Implementing a nurse-led prehabilitation program for patients undergoing spinal surgery.

ABSTRACT: Prehabilitation, or "prehab," helps patients optimize strength, function, and nutrition before surgery. This evidence-based practice project presents strategies for implementing a prehab program to prepare patients for spinal surgery. Nurses play an integral role in educating patients preoperatively about the myriad lifestyle changes associated with spinal surgery.

Going Virtual: Adapting an Institutional Annual Bereavement Event During the COVID-19 Pandemic.

Our institution's annual bereaved family event was modified to a virtual format during the COVID-19 pandemic. While necessary to comply with physical distancing directives, the transition also provided greater accessibility for families. Virtual events were feasible and appreciated by attendees. Future hybrid bereavement events should be considered to allow families more flexibility and accessibility.

Early Bereavement Psychosocial Outcomes in Parents of Children Who Died of Cancer With a Focus on Social Functioning.

PURPOSE: The early grief experience of parents of children who died of cancer remains understudied. Understanding psychosocial symptomology and functioning of parents early in their bereavement is essential to developing supportive interventions aimed at offsetting poor mental and physical outcomes. METHODS: Parents of children from two centers who died of cancer 6 to 24 months before were mailed a survey that included validated tools and additional Likert scale-based questions. We used correlation and univariate and multiple regression analyses to assess the associations between psychosocial and grief outcomes and parental social functioning. RESULTS: One hundred twenty-five parents representing 88 children completed the survey. Most respondents identified as female (63%), White (84%), and non-Hispanic (91%). The mean time since child's death was 14.7 (range, 8-26) months. Bereaved parents' mean score for social functioning was only slightly below normative values, and most parents indicated post-traumatic growth and adaptive coping. Parents had high symptom levels for depression, anxiety, post-traumatic stress, and prolonged grief, with those identifying as female having significantly higher symptom scores. Using multivariate analysis, parental scores for resilience and continuing bonds were associated with higher social functioning scores and parental scores for depressive symptoms and prolonged grief were associated with lower social functioning scores. CONCLUSION: Although bereaved parents exhibit resilience and positive coping, they also show high levels of psychosocial distress in the first 2 years after their child's death, which may reflect the typical parental bereavement experience. Screening for low parental social functioning may identify parents who would benefit from additional support early in bereavement.

Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications.

The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the identification of several receptors that engage in sustained signaling responses from subcellular compartments following internalization of the ligand-receptor complex. This phenomenon was initially discovered for the parathyroid hormone (PTH) type 1 receptor (PTH1R), a vital GPCR for maintaining normal calcium and phosphate levels in the body with the paradoxical ability to build or break down bone in response to PTH binding. The diverse biological processes regulated by this receptor are thought to depend on its capacity to mediate diverse modes of cyclic adenosine monophosphate (cAMP) signaling. These include transient signaling at the plasma membrane and sustained signaling from internalized PTH1R within early endosomes mediated by PTH. Here we discuss recent structural, cell signaling, and in vivo studies that unveil potential pharmacological outputs of the spatial versus temporal dimension of PTH1R signaling via cAMP. Notably, the combination of molecular dynamics simulations and elastic network model-based methods revealed how precise modulation of PTH signaling responses is achieved through structure-encoded allosteric coupling within the receptor and between the peptide hormone binding site and the G protein coupling interface. The implications of recent findings are now being explored for addressing key questions on how location bias in receptor signaling contributes to pharmacological functions, and how to drug a difficult target such as the PTH1R toward discovering nonpeptidic small molecule candidates for the treatment of metabolic bone and mineral diseases.

Understanding SUMO-mediated adaptive responses in plants to improve crop productivity.

The response to abiotic and biotic stresses in plants and crops is considered a multifaceted process. Due to their sessile nature, plants have evolved unique mechanisms to ensure that developmental plasticity remains during their life cycle. Among these mechanisms, post-translational modifications (PTMs) are crucial components of adaptive responses in plants and transduce environmental stimuli into cellular signalling through the modulation of proteins. SUMOylation is an emerging PTM that has received recent attention due to its dynamic role in protein modification and has quickly been considered a significant component of adaptive mechanisms in plants during stress with great potential for agricultural improvement programs. In the present review, we outline the concept that small ubiquitin-like modifier (SUMO)-mediated response in plants and crops to abiotic and biotic stresses is a multifaceted process with each component of the SUMO cycle facilitating tolerance to several different environmental stresses. We also highlight the clear increase in SUMO genes in crops when compared with Arabidopsis thaliana. The SUMO system is understudied in crops, given the importance of SUMO for stress responses, and for some SUMO genes, the apparent expansion provides new avenues to discover SUMO-conjugated targets that could regulate beneficial agronomical traits.

Training in Expression of Authentic Condolences in Healthcare: A Pilot Study.

Background: Bereaved parents value receiving support from their children's health care teams. Pediatric residents are important members of the teams that care for children at end of life and can play a meaningful role in communication with bereaved families. Yet formal training in expressing condolences is currently lacking. Methods: We applied Kern's six step approach to develop, implement, and evaluate an innovative curriculum aimed at increasing pediatric residents' comfort levels with and practice of condolence expression. Results: Twelve residents participated in the pilot study. Quantitative and qualitative data demonstrate that residents' comfort levels with expressing condolences increased after implementation of the curriculum and that residents appreciated and benefitted from receiving this education. Conclusion: We successfully developed and piloted a condolence expression curriculum that was well received by pediatric residents and led to increased comfort level with expressing condolences. Research is ongoing to determine the full impact of this curriculum.

"You are not alone": Connecting through a bereaved parent mentor program for parents whose child died of cancer.

BACKGROUND: Bereavement after the death of a child is devastating and associated with worse physical and psychosocial well-being in parents. Evidence suggests that parents desire and benefit from support provided by other bereaved parents. To foster this peer support, an institutional peer-to-peer mentorship program for bereaved parents was established, through which trained bereaved parent mentors offer support for newly bereaved parents. METHODS: Using a retrospective cohort design, we describe the characteristics of participants of the Bereaved Parent Mentorship program. Trained bereaved parent mentors documented encounters with newly bereaved parent mentees using a secure internet-based form. Mentors summarized each encounter including any concerns or need for professional psychosocial support. Descriptive statistics were used to describe mentor and mentee characteristics; free text from encounter summaries was qualitatively analyzed using content analysis. RESULTS: A total of 1368 documented encounters occurred between 150 mentees and 39 mentors from January 1, 2014 to February 29, 2020. Only seven encounters (0.5%) were flagged as serious concern necessitating professional psychosocial support. Four key themes in the encounters between mentors and mentees emerged, including: descriptions of the grief experience, ways in which a mentor supported their mentee, challenges the mentor experienced in supporting the mentee, and personal benefit gained by the mentor from supporting their mentee. CONCLUSION: This structured Bereaved Parent Mentorship program fostered rich interactions between bereaved parent participants, with very few encounters requiring professional assistance. Future research will assess the impact of bereaved mentor programs on resilience and psychosocial, physical, and functional well-being of parents.

Bereaved Parent Perspectives and Recommendations on Best Practices for Legacy Interventions.

CONTEXT: Many pediatric hospitals offer legacy interventions for families to promote coping and support grief prior to and following the death of a child. Despite this practice, parent perceptions of the value of legacy activities are not well described, and best practices for offering and creating legacy interventions remain poorly understood. OBJECTIVES: To characterize bereaved parents' perspectives on the value of legacy activities; to describe parent recommendations for optimizing provision of legacy activities by child life specialists and music therapists. METHODS: In this qualitative study, a purposive sample of 19 bereaved parents of children who died from cancer participated in semi-structured interviews. Interviews were audio-recorded, transcribed, and analyzed inductively using content analysis to identify key concepts and emerging themes. RESULTS: Analysis of transcripts revealed bereaved parent insights and recommendations across three core themes: 1) the value of legacy items and interventions; 2) the practical roles, uses, and functions of legacy items, and 3) best practices for offering legacy interventions. Bereaved parents sought meaning and purpose in abstract and concrete manifestations of legacy. Parents often used legacy items in specific ways to promote emotional expression and process their grief. Communication, timing, and creativity significantly influenced parent perceptions of legacy-building. Parents recommended individualized assessments to optimize provision of legacy interventions. CONCLUSION: Bereaved parents emphasized the meaningfulness of legacy-building activities and the need for an individualized approach when offering these interventions. Future research should explore the perspectives and recommendations of patients and siblings on legacy activities.

Precise druggability of the PTH type 1 receptor.

Class B G protein-coupled receptors (GPCRs) are notoriously difficult to target by small molecules because their large orthosteric peptide-binding pocket embedded deep within the transmembrane domain limits the identification and development of nonpeptide small molecule ligands. Using the parathyroid hormone type 1 receptor (PTHR) as a prototypic class B GPCR target, and a combination of molecular dynamics simulations and elastic network model-based methods, we demonstrate that PTHR druggability can be effectively addressed. Here we found a key mechanical site that modulates the collective dynamics of the receptor and used this ensemble of PTHR conformers to identify selective small molecules with strong negative allosteric and biased properties for PTHR signaling in cell and PTH actions in vivo. This study provides a computational pipeline to detect precise druggable sites and identify allosteric modulators of PTHR signaling that could be extended to GPCRs to expedite discoveries of small molecules as novel therapeutic candidates.

Spatial bias in cAMP generation determines biological responses to PTH type 1 receptor activation.

The parathyroid hormone (PTH) type 1 receptor (PTHR) is a class B G protein­coupled receptor (GPCR) that regulates mineral ion, vitamin D, and bone homeostasis. Activation of the PTHR by PTH induces both transient cell surface and sustained endosomal cAMP production. To address whether the spatial (location) or temporal (duration) dimension of PTHR-induced cAMP encodes distinct biological outcomes, we engineered a biased PTHR ligand (PTH7d) that elicits cAMP production at the plasma membrane but not at endosomes. PTH7d stabilized a unique active PTHR conformation that mediated sustained cAMP signaling at the plasma membrane due to impaired ß-arrestin coupling to the receptor. Experiments in cells and mice revealed that sustained cAMP production by cell surface PTHR failed to mimic the pharmacological effects of sustained endosomal cAMP production on the abundance of the rate-limiting hydroxylase catalyzing the formation of active vitamin D, as well as increases in circulating active vitamin D and Ca2+ and in bone formation in mice. Thus, similar amounts of cAMP generated by PTHR for similar lengths of time in different cellular locations, plasma membrane and endosomes, mediate distinct physiological responses. These results unveil subcellular signaling location as a means to achieve specificity in PTHR-mediated biological outcomes and raise the prospect of rational drug design based upon spatiotemporal manipulation of GPCR signaling.

Leveraging Grief: Involving Bereaved Parents in Pediatric Palliative Oncology Program Planning and Development.

As pediatric palliative care (PPC) became a recognized medical specialty, our developing clinical PPC team longitudinally partnered with bereaved parents to understand the care that their children received as they transitioned towards end of life. Families developed Eight Priorities, shared within, to improve care for children with a poor chance of survival based on their experience of losing a child to cancer. In this paper, we delineate the top eight PPC needs from a parent perspective to offer multi-layered, individually tailored resources for patients and families. One of these Eight Priorities noted that bereavement care for the remaining family members is vital for healing after the death of a child to promote meaning making and resilience in bereaved families. Here, we outline the creation of a bereaved parent-designed bereavement support program as one example of how we have partnered with parents to fulfill their Eight Priorities for quality care.

Outcomes Associated With the Adjunctive Use of Dipeptidyl Peptidase-4 Inhibitors With Insulin Versus Other Antihyperglycemic Medications in Patients With Prediabetes or Diabetes After Cardiac Surgery.

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) plus basal insulin is noninferior to insulin monotherapy for glycemic control in medical-surgical patients, but data in postoperative cardiac surgery patients are sparse. OBJECTIVE: To compare glucose control in postoperative cardiac surgery patients with prediabetes or diabetes receiving a DPP-4i plus insulin versus other antihyperglycemic regimens. METHODS: We retrospectively identified patients with prediabetes or diabetes who underwent cardiac surgery at our hospital between May 2016 and June 2017. Included patients were stratified into cohorts: (1) DPP-4i plus insulin and (2) other antihyperglycemic regimens. Blood glucose levels were collected on postoperative days 2 to 7. Uncontrolled glucose (≥2 measurements <80 or >180 mg/dL in 1 day), hyperglycemia (>2 measurements ≥180 mg/dL in 1 day), and hypoglycemia (any measurement <70 mg/dL) were compared between cohorts using logistic regression adjusted for home antihyperglycemics. RESULTS: We included 135 cardiac surgery patients, of which 65 received DPP-4i plus insulin. Eighty-two patients received antihyperglycemics at home. Uncontrolled glucose occurred in 61 (45.2%) patients; while hyperglycemia and hypoglycemia occurred in 50 (37.0%) and 24 (17.8%) patients, respectively. There was no difference in the adjusted odds of uncontrolled glucose (odds ratio [OR] = 1.43; 95% confidence interval [CI] = 0.65-3.11), hyperglycemia (OR = 1.20; 95% CI = 0.52-2.78), or hypoglycemia (OR = 0.69; 95% CI = 0.27-1.75) for those receiving DPP-4i plus insulin versus other regimens. CONCLUSION: Glucose control was no different among postoperative cardiac surgery patients receiving a DPP-4i plus insulin versus other regimens. DPP-4i use was not associated with hypoglycemia.

MicroED for the study of protein-ligand interactions and the potential for drug discovery.

Microcrystal electron diffraction (MicroED) is an electron cryo-microscopy (cryo-EM) technique used to determine molecular structures with crystals that are a millionth the size needed for traditional single-crystal X-ray crystallography. An exciting use of MicroED is in drug discovery and development, where it can be applied to the study of proteins and small molecule interactions, and for structure determination of natural products. The structures are then used for rational drug design and optimization. In this Perspective, we discuss the current applications of MicroED for structure determination of protein-ligand complexes and potential future applications in drug discovery.

Allosteric interactions in the parathyroid hormone GPCR-arrestin complex formation.

Peptide ligands of class B G-protein-coupled receptors act via a two-step binding process, but the essential mechanisms that link their extracellular binding to intracellular receptor-arrestin interactions are not fully understood. Using NMR, crosslinking coupled to mass spectrometry, signaling experiments and computational approaches on the parathyroid hormone (PTH) type 1 receptor (PTHR), we show that initial binding of the PTH C-terminal part constrains the conformation of the flexible PTH N-terminal signaling epitope before a second binding event occurs. A 'hot-spot' PTH residue, His9, that inserts into the PTHR transmembrane domain at this second step allosterically engages receptor-arrestin coupling. A conformational change in PTHR intracellular loop 3 permits favorable interactions with ß-arrestin's finger loop. These results unveil structural determinants for PTHR-arrestin complex formation and reveal that the two-step binding mechanism proceeds via cooperative fluctuations between ligand and receptor, which extend to other class B G-protein-coupled receptors.

PTH/PTHrP Receptor Signaling, Allostery, and Structures.

The parathyroid hormone (PTH) type 1 receptor (PTHR) is the canonical G protein-coupled receptor (GPCR) for PTH and PTH-related protein (PTHrP) and the key regulator of calcium homeostasis and bone turnover. PTHR function is critical for human health to maintain homeostatic control of ionized serum Ca2+ levels and has several unusual signaling features, such as endosomal cAMP signaling, that are well-studied but not structurally understood. In this review, we discuss how recently solved high resolution near-atomic structures of hormone-bound PTHR in its inactive and active signaling states and discovery of extracellular Ca2+ allosterism shed light on the structural basis for PTHR signaling and function.

P wave indices, heart rate variability and anthropometry in a healthy South Asian population.

BACKGROUND: South Asians have a low prevalence of atrial fibrillation (AF) in comparison with White Europeans despite a higher burden of hypertension, diabetes mellitus and coronary artery disease. The reason for this disparity is unclear but may relate to electrophysiological or structural differences within the atria or variations in autonomic function. We aimed to assess these areas using a range of non-invasive cardiac investigations. METHODS: A prospective cohort study was performed on 200 South Asian and 200 Caucasian healthy volunteers aged 18-40 years. All subjects underwent electrocardiography (ECG), echocardiography and anthropometric measurements. Eighty subjects in each cohort underwent 24 hour ambulatory ECG and fifty subjects in each cohort underwent exercise testing. RESULTS: Compared with White Europeans, South Asians were of a smaller height with lower lean body mass and smaller left atrial size. They had reduced P wave dispersion and P wave terminal force in lead V1. South Asians had a lower burden of supraventricular ectopy. They had a higher mean heart rate and South Asian males had lower heart rate variability, suggestive of sympathetic predominance. Exercise capacity was lower in South Asians. CONCLUSIONS: South Asians have differences in left atrial size, P wave indices, burden of supraventricular ectopy, heart rate, heart rate variability and anthropometric measurements. These differences may relate to variations in atrial morphology, atrial electrophysiology and autonomic function and might help to explain why South Asians are less susceptible to developing AF.

Improving Communication Between Health Care Providers, Families, and Children with Autism Spectrum Disorder: The Linked Program.

PURPOSE: To provide easy-to-use tools and skills to decrease stress in the perioperative period for families and their children with autism spectrum disorder (ASD). DESIGN: Evidence-based practice project. METHODS: After literature review, a perioperative assessment and management program was developed to guide and individualize the care of pediatric patients with ASD. The program was piloted on a convenience sample of 31 pediatric patients diagnosed with ASD. FINDINGS: Most patients were back to their baseline behavior according to their families or caregivers within 120 minutes of the procedure (n = 29, 93.5%), with two needing more than 24 hours (6.5%). CONCLUSIONS: The Linked Program has enabled staff to be effective in meeting the perioperative needs of families and their children with ASD. Families have expressed great appreciation that they are able to share their knowledge of what their children need.

Structure and dynamics of the active human parathyroid hormone receptor-1.

The parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Here we report the cryo-electron microscopy structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopts an extended helix with its amino terminus inserted deeply into the receptor transmembrane domain (TMD), which leads to partial unwinding of the carboxyl terminus of transmembrane helix 6 and induces a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast to a single TMD structure state, the extracellular domain adopts multiple conformations. These results provide insights into the structural basis and dynamics of PTH binding and receptor activation.

Ca2+ allostery in PTH-receptor signaling.

The parathyroid hormone (PTH) and its related peptide (PTHrP) activate PTH receptor (PTHR) signaling, but only the PTH sustains GS-mediated adenosine 3',5'-cyclic monophosphate (cAMP) production after PTHR internalization into early endosomes. The mechanism of this unexpected behavior for a G-protein-coupled receptor is not fully understood. Here, we show that extracellular Ca2+ acts as a positive allosteric modulator of PTHR signaling that regulates sustained cAMP production. Equilibrium and kinetic studies of ligand-binding and receptor activation reveal that Ca2+ prolongs the residence time of ligands on the receptor, thus, increasing both the duration of the receptor activation and the cAMP signaling. We further find that Ca2+ allostery in the PTHR is strongly affected by the point mutation recently identified in the PTH (PTHR25C) as a new cause of hypocalcemia in humans. Using high-resolution and mass accuracy mass spectrometry approaches, we identified acidic clusters in the receptor's first extracellular loop as key determinants for Ca2+ allosterism and endosomal cAMP signaling. These findings coupled to defective Ca2+ allostery and cAMP signaling in the PTHR by hypocalcemia-causing PTHR25C suggest that Ca2+ allostery in PTHR signaling may be involved in primary signaling processes regulating calcium homeostasis.