modified pull-up, timed push-up, dominant single-arm seated shot-put tests, and nondominant single-arm seated shot-put tests to be intraclass correlation coefficient(3,1) 0.958, 0.989, 0.988, and 0.971, respectively. The MDC for both the push-up and modified pull-up was 2 repetitions. The MDCs for the shot put with the dominant arm and the nondominant arm were 17 and 18 in., respectively. The result of this study indicates that these field tests possess excellent reliability. Normative values have been identified, which require further validation. These tests demonstrate a practical and effective method to measure upper extremity functional power.

B7 costimulation is critical for host control of chronic Mycobacterium tuberculosis infection.

Although much is understood regarding the role of B7/CD28 family of costimulatory molecules in regulating host resistance in the context of several pathogens, analogous information with Mycobacterium tuberculosis is lacking. To address the requirements of B7-mediated costimulation in host resistance against tuberculosis, mice deficient in both B7.1 and B7.2 (B7DKO) were aerosol infected with M. tuberculosis Erdman and disease progression was monitored. We report herein that B7DKO mice are initially able to contain the bacterial load in the lung, but exhibit enhanced susceptibility during chronic infection. Despite the early control of bacterial replication, B7DKO mice essentially start off with compromised Th1 immunity and slower granulomatous response in the lung, characterized by markedly reduced lymphocytic infiltration. As the infection progresses from acute phase to the chronic phase, the nascent granulomas in the B7DKO lungs never fully achieve the architecture of granulomas developing in wild-type mice. Instead, lesions spread progressively to involve much of the lung in the B7DKO mice, ultimately leading to necrosis. Thus, early control of M. tuberculosis growth in the lung can occur in the absence of B7 costimulation and is less dependent on Th1 immunity and formation of a granulomatous structure. However, B7 costimulation is critical for long-term containment of infection within lung granulomas. These findings suggest that the use of costimulation-based immunomodulators may have significant repercussions on the induction of host protective immunity against tuberculosis.

Macro practice teaching and curriculum development from an evidence-based perspective.

This article contributes to the discourse around evidence-based practice (EBP) as an organizing principle and guiding framework for macro-practice education as it has developed in the George Warren Brown School of Social Work at Washington University in St. Louis. In examining the first five years of implementing evidence-based education at the macro level, some lessons learned are provided. This learning has opened the door for continuing the dialogue on surmounting the challenges around training macro social workers in evidence-based practices. The overarching challenge in integrating EBP into the curriculum lies in the complexity of the multi-dimensional conceptualization of evidence.