A non-hallucinogenic psychedelic analogue with therapeutic potential.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Reverse Phase Proteomic Array Profiling of Asparagine Synthetase Expression in Newly Diagnosed Acute Myeloid Leukemia.

Asparaginase-based therapy is a cornerstone in acute lymphoblastic leukemia (ALL) treatment, capitalizing on the methylation status of the asparagine synthetase (ASNS) gene, which renders ALL cells reliant on extracellular asparagine. Contrastingly, ASNS expression in acute myeloid leukemia (AML) has not been thoroughly investigated, despite studies suggesting that AML with chromosome 7/7q deletions might have reduced ASNS levels. Here, we leverage reverse phase protein arrays to measure ASNS expression in 810 AML patients and assess its impact on outcomes. We find that AML with inv(16) has the lowest overall ASNS expression. While AML with deletion 7/7q had ASNS levels slightly lower than those of AML without deletion 7/7q, this observation was not significant. Low ASNS expression correlated with improved overall survival (46 versus 54 weeks, respectively, p = 0.011), whereas higher ASNS levels were associated with better response to venetoclax-based therapy. Protein correlation analysis demonstrated association between ASNS and proteins involved in methylation and DNA repair. In conclusion, while ASNS expression was not lower in patients with deletion 7/7q as initially predicted, ASNS levels were highly variable across AML patients. Further studies are needed to assess whether patients with low ASNS expression are susceptible to asparaginase-based therapy due to their inability to augment compensatory ASNS expression upon asparagine depletion.

Oligodendrocyte-selective deletion of the eIF2α kinase Perk/Eif2ak3 limits functional recovery after spinal cord injury.

After spinal cord injury (SCI), re-establishing cellular homeostasis is critical to optimize functional recovery. Central to that response is PERK signaling, which ultimately initiates a pro-apoptotic response if cellular homeostasis cannot be restored. Oligodendrocyte (OL) loss and white matter damage drive functional consequences and determine recovery potential after thoracic contusive SCI. We examined acute (<48 h post-SCI) and chronic (6 weeks post-SCI) effects of conditionally deleting Perk from OLs prior to SCI. While Perk transcript is expressed in many types of cells in the adult spinal cord, its levels are disproportionately high in OL lineage cells. Deletion of OL-Perk prior to SCI resulted in: (1) enhanced acute phosphorylation of eIF2α, a major PERK substrate and the critical mediator of the integrated stress response (ISR), (2) enhanced acute expression of the downstream ISR genes Atf4, Ddit3/Chop, and Tnfrsf10b/Dr5, (3) reduced acute OL lineage-specific Olig2 mRNA, but not neuronal or astrocytic mRNAs, (4) chronically decreased OL content in the spared white matter at the injury epicenter, (5) impaired hindlimb locomotor recovery, and (6) reduced chronic epicenter white matter sparing. Cultured primary OL precursor cells with reduced PERK expression and activated ER stress response showed: (1) unaffected phosphorylation of eIF2α, (2) enhanced ISR gene induction, and (3) increased cytotoxicity. Therefore, OL-Perk deficiency exacerbates ISR signaling and potentiates white matter damage after SCI. The latter effect is likely mediated by increased loss of Perk-/- OLs.

Computer vision for automated seizure detection and classification: A systematic review.

Computer vision (CV) shows increasing promise as an efficient, low-cost tool for video seizure detection and classification. Here, we provide an overview of the fundamental concepts needed to understand CV and summarize the structure and performance of various model architectures used in video seizure analysis. We conduct a systematic literature review of the PubMed, Embase, and Web of Science databases from January 1, 2000 to September 15, 2023, to identify the strengths and limitations of CV seizure analysis methods and discuss the utility of these models when applied to different clinical seizure phenotypes. Reviews, nonhuman studies, and those with insufficient or poor quality data are excluded from the review. Of the 1942 records identified, 45 meet inclusion criteria and are analyzed. We conclude that the field has shown tremendous growth over the past 2 decades, leading to several model architectures with impressive accuracy and efficiency. The rapid and scalable detection offered by CV models holds the potential to reduce sudden unexpected death in epilepsy and help alleviate resource limitations in epilepsy monitoring units. However, a lack of standardized, thorough validation measures and concerns about patient privacy remain important obstacles for widespread acceptance and adoption. Investigation into the performance of models across varied datasets from clinical and nonclinical environments is an essential area for further research.

Brief virtual intervention associated with increased social engagement and decreased negative affect among people aging with HIV.

Virtual Villages-online communities that deliver supports to promote aging in place-are proposed to mitigate isolation and support the health of aging populations. Using a community-engaged approach, we developed and pilot-tested a Virtual Village intervention tailored for people living with HIV (PLWH) aged 50+ . The intervention employed a Discord server featuring social interaction, regional and national resources, expert presentations, and mindful meditation exercises. In 2022, a sample of PLWH aged 50+ from three U.S. study sites participated in a four-week pilot. Pre- and post-intervention surveys assessed participants' demographic characteristics; degree of loneliness, social connectedness, HIV-related stigma, and technology acceptance; mental wellbeing and physical health outcomes; and user experience. Participants (N = 20) were socioeconomically and racially/ethnically diverse, aged 51-88 years, and predominantly identified as gay or bisexual men (75%). Paired t-tests revealed a significant increase in participants' mean social engagement scores and a significant decrease in participants' mean negative affect scores, following the intervention. User experience scores were acceptable and participants reported a positive sense of connectedness to the Virtual Village community. Results suggest that a virtual community can be accessible to older PLWH and may enhance social engagement and improve aspects of mental wellbeing.

A community-academic partnered approach to designing a Virtual Village to address the needs of older adults living with HIV.

ABSTRACTMany older adults living with HIV face unique challenges, including comorbidities, loneliness, and isolation. This community-academic partnered study elicited viewpoints from older adults living with HIV about the characteristics of a digital environment ("Virtual Village") to combat against loneliness and isolation. We utilized Choice-Based Conjoint Analyses to determine preferred attributes of a Virtual Village. We also conducted focus groups and interviews with older adults living with HIV and used an iterative, data-driven approach to systematically identify emergent themes. Participants (N = 82) were aged 50-82 years and racially/ethnically diverse. The majority were men (78%), gay (66%), and lived with HIV for ≥15 years (83%). Cost was the factor that most drove participants' preference for joining a Virtual Village. Thematic concerns included lack of technological confidence, internet access, potential for harassment in digital environments, privacy, and preference for in-person interactions. Praises centered on convenience and making connections across geographic distances. Participants emphasized the need for purposive strategies to form a cohesive and supportive community for older adults living with HIV. A moderated environment was recommneded to create a safe, structured, and comfortable digital environment for older adults living with HIV. A Virtual Village should be viewed as a bridge to in-person interactions.

Economic and social determinants of health care utilization during the first wave of COVID-19 pandemic among adults in Ghana: a population-based cross-sectional study.

BACKGROUND: The COVID-19 pandemic had socioeconomic effects in Africa. This study assessed the social and economic determinants of healthcare utilization during the first wave of COVID-19 among adults in Ghana. METHODS: Information about individuals residing in Ghana was derived from a survey conducted across multiple countries, aiming to evaluate the impact of the COVID-19 pandemic on the mental health and overall well-being of adults aged 18 and above. The dependent variable for the study was healthcare utilization (categorized as low or high). The independent variables were economic (such as financial loss, job loss, diminished wages, investment/retirement setbacks, and non-refunded travel cancellations) and social (including food scarcity, loss of financial support sources, housing instability, challenges affording food, clothing, shelter, electricity, utilities, and increased caregiving responsibilities for partners) determinants of health. A multinomial logistic regression was conducted to identify factors associated with healthcare utilization after adjusting for confounders (age, gender, access to medical insurance, COVID-19 status, educational background, employment, and marital status of the participants). RESULTS: The analysis included 364 responses. Individuals who encountered a loss of financial support (AOR: 9.58; 95% CI: 3.44-26.73; p < 0.001), a decrease or loss of wages (AOR: 7.44, 95% CI: 3.05-18.16, p < 0.001), experienced investment or retirement setbacks (AOR: 10.69, 95% CI: 2.60-43.88, p = 0.001), and expressed concerns about potential food shortages (AOR: 6.85, 95% CI: 2.49-18.84, p < 0.001) exhibited significantly higher odds of low healthcare utilization during the initial phase of the pandemic. Contrastingly, participants facing challenges in paying for basic needs demonstrated lower odds of low healthcare utilization compared to those who found it easy to cover basic expenses (AOR: 0.19, 95% CI: 0.06-0.67, p = 0.001). CONCLUSION: Economic and social factors were associated with low healthcare utilization in Ghana during the first wave of the pandemic. Investment or retirement loss and financial support loss during the pandemic had the largest effect on healthcare utilization. Further research is needed to understand the connection between concerns about food shortages, welfare losses during pandemics and healthcare utilization during pandemics in Ghana.

Prenatal hydrocolpos: imaging findings and differential diagnosis.

Prenatal hydrocolpos is characterized by fluid distension of the vagina. Hydrocolpos can be caused by multiple underlying etiologies and often demonstrates overlapping imaging features compared to other cystic abdominal and pelvic lesions. The purpose of the current pictorial essay is to provide a systematic prenatal magnetic resonance imaging (MRI) approach to differentiating the primary etiologies leading to hydrocolpos. After discussing the fundamental embryological processes involved in vaginal development, the current essay discusses the most common causes of hydrocolpos with their associated prenatal and postnatal imaging features. An approach to distinguishing the more common differential diagnoses is provided. Given the implications of parental counseling and postnatal management, this essay provides an important approach for narrowing differential diagnoses based on prenatal imaging.

Treatment of Chronic Insomnia in Adults.

Insomnia affects 30% of the U.S. population, with 5% to 15% meeting criteria for chronic insomnia. It can negatively impact quality of life, decrease productivity, increase fatigue and drowsiness, and put patients at higher risk of developing other health problems. Initial treatment focuses on nonpharmacologic therapies such as cognitive behavior therapy, which improves negative thought patterns and behaviors through sleep restriction, stimulus control, and relaxation techniques. Other nonpharmacologic treatments include exercise, mindfulness, and acupuncture. If these approaches are ineffective, pharmacologic agents may be considered. Medications such as benzodiazepines and Z-drugs are often prescribed for insomnia but should be avoided, if possible, due to short- and long-term risks associated with their use. Melatonin receptor agonists are safer and well tolerated but have limited effectiveness. Dual orexin receptor antagonists are effective in patients who have sleep maintenance insomnia or difficulty with sleep onset. Evidence for the use of antihistamines to treat insomnia is generally lacking, but doxylamine is effective for up to four weeks.

Notes on [post]human nursing: What It MIGHT Be, What it is Not.

With this paper, we walk out some central ideas about posthumanisms and the ways in which nursing is already deeply entangled with them. At the same time, we point to ways in which nursing might benefit from further entanglement with other ideas emerging from posthumanisms. We first offer up a brief history of posthumanisms, following multiple roots to several points of formation. We then turn to key flavors of posthuman thought to differentiate between them and clarify our collective understanding and use of the terms. This includes considerations of the threads of transhumanism, critical posthumanism, feminist new materialism, and the speculative, affirmative ethics that arise from critical posthumanism and feminist new materialism. These ideas are fruitful for nursing, and already in action in many cases, which is the matter we occupy ourselves with in the final third of the paper. We consider the ways nursing is already posthuman-sometimes even critically so-and the speculative worldbuilding of nursing as praxis. We conclude with visions for a critical posthumanist nursing that attends to humans and other/more/nonhumans, situated and material and embodied and connected, in relation.

Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels.

The three small-conductance calcium-activated potassium (KCa2) channels and the related intermediate-conductance KCa3.1 channel are voltage-independent K+ channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. KCa2 and KCa3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of KCa channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule KCa2 and KCa3.1 modulators. Finally, we describe the progress that has been made in advancing KCa3.1 blockers and KCa2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges.

Associations between mental health challenges, sexual activity, alcohol consumption, use of other psychoactive substances and use of COVID-19 preventive measures during the first wave of the COVID-19 pandemic by adults in Nigeria.

BACKGROUND: The aims of this study were to assess: 1) the associations among sexual activity, alcohol consumption, use of other psychoactive substances and mental health during the COVID-19 pandemic; and 2) the associations between COVID-19 preventive measures, alcohol consumption and use of psychoactive substances. METHODS: This was a secondary analysis of data collected from adults in Nigeria between July and December 2020. The variables extracted included change in sexual activity, alcohol consumption and use of other psychoactive substances, COVID-19 preventive behaviors (wearing face masks, washing hands, physical distancing), anxiety, depression, post-traumatic stress disorder (PTSD) and sociodemographic variables (age, sex, education, HIV status, employment status). Multivariable logistic regressions were conducted. A model was run to regress depression, anxiety, PTSD, increased alcohol consumption, and increased use of other psychoactive substances, on increased sexual activity. In separate models, anxiety, depression, and PTSD were regressed on increased alcohol consumption and on increased use of other psychoactive substances. Finally, three models were constructed to determine the associations between increased alcohol consumption and increased use of other psychoactive substances on three separate COVID-19 preventive behaviors. All models were adjusted for sociodemographic variables. RESULTS: Increased alcohol consumption (AOR:2.19) and increased use of other psychoactive substances (AOR: 3.71) were significantly associated with higher odds of increased sexual activity. Depression was associated with significantly higher odds of increased alcohol consumption (AOR:1.71) and increased use of other psychoactive substances (AOR:3.21). Increased alcohol consumption was associated with significantly lower odds of physical distancing (AOR:0.59). CONCLUSION: There was a complex inter-relationship between mental health, sexual health, increased use of psychoactive substances. The consumption of alcohol also affected compliance with physical distancing. Further studies are needed to understand the observed relationships.

DNA Damage Response-Related Proteins Are Prognostic for Outcome in Both Adult and Pediatric Acute Myelogenous Leukemia Patients: Samples from Adults and from Children Enrolled in a Children's Oncology Group Study.

The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and 296 strictly validated antibodies, respectively, including those detecting the expression of proteins directly involved in DDR. Unbiased hierarchical clustering identified strong recurrent DDR protein expression patterns in both adult and pediatric AML. Globally, DDR expression was associated with gene mutational statuses and was prognostic for outcomes including overall survival (OS), relapse rate, and remission duration (RD). In adult patients, seven DDR proteins were individually prognostic for either RD or OS. When DDR proteins were analyzed together with DDR-related proteins operating in diverse cellular signaling pathways, these expanded groupings were also highly prognostic for OS. Analysis of patients treated with either conventional chemotherapy or venetoclax combined with a hypomethylating agent revealed protein clusters that differentially predicted favorable from unfavorable prognoses within each therapy cohort. Collectively, this investigation provides insight into variable DDR pathway activation in AML and may help direct future individualized DDR-targeted therapies in AML patients.

Reverse Phase Protein Array Profiling Identifies Recurrent Protein Expression Patterns of DNA Damage-Related Proteins across Acute and Chronic Leukemia: Samples from Adults and the Children's Oncology Group.

DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL (n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly (p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences.

Nursing for the Chthulucene: Abolition, affirmation, antifascism.

Critical posthumanism as a philosophical, antifascist nonhierarchical imagination for nursing offers a liberatory passageway forward amidst environmental collapse, an epic pandemic, global authoritarianism, extreme health and wealth disparities, over-reliance on technology and empirics, and unjust societal systems based in whiteness. Drawing upon philosophical and theoretical works from Black and Indigenous scholars, Haraway's idea of the Chthulucene, Deleuze and Guattari's rhizomatic thought, and Kaba's abolitionist organizing among others, we as activist nurse scholars continue the speculative discussion outlined in prior papers. Here we further imagine how we can engage a radical philosophical mission of care for all beings human and non, walking and working alongside the people and communities nurses accompany, connected as we are on this dystopian celestial orb. Discussion is centred on critical analyses of traditional justice framing in nursing, and on the praxis possibilities found within rhizomatic thought, making kin, and just episteme while knitting filaments of nursing theory and history, humming song lyrics from collective memory, and critically dismantling received wisdoms to stumble toward a more emancipatory present future.

Mattering: Per/forming nursing philosophy in the Chthulucene.

This paper presents an overview of the process of entanglement at the 25th International Philosophy of Nursing Conference (IPNC) at University of California at Irvine held on August 18, 2022. Representing collective work from the US, Canada, UK and Germany, our panel entitled 'What can critical posthuman philosophies do for nursing?' examined critical posthumanism and its operations and potential in nursing. Critical posthumanism offers an antifascist, feminist, material, affective, and ecologically entangled approach to nursing and healthcare. Rather than focusing on the arguments of each of the three distinct but interrelated panel presentation pieces, this paper instead focuses on process and performance (per/formance) and performativity as relational, connected and situated, with connections to nursing philosophy. Building upon critical feminist and new materialist philosophies, we describe intra-activity and performativity as ways to dehierarchise knowledge making practices within traditional academic conference spaces. Creating critical cartographies of thinking and being are actions of possibility for building more just and equitable futures for nursing, nurses, and those they accompany-including all humans, nonhumans, and more than human matter.

Attitudes Toward Payment for Research Participation: Results from a U.S. Survey of People Living with HIV.

Little is known about how payment affects individuals' decisions to participate in HIV research. Using data from a U.S. survey of people living with HIV (N = 292), we examined potential research participants' attitudes toward payment, perceived study risk based on payment amount, and preferred payment forms, and how these factors vary by sociodemographic characteristics. Most respondents agreed people should be paid for HIV research participation (96%) and said payment would shape their research participation decisions (80%). Men, less formally educated individuals, and members of some minoritized racial-ethnic groups were less likely to be willing to participate in research without payment. Higher payment was associated with higher perceived study risks, while preferences for form of payment varied by age, gender, education, race-ethnicity, and census region of residence. Findings suggest payment may influence prospective research participants' risk-benefit calculus and participation, and that a one-size-fits-all approach to payment could differentially influence participation among distinct sociodemographic groups.

RESUMEN: Se sabe poco acerca de cómo el pago afecta a la decisión de participar en investigaciones sobre VIH. Utilizando data de una encuesta de Estados Unidos sobre personas viviendo con VIH (N = 292), se examinó la actitud de potenciales participantes de investigación acerca del pago, el riesgo de estudio percibido basado en la cantidad del pago, las formas de pago preferidas y cómo estos factores varían según las características sociodemográficas. La mayoría de los que respondieron la encuesta estuvieron de acuerdo en que las personas debían recibir un pago por participar en una investigación sobre VIH (96%) y dijeron que el pago podría moldear su decisión de participar en la investigación (80%). Los hombres, individuos con menor educación formal y los miembros de algún grupo racial-étnico minoritario se mostraron menos propensos a participar en una investigación sin recibir pago. Se asoció un pago más alto con una mayor percepción de riesgos en el estudio, mientras que las preferencias por las formas de pago variaron según la edad, el género, la educación, la raza-etnicidad y la región. Los resultados sugirieron que el pago podría influir en el cálculo del riesgo-beneficio y en la participación de los potenciales participantes en una investigación prospectiva, y que un enfoque único para el pago podría influir de manera diferencial entre los distintos grupos sociodemográficos en lo que respecta a su participación.