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The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.

Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.

Objective: A diagnosis of Parkinson's often leads to uncertainty about the future and loss of perceived control. Peer support may offer a means to address these concerns and promote self-management. Design: A programme evaluation of the feasibility and potential effects of 'First Steps', utilising a pragmatic step wedge approach. Comparing First Steps (intervention) to (control) conditions. Setting: In the community at four sites in southern England. Participants: Newly diagnosed (≤ 12months) people with Parkinson's. Intervention: First Steps was a 2-day peer-conceived, developed and led intervention to support self-management. Main measures: At 0, 12 and 24 weeks anxiety and depression (Hospital, Anxiety and Depression Scale, HADS), daily functioning (World Health Organisation Disability Assessment Schedule, WHODAS), physical activity, quality of life (EQ5D), carer strain and service utilisation were assessed. Results: Between February 2018 and July 2019, 36 participants were enrolled into intervention and 21 to control conditions, all were included in statistical analysis. Lost to follow up was n = 1 (intervention) and n = 1 adverse event was reported (control, unrelated). Of the 36 allocated to the intervention n = 22 participants completed both days of First Steps during the study period. Completion of outcome measures was >95% at 24 weeks. Small effects favouring the intervention were found for HADS (odds ratio (OR) = 2.06, 95% confidence interval (CI) 0.24:17.84), Carer Strain Index (OR = 2.22, 95% CI 0.5:9.76) and vigorous (d = 0.42, 95% CI −0.12:0.97) and total physical activity (d = 0.41, 95% CI −0.13:0.95). EQ5D, WHOSDAS and service utilisation, was similar between groups. Conclusions: First Steps was feasible and safe and we found potential to benefit physical activity, mental health and carer strain. Further research with longer-term follow up is warranted. [ABSTRACT FROM AUTHOR]

To explore, in a European cohort of people living with Parkinson's (PD), issues affecting employment and economic consequences, considering age at diagnosis. A cross-sectional survey (European convenience sample). Inclusion criteria were ≥18 years, a PD diagnosis and in work when diagnosed. Data were collected online on demographics, employment status, occupation, and perceived health. For those no longer in paid work, time from diagnosis until loss of employment, reasons for leaving and enablers to stay in work were ascertained. Between April and November 2019, n = 692 enrolled and n = 560 were eligible. Those who had lost paid work (n = 190, 34%) reported worse fatigue, sleep, and general health than those still in work (p < 0.05). Average annual income reduced from €26973.48 ± 12013.22 (year-1) to €14843.85 ± 16969.84 (year-10). Post-diagnosis lost employment potential was 20.1 (95% confidence interval (CI): 16.6–23.6) years at career establishment, 9.8 (95%CI: 8.9–10.7) years at mid working and 1.2 (95%CI: 0.6–1.6) years for those nearing retirement age. A greater proportion of individuals at career establishment age reported dexterity, eating, sleep, fatigue, and anxiety as factors for leaving work (p < 0.05). This study confirms lost productivity after a PD diagnosis, especially in those with many years of potential employment ahead. The study also identified potential targets for interventions. Clinical trial registration: Clincaltrials.gov (NCT03905954). People with Parkinson's diagnosed at career establishment or at mid working age risk losing many years of potential employment. Most people with Parkinson's do not receive early intervention to support self-management of problems identified with leaving work early, such as fatigue. Adaptations to the work environment and more flexible working patterns were identified factors that may help people remain in work. [ABSTRACT FROM AUTHOR]

Two experiments assessed recognition of emotion among physically abused and neglected preschoolers. Results showed that neglected children had more difficulty discriminating emotional expressions that control or abused children. Abused children displayed response bias for angry facial expressions. Control children viewed discrete emotions as dissimilar; neglected children saw fewer distinctions between emotions; abused children showed the most variance across emotions. (Author/KB)

A new optimism is emerging towards psychological approaches to psychosis. Whereas previously the emphasis in services has been almost solely on drug treatments, the past few years have seen the [...]

Before the U.S. Equal Employment Opportunity Commission may sue an employer for violating federal antidiscrimination law, it must first seek to engage the employer in conciliation. Conciliation offers employers an opportunity to resolve discrimination charges voluntarily in a setting analogous to settlement negotiations. In January 2021, EEOC promulgated a rule mandating that, as part of conciliation, employers be given certain information about the underlying charge. Congress subsequently rescinded the rule, however, citing its ostensible pro-employer/anti-worker bias. Congress’s nullification of the conciliation rule has generated considerable uncertainty not only for employers and workers but also for the Commission itself. That is because the rule was rescinded using the Congressional Review Act (CRA), which prohibits a rule from being issued “in substantially the same form” as one previously disapproved. Yet, the Act does not define “in substantially the same form” or otherwise specify what criteria should be used in assessing rules’ similarity. Nor has any court interpreted the phrase in the specific context of CRA. This article examines three possible methodologies for how the Commission might go about issuing a conciliation rule consistent with CRA— based on proposals from the academic literature, other agencies’ experience in reissuing disapproved rules, and procedures specified in CRA’s post-enactment legislative history—and demonstrates that while EEOC retains the discretion to issue a new conciliation rule, it is effectively barred from doing so absent further action by Congress. [ABSTRACT FROM AUTHOR]

Whereas Title VII has always contained an express exemption for religious organizations, ambiguities in the statutory text and legislative history render the exemption susceptible to three conflicting interpretations. This Article provides a detailed critique of each interpretation and demonstrates that while LGBTQ persons stand to retain meaningful employment protections under two Of the three interpretations, the third construction threatens to leave LGBTQ individuals-together with women, pregnant persons, and racial and ethnic minorities-vulnerable to discrimination in a host of non-ministerial, ostensibly secular positions. [ABSTRACT FROM AUTHOR]

Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase Cγ2 (PLCγ2 or PLCG2)--mutations in which are associated with autoinflammatory disorders and Alzheimer's disease--serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2-/- mice showed generally normal proinflammatory cytokine and chemokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in cross-talk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli. [ABSTRACT FROM AUTHOR]

Whereas the Supreme Court recently held that LGBTQ employment bias is actionable under Title VII as a form of sex discrimination, the statute does not protect persons working at small firms, i.e., businesses with fewer than fifteen employees. For these individuals, state law provides the exclusive means of redressing workplace bias, yet only twenty-two states prohibit discrimination on the basis of sexual orientation and gender identity. This article examines a subset of the twenty-eight states lacking explicit, LGBTQ-inclusive employment protections--those with antidiscrimination statutes applying to small firms otherwise exempt from Title VII--and demonstrates that, to varying degrees, these states would be justified in construing their statutes' existing bans on sex discrimination to protect LGBTQ workers. [ABSTRACT FROM AUTHOR]

Effective & Emerging Treatments in Pediatric Psychology By Anthony Spirito and Anne E. Kazak Oxford University Press, New York, 2006, 180 pp. DOI: 10.1037/1091-7527.24.4.471 Attention all health care providers interested [...]

Because federal law does not expressly prohibit employment discrimination on the basis of sexual orientation or gender identity, LGBTQ Americans were thrilled to learn that a preliminary draft of the United States–Mexico–Canada Agreement (USMCA) included a provision (the Provision) requiring each nation to enact LGBTQ‐inclusive nondiscrimination laws. That excitement promptly turned to despair, however, after the Trump administration insisted on the addition of a footnote (the Footnote) designed to exempt the United States from the Provision. To date, the Footnote has been derided by scholars and trade experts alike as a transparent attempt to evade the Provision's LGBTQ‐inclusive mandate. Yet, by focusing only on what the USMCA does not do, these analyses overlook what the agreement does do, even if unintended, to benefit LGBTQ Americans. This article provides the first comprehensive analysis of the USMCA's implications for federal antidiscrimination law and demonstrates that—regardless of how the Supreme Court rules in a trio of LGBTQ employment cases—the Footnote actually stands to help, not hinder, the cause of LGBTQ equality. [ABSTRACT FROM AUTHOR]

The article focuses on the Dementia Training Australia (DTA) Fellowship program that focuses on training and mentoring of staff in an organization. INSET: Building leadership capacity.

Background and Objectives: Chief resident leadership competencies are neither clear nor standardized. The goal of this project was to identify specific leadership skills for chief residents and to develop a self-assessment tool.Methods: Chief residents from 10 family medicine residencies participated in focus groups to identify leadership skills required to be an effective chief resident. The ideas generated by participants were grouped into 10 competencies and a self-assessment tool was developed. The tool has been used to help chief residents self-assess their leadership strengths and weaknesses, and to identify teaching priorities for biannual leadership workshops.Results: The self-assessment instrument was completed by 83 chief residents over 5 years. Mean ratings range from 3.19 to 3.57 on a 5-point scale (low to high competency). The self-ratings of residents starting their chief year compared to residents at the end of their chief year showed an increase in 9 of the 10 competencies.Conclusions: The leadership competencies are a useful tool to identify training priorities and to help chief residents or other leaders within a residency program identify skills for further development. [ABSTRACT FROM AUTHOR]

The article informs about the initiative driven by IRT Group's Journey of Care model which personalizes the care experience for every resident through dedicated care neighborhoods and specialist programs. It mentions that the Journey of Care program has since rolled out across all Intensive Residential Treatment (IRT) aged care centers a desire has grown to extend templates to also include photos and images chosen by the residents and for these to be trialed in non-dementia secure unit areas.

Background: Rural communities throughout the United States are eager to recruit and retain family physicians. This study examined factors that may contribute to a medical student's decision to consider rural family medicine practice using the Community Apgar Questionnaire (CAQ).Methods: Third- and fourth-year medical students from 10 medical schools responded to a survey of 62 identified factors deemed to be present when assessing the strengths and challenges of recruiting family physicians to rural communities. Participants could also respond to six demographic questions. Factors were ranked based on importance to respondents and were compared using demographic information.Results: A total of 282 MS-3 and MS-4 students interested in family medicine from 10 US medical schools completed the survey (response rate 19.5%). Forty percent of participants anticipate practicing in a rural setting, followed by 31% for suburban and 29% for urban. The top three factors participants considered when anticipating a rural practice setting were spousal satisfaction, call frequency, and competition/collegiality. Additional differences were found across CAQ factors by future practice setting, gender, and location where the student was raised.Conclusions: Medical schools, rural preceptors, and rural communities may wish to consider highly rated factors found in the CAQ in the effort to increase the recruitment of family physicians interested in rural practice. [ABSTRACT FROM AUTHOR]

The article focuses on the subjective-perception test's implications for same-sex harassment jurisprudence with the decision of the U.S. Court of Appeals of the Fifth Circuit in the case Equal Employment Opportunity Commission v. Boh Brothers Construction Company on same-sex harassment.

The article discusses legal issues regarding the decision taken by the U.S. Supreme Court in the court case Burwell v. Hobby Lobby Stores, Inc. on June 30, 2014. It mentions that the court opined that for-profit corporations are capable of exercising religion within the meaning of the Religious Freedom Restoration Act of 1993 and therefore be granted exemptions from generally applicable laws if compliance with those laws would substantially burden the corporations' religious freedom.

Background: Practice-based research networks (PBRNs) promote the conduct of research in real-world settings by engaging primary care clinicians as champion research collaborators. Card studies are brief surveys administered to patients or clinicians at the point of care. The objective of this paper is to describe the design and evaluation of a card study methodology that the WWAMI Region Practice and Research Network (WPRN) used to develop research partnerships across multiple member sites. Methods: We used a collaborative model to develop, implement and disseminate the results of a network-wide card study to assess patient preferences for weight loss in primary care. After the card study data collection was completed, we conducted individual and focus group interviews and a brief survey of participating practice champions. Results: Increased research engagement and personal and professional developments were the primary motivators for participating in the development of the card study. Increasing research activity at practices and learning information about patients were motivators for implementing the study. Their participation resulted in champions reporting increased confidence in collaborating on research projects as well as the development of new clinical services for patients. Discussion: This collaborative model positively influenced research capacity in the WPRN and may be a useful strategy for helping PBRNs conducted translational research. [ABSTRACT FROM AUTHOR]

The article focuses on the U.S. Employment Non-Discrimination Act (ENDA) and mentions the need of executive order for legislation to protect LGBT persons against employment discrimination. Topics discussed include opposition of ENDA by legislators, U.S. President Barack Obama may extend explicit status-based protections to a significant number of LGBT workers and LGBT-related employment discrimination is also actionable as sex discrimination under Title VII of the Civil Rights Act of 1964.

This article offers some reflections on how my practice as a systemic psychotherapist has been influenced by my interests in Appreciative Inquiry (AI) and Zen Buddhism. The discussion will particularly focus on how these influences inform my thinking about the therapeutic relationship. From Zen, the idea of 'beginner's mind' is helpful in enhancing appreciative curiosity within the therapist. [ABSTRACT FROM AUTHOR]

The article discusses a randomized controlled trial on the recommended use of direct oral anticoagulants (DOACs) instead of warfarin in the treatment of atrial fibrillation (AF). Topics include the effectiveness of DOACs in preventing systemic emboli and ischemic stroke, the lower bleeding rates of apixaban and dabigatran than warfarin and the health insurance cost of DOAC coverage.

This article provides the first comprehensive analysis of ENDA's shortcomings vis- ` a-vis Title VII of the Civil Rights Act of 1964. Whereas federal courts are increasingly likely to perceive LGBT-related employment discrimination as actionable sex discrimination under Title VII, the inclusion of gender identity protections in recent versions of ENDA has significantly diminished the bill's prospects for passage. This article contends that advocates should abandon their efforts to enact ENDA in favor of allowing Title VII's "sex" provision to continue on its LGBT-inclusive evolution. Title VII stands to provide LGBT persons with three distinct advantages relative to ENDA. First, Title VII allows plaintiffs to contest discrimination on either a disparate treatment or disparate impact theory. ENDA, in contrast, would permit only disparate treatment claims such that facially neutral employment practices having a disproportionately adverse effect on LGBT persons would not be actionable. Second, Title VII permits voluntary affirmative action plans whereas ENDA would prohibit preferential treatment on the basis of sexual orientation or gender identity even if LGBT persons were significantly underrepresented in a given workforce. Third, Title VII allows religious organizations to discriminate on the basis of religion but not race, color, ethnicity, or sex. ENDA, conversely, would allow religious organizations to discriminate on the basis of sexual orientation or gender identity without having to justify the discrimination on religious precepts. This article examines the feasibility of applying Title VII's protections to LGBT persons and concludes that, notwithstanding certain logistical difficulties in the short-run, LGBT individuals would benefit from the availability of disparate impact claims, voluntary affirmative action plans, and limited exemptions for religious organizations so that ENDA should be abandoned in favor of Title VII. [ABSTRACT FROM AUTHOR]

For more than sixty years, the Internal Revenue Service has employed a methodology test in determining whether a nonprofit organization's advocacy of a particular viewpoint is sufficiently educational to warrant its designation as a public charity. The test's focus is not upon the viewpoint advocated, but upon the method used by the organization to communicate its viewpoint to others. Consistent with this purpose, the Service has identified four factors that are indicative of a noneducational methodology. The Service's application of the test, however, suggests the existence of an additional, previously undisclosed factor. This factor regards a refusal to present opposing viewpoints as indicative of a noneducational methodology. This article concludes that the methodology test is unconstitutional for three reasons. First, the test is void for vagueness because it does not disclose one of the factors considered by the Service in evaluating whether an advocacy organization may be said to employ an educational methodology. Second, the test violates the compelled speech doctrine by requiring advocacy organizations to accommodate the very speech they are organized to oppose. Third, the test imposes an unconstitutional condition by conditioning advocacy organizations' eligibility to receive tax-deductible contributions on the absolute forfeiture of their First Amendment rights. [ABSTRACT FROM AUTHOR]

The article the reason behind controversial removal of Lisa Howe from Belmont University. However, had joined the university in 2004 and took the university's team to National Collegiate Athletic Association (NCAA)'s football competition. However, in 2009 she confessed to being a lesbian. The Nashville Metropolitan Council legalized Homophobia to prevent any such issues. The article discusses these laws in terms of the historic Romer v. Evans Supreme Court Case on similar lines.