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Ian A Boggero,1 Jonathan D Cole2 1Department of Psychology, University of Kentucky, 2Bluegrass Health Psychology, Lexington, KY, USAObjective: Bipolar disorder is associated with poor pain outcomes, but the extant literature has not taken into account how mania or hypomania – a central feature of bipolar disorders – influences pain intensity. The objective of this study was to describe whether patients recalled experiencing reduced pain intensity during manic or hypomanic episodes.Design and setting: This study used a retrospective design using archival data from patient's medical records. Subjects: A total of 201 patients with chronic pain with bipolar I (39.6%) or bipolar II (60.4%) disorder who were undergoing a psychological evaluation for an interventional pain procedure were included in this study. Methods: Patients underwent a semistructured interview where they were asked if they recalled reductions in pain intensity during their most recent manic or hypomanic episode. The proportion of patients who responded “yes” versus “no” to this question was the primary outcome variable.Results: Results reveal that 64.2% of patients recalled experiencing a reduction in pain intensity during their most recent manic or hypomanic episode.Conclusion: Perceptions of reduced pain intensity during mania or hypomania may contribute to a cycle of increased activity during manic episodes, which may increase pain over time. It may also lead to false-positive findings on spinal cord stimulator trials and diagnostic pain blocks, among other interventional pain procedures. The preliminary findings of this study highlight the clinical importance of assessing for bipolar disorders in patients with chronic pain.Keywords: affective disorders, bipolar disorder, pain perception, positive affect, psychopathology

Efficient topical drug delivery remains a significant challenge in glaucoma management. Although nanoparticle formulations offer considerable promise, their complex preparation processes, co-delivery issues, and batch consistency have hindered their potential. A scalable fabrication strategy is developed here for preparing solid drug nanoparticles (SDNs) with enhanced drug delivery efficiency. Utilizing hydrophobic antiglaucoma drugs brimonidine (BM) and betaxolol (BX), uniform fixed combination BM/BX SDNs are fabricated through a continuous process, improving batch-to-batch consistency for combined glaucoma treatment. With trehalose being used as a lyoprotectant, BM/BX SDNs can be stored as dry powder and easily reconstituted in phosphate buffered saline. Importantly, reconstituted BM/BX SDNs form clear, homogenous solutions, and exhibit negligible cytotoxicity and irritation, making them well-suited for topical administration as eyedrops. Ex vivo and in vivo studies demonstrated that topically applied BM/BX SDNs permeate through the cornea significantly (about two fold to three fold) compared to their hydrophilic counterparts, i.e., brimonidine tartrate, and betaxolol hydrogen chloride. Notably, BM/BX SDNs displayed consistent intraocular pressure lowering effects in vivo in both normotensive rats and glaucoma mice. Collectively, this study demonstrates the potential of the scalable fabrication strategy and the resultant BM/BX SDNs for improving glaucoma management through eyedrops., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Resilience aids healthcare professionals in navigating through and bouncing back from stressful situations in the workplace. Resilience can increase job satisfaction, work motivation, and professional commitment while decreasing burnout, and ultimately job turnover. More resilient employees experience lower instances of burnout and greater life satisfaction. Objective: The primary study objective is to determine the relationship that pharmacist resilience has on burnout and job performance. Methods: Licensed pharmacists in Florida were sent a Qualtrics survey (Qualtrics, Provo, UT) via email, which included demographics data, and valid and reliable assessment tools for resilience, burnout, and job performance. Linear regressions were used to test if resilience significantly predicted each of the output variables: burnout and job performance. Results: Survey responses were received from 942 pharmacists. The regressions showed that resilience significantly predicted both burnout (β1 = -.701, P < .001) and job performance (β1 = .35, P < .001). As resilience increased, the levels of burnout decreased, and job performance increased. Resilience explained 29% of the variance in burnout, and 11% of the variance in job performance. Conclusion: The results of this study suggest that resilience significantly predicts both pharmacist work-related burnout and job performance. The more resilient the pharmacist, the lower the chances of work-related burnout and the higher the likelihood of better job performance. Organizations should pursue opportunities to educate healthcare workers on methods to increase resilience and to bring attention to the importance of this topic., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aniridia is a panocular condition characterized by a partial or complete loss of the iris. It manifests various developmental deficits in both the anterior and posterior segments of the eye, leading to a progressive vision loss. The homeobox gene PAX6 plays an important role in ocular development and mutations of PAX6 have been the main causative factors for aniridia. In this study, we assessed how Pax6-haploinsufficiency affects retinal morphology and vision of Pax6 Sey mice using in vivo and ex vivo metrics. We used mice of C57BL/6 and 129S1/Svlmj genetic backgrounds to examine the variable severity of symptoms as reflected in human aniridia patients. Elevated intraocular pressure (IOP) was observed in Pax6 Sey mice starting from post-natal day 20 (P20). Correspondingly, visual acuity showed a steady age-dependent decline in Pax6 Sey mice, though these phenotypes were less severe in the 129S1/Svlmj mice. Local retinal damage with layer disorganization was assessed at P30 and P80 in the Pax6 Sey mice. Interestingly, we also observed a greater number of activated Iba1+ microglia and GFAP + astrocytes in the Pax6 Sey mice than in littermate controls, suggesting a possible neuroinflammatory response to Pax6 deficiencies., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: This is a final analysis of longitudinal evaluation of burnout and empathy among a cohort of Doctor of Pharmacy students throughout their 4-year enrollment., Methods: The class of 2021 received sequential Qualtrics (Qualtrics, Provo, UT) surveys containing 2 validated survey instruments, the Jefferson Scale of Empathy and the Maslach Burnout Inventory. Surveys were disseminated at the start of the program (PY1 start ) and the end of each academic year (PY1 end , PY2, PY3, PY4). Linear mixed models accounting for repeated measures, Generalized Estimating Equation, and Cochran's Q statistic were used to evaluate longitudinal change in the Jefferson Scale of Empathy and Maslach Burnout Inventory survey scores, categorized subscales, and burnout., Results: Matched survey responses were included for 91 students (85.8% response rate). Across all years, a decrease in empathy and professional efficacy and an increase in exhaustion and cynicism was seen. High categorical levels of exhaustion and cynicism indicated evidence of burnout throughout the program. Year-to-year analysis indicated statistically significant increases in exhaustion and cynicism between PY1 start and all subsequent assessments, a decrease in professional efficacy from PY1 start to PY1 end and PY2, and a decrease in empathy for PY1 start to PY1 end ., Conclusion: Students reported trends of decreasing empathy and professional efficacy, with a simultaneous increase in exhaustion and cynicism. Further evaluation of the impact of COVID-19 on these results, as well as additional methods to support overall student wellness, is needed., 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 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Pharmacy capstone exams are an example of an assessment strategy to evaluate student competency and practice-readiness. Capstone exam processes have been discussed in the literature; however, description of format, evolution of the process, and implementation in the year prior to rotations is lacking. This manuscript discusses the development, implementation, and utilization of a third professional year pharmacy capstone exam to assess advanced pharmacy practice experience (APPE) readiness., Educational Activity and Setting: A pharmacy year three (PY3) capstone exam was initially developed prior to enrollment of the inaugural graduating class. Since the first iteration, utility has remained the same, but the overall development and implementation process has evolved due to changes in programmatic and student learning outcomes, curricular mapping, student and faculty feedback, and practice expectations., Findings: The entities responsible for exam implementation perceive faculty and students have a positive perception of the exam evolution and improvements implemented. Specifically, feedback from students and faculty mentioned clear expectations, comfort with the new capstone exam process, and an appreciation for the focus on interrater reliability. As assessment is an iterative process, quality improvement strategies continue to be implemented to address feedback regarding the PY3 capstone exam., Summary: Purposeful utilization of capstone exams in the third year is one method to assess APPE readiness. Sharing one college's experience with the evolution of such an exam, quality improvement methods, and experience in implementing reliability and validity measures may provide a model for institutions to implement similar assessment methods efficiently., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Neural stem cells (NSCs) generate new neurons throughout life in the mammalian hippocampus 1 . Advancing age leads to a decline in neurogenesis, which is associated with impaired cognition 2,3 . The cellular mechanisms causing reduced neurogenesis with advancing age remain largely unknown. We genetically labeled NSCs through conditional recombination driven by the regulatory elements of the stem-cell-expressed gene GLI family zinc finger 1 (Gli1) and used chronic intravital imaging to follow individual NSCs and their daughter cells over months within their hippocampal niche 4,5 . We show that aging affects multiple steps, from cell cycle entry of quiescent NSCs to determination of the number of surviving cells, ultimately causing reduced clonal output of individual NSCs. Thus, we here define the developmental stages that may be targeted to enhance neurogenesis with the aim of maintaining hippocampal plasticity with advancing age., (© 2023. The Author(s).)

Objective. To assess the impact of variable leadership development program formats on perceived participant growth. Methods. In 2020, the Phi Lambda Sigma national office began offering national Leader Academies to members, while University of South Florida Health Taneja College of Pharmacy simultaneously offered a Leader Academy program to its Phi Lambda Sigma students. Both programs used virtual leadership development tools from GiANT Worldwide, but differed in meeting frequency, content focus, and participant diversity. A 17-question pre- and postsurvey was developed from the Emotional Intelligence Leadership Inventory. Descriptive and inferential statistics were used to compare the cohorts. Results. Twenty-two respondents in the national cohort (66.7% response rate) and 15 in the single-institution cohort (100% response rate) were included. There was more diversity in age, ethnicity, and previous education in the national cohort. Significant improvements in perceived growth were noted in almost all areas. The only decrease noted was the national cohort response to "I strive to improve myself." The overall change in mean response values was generally higher for the single-institution cohort. Qualitative data supported these results and showed more notable references to emotional intelligence in the national cohorts (∼50%) as compared to the single-institution cohort (<25%). Conclusion. Study results suggest that participation in a longitudinal leadership development program, regardless of cohort format, leads to perceived participant improvement in three categories. However, perceived benefit within each of these categories may vary depending on the cohort. Future studies are needed to further evaluate specific leadership arenas and validate the leadership assessment tool., (© 2023 American Association of Colleges of Pharmacy.)

Background: Team-based learning (TBL) encourages learners to think critically to solve problems they will face in practice. Pharmacokinetic dosing and monitoring are complex skills requiring the application of learned knowledge. The study sought to assess the impact of a TBL, vancomycin dosing activity in a Pharmaceutical Skills IV course measured with exam question performance during the second professional year., Methods: This retrospective, descriptive study relates a TBL activity, assigned to 85 students, which included an individual student pre-preparation quiz, assigned readings, in-class individual and team-based readiness assessments, small group application of a vancomycin patient case, and group discussion/feedback on clinical decisions with supportive reasoning. The class year before and class year of the TBL implementation were compared using the total percentage of points possible earned by the class years, by topic. To minimize potential confounding, the primary outcome was the change in topic performance by the rank difficulty (e.g., the largest possible benefit being the hardest topic becoming the easiest with no other variation in topic rank difficulty)., Results: In the year of implementation, the mean individual readiness assurance test (IRAT) performance was 5.5 ± 1.88 (10 points possible, 55%). The mean team readiness assurance test (TRAT) performance was 10 of 10 points possible (100%). The class exam item performance in the year before ( n = 101) and year of ( n = 84) TBL implementation showed a general decline in exam scores. However, the vancomycin topic difficultly went from fifth easiest, to second easiest, with less than 1% change in raw score., Conclusions: Implementation of a pharmacokinetic TBL activity appeared to moderately support the students' vancomycin learning. Additional studies are warranted on APPE readiness and performance.

Purpose: To review interim data regarding longitudinal burnout and empathy levels in a single Doctor of Pharmacy class cohort., Methods: Students were emailed an electronic survey during their first semester and annually at the end of each academic year for a total of 3 years (2017-2020). Validated survey tools included the Jefferson Scale of Empathy (JSE) and the Maslach Burnout Inventory (MBI) student version. The JSE survey consists of 20 questions, with higher scores denoting more empathy. The MBI student version contains 3 subscales: exhaustion (higher scores are worse), cynicism (higher scores are worse) and professional efficacy (higher scores are better)., Results: The median JSE score at the end of the third academic year (PY3) was 110, with females scoring significantly higher (114.5 vs. 103.5; p<0.02). A majority of the 62 students reported burn out (82.3%), scoring in the highest category for either exhaustion (76%) or cynicism (55%). A majority (66%) also reported a low or moderate professional efficacy score, a negative finding. Measures of student burnout increased after the start of the program and remained at the higher level each subsequent year (p<0.0001). In the Spring of 2020, during the COVID-19 pandemic, nearly every student had moderate or high levels of emotional exhaustion (97%) and cynicism (78%) as measured by the MBI., Conclusion: This interim data suggests high degrees of pharmacy student burnout. Empathy levels remained stable throughout the duration of the study. Pharmacy schools may need to focus on reform regarding well-being and prevention of burnout.

Objective. This integrative review summarizes the literature addressing emotional intelligence among health care professionals and students to better define and incorporate it into the pharmacy curricula. Findings. Emotional intelligence is an essential attribute for relationship building, stress management, and self-regulation. Pharmacy students must develop and improve their emotional intelligence to support their development of successful relationships with patients, pharmacy colleagues, and other health care providers. In addition, awareness of one's own biases and emotions can help with behavioral regulation, which can facilitate enhanced communications with others. Increasing evidence suggests that emotional intelligence can influence academic success, the ability to provide compassionate and competent patient care, the ability to lead and influence others, and the ability to manage stress, all of which are important in pharmacy education. Educators can help learners develop emotional intelligence by designing activities that directly identify and target areas of weakness while leveraging areas of strength. Summary. This article discusses key background studies on emotional intelligence in the health professions literature and identifies specific methods and strategies to develop learners' emotional intelligence within the curriculum., (© 2022 American Association of Colleges of Pharmacy.)

The realism of body and actions in dreams is thought to be induced by simulations based on internal representations used during wakefulness. As somatosensory signals contribute to the updating of body and action representations, these are impaired when somatosensory signals are lacking. Here, we tested the hypothesis that individuals with somatosensory deafferentation have impaired body and actions in their dreams, as in wakefulness. We questioned three individuals with a severe, acquired sensory neuropathy on their dreams. While deafferented participants were impaired in daily life, they could dream of themselves as able-bodied, with some sensations (touch, proprioception) and actions (such as running or jumping) which had not been experienced in physical life since deafferentation. We speculate that simulation in dreams could be based on former, "healthy" body and action representations. Our findings are consistent with the idea that distinct body and action representations may be used during dreams and wakefulness., 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 © 2022 Elsevier Inc. All rights reserved.)

Aniridia is a panocular condition characterized by impaired eye development and vision, which is mainly due to the haploinsufficiency of the paired-box-6 (PAX6) gene. Like what is seen in aniridia patients, Pax6-deficient mice Pax6 Sey -Neu/+ exhibit a varied degree of ocular damage and impaired vision. Our previous studies showed that these phenotypes were partially rescued by PD0325901, a mitogen-activated protein kinase kinase (MEK or MAP2K) inhibitor. In this study, we assessed the long-term efficacy of PD0325901 treatment in retinal health and visual behavior. At about one year after the postnatal treatment with PD0325901, Pax6 Sey-Neu/+ mice showed robust improvements in retina size and visual acuity, and the elevated intraocular pressure (IOP) was also alleviated, compared to age-matched mice treated with vehicles only. Moreover, the Pax6 Sey-Neu/+ eyes showed disorganized retinal ganglion cell (RGC) axon bundles and retinal layers, which we termed as hotspots. We found that the PD treatment reduced the number and size of hotspots in the Pax6 Sey-Neu/+ retinas. Taken together, our results suggest that PD0325901 may serve as an efficacious intervention in protecting retina and visual function in aniridia-afflicted subjects., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Emotional intelligence (EI) is known to improve teamwork, communication, and organizational commitment. The role of EI has also influenced pharmacists' ability to empathize, control emotions, and actively listen. Although EI's impact on work-related components, including occupational stress, job performance, and psychological affective well-being, has been studied, there are no data specific to the practice of pharmacy., Objective: The primary objective of this study was to determine whether a significant correlation exists between pharmacist EI and work-related components., Methods: A voluntary Qualtrics survey (Qualtrics, Provo, UT) was distributed electronically to all active pharmacists licensed by the Florida Board of Pharmacy, which included questions from valid and reliable assessment tools. Spearman correlations were used to examine the association between EI facets and dependent variables of occupational stress, job performance, and psychological affective well-being. A subanalysis was conducted to evaluate demographic data. Statistical significance was set at P < 0.05 for all tests. Incomplete survey responses were included in the analysis., Results: A total of 942 responses were received and analyzed. Most of the respondents were aged 44 years or younger (42.5%), female (46.9%), identified as Caucasian (52.8%), and worked 31-40 hours weekly (20.6%). Most of the respondents reported a primary employment setting within community (29.3%) or hospital (18.6%) pharmacy. Higher EI correlated with lower levels of occupational stress, higher job performance, and higher psychological affective well-being. Secondary outcomes reported increased stress for both females and those practicing in the community setting; hospital-based pharmacists reported higher job performance and psychological affective well-being. Stress decreased with both age and years of experience., Conclusion: Higher EI may support overall wellness for pharmacists on the basis of the results of this study. Additional evaluation of demographic data, including practice settings, and a more robust cohort of participants would provide more insight in this area., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Introduction: To determine the impact of emergent transition from in-person to remote learning on student performance within real-time objective structured clinical examinations (OSCEs)., Methods: A university mandate, due to severe SARS-CoV-2, was issued requiring didactic courses to transition to remote learning in spring 2020. The third-year internal medicine elective had six remaining weekly OSCEs, accounting for 55% of course grades. Full credit was awarded for the first OSCE as students familiarized themselves with the new virtual format. The primary outcome was the overall average OSCE performance for the course's remaining five virtual simulations compared to the traditional in-person offering in 2019. Secondary outcomes included individual OSCE performance, OSCE performance with inclusion of the first OSCE, and overall course grades., Results: There were no statistically significant differences in overall average OSCE performance between 2019 and 2020 cohorts for the five simulations (82.7% vs. 86.8%, P = .20). Secondary outcomes showed statistically significant differences favoring performance in the 2020 cohort for infectious diseases (78.3% vs. 89.4%, P < .001) and anticoagulation (74.4% vs. 90%, P = .002), while cardiology favored the 2019 cohort (91.1% vs. 82.8%, P = .03). There was no statistically significant difference in performance on the cumulative I (86.1% vs. 82.2%, P = .41) or cumulative II (83.3% vs. 89.4%, P = .29) simulations or in final overall course grades (86.6% vs. 90.2%, P = .06)., Conclusions: An emergent transition to remote learning may not negatively impact student performance on real-time OSCE activities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Continuing education (CE) standards by the Accreditation Council for Pharmacy Education emphasize that educational methodologies should contribute to the development of participants' critical thinking and problem-solving skills. Employment of serious gaming can meet this expectation through motivation, timely feedback, and challenging all performance levels. Current literature is lacking regarding use of game-based learning, such as "escape rooms" in pharmacy CE programming., Methods: This pilot study enrolled participants at a two-hour medication error CE presentation. Study investigators utilized the first hour for lecture and the second hour for application through an "escape room" activity. During this activity, participants used critical thinking and teamwork to unlock puzzles for root cause analysis (RCA) creation in a provided timeframe. An optional, online anonymous survey was emailed to attendees. Responses were rated on a five-point Likert scale; descriptive statistics were represented by percent distributions., Results: A total of 40 pharmacists and seven technicians responded to the perception survey. Most respondents felt this activity emphasized critical thinking (87%) and was appropriate for the topic of medication errors (83%). The majority (63%) agreed this activity helped them to better understand a RCA, 48% felt the group sizes were appropriate, and 76% felt instructions for the activity were clear. Over 75% would like to see this type of activity utilized in another CE programs., Conclusions: This activity was well received by participants and may emphasize critical thinking and understanding of topics presented. Further studies assessing pre-/post-program knowledge are needed to ensure adequate retention of information., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Studies of chronically deafferented participants have illuminated how regaining some motor control after adult-onset loss of proprioceptive and touch input depends heavily on cognitive control. In this study we contrasted the performance of one such man, IW, with KS, a woman born without any somatosensory fibres. We postulated that her life-long absence of proprioception and touch might have allowed her to automate some simple visually-guided actions, something IW appears unable to achieve. We tested these two, and two age-matched control groups, on writing and drawing tasks performed with and without an audio-verbal echoing task that added a cognitive demand. In common with other studies of skilled action, the dual task was shown to affect visuo-motor performance in controls, with less well-controlled drawing and writing, evident as increases in path speed and reduction in curvature and trial duration. We found little evidence that IW was able to automate even the simplest drawing tasks and no evidence for automaticity in his writing. In contrast, KS showed a selective increase in speed of signature writing under the dual-task conditions, suggesting some ability to automate her most familiar writing. We also tested tracing of templates under mirror-reversed conditions, a task that imposes a powerful cognitive planning challenge. Both IW and KS showed evidence of a visuo-motor planning conflict, as did the controls, for shapes with sharp corners. Overall, IW was much faster than his controls to complete tracing shapes, consistent with an absence of visuo-proprioceptive conflict, whereas KS was slower than her controls, especially as the corners became sharper. She dramatically improved after a short period of practice while IW did not. We conclude that KS, who developed from birth without proprioception, may have some visually derived control of movement not under cognitive control, something not seen in IW. This allowed her to automate some writing and drawing actions, but impaired her initial attempts at mirror-tracing. In contrast, IW, who lost somatosensation as an adult, cannot automate these visually guided actions., (© 2021. The Author(s).)

The degree to which mental representations of the body can be established and maintained without somatosensory input remains unclear. We contrast two "deafferented" adults, one who acquired large fibre sensory loss as an adult (IW) and another who was born without somatosensation (KS). We compared their responses to those of matched controls in three perceptual tasks: first accuracy of their mental image of their hands (assessed by testing recognition of correct hand length/width ratio in distorted photographs and by locating landmarks on the unseen hand); then accuracy of arm length judgements (assessed by judgement of reaching distance), and finally, we tested for an attentional bias towards peri-personal space (assessed by reaction times to visual target presentation). We hypothesised that IW would demonstrate responses consistent with him accessing conscious knowledge, whereas KS might show evidence of responses dependent on non-conscious mechanisms. In the first two experiments, both participants were able to give consistent responses about hand shape and arm length, but IW displayed a better awareness of hand shape than KS (and controls). KS demonstrated poorer spatial accuracy in reporting hand landmarks than both IW and controls, and appears to have less awareness of her hands. Reach distance was overestimated by both IW and KS, as it was for controls; the precision of their judgements was slightly lower than that of the controls. In the attentional task, IW showed no reaction time differences across conditions in the visual detection task, unlike controls, suggesting that he has no peri-personal bias of attention. In contrast, KS did show target location-dependent modulation of reaction times, when her hands were visible. We suggest that both IW and KS can access a conscious body image, although its accuracy may reflect their different experience of hand action. Acquired sensory loss has deprived IW of any subconscious body awareness, but the congenital absence of somatosensation may have led to its partial replacement by a form of visual proprioception in KS.

Neural stem cells (NSCs) generate neurons throughout life in the mammalian hippocampus. However, the potential for long-term self-renewal of individual NSCs within the adult brain remains unclear. We used two-photon microscopy and followed NSCs that were genetically labeled through conditional recombination driven by the regulatory elements of the stem cell-expressed genes GLI family zinc finger 1 (Gli1) or achaete-scute homolog 1 (Ascl1). Through intravital imaging of NSCs and their progeny, we identify a population of Gli1-targeted NSCs showing long-term self-renewal in the adult hippocampus. In contrast, once activated, Ascl1-targeted NSCs undergo limited proliferative activity before they become exhausted. Using single-cell RNA sequencing, we show that Gli1- and Ascl1-targeted cells have highly similar yet distinct transcriptional profiles, supporting the existence of heterogeneous NSC populations with diverse behavioral properties. Thus, we here identify long-term self-renewing NSCs that contribute to the generation of new neurons in the adult hippocampus.

Competing Interests: Conflict of interest None.

During immature stages, adult-born neurons pass through critical periods for survival and plasticity. It is generally assumed that by 2 months of age adult-born neurons are mature and equivalent to the broader neuronal population, raising questions of how they might contribute to hippocampal function in old age when neurogenesis has declined. However, few have examined adult-born neurons beyond the critical period or directly compared them to neurons born in infancy. Here, we used a retrovirus to visualize functionally relevant morphological features of 2- to 24-week-old adult-born neurons in male rats. From 2 to 7 weeks, neurons grew and attained a relatively mature phenotype. However, several features of 7-week-old neurons suggested a later wave of growth: these neurons had larger nuclei, thicker dendrites, and more dendritic filopodia than all other groups. Indeed, between 7 and 24 weeks, adult-born neurons gained additional dendritic branches, formed a second primary dendrite, acquired more mushroom spines, and had enlarged mossy fiber presynaptic terminals. Compared with neonatal-born neurons, old adult-born neurons had greater spine density, larger presynaptic terminals, and more putative efferent filopodial contacts onto inhibitory neurons. By integrating rates of cell birth and growth across the life span, we estimate that adult neurogenesis ultimately produces half of the cells and the majority of spines in the dentate gyrus. Critically, protracted development contributes to the plasticity of the hippocampus through to the end of life, even after cell production declines. Persistent differences from neonatal-born neurons may additionally endow adult-born neurons with unique functions even after they have matured. SIGNIFICANCE STATEMENT Neurogenesis occurs in the hippocampus throughout adult life and contributes to memory and emotion. It is generally assumed that new neurons have the greatest impact on behavior when they are immature and plastic. However, since neurogenesis declines dramatically with age, it is unclear how they might contribute to behavior later in life when cell proliferation has slowed. Here we find that newborn neurons mature over many months in rats and may end up with distinct morphological features compared with neurons born in infancy. Using a mathematical model, we estimate that a large fraction of neurons is added in adulthood. Moreover, their extended growth produces a reserve of plasticity that persists even after neurogenesis has declined to low rates., (Copyright © 2020 the authors.)

Objectives : Rodent models of optic nerve crush (ONC) have often been used to study degeneration and regeneration of retinal ganglion cells (RGCs) and their axons as well as the underlying molecular mechanisms. However, ONC results from different laboratories exhibit a range of RGC injury with varying degree of axonal damage. We developed instrumented tweezers to measure optic nerve (ON) crush forces in real time and studied the correlation between RGC axon loss and force-impulse, the product of force and duration, applied through the instrumented tweezers in mice. Methods : A pair of standard self-closing #N7 tweezers were instrumented with miniature foil strain gauges at optimal locations on both tweezers' arms. The instrumented tweezers were capable of recording the tip closure forces in the form of voltages, which were calibrated through load cells to corresponding tip closure forces over the operating range. Using the instrumented tweezers, the ONs of multiple mice were crushed with varied forces and durations and the axons in the immunostained sections of the crushed ONs were counted. Results : We found that the surviving axon density correlated with crush force, with longer duration and stronger crush forces producing consistently more axon damage. Discussion : The instrumented tweezers enable a simple technique for measurement of ONC forces in real-time for the first time. Using the instrumented tweezers, experimenters can quantify crush forces during ONC to produce consistent and predictable post-crush cell death. This should permit future studies a way to produce nerve damage more consistently than is available now.

Introduction: Regardless of the practice setting, pharmacists' roles often expand beyond patient-centered services and into health-related educational roles for patients, healthcare providers, and student pharmacists. Teaching roles of a clinical pharmacist can include providing invited presentations (such as continuing education lectures), teaching colleagues about new clinical initiatives, precepting students during advanced pharmacy practice experiences (APPEs) and introductory pharmacy practice experiences (IPPEs), and precepting residents on rotations. This program was designed to evaluate the effect of a university-affiliated pharmacy teaching certificate program on participant knowledge and perceived confidence in specific areas of academic pharmacy and preceptor development., Methods: A 10-month program consisting of four live modules with associated continuing education (CE) credit was offered to pharmacy residents and practicing pharmacists in the surrounding area. The program format utilized didactic and active learning strategies with "at home" assignments to reinforce material presented. Content knowledge was measured with written summative assessments provided at the start and end of each module. Perceived confidence was assessed through online surveys provided at the start and end of the program. All results were evaluated using paired t-tests., Results: Data were obtained from 14 participants in the first cohort and 18 participants in the second cohort. For each of the four modules, there was a significant difference in pre- and post-knowledge assessments. Confidence data was also significantly increased regarding topics in each module., Conclusion: Knowledge assessments and perception surveys suggest that this university-affiliated teaching certificate program improved both knowledge and perceived confidence for program participants., (Copyright © 2019 Elsevier Inc. All rights reserved.)

During hippocampal-dependent memory formation, sensory signals from the neocortex converge in the dentate gyrus. It is generally believed that the dentate gyrus decorrelates inputs in order to minimize interference between codes for similar experiences, often referred to as pattern separation. The proportion of dentate neurons that are activated by experience is therefore likely to impact how memories are stored and separated. Emerging evidence from mouse models suggests that adult-born neurons can both increase and decrease activity levels in the dentate gyrus. However, the conditions that determine the direction of this modulation, and whether it occurs in other species, remains unclear. Furthermore, since the dentate gyrus is composed of a heterogeneous population of cells that are born throughout life, newborn neurons may not modulate all cells equally. We aimed to investigate whether adult neurogenesis in rats regulates activity in dentate gyrus neurons that are born at the peak of early postnatal development. Adult neurogenesis was increased by subjecting rats to an alternating running and memantine treatment schedule, and it was decreased with a transgenic GFAP-TK rat model. Activity was measured by Fos expression in BrdU + cells after rats explored a novel environment. Running+memantine treatment increased adult neurogenesis by only 17%, but completely blocked experience-dependent Fos expression. In contrast, GFAP-TK rats had a 68% reduction in adult neurogenesis but normal experience-dependent Fos expression. The inconsistent relationship between neurogenesis and Fos expression suggests that neurogenesis does not regulate DG activity during exploration of a novel environment. Nonetheless, running and memantine may benefit disorders where there is elevated activity in the dentate gyrus, such as anxiety and age-related memory impairments., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Previous work has highlighted the role of haptic feedback for manual dexterity, in particular for the control of precision grip forces between the index finger and thumb. It is unclear how fine motor skills involving more than just two digits might be affected, especially given that loss of sensation from the hand affects many neurological patients, and impacts on everyday actions. To assess the functional consequences of haptic deficits on multi-digit grasp of objects, we studied the ability of three rare individuals with permanent large-fibre sensory loss involving the entire upper limb. All three reported difficulties in everyday manual actions (ABILHAND questionnaire). Their performance in a reach-grasp-lift task was compared to that of healthy controls. Twenty objects of varying shape, mass, opacity and compliance were used. In the reach-to-grasp phase, we found slower movement, larger grip aperture and less dynamic modulation of grip aperture in deafferented participants compared to controls. Hand posture during the lift phase also differed; deafferented participants often adopted hand postures that may have facilitated visual guidance, and/or reduced control complexity. For example, they would extend fingers that were not in contact with the object, or fold these fingers into the palm of the hand. Variability in hand postures was increased in deafferented participants, particularly for smaller objects. Our findings provide new insights into how the complex control required for whole hand actions is compromised by loss of haptic feedback, whose contribution is, thus, highlighted.

Adult neurogenesis has potential to ameliorate a number of disorders that negatively impact the hippocampus, including age-related cognitive decline, depression, and schizophrenia. A number of treatments enhance adult neurogenesis including exercise, NMDA receptor antagonism, antidepressant drugs and environmental enrichment. Despite the chronic nature of many disorders, most animal studies have only examined the efficacy of neurogenic treatments over short timescales (≤1 month). Also, studies of neurogenesis typically include only 1 sex, even though many disorders differentially impact males and females. We tested whether two known neurogenic treatments, running and the NMDA receptor antagonist, memantine, could cause sustained increases in neurogenesis in male and female rats. We found that continuous access to a running wheel (cRUN) initially increased neurogenesis, but effects were minimal after 1 month and completely absent after 5 months. Similarly, a single injection of memantine (sMEM) transiently increased neurogenesis before returning to baseline at 1 month. To determine whether neurogenesis could be increased over a 2-month timeframe, we next subjected rats to interval running (iRUN), multiple memantine injections (mMEM), or alternating blocks of iRUN and mMEM. Two months of iRUN increased DCX + cells in females and iRUN followed by mMEM increased DCX + cells in males, indicating that neurogenesis was increased in the later stages of the treatments. However, thymidine analogs revealed that neurogenesis was minimally increased during the initial stages of the treatments. These findings highlight temporal limitations and sex differences in the efficacy of neurogenic manipulations, which may be relevant for designing plasticity-promoting treatments., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

It is uncertain how vision and proprioception contribute to adaptation of voluntary arm movements. In normal participants, adaptation to imposed forces is possible with or without vision, suggesting that proprioception is sufficient; in participants with proprioceptive loss (PL), adaptation is possible with visual feedback, suggesting that proprioception is unnecessary. In experiment 1 adaptation to, and retention of, perturbing forces were evaluated in three chronically deafferented participants. They made rapid reaching movements to move a cursor toward a visual target, and a planar robot arm applied orthogonal velocity-dependent forces. Trial-by-trial error correction was observed in all participants. Such adaptation has been characterized with a dual-rate model: a fast process that learns quickly, but retains poorly and a slow process that learns slowly and retains well. Experiment 2 showed that the PL participants had large individual differences in learning and retention rates compared to normal controls. Experiment 3 tested participants' perception of applied forces. With visual feedback, the PL participants could report the perturbation's direction as well as controls; without visual feedback, thresholds were elevated. Experiment 4 showed, in healthy participants, that force direction could be estimated from head motion, at levels close to the no-vision threshold for the PL participants. Our results show that proprioceptive loss influences perception, motor control and adaptation but that proprioception from the moving limb is not essential for adaptation to, or detection of, force fields. The differences in learning and retention seen between the three deafferented participants suggest that they achieve these tasks in idiosyncratic ways after proprioceptive loss, possibly integrating visual and vestibular information with individual cognitive strategies.

Objective. To assess the impact of peer-teaching on student scores and confidence when preparing for a final objective structured clinical examination (OSCE) within a Doctor of Pharmacy program. Methods. First-year pharmacy students (n=45) attended a peer-led training session led by upperclassmen (n=17) on a variety of clinical skills to be assessed on a final course OSCE. Their scores were collected and compared to students who did not attend the training. Confidence scores were also evaluated using voluntary pre- and post-surveys. Results. An overall 3% increase in scores was recorded from the objective skills examination. Student confidence scores also increased for each of the skills evaluated with an overall improvement of 1.1 on a 5-point Likert scale. Conclusion. Peer-assisted learning was effective in increasing student performance and confidence in the OSCE. Based on the positive results, the peer-led training event will be improved upon and used again in the future.

Objectives: To integrate fourth-year student pharmacists on advanced pharmacy practice experience (APPE) rotations within several different ambulatory clinics to perform medication reconciliations and enhance interdisciplinary practice., Methods: The study design was a descriptive, prospective multisite study among a variety of ambulatory care outpatient clinics. Student pharmacists were partnered with physicians to conduct medication reconciliations during clinic visits for 4 hours per week, with data collection from January 2016 to September 2016. This program originated from physician requests for additional pharmacy involvement and led to the development of a successful implementation strategy to involve student pharmacists in the medication reconciliation process., Results: Student pharmacists identified 537 medication discrepancies among 491 patients, including commission of medications (36%), documentation of previously omitted medications (27%), and incomplete patient allergy information (11%). Students spent an average of 10 minutes on each encounter., Conclusion: Documentation from this innovative program suggests improvement in medication reconciliation and enhanced patient care with limited time required of student pharmacists. A similar program could be developed and utilized at other clinical sites.

There is a continuing debate about control of voluntary movement, with conflicted evidence about the balance between control of movement vectors (amplitude control) that implies knowledge of the starting position for accuracy, and equilibrium point or final position control, that is independent of the starting conditions. We tested wrist flexion and extension movements in a man with a chronic peripheral neuronopathy that deprived him of proprioceptive knowledge of his wrist angles. In a series of experiments, we demonstrate that he could scale the amplitude of his wrist movements in flexion/extension, even without visual feedback, and appeared to adopt a strategy of moving via a central wrist position when asked to reach target angles from unknown start locations. When examining the relationship between positional error at the start and end of each movement in long sequences of movements, we report that he appears to have three canonical positions that he can reach relatively successfully, in flexion, in extension and in the centre. These are consistent with end-point or position control. Other positions were reached with errors that suggest amplitude control. Recording wrist flexor and extensor EMG confirmed that the flexion and extension canonical positions were reached by strong flexor and extensor activity, without antagonist activity, and other positions were reached with graded muscle activation levels. The central canonical position does not appear to be reached by either maximal co-contraction or by complete relaxation, but may have been reached by matched low-level co-contraction.

Humans have the remarkable ability to adapt their motor behaviour to changes in body properties and/or environmental conditions, based on sensory feedback such as vision and proprioception. The role of proprioception has been highlighted for the adaptation to new upper-limb dynamics, which is known to generalize to the opposite, non-adapted limb in healthy individuals. Such interlimb transfer seems to depend on sensory feedback, and the present study assessed whether the chronic loss of proprioception precludes interlimb transfer of dynamic adaptation by testing two well-characterized proprioceptively-deafferented subjects. These had to reach toward visual targets with vision of the limb. For both deafferented subjects, we observed adaptation of the dominant arm to Coriolis forces and after-effects on non-dominant arm movements in different movement directions, thus indicating interlimb transfer. Overall, our findings show that motor learning can generalize across limbs and movement directions despite the loss of proprioceptive afferents., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Significant innovations in the field of total ankle replacement surgery have occurred since the early disappointing experiences with first-generation devices. In recent years, total ankle arthroplasties are commonly placed in patients with end-stage ankle osteoarthrosis, supplanting ankle arthrodesis as the procedure of choice at some institutions. Careful clinical and preoperative radiographic evaluation is helpful to plan concomitant ligament release, ligament reconstruction, or osteotomy. Careful attention to radiographic signs of early hardware loosening or subsidence can prompt intervention while bone loss is still minimal, and computed tomography has an adjunct role in the evaluation of periprosthetic lucency and osteolysis., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Signals associated with the command the brain sends to muscles are thought to create the sensation of heaviness when we lift an object. Thus, as a muscle is weakened by fatigue or partial paralysis (neuromuscular blockade), the increase in the motor command needed to lift a weight is thought to explain the increasing subjective heaviness of the lifted object.With different fatiguing contractions we approximately halved the force output of the thumb flexor muscles, which were then used to lift an object. For two deafferented subjects the perceived heaviness of the lifted object approximately doubled, in keeping with the central-signal theory. However, for normal subjects this resulted in objects feeling the same or lighter, inconsistent with the central-signal theory but consistent with the expected effects of the conditioning contractions on the sensitivity of peripheral receptors. In separate experiments we subjected the forearm muscles to complete paralysis with a non-depolarising neuromuscular blocking agent and then allowed them to recover to approximately half-force output. This also resulted in objects feeling lighter when lifted by the semi-paralysed thumb, even though the motor command to the motoneurons must have been greater. This is readily explained by reduced lift-related reafference caused by the prolonged paralysis of muscle spindle intrafusal fibres.We conclude that peripheral signals, including a major contribution from muscle spindles, normally give rise to the sense of exerted force. In concept, however, reafference from peripheral receptors may also be considered a centrally generated signal that traverses efferent and then afferent pathways to feed perceptual centres rather than one confined entirely to the central nervous system. These results therefore challenge the distinction between central- and peripheral-based perception, and the concept that muscle spindles provide only information about limb position and movement.

Background: Although feed-forward mechanisms of grip force control are a prerequisite for skilled object manipulation, somatosensory feedback is essential to acquire, maintain, and adapt these mechanisms., Objective: Individuals with complete peripheral deafferentation provide the unique opportunity to study the function of the motor system deprived of somatosensory feedback., Methods: Two individuals (GL and IW) with complete chronic deafferentation of the trunk and limbs were tested during cyclic vertical movements of a hand-held object. Such movements induce oscillating loads that are typically anticipated by parallel modulations of the grip force. Load magnitude was altered by varying either the movement frequency or object weight., Results: GL and IW employed excessive grip forces probably reflecting a compensatory mechanism. Despite this overall force increase, both deafferented participants adjusted their grip force level according to the load magnitude, indicating preserved scaling of the background grip force to physical demands. The dynamic modulation of the grip force with the load force was largely absent in GL, whereas in IW only slower movements were clearly affected., Conclusions: The authors hypothesize that the deafferented patients may have utilized visual and vestibular cues and/or an efferent copy of the motor command of the arm movement to scale the grip force level. Severely impaired grip force-load coupling in GL suggests that sensory information is important for maintaining a precise internal model of dynamic grip force control. However, comparably better performance in IW argues for the possibility that alternative cues can be used to trigger a residual internal model.

Open tibial shaft fractures were analyzed retrospectively to determine the effect of treatment timing on infection and nonunion rates. The cases of 77 patients with 81 open tibial shaft fractures were reviewed. Patients were treated with initial wound cleansing and splinting in the emergency department and then formally with operative irrigation and débridement and stabilization, which included intramedullary (IM) nailing, external fixation, open reduction and internal fixation, or splinting. All tibial shaft components ultimately were treated with IM nailing. Mean time to operative treatment was 12.97 hours (SD, 10.8 hours). There were 7 infections (8.6%) and 3 nonunions (3.7%). Time was found not to be a significant factor in predicting either infection or nonunion. Increased severity of fracture was a significant factor in predicting infection rate. The infection rate for fractures treated first with external fixation and then with IM nailing was significantly higher than that for fractures treated with IM nailing alone. In addition, a relation was found between patients who received multiple débridements and development of infection. These results show that infection and nonunion rates were not adversely affected by longer time to operative treatment (up to 48 hours) when adequate trauma department open fracture care and early initiation of antibiotics were coupled with standardized and thorough débridement in the operative theater.