Subthalamic nucleus deep brain stimulation programming settings do not correlate with Parkinson's disease severity.

BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease (PD). While the success of DBS is dependent on careful patient selection and accurate lead placement, programming parameters play a pivotal role in tailoring therapy on the individual level. Various algorithms have been developed to streamline the initial programming process, but the relationship between pre-operative patient characteristics and post-operative device settings is unclear. In this study, we investigated how PD severity correlates with DBS settings. METHODS: We conducted a retrospective review of PD patients who underwent DBS of the subthalamic nucleus at one US tertiary care center between 2014 and 2018. Pre-operative patient characteristics and post-operative programming data at various intervals were collected. Disease severity was measured using the Unified Parkinson's Disease Rating Scale score (UPDRS) as well as levodopa equivalent dose (LED). Correlation analyses were conducted looking for associations between pre-operative disease severity and post-operative programming parameters. RESULTS: Fifty-six patients were analyzed. There was no correlation between disease severity and any of the corresponding programming parameters. Pre-operative UPDRS scores on medication were similar to post-operative scores with DBS. Settings of amplitude, frequency, and pulse width increased significantly from 1 to 6 months post-operatively. Stimulation volume, inferred by the distance between contacts used, also increased significantly over time. CONCLUSIONS: Interestingly, we found that patients with more advanced disease responded to electrical stimulation similarly to patients with less advanced disease. These data provide foundational knowledge of DBS programming parameters used in a single cohort of PD patients over time.

Embryonic microglia influence developing hypothalamic glial populations.

BACKGROUND: Although historically microglia were thought to be immature in the fetal brain, evidence of purposeful interactions between these immune cells and nearby neural progenitors is becoming established. Here, we examined the influence of embryonic microglia on gliogenesis within the developing tuberal hypothalamus, a region later important for energy balance, reproduction, and thermoregulation. METHODS: We used immunohistochemistry to quantify the location and numbers of glial cells in the embryonic brain (E13.5-E17.5), as well as a pharmacological approach (i.e., PLX5622) to knock down fetal microglia. We also conducted cytokine and chemokine analyses on embryonic brains in the presence or absence of microglia, and a neurosphere assay to test the effects of the altered cytokines on hypothalamic progenitor behaviors. RESULTS: We identified a subpopulation of activated microglia that congregated adjacent to the third ventricle alongside embryonic Olig2+ neural progenitor cells (NPCs) that are destined to give rise to oligodendrocyte and astrocyte populations. In the absence of microglia, we observed an increase in Olig2+ glial progenitor cells that remained at the ventricle by E17.5 and a concomitant decrease of these Olig2+ cells in the mantle zone, indicative of a delay in migration of these precursor cells. A further examination of maturing oligodendrocytes in the hypothalamic grey and white matter area in the absence of microglia revealed migrating oligodendrocyte progenitor cells (OPCs) within the grey matter at E17.5, a time point when OPCs begin to slow their migration. Finally, quantification of cytokine and chemokine signaling in ex vivo E15.5 hypothalamic cultures +/- microglia revealed decreases in the protein levels of several cytokines in the absence of microglia. We assayed the influence of two downregulated cytokines (CCL2 and CXCL10) on neurosphere-forming capacity and lineage commitment of hypothalamic NPCs in culture and showed an increase in NPC proliferation as well as neuronal and oligodendrocyte differentiation. CONCLUSION: These data demonstrate that microglia influence gliogenesis in the developing tuberal hypothalamus.

Poor postoperative pain control is associated with poor long-term patient-reported outcomes after elective spine surgery: an observational cohort study.

BACKGROUND CONTEXT: A significant proportion of patients experience poorly controlled surgical pain and fail to achieve satisfactory clinical improvement after spine surgery. However, a direct association between these variables has not been previously demonstrated. PURPOSE: To investigate the association between poor postoperative pain control and patient-reported outcomes after spine surgery. STUDY DESIGN: Ambispective cohort study. PATIENT SAMPLE: Consecutive adult patients (≥18-years old) undergoing inpatient elective cervical or thoracolumbar spine surgery. OUTCOME MEASURE: Poor surgical outcome was defined as failure to achieve a minimal clinically important difference (MCID) of 30% improvement on the Oswestry Disability Index or Neck Disability Index at follow-up (3-months, 1-year, and 2-years). METHODS: Poor pain control was defined as a mean numeric rating scale score of >4 during the first 24-hours after surgery. Multivariable mixed-effects regression was used to investigate the relationship between poor pain control and changes in surgical outcomes while adjusting for known confounders. Secondarily, the Calgary Postoperative Pain After Spine Surgery (CAPPS) Score was investigated for its ability to predict poor surgical outcome. RESULTS: Of 1294 patients, 47.8%, 37.3%, and 39.8% failed to achieve the MCID at 3-months, 1-year, and 2-years, respectively. The incidence of poor pain control was 56.9%. Multivariable analyses showed poor pain control after spine surgery was independently associated with failure to achieve the MCID (OR 2.35 [95% CI=1.59-3.46], p<.001) after adjusting for age (p=.18), female sex (p=.57), any nicotine products (p=.041), ASA physical status >2 (p<.001), ≥3 motion segment surgery (p=.008), revision surgery (p=.001), follow-up time (p<.001), and thoracolumbar surgery compared to cervical surgery (p=.004). The CAPPS score was also found to be independently predictive of poor surgical outcome. CONCLUSION: Poor pain control in the first 24-hours after elective spine surgery was an independent risk factor for poor surgical outcome. Perioperative treatment strategies to improve postoperative pain control may lead to improved patient-reported surgical outcomes.

Embryonic Microglia Interact with Hypothalamic Radial Glia during Development and Upregulate the TAM Receptors MERTK and AXL following an Insult.

Despite a growing appreciation for microglial influences on the developing brain, the responsiveness of microglia to insults during gestation remains less well characterized, especially in the embryo when microglia themselves are still maturing. Here, we asked if fetal microglia could coordinate an innate immune response to an exogenous insult. Using time-lapse imaging, we showed that hypothalamic microglia actively surveyed their environment by near-constant "touching" of radial glia projections. However, following an insult (i.e., IUE or AAV transduction), this seemingly passive touching became more intimate and long lasting, ultimately resulting in the retraction of radial glial projections and degeneration into small pieces. Mechanistically, the TAM receptors MERTK and AXL were upregulated in microglia following the insult, and Annexin V treatment inhibited radial glia breakage and engulfment by microglia. These data demonstrate a remarkable responsiveness of embryonic microglia to insults during gestation, a critical window for neurodevelopment.

Medical student wellness in Canada: time for a national curriculum framework.

There is substantial evidence showing that medical student wellness is a worsening problem in Canada. It is apparent that medical students' wellness deteriorates throughout their training. Medical schools and their governing bodies are responding by integrating wellness into competency frameworks and accreditation standards through a combination of system- and individual-level approaches. System-level strategies that consider how policies, medical culture, and the "hidden curriculum" impact student wellness, are essential for reducing burnout prevalence and achieving optimal wellness outcomes. Individual-level initiatives such as wellness programming are widespread and more commonly used. These are often didactic, placing the onus on the student without addressing the learning environment. Despite significant progress, there is little programming consistency across schools or training levels. There is no wellness curriculum framework for Canadian undergraduate medical education that aligns with residency competencies. Creating such a framework would help align individual- and system-level initiatives and smooth the transition from medical school to residency. The framework would organize goals within relevant wellness domains, allow for local adaptability, consider basic learner needs, and be learner-informed. Physicians whose wellness has been supported throughout their training will positively contribute to the quality of patient care, work environments, and in sustaining a healthy Canadian population.

Nous disposons d'un grand nombre de données concrètes démontrant que le bien-être des étudiants en médecine au Canada se détériore tout au long de leur cheminement universitaire et que le problème s'aggrave. Alliant les approches systémique et individuelle, les facultés de médecine et leurs directions réagissent en intégrant le bien-être dans les cadres de compétences et les normes d'agrément. Les stratégies systémiques, qui tiennent compte de l'impact des politiques, de la culture médicale et du «curriculum caché¼ sur le bien-être des étudiants, sont indispensables pour prévenir l'épuisement professionnel et pour obtenir des résultats optimaux en matière de bien-être. Les initiatives au niveau individuel, comme les programmes axés sur le bien-être, sont de plus en plus répandues. Ces programmes sont souvent didactiques et ils sollicitent l'étudiant sans tenir compte de l'environnement d'apprentissage. Bien que ces initiatives aient marqué des progrès importants, il y a peu d'uniformité entre les programmes des diverses facultés et entre les niveaux de formation. Il n'y a pas de cadre pédagogique pour les programmes d'études de premier cycle axés sur le bien-être au Canada s'alignant aux compétences visées dans les programmes de résidence. La création d'un tel cadre permettrait d'harmoniser les initiatives de niveau individuel et celles de niveau systémique et de faciliter la transition de la faculté de médecine vers la résidence. Il comporterait des objectifs organisés selon les domaines de bien-être pertinents, une souplesse permettant son adaptation aux divers milieux, il tiendrait compte des besoins fondamentaux des apprenants et il serait fondé sur une consultation de ces derniers. Les médecins dont le bien-être a été soutenu tout au long de leur formation contribueront de façon positive à la qualité des soins aux patients, à leur environnement de travail et au maintien d'une population canadienne en bonne santé.

Analyzing Recombinant Protein Production in Pichia pastoris with Targeted Proteomics.

New mass spectrometry approaches enable antibody-independent tracking of protein production. Herein, we outline an antibody-independent mass spectrometry method for tracking recombinant protein production in the methylotrophic yeast Pichia pastoris system.