"I'm in My Feelings Now": Examination of Advance Care Planning Video Declarations by People with Advanced Cancer from a Safety Net Hospital.

Background: Advance care planning (ACP) is underutilized among those with advanced cancer, leading to the potential of not receiving goal-concordant care. Objectives: To understand the experience of patients in creating a video declaration (ViDec) of their ACP preferences and their family member/caregivers' perceptions after viewing their ViDec. Design: Qualitative study among patients and family members/caregivers. Setting/Subjects: Patients were recruited from a large safety net hospital in the United States. Patients with any type of advanced cancer were enrolled to create a ViDec and participate in an individual interview. Patients also identified a family member/caregiver to participate. Measurements: Content and perceptions of usefulness of ViDecs among patients and family members/caregivers. Results: In total, 32 patients participated. Patients had a mean age of 61 (10) years, 15 (47%) were women, 14 (44%) were Black or African American, and 12 (37%) had a high school education or less; 25 family members/caregivers participated. Across all ViDecs, the most common theme pertained to ACP for preferred medical treatments (97%). We describe three case studies of patient and caregiver pairs to represent salient dimensions of our data: (1) high perceived usefulness of ViDec, (2) populations at risk for not receiving goal-concordant care, and (3) varied responses to ViDec among family members/caregivers. Recommendations to improve the ViDec process included providing structured prompts to patients. Conclusions: These case studies highlight the potential high-perceived usefulness of ViDecs across patients and caregivers. ViDecs have the potential to improve care among patients with advanced cancer.

Study protocol for Video Images about Decisions to Improve Ethical Outcomes with Palliative Care Educators (VIDEO-PCE): a pragmatic stepped wedge cluster randomised trial of older patients admitted to the hospital

INTRODUCTION: Despite the known benefit to patients and families, discussions about goals, values and preferences for medical care in advancing serious illness often do not occur. Many system and clinician factors, such as patient and clinician reticence and shortage of specialty palliative care teams, contribute to this lack of communication. To address this gap, we designed an intervention to promote goals-of-care conversations and palliative care referrals in the hospital setting by using trained palliative care educators and video decision aids. This paper presents the rationale, design and methods for a trial aimed at addressing barriers to goals-of-care conversations for hospitalised adults aged 65 and older and those with Alzheimer's disease and related Dementias, regardless of age. METHODS AND ANALYSIS: The Video Image about Decisions to Improve Ethical Outcomes with Palliative Care Educators is a pragmatic stepped wedge, cluster randomised controlled trial, which aims to improve and extend goals-of-care conversations in the hospital setting with palliative care educators trained in serious illness communication and video decision aids. The primary outcome is the proportion of patients with goals-of-care documentation in the electronic health record. We estimate that over 9000 patients will be included. ETHICS AND DISSEMINATION: The Institutional Review Board (IRB) at Boston Medical Center will serve as the single IRB of record for all regulatory and ethical aspects of this trial. BMC Protocol Number: H-41482. Findings will be presented at national meetings and in publications. This trial is registered at ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT04857060; ClinicalTrials.gov.

Sox11 modulates brain-derived neurotrophic factor expression in an exon promoter-specific manner.

Sox11 is a high-mobility group (HMG)-containing transcription factor that is significantly elevated in peripheral neurons in response to nerve injury. In vitro and in vivo studies support a central role for Sox11 in adult neuron growth and survival following injury. Brain-derived neurotrophic factor (BDNF) is a pleiotropic growth factor that has effects on neuronal survival, differentiation, synaptic plasticity, and regeneration. BDNF transcription is elevated in the dorsal root ganglia (DRG) following nerve injury in parallel with Sox11, allowing for the possible regulation by Sox11. To begin to assess the possible influence of Sox11, we used reverse transcriptase PCR assays to determine the relative expression of the nine (I-IXa) noncoding exons and one coding exon (exon IX) of the BDNF gene after sciatic nerve axotomy in the mouse. Exons with upstream promoter regions containing the Sox binding motif 5'-AACAAAG-3' (I, IV, VII, and VIII) were increased at 1 or 3 days following axotomy. Exons 1 and IV showed the greatest increase, and only exon 1 remained elevated at 3 days. Luciferase assays showed that Sox11 could activate the most highly regulated exons, I and IV, and that this activation was reduced by mutation of putative Sox binding sites. Exon expression in injured DRG neurons had some overlap with Neuro2a cells that overexpress Sox11, showing elevation in exon IV and VII transcripts. These findings indicate cell type and contextual specificity of Sox11 in modulation of BDNF transcription.

Sox11 transcription factor modulates peripheral nerve regeneration in adult mice.

The ability of adult peripheral sensory neurons to undergo functional and anatomical recovery following nerve injury is due in part to successful activation of transcriptional regulatory pathways. Previous in vitro evidence had suggested that the transcription factor Sox11, a HMG-domain containing protein that is highly expressed in developing sensory neurons, is an important component of this regenerative transcriptional control program. To further test the role of Sox11 in an in vivo system, we developed a new approach to specifically target small interfering RNAs (siRNAs) conjugated to the membrane permeable molecule Penetratin to injured sensory afferents. Injection of Sox11 siRNAs into the mouse saphenous nerve caused a transient knockdown of Sox11 mRNA that transiently inhibited in vivo regeneration. Electron microscopic level analysis of Sox11 RNAi-injected nerves showed that regeneration of myelinated and unmyelinated axons was inhibited. Nearly all neurons in ganglia of crushed nerves that were Sox11 immunopositive showed colabeling for the stress and injury-associated activating transcription factor 3 (ATF3). In addition, treatment with Sox11 siRNAs in vitro and in vivo caused a transcriptional and translational level reduction in ATF3 expression. These anatomical and expression data support an intrinsic role for Sox11 in events that underlie successful regeneration following peripheral nerve injury.

The function of the small insertion in the hinge subdomain in the control of constitutive mammalian nitric-oxide synthases.

Control of nitric oxide (NO) synthesis in the constitutive nitric-oxide synthases (NOS) by calcium/calmodulin is exerted through the regulation of electron transfer from NADPH through the reductase domains. This process has been shown previously to involve the calmodulin binding site, the autoinhibitory insertion in the FMN binding domain, and the C-terminal tail. Smaller sequence elements also appear to correlate with control. Although some of these elements appear well positioned to function in control, they are poorly conserved; their role in control is neither well established nor defined by available information. In this study mutations have been induced in the small insertion of the hinge subdomain, which has been shown recently to form a beta hairpin in structural studies of the neuronal NOS reductase domains adjacent to the calmodulin site and the autoinhibitory element. Modification of the small insertion in neuronal NOS tends to increase cytochrome c reduction but not NO synthetic activity; some modifications or deletions in the corresponding region in endothelial NOS modestly increase activity under some conditions. Unexpectedly, some minor changes in the sequence introduce a loss in the content of heme relative to flavin cofactors. Taken together, these results suggest that the small insertion protects the calmodulin binding site and that it may be a modulator of NOS activity.

Structural diversity in the small heat shock protein superfamily: control of aggregation by the N-terminal region.

The small heat shock protein superfamily, extending over all kingdoms, is characterized by a common core domain with variable N- and C-terminal extensions. The relatively hydrophobic N-terminus plays a critical role in promoting and controlling high-order aggregation, accounting for the high degree of structural variability within the superfamily. The effects of N-terminal volume on aggregation were studied using chimeric and truncated proteins. Proteins lacking the N-terminal region did not aggregate above the tetramers, whereas larger N-termini resulted in large aggregates, consistent with the N-termini packing inside the aggregates. Variation in an extended internal loop differentiates typical prokaryotic and plant superfamily members from their animal counterparts; this implies different geometry in the dimeric building block of high-order aggregates.