Citations

Significance By evaluating children with a malformed cerebral cortex, we identified an ATPase pump (ATP1A3) with an early role in brain development. The ATP1A3 pump maintains the physiological concentration of sodium and potassium ions in cells, a process critical for osmotic equilibrium and membrane potential across several developing cell populations. We employed single-cell sequencing approaches to identify key enrichments for ATP1A3 expression during human cortex development. Unravelling this early cell-type–specific pathophysiology in the developing brain offers a potential basis for the treatment of ATP1A3 -related diseases affecting prenatal and early childhood development.

e20554 Background: The paradigm for locally advanced non-small cell lung cancer has been markedly altered to include maintenance durvalumab (D) post completion of definitive chemoradiation (CRT) following the publication of the Pacific trial in 2018. The toxicity of this treatment has not been well evaluated in the real-world setting. Methods: We identified 42 patients (pts) with Stage IIB-IIIC NSCLC treated at Mayo Clinic Rochester between 6/1/2018 and 10/1/2020 who received definitive CRT followed by maintenance D. Data were abstracted by retrospective chart review under an IRB approved protocol. Results: Median age was 66 yrs (range 47-90) and 62% were women. Primary lung cancer histology included 19 adenocarcinoma, 20 squamous cell, and 3 adenosquamous. The distribution of stages was: IIB (4/42), IIIA (15/42), IIIB (19/42), IIIC (4/42). Approximately half of patients had PDL1 expression > 25% (20/42). With a median follow up of 12.2 months (calculated from first cycle of D; range 4.2-30.5 months), 14 had completed one year of maintenance D, 16 were receiving ongoing D, and 10 stopped D early with 6/12 discontinuing due to disease progression (4/6 local progression, 2/6 distant progression). Other reasons for discontinuation (5/10) included grade 3 colitis, grade 2 hepatitis, aspergillus lung infection, and flare of autoimmune disorders. One quarter of patients experienced grade 2 radiation pneumonitis (RP; 10/42) with median time to development of RP 78 days from end of CRT and 45 days from start of D. RP was determined by multidisciplinary review of imaging and treatment fields. 17/42 patients developed immune related adverse events (see Table for details). There was minimal overlap between the patients who experienced pneumonitis and immune related toxicity; 2/17 had both pneumonitis and immune related toxicity (hepatitis, thyroiditis). Conclusions: In our early experience with the Pacific regimen, 29% of patients did not complete D due to either toxicity or progression during D administration. Pneumonitis was common (10/42 patients) although there were no grade 3 events. Nearly half of the patients developed an immune-related adverse event. Further analysis is needed to evaluate the real-world toxicity of this treatment as well as oncologic outcomes.[Table: see text]

AimsTibial cones are often utilized in revision total knee arthroplasty (TKA) with metaphyseal defects. Because there are few studies evaluating mid-term outcomes with a sufficient cohort, the purpose of this study was to evaluate tibial cone survival and complications in revision TKAs with tibial cones at minimum follow-up of five years.MethodsA retrospective review was completed from September 2006 to March 2015, evaluating 67 revision TKAs (64 patients) that received one specific porous tibial cone during revision TKA. The final cohort was composed of 62 knees (59 patients) with five years of clinical follow-up or reoperation. The mean clinical follow-up of the TKAs with minimum five-year clinical follow-up was 7.6 years (5.0 to 13.3). Survivorship analysis was performed with the endpoints of tibial cone revision for aseptic loosening, tibial cone revision for any reason, and reoperation. We also evaluated periprosthetic joint infection (PJI), risk factors for failure, and performed a radiological review.ResultsThe rate of cone revision for aseptic loosening was 6.5%, with an eight-year survival of 95%. Significant bone loss (Anderson Orthopaedic Research Institute grade 3) was associated with cone revision for aseptic loosening (p = 0.002). The rate of cone revision for any reason was 17.7%, with an eight-year survival of 84%. Sixteen percent of knees developed PJI following revision. A pre-revision diagnosis of reimplantation as part of a two-stage exchange protocol for infection was associated with both PJI (p < 0.001) and tibial cone revision (p = 0.001).ConclusionMid-term results of tibial cones showed a survivorship free of cone revision for aseptic loosening of 95%. Patients with significant bone loss were more likely to have re-revision for tibial cone failure. Infection was common, and patients receiving cones at reimplantation were more likely to develop PJI and undergo cone revision. Cite this article: Bone Joint J 2021;103-B(6 Supple A):158–164.

AbstractBackgroundRandomized studies of intra‐aortic balloon pump (IABP) in cardiogenic shock (CS) have only included on patients with acute coronary syndromes (ACS) without stratification according to shock severity. We examined the association between IABP and mortality in CS patients across the Society for Cardiovascular Angiography and Intervention (SCAI) shock stages.MethodsWe included cardiac intensive care unit patients admitted from 2007 to 2015 with CS from any etiology. In‐hospital mortality associated with IABP was examined in each SCAI shock stage. Multivariable logistic regression was performed using inverse probability of treatment weighting (IPTW) to determine the association between IABP and in‐hospital mortality.ResultsWe included 934 patients, with a mean age of 68 ± 14 years; 60% had ACS. The distribution of SCAI shock stages was: B, 41%; C, 13%; D, 38%; E, 8%. In‐hospital mortality was lower in the 39% of patients who received IABP (27% vs. 43%, adjusted OR with IABP after IPTW 0.53, 95% CI 0.40–0.72, p < .0001). IABP use was associated with lower crude in‐hospital mortality in each SCAI shock stage (all p < .05, except p = .08 in SCAI shock stage E). We did not observe any significant heterogeneity in the association between IABP use and in‐hospital mortality as a function of SCAI shock stage.ConclusionsPatients with CS who were selected to receive an IABP had lower in‐hospital mortality, without differences in this effect across the SCAI shock stages. Future studies should account for the severity and etiology of shock when evaluating the efficacy of IABP for CS.

Abstract Self‐affirmation interventions have been shown to mitigate the negative psychological effects of stereotype threat on Black students in secondary and undergraduate education. However, there is currently limited research testing whether Black students in medical schools may also experience the negative influences of stereotype threat. Until now, it has been unclear whether Black (vs. White) students experience a lower sense of belonging in medical school and whether they can benefit from self‐affirmation interventions during medical training. With a longitudinal field experiment, we tested (a) whether Black (vs. White) medical students in the US experience decrements in psychological well‐being (i.e., fatigue, depression, anxiety), sense of belonging, perceived residency competitiveness, and residency goal stability; and (b) the extent to which a self‐affirmation intervention would ameliorate any observed disparities in these outcomes for Black students. With a sample of 234 Black and 182 White medical students across 50 schools in the United States, we found that Black students tended to report more fatigue and less belonging than White students; however, the self‐affirmation intervention did not significantly influence students’ fatigue, depression, anxiety, or belonging. Unexpectedly, Black students in the self‐affirmation (vs. control) condition reported lower perceived competitiveness for residency. White students’ perceived competitiveness for residency was unaffected by the intervention. Exploratory analyses revealed that Black (vs. White) students were less likely to indicate stable residency goals over time, which may be an indication of threat; however, this racial gap was eliminated with the intervention. We discuss the plausible reasons for these findings and provide recommendations for future work in this area.

Abstract While combination radiotherapy (RT) and immunotherapy is not novel there is still much to learn about this approach. Some initial pre-clinical and clinical evidence suggests triple therapy with RT and dual immune checkpoint blockade (anti-CTLA-4 + anti-PD-1/PD-L1) is a complimentary technique. We present two cases using the same novel regime of combination RT plus nivolumab and ipilimumab to treat metastatic melanoma. In both cases the burden of disease was significant within a lower extremity. Additionally, in both cases using this treatment plan, we were able establish sustained local disease control with additional systemic benefit which allowed both patients to avoid significant debility from surgical amputation. Given the response and safety we observed, this technique could be used as a potentially safe approach for future patients who are not eligible for traditional RT palliation or clinical trials.

ABSTRACT Background: Acidosis and higher lactate predict worse outcomes in cardiogenic shock (CS) patients. We sought to determine whether overall acidosis severity on admission predicted in-hospital mortality in CS patients. Methods: This retrospective descriptive analysis included CS patients admitted to a single academic tertiary cardiac intensive care unit from 2007 to 2015. Admission arterial pH, base excess, and anion gap values were used to generate a Composite Acidosis Score (range 0–5, with a score ≥2 defining Severe Acidosis). Adjusted in-hospital mortality was analyzed using multivariable logistic regression. Results: We included 1,065 patients with median age of 68.9 (59.0, 77.2) years (36.4% females). Concomitant diagnoses included cardiac arrest in 38.1% and acute coronary syndrome in 59.1%. Severe Acidosis was present in 35.2%, and these patients had worse shock and more organ failure. In-hospital mortality occurred in 34.1% and was higher among patients with Severe Acidosis (54.9% vs. 22.4%, adjusted odds ratio [OR] 2.01, 95% CI 1.43–2.83, P < 0.001). Increasing Composite Acidosis Score was associated with higher in-hospital mortality (adjusted OR 1.25 per point, 95% CI 1.11–1.40, P < 0.001). Severe Acidosis was associated with higher hospital mortality at every level of shock severity and organ failure (all P < 0.05). Admission lactate level had equivalent discrimination for in-hospital mortality as the Composite Acidosis Score (0.69 vs. 0.66; P = 0.32 by De Long test). Conclusion: Given its incremental association with higher in-hospital mortality among CS patients beyond shock severity and organ failure, we propose Severe Acidosis as a marker of hemometabolic shock. Lactate levels performed as well as a composite measure of acidosis for predicting mortality.

Background: Optic neuritis (ON) is often the presenting symptom in inflammatory central nervous system demyelinating disorders. Objective: To compare the frequency and pattern of optic chiasm involvement in patients with aquaporin-4-immunoglobulin G (AQP4-IgG)-associated ON to patients with myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated ON. Methods: Retrospective review of all patients evaluated at Mayo Clinic, Stanford University and Ramathibodi Hospital who were found to have: (1) ON, (2) either MOG-IgG or AQP4-IgG by cell-based assay, and (3) magnetic resonance imaging (MRI) at the time of ON. MRI was reviewed for contrast enhancement of the optic chiasm and the pattern of involvement. Results: One hundred and fifty-four patients (74 AQP4-IgG and 80 MOG-IgG) were included. Among patients with AQP4-IgG-ON, 20% had chiasmal involvement, compared with 16% of patients with MOG-IgG-ON ( p = 0.66). In patients with chiasmal involvement, longitudinally extensive optic nerve enhancement (from orbit extending to chiasm) was identified in 54% of MOG-IgG-ON patients, compared with 7% of AQP4-IgG-ON patients ( p = 0.01). Conclusion: Chiasmal involvement of MOG-IgG-ON and AQP4-IgG-ON occur at more similar frequencies than previously reported. Furthermore, MOG-IgG-ON chiasmal involvement is more likely to be part of a longitudinally extensive optic nerve lesion.

Background Several animal studies have demonstrated that mechanical thrombectomy (MT) for acute ischemic stroke (AIS) may cause vessel wall injury (VWI). However, the histological changes in human cerebral arteries following MT are difficult to determine. Objective To investigate the occurrence of VWI during MT by histological and immunohistochemical evaluation of AIS clots. Methods As part of the multicenter STRIP registry, 277 clots from 237 patients were analyzed using Martius Scarlett Blue stain and immunohistochemistry for CD34 (endothelial cells) and smooth muscle actin (smooth muscle cells). Results MT devices used were aspiration catheters (100 cases), stentriever (101 cases), and both (36 cases). VWI was found in 33/277 clots (12%). There was no significant correlation between VWI and MT device. The degree of damage varied from grade I (mild intimal damage, 24 clots), to grade II (relevant intimal and subintimal damage, 3 clots), and III (severe injury, 6 clots). VWI clots contained significantly more erythrocytes (p=0.006*) and less platelets/other (p=0.005*) than non-VWI clots suggesting soft thrombus material. Thrombolysis correlated with a lower rate of VWI (p=0.04*). VWI cases showed a significantly higher number of passes (2 [1–4] vs 1 [1–3], p=0.028*) and poorer recanalization outcome (p=0.01*) than cases without VWI. Conclusions Histological markers of VWI were present in 12% of AIS thrombi, suggesting that VWI might be related to MT. VWI was associated with soft thrombus consistency, higher number of passes and poorer revascularization outcome. There was no significant correlation between VWI and MT device.