Structural basis for the tRNA-dependent activation of the terminal complex of selenocysteine synthesis in humans.

O-Phosphoseryl-tRNASec selenium transferase (SepSecS) catalyzes the terminal step of selenocysteine (Sec) synthesis in archaea and eukaryotes. How the Sec synthetic machinery recognizes and discriminates tRNASec from the tRNA pool is essential to the integrity of the selenoproteome. Previously, we suggested that SepSecS adopts a competent conformation that is pre-ordered for catalysis. Herein, using high-resolution X-ray crystallography, we visualized tRNA-dependent conformational changes in human SepSecS that may be a prerequisite for achieving catalytic competency. We show that tRNASec binding organizes the active sites of the catalytic protomer, while stabilizing the N- and C-termini of the non-catalytic protomer. Binding of large anions to the catalytic groove may further optimize the catalytic site for substrate binding and catalysis. Our biochemical and mutational analyses demonstrate that productive SepSecS•tRNASec complex formation is enthalpically driven and primarily governed by electrostatic interactions between the acceptor-, TΨC-, and variable arms of tRNASec and helices α1 and α14 of SepSecS. The detailed visualization of the tRNA-dependent activation of SepSecS provides a structural basis for a revised model of the terminal reaction of Sec formation in archaea and eukaryotes.

Nurses in health policy: Lessons learned from one cohort of the American Academy of Nursing Jonas Policy Scholars Program.

Nurses are underrepresented in health policy. The Jonas Policy Scholars Program is a vital and effective program that promotes mentoring, health policy, and engagement among early nurse researchers. The Jonas Policy Scholars Program should continue and be replicated by other organizations. Nurses must serve as health policy leaders within and beyond the field of nursing. Health policy content and immersion should be integrated throughout nursing education.

"I Just Need Proper Treatment": Being Hospitalized for Endocarditis among Individuals Who Inject Drugs Being Hospitalized for Endocarditis.

BACKGROUND: Rates of hospitalization for injection drug use-associated infective endocarditis (IDU-IE) are increasing. Much is known about the poor outcomes of patients with IDU-IE; less is known about the patient experience during hospitalization. OBJECTIVE: To explore the experience of being hospitalized for endocarditis among individuals who inject drugs, providing a foundation on which to develop strategies to improve care for these patients. DESIGN: Qualitative interviews with hospitalized patients undergoing cardiothoracic surgery with a history of injection drug use between February 2021 and May 2022 at the Hospital of the University of Pennsylvania. PARTICIPANTS: Cardiothoracic surgery patients with a documented history of injection drug use and the ability to speak English were recruited during their hospital stay. APPROACH: Thematic analysis of interviews guided by phenomenology and harm reduction theory was used to identify recurrent themes. Interviews were digitally recorded and transcribed and analyzed using NVIVO software. KEY RESULTS: Interviews from 13 participants resulted in four major themes around Hospital Experience: (1) Kindness as an Antidote to Dehumanizing Treatment; (2) Relationships with the Care Team; (3) Withdrawal and Pain Management; and (4) Anticipating and Experiencing the Transition out the Hospital. Participants recounted long histories of dehumanizing care during previous hospitalizations, noted the value of open, sincere, and non-judgmental communication with clinical teams, expressed overall satisfaction with the management of their symptoms during the current hospitalization, reported self-discharging during previous hospitalizations due to undertreated pain and withdrawal, and noted significant challenges around discharge planning and execution. CONCLUSIONS: Participants noted structural (e.g., discharge planning) and interpersonal (e.g., stigma from care team) barriers to quality hospital care. They also noted that expressions of kindness from hospital staff were meaningful and comforting. Patients with IDU-IE face multi-dimensional challenges in the hospital. Their perspectives can meaningfully inform programs and initiatives to improve their outcomes and support recovery.

Specific RNA interactions promote TDP-43 multivalent phase separation and maintain liquid properties.

TDP-43 is an RNA-binding protein that forms ribonucleoprotein condensates via liquid-liquid phase separation (LLPS) and regulates gene expression through specific RNA interactions. Loss of TDP-43 protein homeostasis and dysfunction are tied to neurodegenerative disorders, mainly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Alterations of TDP-43 LLPS properties may be linked to protein aggregation. However, the mechanisms regulating TDP-43 LLPS are ill-defined, particularly how TDP-43 association with specific RNA targets regulates TDP-43 condensation remains unclear. We show that RNA binding strongly promotes TDP-43 LLPS through sequence-specific interactions. RNA-driven condensation increases with the number of adjacent TDP-43-binding sites and is also mediated by multivalent interactions involving the amino and carboxy-terminal TDP-43 domains. The physiological relevance of RNA-driven TDP-43 condensation is supported by similar observations in mammalian cellular lysate. Importantly, we find that TDP-43-RNA association maintains liquid-like properties of the condensates, which are disrupted in the presence of ALS-linked TDP-43 mutations. Altogether, RNA binding plays a central role in modulating TDP-43 condensation while maintaining protein solubility, and defects in this RNA-mediated activity may underpin TDP-43-associated pathogenesis.

"There's absolutely no downside to this, I mean, except community opposition:" A qualitative study of the acceptability of vending machines for harm reduction.

BACKGROUND: Vending machines for harm reduction (VMHR) are an innovative approach to deliver life-saving materials, information, and treatment for hard-to-reach populations, particularly for persons who inject drugs. The current study explores stakeholders' perspectives on the feasibility and acceptability of VMHR in Philadelphia. METHODS: From October 2021 to February 2022, we conducted 31 semi-structured interviews with potential end users, staff, and leadership at a local federally qualified health center, and community members. Trained coders extracted themes from interview transcripts across four key domains: materials and logistics, location, access, and community introduction. RESULTS: Interviewees from all stakeholder groups endorsed using VMHR to provide supplies for wound care, fentanyl test strips, naloxone, and materials to connect individuals to treatment and other services. Dispensing syringes and medications for opioid use disorder were commonly endorsed by health center staff but were more controversial among potential end users. Even within stakeholder groups, views varied with respect to where to locate the machines, but most agreed that the machine should be placed in the highest drug use areas. Across stakeholder groups, interviewees suggested several strategies to introduce and gain community acceptance of VMHR, including community education, one-on-one conversations with community members, and coupling the machine with safe disposal of syringes and information to link individuals to treatment. CONCLUSIONS: Stakeholders were generally receptive to VMHR. The current study findings are consistent with qualitative analyses from outside of the USA and contribute new ideas regarding the anticipated community response and best methods for introducing these machines to a community. With thoughtful planning and design, VMHR could be a feasible and acceptable modality to reduce death and disease transmission associated with the opioid and HIV epidemics in cities like Philadelphia.

Perspectives and corrective processes: Evaluating social justice in a nursing PhD program.

Efforts to integrate tenets of social justice into PhD nursing programs are long-standing but have intensified in the past few years in response to civil unrest, threats to human rights, and health inequities exacerbated during the COVID-19 pandemic. In this paper, we present an overview of our School of Nursing's efforts and processes to evaluate and ensure that social justice principles were reflected throughout the PhD program. Components of this initiative included (a) forming a Social Justice Taskforce, (b) conducting listening sessions with alumni and currently enrolled PhD students to understand student experiences, (c) surveying PhD students to aid in prioritization of recommendations for improvement, and (d) convening key stakeholders to connect student priority areas to institutional programs and practices. Lessons learned through these activities highlighted the importance of gaining the perspective of diverse constituents and stakeholders, acknowledging areas for improvement, engaging students in transformative action, and partnering with faculty, staff, and leaders in solution development as we work to eliminate systemic injustices in PhD nursing education.

Racial Disparities in Stroke Readmissions Reduced in Hospitals With Better Nurse Staffing.

BACKGROUND: Racial minorities are disproportionately affected by stroke, with Black patients experiencing worse poststroke outcomes than White patients. A modifiable aspect of acute stroke care delivery not yet examined is whether disparities in stroke outcomes are related to hospital nurse staffing levels. OBJECTIVES: The aim of this study was to determine whether 7- and 30-day readmission disparities between Black and White patients were associated with nurse staffing levels. METHODS: We conducted a secondary analysis of 542 hospitals in four states. Risk-adjusted, logistic regression models were used to determine the association of nurse staffing with 7- and 30-day all-cause readmissions for Black and White ischemic stroke patients. RESULTS: Our sample included 98,150 ischemic stroke patients (87% White, 13% Black). Thirty-day readmission rates were 10.4% (12.7% for Black patients, 10.0% for White patients). In models accounting for hospital and patient characteristics, the odds of 30-day readmissions were higher for Black than White patients. A significant interaction was found between race and nurse staffing, with Black patients experiencing higher odds of 30- and 7-day readmissions for each additional patient cared for by a nurse. In the best-staffed hospitals (less than three patients per nurse), Black and White stroke patients' disparities were no longer significant. DISCUSSION: Disparities in readmissions between Black and White stroke patients may be linked to the level of nurse staffing in the hospitals where they receive care. Tailoring nurse staffing levels to meet the needs of Black ischemic stroke patients represents a promising intervention to address systemic inequities linked to readmission disparities among minority stroke patients.

Hospital nurses' moral distress and mental health during COVID-19.

AIMS: To explore factors associated with nurses' moral distress during the first COVID-19 surge and their longer-term mental health. DESIGN: Cross-sectional, correlational survey study. METHODS: Registered nurses were surveyed in September 2020 about their experiences during the first peak month of COVID-19 using the new, validated, COVID-19 Moral Distress Scale for Nurses. Nurses' mental health was measured by recently experienced symptoms. Analyses included descriptive statistics and regression analysis. Outcome variables were moral distress and mental health. Explanatory variables were frequency of COVID-19 patients, leadership communication and personal protective equipment/cleaning supplies access. The sample comprised 307 nurses (43% response rate) from two academic medical centres. RESULTS: Many respondents had difficulty accessing personal protective equipment. Most nurses reported that hospital leadership communication was transparent, effective and timely. The most distressing situations were the transmission risk to nurses' family members, caring for patients without family members present, and caring for patients dying without family or clergy present. These occurred occasionally with moderate distress. Nurses reported 2.5 days each in the past week of feeling anxiety, withdrawn and having difficulty sleeping. Moral distress decreased with effective communication and access to personal protective equipment. Moral distress was associated with longer-term mental health. CONCLUSION: Pandemic patient care situations are the greatest sources of nurses' moral distress. Effective leadership communication, fewer COVID-19 patients, and access to protective equipment decrease moral distress, which influences longer-term mental health. IMPACT: Little was known about the impact of COVID-19 on nurses' moral distress. We found that nurses' moral distress was associated with the volume of care for infected patients, access to personal protective equipment, and communication from leaders. We found that moral distress was associated with longer-term mental health. Leaders should communicate transparently to decrease nurses' moral distress and the negative effects of global crises on nurses' longer-term mental health.

Interventions for hospitalized medical and surgical patients with opioid use disorder: A systematic review.

Background: Concurrent with the opioid overdose crisis there has been an increase in hospitalizations among people with opioid use disorder (OUD), with one in ten hospitalized medical or surgical patients having comorbid opioid-related diagnoses. We sought to conduct a systematic review of hospital-based interventions, their staffing composition, and their impact on outcomes for patients with OUD hospitalized for medical or surgical conditions. Methods: Authors searched PubMed MEDLINE, PsychINFO, and CINAHL from January 2015 through October 2020. The authors screened 463 titles and abstracts for inclusion and reviewed 96 full-text studies. Seventeen articles met inclusion criteria. Extracted were study characteristics, outcomes, and intervention components. Methodological quality was evaluated using the Methodological Quality Rating Scale. Results: Ten of the 17 included studies were controlled retrospective cohort studies, five were uncontrolled retrospective studies, one was a prospective quasi-experimental evaluation, and one was a secondary analysis of a completed randomized clinical trial. Intervention components and outcomes varied across studies. Outcomes included in-hospital initiation and post-discharge connection to medication for OUD, healthcare utilization, and discharge against medical advice. Results were mixed regarding the impact of existing interventions on outcomes. Most studies focused on linkage to medication for OUD during hospitalization and connection to post-discharge OUD care. Conclusions: Given that many individuals with OUD require hospitalization, there is a need for OUD-related interventions for this patient population. Interventions with the best evidence of efficacy facilitated connection to post-discharge OUD care and employed an Addiction Medicine Consult model.

Care Quality, Patient Safety, and Nurse Outcomes at Hospitals Serving Economically Disadvantaged Patients: A Case for Investment in Nursing.

We sought to evaluate if better work environments or staffing were associated with improvements in care quality, patient safety, and nurse outcomes across hospitals caring for different proportions of patients who are economically disadvantaged. Few actionable approaches for hospitals with quality and resource deficits exist. One solution may be to invest in the nurse work environment and staffing. This cross-sectional study utilized secondary data from 23,629 registered nurses in 503 hospitals from a four-state survey collected in 2005-2008. Each 10% increase in the proportion of patients who are economically disadvantaged was associated with 27% and 22% decreased odds of rating unit-level care quality as excellent and giving an "A" safety grade, respectively. Each 10% increase was also associated with 9%, 25%, and 11% increased odds of job dissatisfaction, intent to leave, and burnout, respectively. The work environment had the largest association with each outcome. Accounting for the nurse work environment lessened or eliminated the negative outcomes experienced at hospitals serving high proportions of patients who are economically disadvantaged. Leaders at hospitals serving high proportions of patients who are economically disadvantaged, as well as state and federal policymakers, should work to improve quality, safety, and nurse outcomes by strengthening nurse work environments. Improving work environments highlights the role of nursing in the health care system, and policies focused on work environments are needed to improve the experiences of patients and nurses, especially at hospitals that care for many patients who are economically disadvantaged.

Is Hospital Nurse Staffing Legislation in the Public's Interest?: An Observational Study in New York State.

BACKGROUND: The Safe Staffing for Quality Care Act under consideration in the New York (NY) state assembly would require hospitals to staff enough nurses to safely care for patients. The impact of regulated minimum patient-to-nurse staffing ratios in acute care hospitals in NY is unknown. OBJECTIVES: To examine variation in patient-to-nurse staffing in NY hospitals and its association with adverse outcomes (ie, mortality and avoidable costs). RESEARCH DESIGN: Cross-sectional data on nurse staffing in 116 acute care general hospitals in NY are linked with Medicare claims data. SUBJECTS: A total of 417,861 Medicare medical and surgical patients. MEASURES: Patient-to-nurse staffing is the primary predictor variable. Outcomes include in-hospital mortality, length of stay, 30-day readmission, and estimated costs using Medicare-specific cost-to-charge ratios. RESULTS: Hospital staffing ranged from 4.3 to 10.5 patients per nurse (P/N), and averaged 6.3 P/N. After adjusting for potential confounders each additional patient per nurse, for surgical and medical patients, respectively, was associated with higher odds of in-hospital mortality [odds ratio (OR)=1.13, P=0.0262; OR=1.13, P=0.0019], longer lengths of stay (incidence rate ratio=1.09, P=0.0008; incidence rate ratio=1.05, P=0.0023), and higher odds of 30-day readmission (OR=1.08, P=0.0002; OR=1.06, P=0.0003). Were hospitals staffed at the 4:1 P/N ratio proposed in the legislation, we conservatively estimated 4370 lives saved and $720 million saved over the 2-year study period in shorter lengths of stay and avoided readmissions. CONCLUSIONS: Patient-to-nurse staffing varies substantially across NY hospitals and higher ratios adversely affect patients. Our estimates of potential lives and costs saved substantially underestimate potential benefits of improved hospital nurse staffing.

Why Some Nurses Obtain Specialty Certification and Others Do Not.

OBJECTIVE: The aim of this study was to determine whether there are modifiable characteristics of nurses and hospitals associated with nurse specialty certification. BACKGROUND: Hospitals, nurses, and patients benefit from nurse specialty certification, but little actionable evidence guides administrators seeking higher hospital certification rates. METHODS: This is a cross-sectional, secondary data analysis of 20 454 nurses in 471 hospitals across 4 states. RESULTS: Rates of certified nurses varied significantly across hospitals. Higher odds of certification were associated with Magnet® recognition and better hospital work environments at the facility level, and with BSN education, unit type (most notably, oncology), older age, more years of experience, and full-time employment at the individual nurse level. CONCLUSION: Two strategies that hold promise for increasing nurse specialty certification are improving hospital work environments and preferentially hiring BSN nurses.

Comparing medication adherence using a smartphone application and electronic monitoring among patients with acute coronary syndrome.

AIM: The purpose of this study was to determine the extent of agreement between adherence measures obtained using two technological interventions, electronic monitoring (EM) and a smartphone application (App). BACKGROUND: Clinicians, patients, and researchers depend on valid measurements of medication adherence to inform the delivery of preemptive care when needed. Technology is routinely used for monitoring medication adherence in both clinical practice and research, yet there is a dearth of research comparing novel App based approaches to traditional approaches used for assessing medication adherence. METHODS: Adherence rates were captured on both the EM and the App for 3697 daily observations from 44 participants with acute coronary syndrome over 90 days immediately following discharge from acute care. For EM, adherence was measured using EM equipped pill bottles. For the App, adherence was measured by having participants upload daily photos to the App prior to taking their daily aspirin. Agreement was assessed using a Bland-Altman analysis. RESULTS: The mean adherence rate was higher on the App, 92%, than the EM, 78% (p < 0.001). The mean difference in adherence rates between these methods was 14% (95% Confidence Interval: -23%, -5%). CONCLUSIONS: These findings illustrate a lack of agreement between technological interventions used for measuring adherence in cardiovascular patient populations, with higher adherence rates observed with the App compared to EM. These findings are salient given the increased reliance on telehealth due to the ongoing COVID-19 pandemic.

Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation.

Aggregates of the RNA-binding protein TDP-43 (TAR DNA-binding protein) are a hallmark of the overlapping neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The process of TDP-43 aggregation remains poorly understood, and whether it includes formation of intermediate complexes is unknown. Here, we analyzed aggregates derived from purified TDP-43 under semidenaturing conditions, identifying distinct oligomeric complexes at the initial time points before the formation of large aggregates. We found that this early oligomerization stage is primarily driven by TDP-43's RNA-binding region. Specific binding to GU-rich RNA strongly inhibited both TDP-43 oligomerization and aggregation, suggesting that RNA interactions are critical for maintaining TDP-43 solubility. Moreover, we analyzed TDP-43 liquid-liquid phase separation and detected similar detergent-resistant oligomers upon maturation of liquid droplets into solid-like fibrils. These results strongly suggest that the oligomers form during the early steps of TDP-43 misfolding. Importantly, the ALS-linked TDP-43 mutations A315T and M337V significantly accelerate aggregation, rapidly decreasing the monomeric population and shortening the oligomeric phase. We also show that aggregates generated from purified TDP-43 seed intracellular aggregation detected by established TDP-43 pathology markers. Remarkably, cytoplasmic aggregate seeding was detected earlier for the A315T and M337V variants and was 50% more widespread than for WT TDP-43 aggregates. We provide evidence for an initial step of TDP-43 self-assembly into intermediate oligomeric complexes, whereby these complexes may provide a scaffold for aggregation. This process is altered by ALS-linked mutations, underscoring the role of perturbations in TDP-43 homeostasis in protein aggregation and ALS-FTD pathogenesis.

Linking the work environment to missed nursing care in labour and delivery.

AIM: To measure the association between the nurse work environment (NWE) and missed nursing care on labour and delivery (L&D) units. BACKGROUND: L&D units provide a sizable fraction of acute hospital services to a unique population that is a national and global priority. L&D nurses are the frontline providers during labour. Maternal morbidity and mortality may be influenced by the NWE and missed care. METHODS: This cross-sectional study utilized secondary data from 1,313 L&D staff nurses in 247 hospitals from a four-state nurse survey collected in 2005-2008. RESULTS: Half of nurses missed care (range: zero to 100% across hospitals). Nurses on average missed 1.25 of 10 activities. The most commonly missed activities were comforting/talking with patients and teaching/counselling. In better as compared to poor NWEs, the odds and frequency of missed care were significantly lower. CONCLUSIONS: L&D nurses routinely miss necessary nursing activities. Labouring women's psychosocial, comfort and educational needs are compromised most often, likely impacting quality and outcomes. Nurse communication with colleagues and managers about missed care is warranted. IMPLICATIONS FOR NURSING MANAGEMENT: The L&D NWE is modifiable and appears to influence missed care. Managers should discuss missed care with staff and measure their NWE to identify actionable weaknesses.

A Systematic Review of Care Needs for Surgical Patients with Chronic Opioid Use.

An understudied aspect of the opioid crisis with implications for nursing is care of hospitalized surgical patients with chronic opioid use. Care needs of these patients are not well understood. This systematic review identified salient care needs and explored the role of nursing in meeting these needs.

Heat Shock-induced Phosphorylation of TAR DNA-binding Protein 43 (TDP-43) by MAPK/ERK Kinase Regulates TDP-43 Function.

TAR DNA-binding protein (TDP-43) is a highly conserved and essential DNA- and RNA-binding protein that controls gene expression through RNA processing, in particular, regulation of splicing. Intracellular aggregation of TDP-43 is a hallmark of amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration. This TDP-43 pathology is also present in other types of neurodegeneration including Alzheimer's disease. We report here that TDP-43 is a substrate of MEK, a central kinase in the MAPK/ERK signaling pathway. TDP-43 dual phosphorylation by MEK, at threonine 153 and tyrosine 155 (p-T153/Y155), was dramatically increased by the heat shock response (HSR) in human cells. HSR promotes cell survival under proteotoxic conditions by maintaining protein homeostasis and preventing protein misfolding. MEK is activated by HSR and contributes to the regulation of proteome stability. Phosphorylated TDP-43 was not associated with TDP-43 aggregation, and p-T153/Y155 remained soluble under conditions that promote protein misfolding. We found that active MEK significantly alters TDP-43-regulated splicing and that phosphomimetic substitutions at these two residues reduce binding to GU-rich RNA. Cellular imaging using a phospho-specific p-T153/Y155 antibody showed that phosphorylated TDP-43 was specifically recruited to the nucleoli, suggesting that p-T153/Y155 regulates a previously unappreciated function of TDP-43 in the processing of nucleolar-associated RNA. These findings highlight a new mechanism that regulates TDP-43 function and homeostasis through phosphorylation and, therefore, may contribute to the development of strategies to prevent TDP-43 aggregation and to uncover previously unexplored roles of TDP-43 in cell metabolism.

Structural asymmetry of the terminal catalytic complex in selenocysteine synthesis.

Selenocysteine (Sec), the 21(st) amino acid, is synthesized from a serine precursor in a series of reactions that require selenocysteine tRNA (tRNA(Sec)). In archaea and eukaryotes, O-phosphoseryl-tRNA(Sec):selenocysteinyl-tRNA(Sec) synthase (SepSecS) catalyzes the terminal synthetic reaction during which the phosphoseryl intermediate is converted into the selenocysteinyl moiety while being attached to tRNA(Sec). We have previously shown that only the SepSecS tetramer is capable of binding to and recognizing the distinct fold of tRNA(Sec). Because only two of the four tRNA-binding sites were occupied in the crystal form, a question was raised regarding whether the observed arrangement and architecture faithfully recapitulated the physiologically relevant ribonucleoprotein complex important for selenoprotein formation. Herein, we determined the stoichiometry of the human terminal synthetic complex of selenocysteine by using small angle x-ray scattering, multi-angle light scattering, and analytical ultracentrifugation. In addition, we provided the first estimate of the ratio between SepSecS and tRNA(Sec) in vivo. We show that SepSecS preferentially binds one or two tRNA(Sec) molecules at a time and that the enzyme is present in large molar excess over the substrate tRNA in vivo. Moreover, we show that in a complex between SepSecS and two tRNAs, one enzyme homodimer plays a role of the noncatalytic unit that positions CCA ends of two tRNA(Sec) molecules into the active site grooves of the other, catalytic, homodimer. Finally, our results demonstrate that the previously determined crystal structure represents the physiologically and catalytically relevant complex and suggest that allosteric regulation of SepSecS might play an important role in regulation of selenocysteine and selenoprotein synthesis.