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Heather L Gelhorn,1 Beatrice Osumili,2 Katelyn Brown,2 Melissa M Ross,1 Andrea Schulz,1 Gabriela Fernandez,1 Kristina S Boye2 1Patient-Centered Research, Evidera, Inc., Bethesda, MD, USA; 2Value, Evidence, and Outcomes, Eli Lilly and Company, Indianapolis, IN, USACorrespondence: Heather L Gelhorn, Patient-Centered Research, Evidera, Inc., 7101 Wisconsin Avenue, Suite 1400, Bethesda, MD, 20814, USA, Tel +1-970-363-7333, Email heather.gelhorn@evidera.comPurpose: To quantify the preferences of people with type 2 diabetes (T2D) for treatment attributes of a glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (RA) versus an injectable GLP-1 RA medication profile.Patients and Methods: Injection-naive people taking oral medications for T2D in the US and UK completed a web survey including a discrete choice experiment to quantify patients’ preferences for five treatment attributes: delivery system, frequency of nausea, frequency of hypoglycemia, HbA1c reduction, and weight reduction. Attributes and levels were based on head-to-head clinical trial data of tirzepatide 5mg, 10mg, and 15mg versus semaglutide 1mg. Preference data were analyzed separately by country using multinomial mixed logit (MXL) models. MXL parameters were used to estimate the predicted preference for each tirzepatide dose versus semaglutide 1mg. Direct preferences for each dose of tirzepatide versus semaglutide 1mg were elicited.Results: Participants (N=620) in the US (N=301) and UK (N=319) were 50.8% and 50.5% female with mean ages of 60.7 years and 58.9 years, respectively. The order and magnitude of relative attribute importance (RAI) scores differed between countries. HbA1c reduction (26.3%) had the greatest impact on US participants’ preferences, and hypoglycemia (32.8%) did among UK participants. Attribute-level marginal utility results indicated preferences for greater HbA1c improvements, the single-use pre-filled pen, lower hypoglycemia, greater weight reductions, and lower frequency of nausea. Assuming the availability of only tirzepatide or semaglutide 1mg, the predicted preference for tirzepatide (5, 10, and 15mg) in the US is 95.6% (vs 4.4% for semaglutide 1mg) and in the UK was 86.3% (vs 13.7% for semaglutide 1mg).Conclusion: HbA1c reduction, frequency of hypoglycemia, and weight reduction are key drivers of preferences among people with T2D when considering medication options. Overall, people with T2D are likely to prefer the tirzepatide over the semaglutide 1mg medication profiles.Keywords: patient preferences, discrete choice experiment, patient perspective, incretin

Heather L Gelhorn,1 Melissa M Ross,1 Shraddha Shinde,2 Vivian Thuyanh Thieu,3 Kristina S Boye2 1Patient-Centered Research, Evidera, Inc, Bethesda, MD, USA; 2Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, IN, USA; 3Global Medical Affairs, Eli Lilly and Company, Indianapolis, IN, USACorrespondence: Heather L Gelhorn, Patient-Centered Research, Evidera, Inc, 7101 Wisconsin Ave, Suite 1400, Bethesda, MD, 20814, USA, Tel +1-970-363-7333, Email heather.gelhorn@evidera.comPurpose: To understand the perspectives of people with type 2 diabetes (T2D) on safely reaching near normoglycemia, defined as a glycated hemoglobin A1c (HbA1c) value of < 6%. HbA1c indicates the average blood sugar level over the past few months.Patients and Methods: This cross-sectional online quantitative survey of people with T2D asked about the current impacts of T2D, the anticipated benefits of safely achieving near normoglycemia among participants with a current HbA1c ≥ 6%, or the actual benefits of safely achieving near normoglycemia among participants who had an HbA1c < 6%. Participants reported on specific areas of psychological/emotional impact of T2D and the psychological/emotional benefits of achieving near normoglycemia.Results: Participants (N = 1000; United States = 500 and United Kingdom = 500) were 53.1% male and had a mean age of 62.9 years (SD = 13.3). The majority reported that the current HbA1c ≥ 6% (81.2%) and 49.2% had been diagnosed more than 10 years ago. The vast majority of participants (> 90%) indicated that achieving near normoglycemia was meaningful, with 95% of the participants indicating that achieving near normoglycemia would be of somewhat or extreme importance to them. In total, 93.8% of participants with a current HbA1c ≥ 6% and 80.3% of those with a current HbA1c < 6% anticipated/reported having experienced improvements as a result of achieving near normoglycemia. Among those who experienced or anticipated positive psychological/emotional impacts (n = 247), the most commonly reported impacts included less worry about future diabetes-related complications (79.8%), feeling in control over one’s life (72.9%), and overall health-related quality of life (59.9%).Conclusion: Achieving near normoglycemia is both meaningful and important to the majority of people with T2D, including both those who have and those who have not experienced reaching near normoglycemia. A wide range of specific impacts, including psychological/emotional concepts, are experienced by people with T2D, many of which may be improved through achieving near normoglycemia.Keywords: burden of disease, emotional impact, patient perspective, psychological impact, quality of life

Family caregiving within institutional settings is a neglected area of research. In an era of cost containment, more and more is being asked offamilies of institutionalized persons. This article presents the results of a study designed to investigate family caregiving following the admission of an elderly relative to a longterm care facility. Beginning with a brief summary of findings from previous research, the article reports on visiting and task performance by families within the long-term care facility. Continuing with descriptions of families' satisfaction with institutional care and their care-related learning needs, the article concludes with recommendations for policy and practice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Musculoskeletal pain is a problem with which many seniors must contend, many on a daily basis. Little is known, however, of the self-care decisions that seniors make regarding the management and control of this pain. These decisions can influence in a significant manner the delivery of health care to seniors and their overall health and well-being. Purpose. The purpose of our exploratory-descriptive study was to investigate seniors' decision making regarding the management and control of musculoskeletal pain by gathering data about the context of decision making, the types of decisions seniors made, their decisional conflict and the resources they used in decision making. METHODS: Focus groups and a mail-back questionnaire were used. Data were gathered in 1997 from a convenience sample of 50 seniors in Canada who experienced musculoskeletal pain of a noteworthy nature. RESULTS: Findings revealed that participants made decisions within a context of ageing and the health and social consequences of advancing age. The types of decisions they made included to ignore their pain and to use distraction. They also used exercise, the application of heat and cold, and medications to manage pain. Decisional conflict was minimal and consultation with family and friends superseded that with professionals. CONCLUSIONS: This study contributed to knowledge of decision making in later life about health matters generally, and the management and control of pain specifically. Findings point to the resourcefulness of seniors with respect to self-care and decision making. Seniors want to make informed decisions. However, they need information about the risks and benefits of decisions. [ABSTRACT FROM AUTHOR]

Despite increasing evidence that pain is a problem with which many in their later years must contend, little is known about the experience of community-dwelling seniors who require the assistance of home nursing services to remain independent and functional in their homes. This study investigated the prevalence and experience of pain among seniors who were recipients of home nursing services. The study was guided by the World Health Organization Classification of Impairment, Disability and Handicap. Face to face interviews were conducted with 66 individuals who reported whether they were often troubled by pain and/or had experienced pain of a noteworthy nature within the 2 weeks prior to the interview. In addition, they responded to standardized questions about their pain experience and their levels of disability and functional competence. Findings revealed that although three-quarters of respondents reported pain, there was no association between pain and measures of disability. Findings, however, revealed an association between pain and measures of functional competence, more specifically, global function, level of depressive symptomatology, sleep impairment and satisfaction with life. Implications for nursing include the need for a heightened awareness of the prevalence of pain in community-dwelling older adults and the development of assessment and intervention strategies that support their quality of life. [ABSTRACT FROM AUTHOR]

This paper describes the process and outcomes of a study to develop a tool to measure nurses' knowledge of palliative care. The development of the palliative care quiz for nursing (PCQN) entailed the convening of an advisory committee, a wide process of consultation, the development of a conceptual framework, determination of format, generating of items and pre-testing, piloting and further testing of the quiz. The PCQN is a 20-item true, false and 'I don't know' test of knowledge that is easily administered and has utility for assessing knowledge, stimulating discussion and identifying misconceptions about palliative care nursing. [ABSTRACT FROM AUTHOR]

A large body of research reveals the contribution of families to the care of elderly and health-impaired community-dwelling individuals. Less is known about the contribution of families to the provision of care following the admission of elderly relatives to a long-term care institution. Still less is known of the experience of elderly wives following the institutionalization of their husbands. The purpose of this paper is to increase nurses' awareness, through a review of the literature on family caregiving in later life, of the contribution to care made by elderly wives following the institutionalization of their husbands. We also hope to provide direction for clinicians with respect to the needs and concerns of wives, particularly at the time of, and following, the admission of their husbands to long-term care institutions. [ABSTRACT FROM AUTHOR]

This paper seeks to demonstrate the significance of the time budget methodology for nursing as a means of exploring the use of time in later life and its relation to health and well-being. With increasing concern for quality of life issues, the use of time and the proportion of time that is allocated to specific domains of life become important life-style decisions that merit both personal concern and professional inquiry. The paper begins with a review of the time budget methodology and the research employing the time budget methodology dating back to the 1960s. It continues with a description of how people allocate and use their time in later life as revealed by these studies, and concludes with the significance of this method of inquiry for nursing. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the visiting experience of wives whose husbands had been admitted to a long-term care institution. The study employed a longitudinal and prospective design and combined qualitative and quantitative approaches. The data were drawn from a larger study designed to explore the transition to quasi-widowhood. This article reports on one aspect of spousal caregiving following the admission of a husband to a long-term care setting, i.e. visiting. In this study, wives visited frequently. Their reasons for visiting included love and devotion, duty and obligation, the monitoring of husbands' well-being and the provision of assistance to both husbands and staff. They engaged in task performance and social interaction during visiting. Their feelings of satisfaction and enjoyment with visiting were associated with their husbands' well-being and feeling useful. Over the 9-month period of the study, two patterns of visiting and involvement emerged that were associated with different outcomes related to depression, morale and satisfaction with institutional dimensions of care. [ABSTRACT FROM AUTHOR]

BACKGROUND: Non-invasive methods for diagnosis of urothelial carcinoma have reduced specificity in patients with non-malignant genitourinary disease or other disorders. We aimed to use mass spectrometry and bioinformatics to define and validate a cancer-specific proteomic pattern. METHODS: We used capillary-electrophoresis-coupled mass spectrometry to obtain polypeptide patterns from urine samples of 46 patients with urothelial carcinoma and 33 healthy volunteers. From signatures of polypeptide mass, we established a model for predicting the presence of cancer. The model was refined further by use of 366 urine samples obtained from other healthy volunteers and patients with malignant and non-malignant genitourinary disease. We estimated the proportion of correct classifications from the refined model by applying it to a masked group containing 31 patients with urothelial carcinoma, 11 healthy individuals, and 138 patients with non-malignant genitourinary disease. We also sequenced several diagnostic polypeptides for urothelial carcinoma. FINDINGS: We identified a diagnostic urothelial-carcinoma pattern of 22 polypeptide masses. On masked assessment, prediction models based on these polypeptides correctly classified all samples of urothelial carcinoma (sensitivity 100% [95% CI 87-100) and all healthy samples (specificity 100% [84-100]). Correct identification of patients with urothelial carcinoma from those with other malignant and non-malignant genitourinary disease ranged from 86% to 100%. A prominent polypeptide from the diagnostic pattern for urothelial carcinoma was identified as fibrinopeptide A-a known biomarker of ovarian cancer and gastric cancer. INTERPRETATION: Validation of a highly specific biomarker pattern for urothelial carcinoma in a large group of patients with various urological disorders could be used in the diagnosis of other diseases that are identified in urine samples or in other body fluids. [ABSTRACT FROM AUTHOR]

DELLA proteins are conserved master growth regulators that play a central role in controlling plant development in response to internal and environmental cues. DELLAs function as transcription regulators, which are recruited to target promoters by binding to transcription factors (TFs) and histone H2A via their GRAS domain. Recent studies showed that DELLA stability is regulated post-translationally via two mechanisms, phytohormone gibberellin-induced polyubiquitination for its rapid degradation, and Small Ubiquitin-like Modifier (SUMO)-conjugation to increase its accumulation. Moreover, DELLA activity is dynamically modulated by two distinct glycosylations: DELLA-TF interactions are enhanced by O-fucosylation, but inhibited by O-linked N-acetylglucosamine (O-GlcNAc) modification. However, the role of DELLA phosphorylation remains unclear as previous studies showing conflicting results ranging from findings that suggest phosphorylation promotes or reduces DELLA degradation to others indicating it has no effect on its stability. Here, we identify phosphorylation sites in REPRESSOR OF ga1-3 (RGA, an AtDELLA) purified from Arabidopsis by mass spectrometry analysis, and show that phosphorylation of two RGA peptides in the PolyS and PolyS/T regions enhances RGA activity by promoting H2A binding and RGA association with target promoters. Notably, phosphorylation does not affect RGA-TF interactions or RGA stability. Our study has uncovered a molecular mechanism of phosphorylation-induced DELLA activity., (© 2024. The Author(s).)

Objectives: To estimate the preferences of patients with asthma and asthma-treating clinicians for attributes of biologic treatments, to compare patients' and clinicians' preferences, and to better understand the reasons for their preferences., Methods: Adults with moderate-to-severe asthma and clinicians who treat asthma in the US completed a cross-sectional, online survey including a discrete choice experiment (DCE) that consisted of seven attributes spanning treatment efficacy, risk and convenience. Marginal utilities were estimated using a mixed logit model, and relative attribute importance scores calculated. Clinicians were also asked about the value of biomarker agnostic biologic treatments. The survey was followed by qualitative interviews targeting a sub-sample of survey participants, in which the rationale behind their survey responses was discussed., Results: In the DCE, both patients and clinicians placed the most importance on exacerbation and hospitalization rate reduction, and risk of injection site reaction. Patients valued location of administration more than clinicians. Rationale for individual-level preferences varied, with patients and clinicians reporting their preference depended on event frequency and anticipated quality of life impacts. Clinicians mentioned compliance and financial impacts, while patients mentioned personal experience, particularly around site reactions. Most patients and clinicians would value a biomarker agnostic asthma treatment., Conclusions: Asthma treatment preferences are largely driven by treatment efficacy and minimizing the risk of site reactions, although preferences differ between patients and clinicians across other attributes, highlighting the need for shared decision-making and individualized care.

Oligodendrocytes develop through sequential stages and understanding pathways regulating their differentiation remains an important area of investigation. Zinc is required for the function of enzymes, proteins and transcription factors, including those important in myelination and mitosis. Our previous studies using the ratiometric zinc sensor chromis-1 demonstrated a reduction in intracellular free zinc concentrations in mature MBP+ oligodendrocytes compared with earlier stages (Bourassa et al., 2018). We performed a more detailed developmental study to better understand the temporal course of zinc homeostasis across the oligodendrocyte lineage. Using chromis-1, we found a transient increase in free zinc after O4+,O1- pre-oligodendrocytes were switched from proliferation medium into terminal differentiation medium. To gather other evidence for dynamic regulation of free zinc during oligodendrocyte development, qPCR was used to evaluate mRNA expression of major zinc storage proteins metallothioneins (MTs) and metal regulatory transcription factor 1 (MTF1), which controls expression of MTs. MT1, MT2 and MTF1 mRNAs were increased several fold in mature oligodendrocytes compared to oligodendrocytes in proliferation medium. To assess the depth of the zinc buffer, we assayed zinc release from intracellular stores using the oxidizing thiol reagent 2,2'-dithiodipyridine (DTDP). Exposure to DTDP resulted in ∼ 100% increase in free zinc in pre-oligodendrocytes but, paradoxically more modest ∼ 60% increase in mature oligodendrocytes despite increased expression of MTs. These results suggest that zinc homeostasis is regulated during oligodendrocyte development, that oligodendrocytes are a useful model for studying zinc homeostasis in the central nervous system, and that regulation of zinc homeostasis may be important in oligodendrocyte differentiation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Hematopoietic stem cell transplantation (HSCT) is a common and effective treatment for multiple malignant and non-malignant pediatric conditions. Graft-versus-host disease (GVHD) is a common complication of HSCT that can be prevented with prophylactic use of calcineurin inhibitor (CNI) immunosuppressants. A complication of HSCT and CNI use is pericardial effusion (PEF), which is frequently treated by CNI discontinuation with or without surgical intervention. No studies to date have evaluated the management of PEF without CNI discontinuation as a means of preventing GVHD flares., Methods: In this single-center retrospective study, we reviewed the management of PEF in pediatric patients post-HSCT who received conservative or surgical intervention with or without CNI discontinuation between May 2012 and June 2022., Results: Of the patients found to have PEF, all were given tacrolimus for GVHD prophylaxis. Management of PEF included surgical intervention for 83% of patients, and CNI was not discontinued for 83%. None of the patients developed GVHD during the management of PEF., Conclusions: Our results demonstrate that continuation of CNI therapy for GVHD prophylaxis did not negatively impact the disease course of PEF in post-HSCT patients., (© 2023 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Zinc is a tightly regulated trace mineral element playing critical roles in growth, immunity, neurodevelopment, and synaptic and hormonal signaling. Although severe dietary zinc deficiency is relatively uncommon in the United States, dietary zinc deficiency is a substantial public health concern in low- and middle-income countries. Zinc status may be a key determinant of neurodevelopmental processes. Indeed, limited cohort studies have shown that serum zinc is lower in people diagnosed with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and depression. These observations have sparked multiple studies investigating the mechanisms underlying zinc status and neurodevelopmental outcomes. Animal models of perinatal and adult dietary zinc restriction yield distinct behavioral phenotypes reminiscent of features of ASD, ADHD, and depression, including increased anxiety and immobility, repetitive behaviors, and altered social behaviors. At the cellular and molecular level, zinc has demonstrated roles in neurogenesis, regulation of cellular redox status, transcription factor trafficking, synaptogenesis, and the regulation of synaptic architecture via the Shank family of scaffolding proteins. Although mechanistic questions remain, the current evidence suggests that zinc status is important for adequate neuronal development and may be a yet overlooked factor in the pathogenesis of several psychiatric conditions. This review aims to summarize current knowledge of the role of zinc in the neurophysiology of the perinatal period, the many cellular targets of zinc in the developing brain, and the potential consequences of alterations in zinc homeostasis in early life., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

An immortalized neural cell line derived from the human ventral mesencephalon, called ReNCell, and its MeCP2 knock out were used. With it, we characterized the chromatin compositional transitions undergone during differentiation, with special emphasis on linker histones. While the WT cells displayed the development of dendrites and axons the KO cells did not, despite undergoing differentiation as monitored by NeuN. ReNCell expressed minimal amounts of histone H1.0 and their linker histone complement consisted mainly of histone H1.2, H1.4 and H1.5. The overall level of histone H1 exhibited a trend to increase during the differentiation of MeCP2 KO cells. The phosphorylation levels of histone H1 proteins decreased dramatically during ReNCell's cell differentiation independently of the presence of MeCP2. Immunofluorescence analysis showed that MeCP2 exhibits an extensive co-localization with linker histones. Interestingly, the average size of the nucleus decreased during differentiation but in the MeCP2 KO cells, the smaller size of the nuclei at the start of differentiation increased by almost 40% after differentiation by 8 days (8 DIV). In summary, our data provide a compelling perspective on the dynamic changes of H1 histones during neural differentiation, coupled with the intricate interplay between H1 variants and MeCP2. Abbreviations : ACN, acetonitrile; A 230 , absorbance at 230 nm; bFGF, basic fibroblast growth factor; CM, chicken erythrocyte histone marker; CNS, central nervous system; CRISPR, clustered regulated interspaced short palindromic repeatsDAPI, 4,'6-diaminidino-2-phenylindole; DIV, days in vitro (days after differentiation is induced); DMEM, Dulbecco's modified Eagle medium; EGF, epidermal growth factor; ESC, embryonic stem cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic proteinHPLC, high-performance liquid chromatography; IF, immunofluorescence; iPSCs, induced pluripotent stem cells; MAP2, microtubule-associated protein 2; MBD, methyl-binding domain; MeCP2, methyl-CpG binding protein 2; MS, mass spectrometry; NCP, nucleosome core particle; NeuN, neuron nuclear antigen; NPC, neural progenitor cellPAGE, polyacrylamide gel electrophoresis; PBS, phosphate buffered saline; PFA, paraformaldehyde; PTM, posttranslational modification; RP-HPLC, reversed phase HPLC; ReNCells, ReNCells VM; RPLP0, ribosomal protein lateral stalk subunit P0; RT-qPCR, reverse transcription quantitative polymerase-chain reaction; RTT, Rett Syndrome; SDS, sodium dodecyl sulphate; TAD, topologically associating domain; Triple KO, triple knockout.

Introduction: Newer treatment options for relapsed/refractory multiple myeloma (RRMM) with efficacy and safety profiles that differ from traditional therapies have facilitated personalized management strategies to optimize patient outcomes. In the context of such personalized management, understanding how treatment characteristics influence patients' preferences is essential. This study assessed patients' preferences for RRMM treatment attributes and determined trade-offs between potential benefits, administration procedures, and adverse effects., Methods: Patients' preferences were evaluated using a discrete choice experiment (DCE). Patients with RRMM who reported failing two lines of anti-myeloma treatment (immunomodulatory agent and a proteasome inhibitor [PI]) or ≥ 3 lines (including ≥1 PI, immunomodulatory agent, or anti-CD38 monoclonal antibody), were recruited across the US, UK, Italy, Germany, France, and Spain. DCE attributes and levels were identified using a targeted literature review, a review of clinical data for relevant RRMM treatments, qualitative patient interviews, and input from clinical and myeloma patient experts. The DCE was administered within an online survey from February-June 2022. Preference data were analyzed using an error-component logit model and willingness to make trade-offs for potential benefits, and relative attribute importance scores were calculated., Results: Overall, 296 patients from the US ( n = 100), UK ( n = 49), Italy ( n = 45), Germany ( n = 43), France ( n = 39), and Spain ( n = 20) participated in the DCE. Mean (standard deviation) age was 63.8 (8.0) years, 84% had a caregiver, and patients had a median of 3 (range: 2-8) prior lines of therapy. Efficacy attributes most influenced patients' preferences, with increasing overall response rate (25-85%) and overall survival (6 months to 2 years) contributing to ~50% of treatment decision-making. Administration procedures were also considered important to patients. Avoiding individual side effects was considered relatively less important, with patients willing to tolerate increases in side effects for gains in efficacy. Patient characteristics such as rate of disease progression, sociodemographics, or clinical characteristics also influenced treatment preferences., Conclusion: Patients with RRMM were willing to tolerate increased risk of side effects for higher efficacy. Preferences and risk tolerance varied between patients, with preference patterns differing by certain patient characteristics. This highlights the importance of shared decision-making for optimal treatment selection and patient outcomes., Competing Interests: CT, MR, SM, NK, and HG are salaried employees of Evidera who received funding from GSK to conduct this study. MR and HG hold shares in Evidera. SA reports consultancy for Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, Janssen, GSK, Pharmacyclics, Regeneron, Sanofi, and Takeda and has research funding from, AbbVie, Amgen, Ascentage Pharma, Bristol Myers Squibb, Cellectar, Janssen, GSK, Medimmune, Pharmacyclics, and Xencor. RP reports personal fees and non-financial support from Janssen, Celgene, and GSK and personal fees from AbbVie. DK reports consultancy for GSK and Triphase Accelerator Corporation and has management, advisory roles, and an ownership interest in Calm Water Therapeutics LLC. BG, MH, and SP are employees of and hold stocks and shares in GSK. AO’N and AM are employees of GSK. PP was an employee of GSK at the time this analysis was completed and currently hold stocks and shares in GSK., (Copyright © 2023 Thomas, Ailawadhi, Popat, Kleinman, Ross, Gorsh, Mulnick, O’Neill, Paka, Hanna, Krucien, Molinari, Gelhorn and Perera.)

Copper is an essential enzyme cofactor in oxidative metabolism, anti-oxidant defenses, and neurotransmitter synthesis. However, intracellular copper, when improperly buffered, can also lead to cell death. Given the growing interest in the use of copper in the presence of the ionophore elesclomol (CuES) for the treatment of gliomas, we investigated the effect of this compound on the surround parenchyma-namely neurons and astrocytes in vitro. Here, we show that astrocytes were highly sensitive to CuES toxicity while neurons were surprisingly resistant, a vulnerability profile that is opposite of what has been described for zinc and other toxins. Bolstering these findings, a human astrocytic cell line was similarly sensitive to CuES. Modifications of cellular metabolic pathways implicated in cuproptosis, a form of copper-regulated cell death, such as inhibition of mitochondrial respiration or knock-down of ferredoxin 1 (FDX1), did not block CuES toxicity to astrocytes. CuES toxicity was also unaffected by inhibitors of apoptosis, necrosis or ferroptosis. However, we did detect the presence of lipid peroxidation products in CuES-treated astrocytes, indicating that oxidative stress is a mediator of CuES-induced glial toxicity. Indeed, treatment with anti-oxidants mitigated CuES-induced cell death in astrocytes indicating that oxidative stress is a mediator of CuES-induced glial toxicity. Lastly, prior induction of metallothioneins 1 and 2 in astrocytes with zinc plus pyrithione was strikingly protective against CuES toxicity. As neurons express high levels of metallothioneins basally, these results may partially account for their resistance to CuES toxicity. These results demonstrate a unique toxic response to copper in glial cells which contrasts with the cell selectivity profile of zinc, another biologically relevant metal., (© 2023 International Society for Neurochemistry.)

Interactions between AMPA receptors and synaptic scaffolding proteins are key regulators of synaptic receptor density and, thereby, synapse strength. Shank3 is one such scaffolding protein with high clinical relevance, as genetic variants and deletions of this protein have been linked to autism spectrum disorder. Shank3 acts as a master regulator of the postsynaptic density of glutamatergic synapses, interacting with ionotropic and metabotropic glutamate receptors and cytoskeletal elements to modulate synaptic structure. Notably, Shank3 has been shown to interact directly with the AMPAR subunit GluA1, and Shank3 knockout animals show deficits in AMPAR-mediated synaptic transmission. In this study, we sought to characterize the stability of GluA1-Shank3 interaction in response to chronic stimuli using a highly sensitive and specific proximity ligation assay. We found that GluA1-Shank3 interactions decrease in response to prolonged neuronal depolarization induced by elevated extracellular potassium, and that this reduced interaction is blocked by NMDA receptor antagonism. These results firmly establish the close interaction of GluA1 and Shank3 in cortical neurons in vitro, and that this select interaction is subject to modulation by depolarization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Diacylglycerol kinases (DGKs) are metabolic kinases involved in regulating cellular levels of diacylglycerol and phosphatidic lipid messengers. The development of selective inhibitors for individual DGKs would benefit from discovery of protein pockets available for inhibitor binding in cellular environments. Here we utilized a sulfonyl-triazole probe (TH211) bearing a DGK fragment ligand for covalent binding to tyrosine and lysine sites on DGKs in cells that map to predicted small molecule binding pockets in AlphaFold structures. We apply this chemoproteomics-AlphaFold approach to evaluate probe binding of DGK chimera proteins engineered to exchange regulatory C1 domains between DGK subtypes (DGKα and DGKζ). Specifically, we discovered loss of TH211 binding to a predicted pocket in the catalytic domain when C1 domains on DGKα were exchanged that correlated with impaired biochemical activity as measured by a DAG phosphorylation assay. Collectively, we provide a family-wide assessment of accessible sites for covalent targeting that combined with AlphaFold revealed predicted small molecule binding pockets for guiding future inhibitor development of the DGK superfamily., Competing Interests: K.-L. H. is a founder and scientific advisory board member of Umbra Therapeutics., (This journal is © The Royal Society of Chemistry.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common class of drugs utilized for a variety of disorders, including headaches, pain states, fever, and other common conditions. In recent years, a link between NSAIDs and adverse effects has been identified, including renal, heart, and liver disease, bleeding, and increased mortality. NSAID-mediated renal disease is associated with interference with the cyclooxygenase enzyme. Literature evaluating NSAID renal effects has indicated that a number of factors are associated with acute and chronic kidney injury (AKI). Early diagnosis can identify changes in renal function and allow for cessation of NSAID use, limiting the risk for long-term chronic renal disease and in some cases reversal of renal injury. Alternative medications should be considered in those patients identified with morbidity linked to NSAID use. Nephrotoxicity is increased in the elderly population and in hypovolemia, high dose exposure, use of vasoconstrictors such as calcineurin inhibitors, and use of renin-angiotensin-aldosterone system (RAAS) inhibitors or diuretics. Careful risk/benefit considerations from healthcare professionals can limit the incidence and degree of morbidity and mortality, including in NSAID-mediated renal disease. Selective NSAID cyclooxygenase-2 inhibitors also possess risks and therefore clinicians should always recommend short-term courses of this class of drugs versus long-term dosing because of the risk of morbidity and mortality. Given that these drugs are available over the counter as well by prescribing, clinicians must communicate the risks and benefits of NSAIDs and provide sound recommendations to their patients regarding use short and long term., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background and Aims: Healthcare workers (HCWs) throughout the world have been exposed to economic and existential stress during the Covid-19 pandemic. The American Medical Association (AMA) has documented that increased healthcare burden correlates with increased stress, burnout, and psychological burden in HCWs. However, limits on personnel, time, and in person interactions make it challenging to assess mental health outcomes during a pandemic. This pilot study used virtual technology to efficiently assess these outcomes., Setting: Data were collected based on voluntary participation in the Coping with Covid-19 for Caregivers Survey created by AMA. The survey was sent out to approximately 300 participants who included local physicians, medical residents, medical students, and allied health professionals and students who attended a virtual Mental Health Summit., Methods: The AMA developed survey included questions about demographics, overall stress, fear of infection and transmission of the virus, perceived anxiety or depression due to Covid-19, work overload, childcare issues, and sense of meaning and purpose. The AMA allows for up to five additional questions to be added to their survey, therefore five questions regarding support service utilization, perseverance, and resilience during the Covid-19 pandemic, and two items to further understand students' areas of medical interest. The survey was administered using an online platform through the AMA. The data were analyzed using descriptive statistics., Results: There were 81 survey respondents. Based on the results of the survey, "high stress" was found in 52 (64%) participants. 66 (81%) were afraid (moderately or to a great extent) of exposure or transmission, 61 (75%) described high levels of anxiety or depression, and 67 (84%) noted work overload. Despite this increase in stress, most respondents (77%) said they were not likely to reduce their devoted hours to clinical care or research in the next 12 months, and 81% answered that they would not leave their practice or research within two years., Conclusion: Covid-19 has negatively affected the well-being of HCWs. This is a similar trend seen during other times of healthcare strain. Mental health support, work modulation, and various provisions should be explored as means to reduce Covid-19-related negative impacts. The use of an online summit and online data collection methods were appropriate for collecting data on the impact of the Covid-19 pandemic on mental health. This pilot study supports the larger scale implementation of this technology for health informatics research., (© 2022 Elsevier Masson SAS. All rights reserved.)

Background: Emerging blood-based multi-cancer early detection (MCED) tests can detect a variety of cancer types across stages with a range of sensitivity, specificity, and ability to predict the origin of the cancer signal. However, little is known about the general US population's preferences for MCED tests., Objective: To quantify preferences for MCED tests among US adults aged 50-80 years using a discrete choice experiment (DCE)., Methods: To quantify preferences for attributes of blood-based MCED tests, an online DCE was conducted with five attributes (true positives, false negatives, false positives, likelihood of the cancer type unknown, number of cancer types detected), among the US population aged 50-80 years recruited via online panels and social media. Data were analyzed using latent class multinomial logit models and relative attribute importance was obtained., Results: Participants (N = 1700) were 54% female, mean age 63.3 years. Latent class modeling identified three classes with distinct preferences for MCED tests. The rank order of attribute importance based on relative attribute importance varied by latent class, but across all latent classes, participants preferred higher accuracy (fewer false negatives and false positives, more true positives) and screenings that detected more cancer types and had a lower likelihood of cancer type unknown. Overall, 72% of participants preferred to receive an MCED test in addition to currently recommended cancer screenings., Conclusions: While there is significant heterogeneity in cancer screening preferences, the majority of participants preferred MCED screening and the accuracy of these tests is important. While the majority of participants preferred adding an MCED test to complement current cancer screenings, the latent class analyses identified a small (16%) and specific subset of individuals who value attributes differently, with particular concern regarding false-negative and false-positive test results, who are significantly less likely to opt-in., (© 2022. The Author(s).)

Zinc, loaded into glutamate-containing presynaptic vesicles and released into the synapse in an activity-dependent manner, modulates neurotransmission through its actions on postsynaptic targets, prominently via high-affinity inhibition of GluN2A-containing NMDA receptors. Recently, we identified a postsynaptic transport mechanism that regulates endogenous zinc inhibition of NMDARs. In this new model of zinc regulation, the postsynaptic transporter ZnT1 mediates zinc inhibition of NMDARs by binding to GluN2A. Through this interaction, ZnT1, a transporter that moves zinc from the cytoplasm to the extracellular domain, generates a zinc microdomain that modulates NMDAR-mediated neurotransmission. As ZnT1 expression is transcriptionally driven by the metal-responsive transcription factor 1 (MTF-1), we found that intracellular zinc strongly drives MTF-1 in cortical neurons in vitro and increases the number of GluN2A-ZnT1 interactions, thereby enhancing tonic zinc inhibition of NMDAR-mediated currents. Importantly, this effect is absent when the interaction between GluN2A and ZnT1 is disrupted by a cell-permeable peptide. These results suggest that zinc-regulated gene expression can dynamically regulate NMDAR-mediated synaptic processes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Drs. Aizenman and Tzounopoulos have submitted a patent application for the peptide N2AZ: “PEPTIDES THAT ENHANCE NMDA RECEPTOR FUNCTION AND USE THEREOF;” Application No. PCT/US2020/063016, filed December 3, 2020., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Male sexual dysfunction is a series of conditions, most notably including erectile dysfunction (ED), Peyronie's disease (PD), and premature ejaculation (PE), defined by impaired sexual functioning. The prevalence of male sexual dysfunction increases with age and is relatively high with greater than 50% of men aged 40 to 70 describing some degree of erectile dysfunction. Risk factors for male sexual dysfunction include age, diabetes mellitus (DM), cancer, stroke, hypertension, penile trauma, depression, anxiety, and disturbance in central serotonin neurotransmission and 5-HT postsynaptic receptor functioning. Sexual questionnaires including the International Index of Erectile Dysfunction, Sexual Health Inventory for Men, and the Premature Ejaculation Diagnostic Tool are useful in screening for these disorders. Focused history and physical can establish diagnoses. For a condition to be diagnosed as male sexual dysfunction, the patient or their partner must view their sexual functioning as impaired. Treatment of male sexual dysfunction is etiology dependent. For ED, first-line therapy is a phosphodiesterase-5 inhibitor or mental health care for psychogenic ED. More complicated cases may be treated with injections, surgery, or shockwave therapy. PD is either treated with medications for pain management, collagenase clostridium histolyticum injection, corpoplasty, plication, or shockwave therapy. PE may be treated behaviorally or with SSRIs as first line medication.

Chemical proteomics is widely used for the global investigation of protein activity and binding of small molecule ligands. Covalent probe binding and inhibition are assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to gain molecular information on targeted proteins and probe-modified sites. The identification of amino acid sites modified by large complex probes, however, is particularly challenging because of the increased size, hydrophobicity, and charge state of peptides derived from modified proteins. These studies are important for direct evaluation of proteome-wide selectivity of inhibitor scaffolds used to develop targeted covalent inhibitors. Here, we disclose reverse-phase chromatography and MS dissociation conditions tailored for binding site identification using a clickable covalent kinase inhibitor containing a sulfonyl-triazole reactive group (KY-26). We applied this LC-MS/MS strategy to identify tyrosine and lysine sites modified by KY-26 in functional sites of kinases and other ATP-/NAD-binding proteins (>65 in total) in live cells. Our studies revealed key bioanalytical conditions to guide future chemical proteomic workflows for direct target site identification of complex irreversible probes and inhibitors.

Animal studies have demonstrated the therapeutic potential of polyphenol-rich pomegranate juice. We recently reported altered white matter microstructure and functional connectivity in the infant brain following in utero pomegranate juice exposure in pregnancies with intrauterine growth restriction (IUGR). This double-blind exploratory randomized controlled trial further investigates the impact of maternal pomegranate juice intake on brain structure and injury in a second cohort of IUGR pregnancies diagnosed at 24-34 weeks' gestation. Ninety-nine mothers and their eligible fetuses (n = 103) were recruited from Brigham and Women's Hospital and randomly assigned to 8 oz pomegranate (n = 56) or placebo (n = 47) juice to be consumed daily from enrollment to delivery. A subset of participants underwent fetal echocardiogram after 2 weeks on juice with no evidence of ductal constriction. 57 infants (n = 26 pomegranate, n = 31 placebo) underwent term-equivalent MRI for assessment of brain injury, volumes and white matter diffusion. No significant group differences were found in brain volumes or white matter microstructure; however, infants whose mothers consumed pomegranate juice demonstrated lower risk for brain injury, including any white or cortical grey matter injury compared to placebo. These preliminary findings suggest pomegranate juice may be a safe in utero neuroprotectant in pregnancies with known IUGR warranting continued investigation.Clinical trial registration: NCT04394910, https://clinicaltrials.gov/ct2/show/NCT04394910 , Registered May 20, 2020, initial participant enrollment January 16, 2016.

We evaluated a full-face snorkel mask with an airway circuit filter to protect health care providers against airborne pathogens. First, a quantified N95 fit test was performed using aerosolized saline. Second, cardiorespiratory variables (heart rate, peripheral oxygen saturation, end-tidal carbon dioxide tension, and inspired fraction of carbon dioxide) were measured at rest and during moderate exercise. The modified mask passed the United States Occupational Safety and Health Administration (OSHA) N95 respirator (N95) fit test requirements with a fit factor of 142. Neither hypercapnia nor hypoxemia occurred. This modified mask has the potential to protect providers who care for patients with coronavirus disease 2019 (COVID-19).