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It has been proposed that, during development, clonally related neurons migrate along the same radial glial fibre to form clusters of functionally similar cells; here, sister neurons in the same radial clone are shown to have similar orientation preferences in mice, providing support for this hypothesis. Sister neurons in the developing neocortex It has been proposed that during development clonally related neurons migrate along the same radial glial fibre, forming clusters of functionally similar cells. However, this has not been shown experimentally. Two groups now demonstrate electrical coupling between sister neurons in the developing cerebral cortex that shapes subsequent functional relationships. Song-Hai Shi and colleagues report that in neocortical tissue from postnatal mice, long-range connections between sister neurons are maintained through electrical couplings that precede the formation of chemical synapses between them. Any blockade of gap junctions during development disrupts the eventual synaptic connectivity of sister cells and prevents their synchronous firing. Yang Dan and colleagues show that, in the mouse visual cortex, sister neurons in the same radial clone have similar orientation preferences. Disrupting gap-junction coupling shortly after birth diminishes the functional similarity between sister neurons, suggesting that the development of functional organization from ontogenetically related neurons requires this form of neural communication. A fundamental feature of the mammalian neocortex is its columnar organization 1 . In the visual cortex, functional columns consisting of neurons with similar orientation preferences have been characterized extensively 2 , 3 , 4 , but how these columns are constructed during development remains unclear 5 . The radial unit hypothesis 6 posits that the ontogenetic columns formed by clonally related neurons migrating along the same radial glial fibre during corticogenesis 7 provide the basis for functional columns in adult neocortex 1 . However, a direct correspondence between the ontogenetic and functional columns has not been demonstrated 8 . Here we show that, despite the lack of a discernible orientation map in mouse visual cortex 4 , 9 , 10 , sister neurons in the same radial clone exhibit similar orientation preferences. Using a retroviral vector encoding green fluorescent protein to label radial clones of excitatory neurons, and in vivo two-photon calcium imaging to measure neuronal response properties, we found that sister neurons preferred similar orientations whereas nearby non-sister neurons showed no such relationship. Interestingly, disruption of gap junction coupling by viral expression of a dominant-negative mutant of Cx26 (also known as Gjb2) or by daily administration of a gap junction blocker, carbenoxolone, during the first postnatal week greatly diminished the functional similarity between sister neurons, suggesting that the maturation of ontogenetic into functional columns requires intercellular communication through gap junctions. Together with the recent finding of preferential excitatory connections among sister neurons 11 , our results support the radial unit hypothesis and unify the ontogenetic and functional columns in the visual cortex.

Respect for patient autonomy is paramount in resolving ethical tensions in end-of-life care. The concept of relational autonomy has contributed to this debate; however, scholars often use this concept in a fragmented manner. This leads to partial answers on ascertaining patients’ true wishes, meaningfully engaging patients’ significant others, balancing interests among patients and significant others, and determining clinicians’ obligations to change patients’ unconventional convictions to enhance patient autonomy. A satisfactory solution based on relational autonomy must incorporate patients’ competence (apart from decisional capacity), authenticity (their true desires or beliefs) and the involvement level of their significant others. To that end, we argue that John Christman’s procedural approach to relational autonomy provides critical insights, such as the diachronic or socio-historical personhood, sustained critical reflection and his recent explication of the nature of asymmetrical relationships and helpful interlocutors. This study reviews Christman’s account, proposes minor modifications and advocates for an integrated three-dimensional model for medical decision-making. Clarifying the relationship among the three elements promotes an ethical framework with a coherent understanding of relational autonomy. This model not only provides a descriptive and normative framework for end-of-life care practice but also reconsiders the nature of the clinician–patient relationship and its normative implications. We further present a case study to illustrate the merits of our proposed model. Altogether, our proposal will help navigate complex medical decision-making, foster trust and negotiate shared values between patients and their significant others, particularly in end-of-life care.

ObjectivesAdvance care planning (ACP) interventions are supposed to affect patients’ autonomy and family health-care outcomes positively. However, the clinical benefits of ACP actualization and associated contextual factors merit questioning. Therefore, this study explores the critical contextual and procedural factors related to ACP decision-making based on the actual situation of older patients with cancer encountering end-of-life care in Taiwan.MethodsThis retrospective qualitative secondary analysis used the Kipling method (5W1H) to explore further the critical contextual and procedural factors related to ACP decision-making processes. We applied thematic analysis and dual coding for 35 narratives, including 10 patients with cancer, 10 family caregivers, and 15 health-care staff, derived from a preliminary qualitative study regarding palliative care decision-making among patients with advanced cancer, their families, and health-care staff.ResultsWe identified 6 domains detailing the contextual factors for ACP decision-making: (1) WHO (decision makers); (2) WHAT (discussion content); (3) WHEN (care plan for which disease stage); (4) WHERE (patient’s situational location); (5) WHY (reasons underpinning the decisions); and (6) HOW (the way to form the decisions).Significance of resultsUsing the Kipling method to elaborate the contextual factors for ACP decision-making among older patients with cancer strengthens the understanding of complicated end-of-life care decision-making procedure. This study also demonstrates the dynamic and cultural complexity and the various factors considered during end-of-life care and future ACP discussion.

A critical step in neuronal development is the formation of axon/dendrite polarity, a process involving symmetry breaking in the newborn neuron. Local self-amplifying processes could enhance and stabilize the initial asymmetry in the distribution of axon/dendrite determinants, but the identity of these processes remains elusive. We here report that BDNF, a secreted neurotrophin essential for the survival and differentiation of many neuronal populations, serves as a self-amplifying autocrine factor in promoting axon formation in embryonic hippocampal neurons by triggering two nested positive-feedback mechanisms. First, BDNF elevates cytoplasmic cAMP and protein kinase A activity, which triggers further secretion of BDNF and membrane insertion of its receptor TrkB. Second, BDNF/TrkB signaling activates PI3-kinase that promotes anterograde transport of TrkB in the putative axon, further enhancing local BDNF/TrkB signaling. Together, these self-amplifying BDNF actions ensure stable elevation of local cAMP/protein kinase A activity that is critical for axon differentiation and growth.

Type 2 diabetes is a chronic disease with a significant medical burden. eHealth care integrates medicine and technology to enhance the outcomes of such patients; however, adequate eHealth literacy (eHL) is necessary for that to happen. Fostering eHL is crucial for patients with diabetes to engage with eHealth care and receive quality care and timely support. Experiential learning theory can enhance patients' eHL and skills to use eHealth care technology in their daily care. This study explored the effectiveness of an eHealth care experiential learning program in improving eHL, patient health engagement, and eHealth care use status among patients with type 2 diabetes in 3 months. In this randomized controlled trial, patients under case management services from various clinics in Taiwan were randomly assigned to either the intervention group receiving the 6-session eHealth care experiential learning program or the control group receiving the usual care. Data were collected using structured questionnaires at 3 time points: pretest, postintervention, and 3 months after the intervention. Descriptive data were presented using frequency distribution, percentage, mean, and SD. The outcomes were analyzed using a generalized estimating equation method by intention-to-treat analysis. A total of 92 participants (46 in each group) were recruited in this study. Of these, 86 completed the course and follow-up evaluations with a mean age of 62.38 (SD 12.91) years. After completing the intervention, the intervention group had significantly higher posttest scores in eHL (β=19.94, SE 3.52; P<.001), patient health engagement (β=.28, SE 0.13; P=.04), and eHealth use (β=3.96, SE 0.42; P<.001) than the control group. Furthermore, the intervention group maintained these significant improvements in eHL (β=18.19, SE 3.82; P<.001) and eHealth use (β=3.87, SE 0.49; P<.001) after 3 months. Participating in the eHealth care experiential learning program resulted in significant improvements in eHL, patient health engagement, and eHealth use among patients with type 2 diabetes. Our interventional program can inform future clinical practice and policies to strengthen self-management skills and facilitate the use of health technology in caring for patients with chronic diseases. ClinicalTrials.gov NCT05180604; https://clinicaltrials.gov/ct2/show/NCT05180604.

The interaction of light with biological tissues has been considered for various therapeutic applications. Light-induced neurite growth has the potential to be a clinically useful technique for neuron repair. However, most previous studies used either a large illumination area to accelerate overall neurite growth or employed a light spot to guide a growing neurite. It is not clear if optical stimulation can induce the regrowth of a retracted neurite. In the present work, we used blue light (wavelength: 473 nm) to cause neurite retraction, and we proved that using a red-light (wavelength: 650 nm) spot to illuminate the soma near the junction of the retracted neurite could induce neurite regrowth. As a comparison, we found that green light (wavelength 550 nm) had a 62% probability of inducing neurite regrowth, while red light had a 75% probability of inducing neurite regrowth at the same power level. Furthermore, the neurite regrowth length induced by red light was increased by the pre-treatment with inhibitors of myosin functions. We also observed actin propagation from the soma to the tip of the re-growing neurite following red-light stimulation of the soma. The red light-induced extension and regrowth were abrogated in the calcium-free medium. These results suggest that illumination with a red-light spot on the soma may trigger the regrowth of a neurite after the retraction caused by blue-light illumination.

Background: Withdrawal from dialysis in patients with end-stage renal disease (ESRD) can mitigate futile treatments and facilitate early end-of-life care preparation. However, the reasons patients willingly withdraw from elective dialysis under varying disease prognoses, and the factors that influence these decisions, remain unclear. Purpose: To explore the factors influencing the willingness to electively withdraw from dialysis in patients with ESRD at different disease prognoses. Methods: This cross-sectional observational study was conducted in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Using convenience sampling, patients aged ≥ 45 who had regularly undergone hemodialysis for more than 6 months were recruited from a medical center and a local clinic. We used structured questionnaires and chart reviews to collect data from February to April 2021. Descriptive analysis, Pearson's correlations, and stepwise regression were employed to assess willingness to electively withdraw from dialysis. Results: The 121 participants enrolled were of an average age of 61.09 years, had undergone dialysis for 7 years, and had a median of four comorbidities. Willingness to withdraw from dialysis increased as their disease worsened. However, more than half preferred to continue dialysis, with the number of patients decreasing from 76% to 53.7% across the disease deterioration trajectory. The participants identified nephrologists as the most influential individuals in their dialysis withdrawal discussions. Factors associated with dialysis withdrawal decisions across all hypothetical prognosis scenarios (current disease conditions, irreversible complications, and estimated survival ＜ 6 mo) included poor quality of dialysis, lower educational level (junior high school), and better knowledge of palliative care. Conclusions/Implications for Future Practice: Willingness to withdraw from dialysis is associated with dialysis quality, educational level, and palliative care knowledge under different hypothetical prognosis scenarios. Nephrologists play a pivotal role in initiating withdrawal discussions and influencing decision-making. Health care providers should consider these factors during routine renal nursing care and identify the appropriate time to initiate advanced care planning discussions. Regular monitoring of dialysis-related symptoms and quality (measured by Kt/V) and evaluating patients' understanding of palliative care are both essential in ESRD care. As primary caregivers, nurses play a crucial role in integrating these assessments into routine care to identify patients considering dialysis withdrawal. Collaborative efforts between nurses and nephrologists are vital to initiate timely end-of-life care discussions and preparations, improve patient-centered care, and improve end-of-life outcomes in ESRD management.

Advance care planning (ACP) provides access to complete advance decisions (ADs). Despite the legalization of ACP in Taiwan, it is underutilized in community settings. The objective of this study is to describe the service at a community hospital in Southern Taiwan. We retrospectively analyzed participants who were engaged in ACP consultations from January 2019 to January 2020. The characteristics, motivations, content, and satisfaction of participants are reported. Factors associated with refusing life-sustaining treatments (LST) or artificial nutrition/hydration (ANH) were analyzed using multivariate logistic regression. Of the 178 participants, 123 completed the ACP. The majority were female (64.2%), aged 61 on average and more than 80% had never signed a do-not-resuscitate order. In the ADs, most participants declined LST (97.2%) and ANH (96.6%). Family-related issues (48.9%) were the most prevalent motivations. Rural residence (OR 8.6, p = 0.005), increased age (OR 7.2, p = 0.025), and reluctance to consent to organ donation (OR 5.2, p = 0.042) correlated with refusing LST or ANH. Participants provided a positive feedback regarding overall satisfaction (good, 83%) compared to service charge (fair/poor, 53%). The study demonstrated high AD completion when refusing LST or ANH. These findings may facilitate the development of ACP as a community-based service.

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset degenerative disorder of motor neurons. The diseased spinal cord motor neurons of more than 95% of amyotrophic lateral sclerosis (ALS) patients are characterized by the mis-metabolism of the RNA/DNA-binding protein TDP-43 (ALS-TDP), in particular, the presence of cytosolic aggregates of the protein. Most available mouse models for the basic or translational studies of ALS-TDP are based on transgenic overexpression of the TDP-43 protein. Here, we report the generation and characterization of mouse lines bearing homologous knock-in of fALS-associated mutation A315T and sALS-associated mutation N390D, respectively. Remarkably, the heterozygous TDP-43 (N390D/+) mice but not those heterozygous for the TDP-43 (A315T/+) mice develop a full spectrum of ALS-TDP-like pathologies at the molecular, cellular and behavioral levels. Comparative analysis of the mutant mice and spinal cord motor neurons (MN) derived from their embryonic stem (ES) cells demonstrates that different ALS-associated TDP-43 mutations possess critical ALS-causing capabilities and pathogenic pathways, likely modified by their genetic background and the environmental factors. Mechanistically, we identify aberrant RNA splicing of spinal cord Bcl-2 pre-mRNA and consequent increase of a negative regulator of autophagy, Bcl-2, which correlate with and are caused by a progressive increase of TDP-43, one of the early events associated with ALS-TDP pathogenesis, in the spinal cord of TDP-43 (N390D/+) mice and spinal cord MN derived from their ES cells. The TDP-43 (N390D/+) knock-in mice appear to be an ideal rodent model for basic as well as translational studies of ALS- TDP.

Evidence shows that community-based palliative home care (PHC) provision enhances continuous care and improves patient outcomes. This study compared patient survival, place of death, and medical utilization in community- versus hospital-based PHC. A retrospective cohort study was conducted of patients aged over 18 referred to either community- or hospital-based PHC from May to December 2018 at a tertiary hospital and surrounding communities in Southern Taiwan. A descriptive analysis, Chi-square test, t-test, and Log-rank test were used for the data analysis of 131 hospital-based PHC patients and 43 community-based PHC patients, with 42 paired patient datasets analyzed after propensity score matching. More nurse visits (p = 0.02), fewer emergency-room visits (p = 0.01), and a shorter waiting time to access PHC (p = 0.02) were found in the community group. There was no difference in the duration of survival and hospitalization between groups. Most hospital-based patients (57%) died in hospice wards, while most community-based patients died at home (52%). Community-based PHC is comparable to hospital-based PHC in Taiwan. Although it has fewer staffing and training requirements, it is an alternative for terminal patients to meet the growing end-of-life care demand.