Residency interviews in the digital era.

In the midst of the SARS-CoV-2 pandemic, the US Association of American Medical Colleges (AAMC) required residency programme transition from in-person to virtual interviews for all applicants. The new virtual format upended a system that has relied on programmes and applicants balancing the likelihood of acceptance with the financial and time demands of cross-country travel.In this commentary, we address the history of residency interviewing in the USA and the emerging changes that are taking place in light of virtual interviews. We discuss the advantages of the new online format, including the reduced cost for applicants and programmes, as well as the decreased carbon footprint.We also discuss the inequities of virtual interviewing, involving a national maldistribution of interviews to only the top-tier candidates. We share previously unpublished data on the number of virtual interviews accepted by Stanford's 2020 residency applicants, compared with those conducted in person in 2019. We find Stanford applicants in all fields accepted more interviews: from a mean of 8 in 2019 to 14 in 2020, a change of 160% on average. Despite this, only half of Stanford 2020 applicants interviewing in the virtual format thought they had accepted more interviews than they would have in person.We comment on how transitions to online interviewing may be affecting medical schools and applicants disproportionately. Ultimately, we highlight the need and offer ideas for additional regulation on behalf of the AAMC to ensure a more equitable distribution of interview opportunities.

Quality of Life in Physical, Social, and Cognitive Domains Improves With Endovascular Therapy in the DEFUSE 3 Trial.

BACKGROUND AND PURPOSE: The DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) randomized clinical trial demonstrated the efficacy of endovascular therapy in treating ischemic stroke 6 to 16 hours after onset, resulting in better functional outcomes than standard medical therapy alone. The objective of this secondary analysis is to analyze the effect of late-window endovascular treatment of ischemic stroke on quality of life (QoL) outcomes. METHODS: Patients (n=182) who presented between 6 and 16 hours after they were last known to be well with acute anterior circulation ischemic stroke were randomized to endovascular thrombectomy plus standard medical therapy or standard medical therapy alone and followed-up through 90 days poststroke. QoL at day 90 was assessed with the QoL in Neurological Disorders measurement tool. RESULTS: Of the 146 subjects alive at day 90, 136 (95%) filled out QoL in Neurological Disorders short forms. Patients treated with endovascular therapy had better QoL scores in each domain: mobility, social participation, cognitive function, and depression (P<0.01 for all). Variables other than endovascular therapy that were independently associated with better QoL included lower baseline National Institutes of Health Stroke Scale, younger age, and male sex. The degree to which the modified Rankin Scale captures differences in QoL between patients varied by domain; the modified Rankin Scale score accounted for a high proportion of the variability in mobility (Rs2=0.82), a moderate proportion in social participation (Rs2=0.62), and a low proportion in cognition (Rs2=0.31) and depression (Rs2=0.19). CONCLUSIONS: Patients treated with endovascular therapy 6 to 16 hours after stroke have better QoL than patients treated with medical therapy alone, including better mobility, more social participation, superior cognition, and less depression. The modified Rankin Scale fails to capture patients' outcomes in cognition and depression, which should therefore be assessed with dedicated QoL tools. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02586415.

Dentate Nucleus Neuronal Density: A Postmortem Study of Essential Tremor Versus Control Brains.

BACKGROUND: Essential tremor involves the cerebellum, yet quantitative analysis of dentate nucleus neurons has not been conducted. OBJECTIVES: To quantitatively compare neuronal density or neuronal number in the dentate nucleus of essential tremor versus age-matched controls. METHODS: Using a 7-µm thick Luxol fast blue hematoxylin and eosin-stained paraffin section, dentate nucleus neuronal density (neurons/mm2 ) was determined in 25 essential tremor cases and 25 controls. We also applied a stereological approach in a subset of four essential tremor cases and four controls to estimate total dentate nucleus neuronal number. RESULTS: Dentate nucleus neuronal density did not differ between essential tremor cases and controls (P = 0.44). Total dentate nucleus neuronal number correlated with neuronal density (P = 0.007) and did not differ between essential tremor cases and controls (P = 0.95). CONCLUSIONS: Neuronal loss, observed in the Purkinje cell population in essential tremor, did not seem to similarly involve the dentate nucleus in essential tremor. © 2020 International Parkinson and Movement Disorder Society.

Thrombectomy Results in Reduced Hospital Stay, More Home-Time, and More Favorable Living Situations in DEFUSE 3.

Background and Purpose- The DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) demonstrated that endovascular thrombectomy in the 6- to 16-hour time window improves functional outcomes of patients with evidence of salvageable tissue on baseline computed tomography or magnetic resonance imaging. The purpose of this study is to assess the effect of endovascular therapy on length of hospital stay, home-time during the first 3 months poststroke, and living situation poststroke in DEFUSE 3. Methods- Duration of hospital stay and home-time (number of days during the 90-day poststroke period that the patient resides in their own home or in that of a relative) were compared between treatment groups using the Wilcoxon rank-sum test. Patient living situation was assessed at discharge, 30 days, and 90 days on an ordinal 4-point scale (home, acute rehabilitation unit, institutionalized care, or hospice/death) and differences between groups were analyzed using the Cochran-Armitage trend test. Results- Median length of hospital stay was 9.1 (interquartile range, 6.2-15.0) days in the medical group versus 6.5 (interquartile range, 3.7-9.3) days in the endovascular group (P<0.001). Median home-time during the first 90 days after stroke was 0 (interquartile range, 0-53) days in the medical group versus 55 (interquartile range, 0-83) days in the endovascular group (P<0.001). The endovascular group had more favorable living situations at time of discharge (P<0.001), 30 days (P<0.001), and 90 days (P<0.001) poststroke. Conclusions- Endovascular thrombectomy resulted in reduced hospital stay, more home-time, and more desirable living situations in the 90 days after stroke. These results provide evidence that endovascular therapy in the delayed time window can improve quality of life for stroke patients and reduce healthcare costs. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02586415.

Heterotopic Purkinje Cells: a Comparative Postmortem Study of Essential Tremor and Spinocerebellar Ataxias 1, 2, 3, and 6.

Essential tremor (ET) is among the most common neurological diseases. Postmortem studies have noted a series of pathological changes in the ET cerebellum. Heterotopic Purkinje cells (PCs) are those whose cell body is mis-localized in the molecular layer. In neurodegenerative settings, these are viewed as a marker of the progression of neuronal degeneration. We (1) quantify heterotopias in ET cases vs. controls, (2) compare ET cases to other cerebellar degenerative conditions (spinocerebellar ataxias (SCAs) 1, 2, 3, and 6), (3) compare these SCAs to one another, and (4) assess heterotopia within the context of associated PC loss in each disease. Heterotopic PCs were quantified using a standard LH&E-stained section of the neocerebellum. Counts were normalized to PC layer length (n-heterotopia count). It is also valuable to consider PC counts when assessing heterotopia, as loss of PCs extends both to normally located as well as heterotopic PCs. Therefore, we divided n-heterotopias by PC counts. There were 96 brains (43 ET, 31 SCA [12 SCA1, 7 SCA2, 7 SCA3, 5 SCA6], and 22 controls). The median number of n-heterotopias in ET cases was two times higher than that of the controls (2.6 vs. 1.2, p < 0.05). The median number of n-heterotopias in the various SCAs formed a spectrum, with counts being highest in SCA3 and SCA1. In analyses that factored in PC counts, ET had a median n-heterotopia/Purkinje cell count that was three times higher than the controls (0.35 vs. 0.13, p < 0.01), and SCA1 and SCA2 had counts that were 5.5 and 11 times higher than the controls (respective p < 0.001). The median n-heterotopia/PC count in ET was between that of the controls and the SCAs. Similarly, the median PC count in ET was between that of the controls and the SCAs; the one exception was SCA3, in which the PC population is well known to be preserved. Heterotopia is a disease-associated feature of ET. In comparison, several of the SCAs evidenced even more marked heterotopia, although a spectrum existed across the SCAs. The median n-heterotopia/PC count and median PC in ET was between that of the controls and the SCAs; hence, in this regard, ET could represent an intermediate state or a less advanced state of spinocerebellar atrophy.

Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases.

Changes in climbing fiber-Purkinje cell (CF-PC) synaptic connections have been found in the essential tremor (ET) cerebellum, and these changes are correlated with tremor severity. Whether these postmortem changes are specific to ET remains to be investigated. We assessed CF-PC synaptic pathology in the postmortem cerebellum across a range of degenerative movement disorders [10 Parkinson's disease (PD) cases, 10 multiple system atrophy (MSA) cases, 10 spinocerebellar ataxia type 1 (SCA1) cases, and 20 ET cases] and 25 controls. We observed differences in terms of CF pathological features across these disorders. Specifically, PD cases and ET cases both had more CFs extending into the parallel fiber (PF) territory, but ET cases had more complex branching and increased length of CFs in the PF territory along with decreased CF synaptic density compared to PD cases. MSA cases and SCA1 cases had the most severely reduced CF synaptic density and a marked paucity of CFs extending into the PF territory. Furthermore, CFs in a subset of MSA cases formed collateral branches parallel to the PC layer, a feature not seen in other diagnostic groups. Using unsupervised cluster analysis, the cases and controls could all be categorized into four clusters based on the CF pathology and features of PC pathology, including counts of PCs and their axonal torpedoes. ET cases and PD cases co-segregated into two clusters, whereas SCA1 cases and MSA cases formed another cluster, separate from the control cluster. Interestingly, the presence of resting tremor seemed to be the clinical feature that separated the cases into the two ET-PD clusters. In conclusion, our study demonstrates that these degenerative movement disorders seem to differ with respect to the pattern of CF synaptic pathology they exhibit. It remains to be determined how these differences contribute to the clinical presentations of these diseases.

Cerebellar Pathology in Familial vs. Sporadic Essential Tremor.

Familial and sporadic essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes has yet to be studied. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes, a host of associated axonal changes, heterotopic PCs, and hairy basket ratings) in 60 ET cases and 30 controls. Familial ET was defined using both liberal criteria (n = 27) and conservative criteria (n = 20). When compared with controls, ET cases had lower PC counts, more torpedoes, more heterotopic PCs, a higher hairy basket rating, an increase in PC axonal collaterals, an increase in PC thickened axonal profiles, and an increase in PC axonal branching. Familial and sporadic ET had similar postmortem changes, with few exceptions, regardless of the definition criteria. The PC counts were marginally lower in familial than sporadic ET (respective p values = 0.059 [using liberal criteria] and 0.047 [using conservative criteria]). The PC thickened axonal profile count was marginally lower in familial ET than sporadic ET (respective p values = 0.037 [using liberal criteria] and 0.17 [using conservative criteria]), and the PC axonal branching count was marginally lower in familial than sporadic ET (respective p values = 0.045 [using liberal criteria] and 0.079 [using conservative criteria]). After correction for multiple comparisons, however, there were no significant differences. Overall, familial and sporadic ET cases share very similar cerebellar postmortem features. These data indicate that pathological changes in the cerebellum are a part of the pathophysiological cascade of events in both forms of ET.

Cerebellar Pathology in Early Onset and Late Onset Essential Tremor.

Early onset and late onset essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes remains to be determined. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes and associated axonal changes, heterotopic PCs, and hairy basket ratings) in 30 ET cases with age of tremor onset <50 years, 30 ET cases with age of tremor onset ≥50 years, and 30 controls (total n = 90). We also used two alternative age of onset cut-points (<40 vs. ≥40 years, and <60 vs. ≥60 years) to define early onset vs. late onset ET. We found that ET cases with tremor onset <50 years and tremor onset ≥50 years had similar PC counts (8.78 ± 1.70 vs. 8.86 ± 1.24, p = 0.839), PC axonal torpedo counts (17.87 ± 18.27 [median =13.00] vs. 12.90 ± 10.60 [median =9.0], p = 0.486) and associated axonal pathology (all p values >0.05), heterotopic PC counts (9.90 ± 11.55 [median =6.00] vs. 5.40 ± 5.10 [median =3.50], p = 0.092), and hairy basket ratings (1.95 ± 0.62 [median =2.00] vs. 2.05 ± 0.92 [median =2.00], p = 0.314). When using the age of onset cut-points of 40 or 60 years, results were similar. Early onset and late onset ET cases share similar cerebellar postmortem features. These data do not support the notion that these age-of-onset related forms of ET represent distinct clinical-pathological entities.

Mapping Purkinje Cell Placement Along the Purkinje Cell Layer: an Analysis of Postmortem Tissue from Essential Tremor Patients vs. Controls.

Postmortem studies have reported Purkinje cell loss in essential tremor (ET), and we recently demonstrated a significant increase in the mean distance between Purkinje cell bodies (i.e., a larger gap length distance) in ET cases vs. controls, likely reflecting a disease-associated reduction in Purkinje cells. We now analyze the regularity of distribution of Purkinje cells along the Purkinje cell layer to determine whether there is greater disorganization in ET cases than in age-matched controls. A standard parasagittal, formalin-fixed, tissue block was harvested from the neocerebellum of 50 ET cases and 25 age-matched controls. The gap length distance (µm) between Purkinje cells was quantified using a nearest neighbor analysis in which the distance between each Purkinje cell body was measured in OpenLAB software, version 5 (Improvision, Waltham, MA) by drawing a freehand line between adjacent Purkinje cell bodies along the entirety of the Purkinje cell layer within a given image. We analyzed the subject-specific variation in the organization of Purkinje cells along the Purkinje cell layer. The 50 ET cases and 25 controls were similar in age at death, gender, and brain weight. Overall, greater variation in gap length distance (i.e., more disorganization) was associated with greater gap length distance (p < 0.001) and younger age (p = 0.020). However, the variation in the Purkinje cell gap length distance (i.e., Purkinje cell organization) did not differ in ET cases and controls (p = 0.330). We observed that the regularity of the distribution of Purkinje cells along the Purkinje cell layer did not differ between ET cases and controls. Several alternative biological interpretations for this finding are discussed.

Predictors of Early and Late Infarct Growth in DEFUSE 3.

Introduction: The goal of this study is to explore the impact of reperfusion and collateral status on infarct growth in the early and late time windows. Materials and Methods: Seventy patients from the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) with baseline, 24-h, and late follow-up scans were evaluated. Scans were taken with DWI or CTP at time of enrollment (Baseline), with DWI or CT 24-h after enrollment (24-h), and with DWI or CT 5 days after enrollment (Late). Early infarct growth (between baseline and 24-h scans) and late infarct growth (between 24-h and late scans) was assessed for each patient. The impact of collateral and reperfusion status on infarct growth was assessed in univariate and multivariate regression. Results: The median early infarct growth was 30.3 ml (IQR 16.4-74.5) and the median late infarct growth was 6.7 ml (IQR -3.5-21.6) in the overall sample. Patients with poor collaterals showed greater early infarct growth (Median 58.5 ml; IQR 18.6-125.6) compared to patients with good collaterals (Median 28.4 ml; IQR 15.8-49.3, unadjusted p = 0.04, adjusted p = 0.06) but showed no difference in late infarct growth. In contrast, patients who reperfused showed no reduction in early infarct growth but showed reduced late infarct growth (Median 1.9 ml; IQR -6.1-8.5) compared to patients without reperfusion (Median 11.2 ml; IQR -1.1-27.2, unadjusted p < 0.01, adjusted p = 0.04). Discussion: In the DEFUSE 3 population, poor collaterals predict early infarct growth and absence of reperfusion predicts late infarct growth. These results highlight the need for timely reperfusion therapy, particularly in patients with poor collaterals and indicate that the 24-h timepoint is too early to assess the full impact of reperfusion therapy on infarct growth. Clinical Trial Registration: http://www.clinicaltrials.gov, Unique identifier [NCT02586415].

Impact of the Patient Protection and Affordable Care Act on 1-year survival in glioblastoma patients.

BACKGROUND: Glioblastoma (GBM) treatment requires access to complex medical services, and the Patient Protection and Affordable Care Act (ACA) sought to expand access to health care, including complex oncologic care. Whether the implementation of the ACA was subsequently associated with changes in 1-year survival in GBM is not known. METHODS: A retrospective cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER) database. We identified patients with the primary diagnosis of GBM between 2008 and 2016. A multivariable-adjusted Cox proportional hazards model was developed using patient and clinical characteristics to determine the main outcome: the 1-year cumulative probability of death by state expansion status. RESULTS: A total of 25 784 patients and 14 355 deaths at 1 year were identified and included in the analysis, 49.7% were older than 65 at diagnosis. Overall 1-year cumulative probability of death for GBM patients in non-expansion versus expansion states did not significantly worsen over the 2 time periods (2008-2010: hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.04-1.19; 2014-2016: HR 1.18, 95% CI 1.09-1.27). In GBM patients younger than age 65 at diagnosis, there was a nonsignificant trend toward the poorer 1-year cumulative probability of death in non-expansion versus expansion states (2008-2010: HR 1.09, 95% CI 0.97-1.22; 2014-2016: HR 1.23, 95% CI 1.09-1.40). CONCLUSIONS: No differences were found over time in survival for GBM patients in expansion versus non-expansion states. Further study may reveal whether GBM patients diagnosed younger than age 65 in expansion states experienced improvements in 1-year survival.

Cerebellar pathology in childhood-onset vs. adult-onset essential tremor.

Although the incidence of ET increases with advancing age, the disease may begin at any age, including childhood. The question arises as to whether childhood-onset ET cases manifest the same sets of pathological changes in the cerebellum as those whose onset is during adult life. We quantified a broad range of postmortem features (Purkinje cell [PC] counts, PC axonal torpedoes, a host of associated axonal changes [PC axonal recurrent collateral count, PC thickened axonal profile count, PC axonal branching count], heterotopic PCs, and basket cell rating) in 60 ET cases (11 childhood-onset and 49 adult-onset) and 30 controls. Compared to controls, childhood-onset ET cases had lower PC counts, higher torpedo counts, higher heterotopic PC counts, higher basket cell plexus rating, and marginally higher PC axonal recurrent collateral counts. The median PC thickened axonal profile count and median PC axonal branching count were two to five times higher in childhood-onset ET than controls, but the differences did not reach statistical significance. Childhood-onset and adult-onset ET had similar PC counts, torpedo counts, heterotopic PC counts, basket cell plexus rating, PC axonal recurrent collateral counts, PC thickened axonal profile count and PC axonal branching count. In conclusion, we found that childhood-onset and adult-onset ET shared similar pathological changes in the cerebellum. The data suggest that pathological changes we have observed in the cerebellum in ET are a part of the pathophysiological cascade of events in both forms of the disease and that both groups seem to reach the same pathological endpoints at a similar age of death.

Excitatory Amino acid transporter expression in the essential tremor dentate nucleus and cerebellar cortex: A postmortem study.

BACKGROUND: Genome-wide association studies have revealed a link between essential tremor (ET) and the gene SLC1A2, which encodes excitatory amino acid transporter type 2 (EAAT2). We explored EAAT biology in ET by quantifying EAAT2 and EAAT1 levels in the cerebellar dentate nucleus, and expanded our prior analysis of EAAT2 levels in the cerebellar cortex. OBJECTIVE: To quantify EAAT2 and EAAT1 levels in the cerebellar dentate nucleus and cerebellar cortex of ET cases vs. METHODS: We used immunohistochemistry to quantify EAAT2 and EAAT1 levels in the dentate nucleus of a discovery cohort of 16 ET cases and 16 controls. Furthermore, we quantified EAAT2 levels in the dentate nucleus in a replicate cohort (61 ET cases, 25 controls). Cortical EAAT2 levels in all 77 ET cases and 41 controls were quantified. RESULTS: In the discovery cohort, dentate EAAT2 levels were 1.5-fold higher in 16 ET cases vs. 16 controls (p = 0.007), but EAAT1 levels did not differ significantly (p = 0.279). Dentate EAAT2 levels were 1.3-fold higher in 61 ET cases vs. 25 controls in the replicate cohort (p = 0.022). Cerebellar cortical EAAT2 levels were 20% and 40% lower in ET cases vs. controls in the discovery and the replicate cohorts (respective p values = 0.045 and < 0.001). CONCLUSION: EAAT2 expression is enhanced in the ET dentate nucleus, in contrast to differentially reduced EAAT2 levels in the ET cerebellar cortex, which might reflect a compensatory mechanism to maintain excitation-inhibition balance in cerebellar nuclei.